Pharmacology test 1

Parasympathomimetic

- -AKA cholinergic, resembles effects caused by stim of postgang parasympathetic neurons EX; direct acting are cholinergic receptors agonist ACH - AKA cholinomimetic, stimulates effects of ACH EX; indirect acting such as op's

Define/Describe; difference between brand/generic or generic/pioneer drugs.

- A brand medication is the "innovator" or pioneer, gets patent — has exclusivity protection so generics can't compete right away. - Generic medications must meet the same quality, strength, and purity standards as brands, so they have the same benefits and effects. —- GADPTRA (Generic Animal Drug and Patent Term Restoration Act): amends the Federal Food, Drug, and Cosmetic Act to provide for the approval of generic copies of animal drug products that have been previously approved and shown to be safe and effective when used in accordance with their labeling. —- Under GADPTRA, a generic animal drug product may be approved by providing evidence that it has the same active ingredients, in the same concentration, as the approved animal drug product, and that it is bioequivalent to the approved animal drug product. — GADPTRA provides for a period of 3 years of marketing exclusivity for a new use of an animal drug (a use that required reports of new clinical or field investigations for its approval), during which time no abbreviated application for a generic copy may be approved for the new use.

Parasympatholytic

- AKA cholinergic blocking drugs, receptors blocking effects, inhibit effects of ACH, EX; block N or M receptors. Atropine is the prototypical muscarinic blocking drug - AKA anticholinergic, neuronal blocking effects, inhibit release of ACH from nerve terminal such as botulinum toxin. Anto- diarrheal medications such as lomotil

Define/Describe: distribution

- If you're a drug maker and want to get a drug approved for food animals' patients you need to go through even more testing to make sure we know how that drug is distributed, metabolized and excreted because you can't have residue of most products in edible tissues A toxicant absorbed into the systemic circulation following any route of administration must reach its site of action at a high enough concentration for a sufficient period of time to elicit a biological response. — Distribution processes determine this outcome. There are numerous tissues to which a chemical may be distributed, some of them capable of eliciting a pharmacological or toxicological (intended versus unintended) response while others serve only as a sink or depot for the chemical. — Sinks may also be formed as a result of chemical binding to tissue or plasma proteins. — Toxicological significance of such sinks are that chemicals will be distributed to, and in some cases stored in, these tissues and only slowly released back into the systemic circulation for elimination. —- Such tissue binding may protect against acute adverse effects by providing an "inert" site for toxicant localization. — Storage may prolong the overall residence time of a compound in the body and promote accumulation during chronic exposure, leading to chronic toxicity. — If the animal is a food-producing spp, such tissue storage may result in residues in meat products. Tissue concentrations thus become an endpoint in themselves, devoid of a biological or toxicological relevance in the tissue they are found. — Significance is set by regulations that legally establish safe tissue tolerances or max residue levels for specific tissues and species. — Limits are based upon amount of safety to the consuming human population and food consumption patterns. — Distribution of chemicals to peripheral tissues is dependent on 4 factors: 1) Physiochemical properties of the compound (pKa, lipid solubility, molecular weight) 2) Concentration gradient established between the blood and tissue 3) Ratio of blood flow to tissue mass 4) Affinity of the chemical for tissue constituents. - The physiochemical properties of the chemical are most important in determining its likelihood to distribute to a specific tissue. - For most molecules, distribution out of the blood into tissue is via bulk flow through the capillary pores or by simple diffusion down a concentration gradient - distribution is generally described by first-order rate constants. — Distribution can be considered as "absorption" into the tissues from the blood. - Complicating factors are that the driving concentration is dependent on blood flow — Surface area for "absorption into tissues" is dependent upon capillary density and tissue mass — Relevant partition coefficient is the blood/tissue ratio, and plasma/tissue protein binding complicates the picture. An understanding of distribution is a prerequisite to predicting pharmacological response.

define VD

- If you're a drug maker and want to get a drug approved for food animals' patients you need to go through even more testing to make sure we know how that drug is distributed, metabolized and excreted because you can't have residue of most products of edible tissues A toxicant absorbed into the systemic circulation following any route of administration must reach its site of action at a high enough concentration for a sufficient period of time to elicit a biological response. Distribution processes determine this outcome. There are numerous tissues to which a chemical may be distributed, some of them capable of eliciting a pharmacological or toxicological (intended versus unintended) response while others serve only as a sink or depot for the chemical. Sinks may also be formed as a result of chemical binding to tissue or plasma proteins. The toxicological significance of such sinks is that chemicals will be distributed to, and in some cases stored in, these tissues and only slowly released back into the systemic circulation for ultimate elimination. Such tissue binding may actually protect against acute adverse effects by providing an "inert" site for toxicant localization. Storage may, however, prolong the overall residence time of a compound in the body and promote accumulation during chronic exposure, two processes that would potentiate chronic toxicity. If the animal is a food-producing species, such tissue storage may result in residues in the edible meat products. Tissue concentrations thus become an endpoint in themselves, devoid of a biological or toxicological relevance in the tissue they are found. Their relevance is set by regulations that legally establish safe tissue tolerances or maximum residue levels for specific tissues and species. These are based upon extrapolations of safety to the consuming human population and food consumption patterns. These concepts are developed in Chapter 61. Distribution of chemicals to peripheral tissues is dependent on four factors: 1) Physiochemical properties of the compound (pKa, lipid solubility, molecular weight) 2) Concentration gradient established between the blood and tissue 3) Ratio of blood flow to tissue mass 4) Affinity of the chemical for tissue constituents. The physiochemical properties of the chemical are most important in determining its propensity to distribute to a specific tissue. For most molecules, distribution out of the blood into tissue is via bulk flow through the capillary pores or by simple diffusion down a concentration gradient; hence distribution is generally described by first-order rate constants. One can conceptualize distribution as "absorption" into the tissues from the blood. The complicating factors are that the driving concentration is now dependent upon blood flow, the surface area for "absorption into tissues" is dependent upon capillary density and tissue mass, the relevant partition coefficient is the blood/tissue ratio, and plasma/tissue protein binding complicates the picture. An understanding of distribution is a prerequisite to predicting pharmacological response.

Distribution

- If you're a drug maker and want to get a drug approved for food animals' patients you need to go through even more testing to make sure we know how that drug is distributed, metabolized and excreted because you can't have residue of most products of edible tissues A toxicant absorbed into the systemic circulation following any route of administration must reach its site of action at a high enough concentration for a sufficient period of time to elicit a biological response. Distribution processes determine this outcome. There are numerous tissues to which a chemical may be distributed, some of them capable of eliciting a pharmacological or toxicological (intended versus unintended) response while others serve only as a sink or depot for the chemical. Sinks may also be formed as a result of chemical binding to tissue or plasma proteins. The toxicological significance of such sinks is that chemicals will be distributed to, and in some cases stored in, these tissues and only slowly released back into the systemic circulation for ultimate elimination. Such tissue binding may actually protect against acute adverse effects by providing an "inert" site for toxicant localization. Storage may, however, prolong the overall residence time of a compound in the body and promote accumulation during chronic exposure, two processes that would potentiate chronic toxicity. If the animal is a food-producing species, such tissue storage may result in residues in the edible meat products. Tissue concentrations thus become an endpoint in themselves, devoid of a biological or toxicological relevance in the tissue they are found. Their relevance is set by regulations that legally establish safe tissue tolerances or maximum residue levels for specific tissues and species. These are based upon extrapolations of safety to the consuming human population and food consumption patterns. These concepts are developed in Chapter 61. Distribution of chemicals to peripheral tissues is dependent on four factors: 1) Physiochemical properties of the compound (pKa, lipid solubility, molecular weight) 2) Concentration gradient established between the blood and tissue 3) Ratio of blood flow to tissue mass 4) Affinity of the chemical for tissue constituents. The physiochemical properties of the chemical are most important in determining its propensity to distribute to a specific tissue. For most molecules, distribution out of the blood into tissue is via bulk flow through the capillary pores or by simple diffusion down a concentration gradient; hence distribution is generally described by first-order rate constants. One can conceptualize distribution as "absorption" into the tissues from the blood. The complicating factors are that the driving concentration is now dependent upon blood flow, the surface area for "absorption into tissues" is dependent upon capillary density and tissue mass, the relevant partition coefficient is the blood/tissue ratio, and plasma/tissue protein binding complicates the picture. An understanding of distribution is a prerequisite to predicting pharmacological response.

Know what must be included on written/verbal prescriptions for Rx drugs and controlled substances.

- The elements listed below are required by law to be included on the written prescription document: 1). Printed or stamped name, address, and telephone number of the licensed practitioner 2). Legal signature of the licensed practitioner 3). Name and strength of drug 4). Directions for use 5). Full name and address of the client 6). Animal identification (name and/or species) 7). Cautionary statements including, if applicable, withdrawal times for food animals 8). Number of refills, if any

Absorption in a One-Compartment Open Model

- almost as fast as you are putting the drug in the body the kidney is kicking the drug back out of the body, so the drug has not metabolized, and it is not really interacting with a receptor its staying in one compartment, the circulatory volume The analysis above assumes that the drug was injected into the body, which behaves as a single space into which the drug is uniformly dissolved. The first real-world complication is when the drug is administered by one of the extravascular routes discussed in Chapter 2. In this case, the drug must be absorbed from the dosing site into the bloodstream. The resulting semilogarithmic concentration-time profile, depicted in Figure 3.7, now is characterized by an initial rising component that peaks and then undergoes the same log-linear decline. The proper pharmacokinetic model for this scenario is depicted in Figure 3.8. The rate of the drug's absorption is governed by the rate constant Ka . When the absorption process is finally complete, elimination is still described by Kel as depicted in Figure 3.5. The overall elimination half-life can still be calculated using Kel if this terminal slope is taken after the peak (Cmax) in the linear portion of the semilogarithmic plot (providing Ka ≫ Kel).

Sympathetic Nervous System

- fight or flight In these conditions, SNS activation mediates increased heart rate and cardiac contractility, vascular vasoconstriction in skin and viscera with shunting of blood flow to skeletal muscles, hepatic glycogenolysis, bronchiolar and pupillary dilation, and contraction of the spleen. This physiological response profile is mediated by the combined activation of peripheral sympathetic nerves innervating specific target organs (e.g., heart, blood vessels) and the adrenal medulla. This prominent activation state led to the concept that the SNS acts as a unit. However, it is now well understood that a fundamental regulatory strategy of the SNS involves selectively controlling the level of activity in nerves innervating different targets in response to a number of physiological conditions (i.e., nonuniform

Storage and Security of Controlled Substances

- must be stored under 2 locks Controlled substances "must be stored in a securely locked, substantially constructed cabinet." If there is loss or theft, upon discovery of loss of theft of controlled substances, the registrant must immediately notify the region office of the DEA and then must complete DEA form 106 describing the loss. If a theft is verified, the local police department must also be notified.

Gastrointestinal Absorption

- oral drugs are absorbed across the small intestines - for oral absoption to be sucessful a drug to be capable of surviving harsh environments since the stomch is acidic many drugs can not survive that One of the primary routes of drug administration is oral ingestion of a pill or tablet that is designed to deliver a drug across the gastrointestinal mucosa. The common factor in all forms of oral drug administration is a method to deliver a drug such that it gets into solution in the gastrointestinal fluids from which it can then be absorbed across the mucosa and ultimately reach the submucosal capillaries and the systemic circulation. Examples of oral drug delivery systems include solutions (aqueous, elixirs) and suspensions, pills, tablets, boluses for food animals, capsules, pellets, and sustained release mechanical devices for ruminants. The major obstacle encountered in comparative and veterinary medicine is the enormous interspecies diversity in comparative gastrointestinal anatomy and physiology, which results in major species differences in strategies for and efficiency of oral drug administration. This is often appreciated but overlooked when laboratory animal data is extrapolated to humans. Rats and rabbits are widely utilized in preclinical disposition and toxicology studies, although many investigators fail to appreciate that these species' gastrointestinal tracts are very different from one another and from humans. The simple mucosal lining of the stomach allows absorption; however, the presence of surface mucus, which protects the epithelium from self-digestion secondary to acid and enzyme secretion, may be a barrier for some drugs. The acidity and motility of the stomach also creates a hostile environment for drugs and even influences the absorption of drugs farther down the tract. For oral drug absorption to be successful, the drug must be capable of surviving this relatively harsh environment. For some drugs (e.g., penicillin G) susceptible to acid hydrolysis, minimal absorption by the oral route will occur unless they are administered in a formulation that protects them in an acid environment but liberates them in the more alkaline environment of the intestines. Release of the drug from the stomach, a process controlled by gastric emptying, is a major ratedetermining step in the onset and duration of oral drug activity. Species differences in the size of the pyloric orifice also limit use of some dosage forms in small animals versus humans. The primary site for most drug absorption is the small intestine. In this region of the gastrointestinal tract, the pH of the contents are more alkaline and the epithelial lining is conducive to drug absorption. The blood flow to this region is also much greater than to the stomach. The small intestine is lined by simple columnar epithelium resting on a basement membrane and a submucosal tissue bed that is very well perfused by an extensive capillary and lymphatic network. This capillary bed drains into the hepatic portal vein. One of the major anatomical adaptations for absorption in this region is the presence of microvilli, which increase the surface area of the small intestine some 600-fold over that of a simple tube. The second anatomical adaptation are the villi of the intestine, which can be easily appreciated by examining a cross section (Figure 2.5). Since diffusion is the primary mechanism for drug absorption, the increase in area due to these two anatomical configurations significantly increases absorption, as can be seen from reviewing the area contribution to Equation 2.1. There are species differences in inherent permeability of the intestinal mucosa to chemicals, with the dog recently being recognized as having a higher permeability to many drugs than humans.

Methods for Assessing Protein Binding

- plasma protein binding is always representing as a percent; higher the protein binding is considered a bad thing because it will be bound to albumin you will need to add more drugs to exceed that, and the unbound form will go elicit its pharmacologic effect A number of methods have been employed to study drug-protein interactions, including ultrafiltration, electrophoresis, equilibrium dialysis, solvent extraction, solvent partition, ultracentrifugation, spectrophotometry, and gel filtration. The most widely used techniques are ultrafiltration and equilibrium dialysis. The basic concept is that a semipermeable membrane is used, which restricts passage of protein but allows unbound drug to cross the barrier according the diffusion. Bound drug is placed on one side of the membrane and samples are collected from the protein-free side. Ultrafiltration allows rapid protein-drug separation while equilibrium dialysis requires time for the separation to occur. The fraction of free drug is then calculated based on the amount of total drug used. Protein-binding data are frequently expressed in terms of percent of drug bound. Although useful, the limitations should be recognized, for as drug concentration is lowered, the percentage of binding increases. When a compound has a high affinity for a protein (e.g., albumin), percent binding falls sharply when the total drug concentration exceeds a certain value that saturates the binding sites available.

Enterohepatic Recycling and Coprophagy

- some drugs can get trapped in a type of circulation; a drug goes into the bile which then dumps it into the small intestine gets absorbed into the small intestines and then back into the systemic circulation, so it gets trapped into this never-ending circle The gastrointestinal tract has also evolved into an excretory organ for elimination of nonabsorbed solid wastes and other metabolic byproducts excreted in the bile. The bile duct drains into the upper small intestine. For some drugs, this results in a phenomenon called enterohepatic recycling whereby a drug from the systemic circulation is excreted into the bile and is reabsorbed from the small intestine back into the bloodstream. In many cases, drugs that are metabolized by Phase II conjugation reactions are "unconjugated" by resident bacterial flora, which generates free drug for reabsorption. Thus compounds that are excreted into the bile may have a prolonged sojourn in the body because of the continuous opportunity for intestinal reabsorption. The cardinal sign of this process is a "hump" in the plasma drug concentration-time profile after administration (Figure 2.6). Bile also serves to emulsify fatty substances that are not capable of solubilizing in the primarily aqueous environment of the intestines. The result of this detergent-like action of bile is to form large surface area micelles having a hydrophilic surface and hydrophobic interior. These act as transport vehicles to deliver fat-soluble drugs to the intestinal brush border surface for diffusion across the lipid membrane into the cell. Without the interaction of bile acids, fatty substances would not be available for absorption since they could not traverse this "dissolution" barrier. Thus unlike most drugs, compounds that are absorbed by this route often must be administered with a meal to promote bile acid secretion and associated micelle formation. Enterohepatic recycling has also been suggested as an important mechanism for enhanced activity of certain antiparasitic drugs such as the avermectins. As discussed in Chapter 41, the recycling of active drug is a major contributor to enhanced parasite exposure. Finally, some species such as rabbits, routinely ingest fresh feces for nutritional purposes, which provides another opportunity for drug to be reabsorbed into the body

An Overview of Drug Disposition

- the liver job is to make a drug that is lipophilic more hydrophilic to allow the drug to be excreted through the urine - water is polar so understand what polar drug refers to To fully appreciate the ADME processes governing the fate of drugs in animals, the various steps involved must be defined and ultimately quantitated. The processes relevant to a discussion of the absorption and disposition of a drug administered by the intravenous (IV), intramuscular (IM), subcutaneous (SC), oral (PO), or topical (TOP) routes are illustrated in Figure 2.1. The normal reference point for pharmacokinetic discussion and analysis is the concentration of free, non-protein-bound drug dissolved in the serum (or plasma), because this is the body fluid that carries the drug throughout the body and from which samples for drug analysis can be readily and repeatedly collected. For the majority of drugs studied, concentrations in the systemic circulation are in equilibrium with the extracellular fluid of well-perfused tissues; thus, serum or plasma drug concentrations generally reflect extracellular fluid drug concentrations. A fundamental axiom of using pharmacokinetics to predict drug effect is that the drug must be present at its site of action in a tissue at a sufficient concentration for a specific period of time to produce a pharmacological effect. Since tissue concentrations of drugs are reflected by extracellular fluid and thus serum drug concentrations, a pharmacokinetic analysis of the disposition of drug in the scheme outlined in Figure 2.1 is useful to assess the activity of a drug in the in vivo setting. This conceptualization is especially important in veterinary medicine where species differences in any of the ADME processes may significantly affect the extent and/or time course of drug absorption and disposition in the body. By dividing the overall process of drug fate into specific phases, this relatively complex situation can be more easily handled. Despite the myriad of anatomical and physiological differences among animals, the biology of drug absorption and distribution, and in some cases even elimination, is very similar in that it involves drug molecules crossing a series of biological membranes. As illustrated in Figure 2.2, these membranes may be associated with either several layers of cells (tissue) or a single cell, and both living and dead protoplasm may be involved. Despite the different biochemical and morphological attributes of each of these membranes, a unifying concept of biology is the basic similarity of all membranes, whether they be tissue, cell, or organelle. Although the specific biochemical components may vary, the fundamental organization is the same. This fact simplifies the understanding of the major determinants of drug absorption, distribution, and excretion. hydrophobic (nonpolar) tails forming the interior. The specific lipid composition varies widely across different tissues and levels of biological organization. The location of the proteins in the lipid matrix is primarily a consequence of their hydrophobic regions residing in the lipid interior and their hydrophilic and ionic regions occupying the surface. This is thermodynamically the most stable configuration. Changes in the fluidity of the lipids alter protein conformations, which then may modulate their activity. This was one of the mechanisms of action proposed for gaseous anesthetics, although recently specific protein receptors have now been suggested. In some cases, aqueous channels form from integral proteins that traverse the membrane. In other cases, these integral proteins may actually be enzymatic transport proteins that function as active or facilitative transport systems. The primary pathway for drugs to cross these lipid membranes is by passive diffusion through the lipid environment. Thus, in order for a drug to be absorbed or distributed throughout the body, it must be able to pass through a lipid membrane on some part of its sojourn through the body. In some absorption sites and in many capillaries, fenestrated pores exist, which allow some flow of small molecules. This is contrasted to some protected sites of the body (e.g., brain, cerebral spinal fluid) where additional membranes (e.g., glial cells) may have to be traversed before a drug arrives at its target site. These specialized membranes could be considered a general adaptation to further shelter susceptible tissues from hostile lipophilic chemicals. In this case, drug characteristics that promote transmembrane diffusion would favor drug action and effect (again unless specific transport systems intervene). This general phenomenon of the enhanced absorption and distribution of lipophilic compounds is a unifying tenet that runs throughout the study of drug fate. The body's elimination organs can also be viewed as operating along a somewhat similar principle. The primary mechanism by which a chemical can be excreted from the body is by becoming less lipophilic and more hydrophilic, the latter property being required for excretion in the aqueous fluids of the urinary or biliary systems. When a hydrophilic or polar drug is injected into the bloodstream, it will be minimally distributed and rapidly excreted by one of these routes. However, if a compound's lipophilicity evades this easy excretion, the

Disintegration, Dissolution, Diffusion, and Other Transport Phenomenon for GI tract

- there almost no antibiotics that can go oral for cattle, sheep, goats because the rumen is hard on drugs, it causes disintegration, sometimes the PH will cause the drugs to become inactivated, the rumen is not a favorable place for drugs -dogs and cats have shorter GI transit times then people so it comes into play if you use a prolonged release dosage drug in a canine patient, those were designed for 150-pound person who has a much longer GI transit time compared to a canine patient In order for a drug to be absorbed across the intestinal mucosa, the drug must first be dissolved in the aqueous intestinal fluid. Two steps, disintegration and dissolution, may be required for this to occur. Disintegration is the process whereby a solid dosage form (e.g., tablet) physically disperses so that its constituent particles can be exposed to the gastrointestinal fluid. Dissolution occurs when the drug molecules then enter into solution. This component of the process is technically termed the pharmaceutical phase and is controlled by the interaction of the formulation with the intestinal contents. These concepts are further elaborated on in Chapter 5. Some dosage forms, such as capsules and lozenges, may not be designed to disintegrate, but rather to allow a drug to slowly elute from their surface. Dissolution is often the rate-limiting step controlling the absorption process and can be enhanced by formulating the drug in salt form (e.g., sodium or hydrochloride salts), buffering the preparation (e.g., buffered aspirin), or decreasing dispersed particle size (micronization) so as to maximize exposed surface area. This is extensively discussed in Chapter 5 (see equation 5.7). Alternatively, disintegration and dissolution can be decreased so as to deliberately provide slow release of the drug. This strategy is used in prolonged-release or controlled-release dosage forms and involves complex pharmaceutical formulations that produce different rates of dissolution. This may be accomplished by dispersing the dosage form into particles with different rates of dissolution or by using multilaminated dosage forms, which delays release of the drug until its layer is exposed. All of these strategies decrease the overall rate of absorption. Similar strategies can also be used to target drugs to the distal segments of the gastrointestinal tract by using enteric coatings that dissolve only at specific pH ranges, thereby preventing dissolution until the drug is in the region targeted. This strategy has been applied for colonic delivery of drugs in humans for treatment of Crohn's disease. In slow-release or long-acting formulations, the end result is that absorption becomes slower than all other distribution and elimination processes, making the pharmaceutical phase the rate-limiting or rate-controlling step in the subsequent absorption and disposition of the drug. When this occurs, as will be seen in the pharmacokinetic modeling chapters to follow, the rate of absorption controls the rate of apparent drug elimination from the body and a so-called flip-flop scenario becomes operative. There are significant species differences in the ability to use controlled-release oral medications designed in humans, by far the largest market, in other species. The first limitation involves the inability to use cellulose based systems in ruminants due to the ability of rumen microbes to digest the normally inert cellulose matrix that controls rates of drug delivery. The second arises because of shorter gastrointestinal transit times in small carnivores, such as domestic cats and dogs, compared to humans. In this instance, drug release is designed to occur in the longer transit times seen in humans (approx. 24 hours). In dogs and cats, which have transit times half that of humans, drug release may still be occurring even after the tablet has been eliminated in the feces due to the shorter transit times. Other examples include the narrower pyloric opening in dogs, compared to humans, that may increase gastric retention of some larger dosage forms. These are but a few examples of significant species differences that, based on anatomical and physiological factors, prevent the ready transferability of complex dosage forms across species. There are also specific active transport systems present within the intestinal mucosa of the microvilli that are responsible for nutrient absorption. However, these systems have a very high capacity and if a specific drug or toxicant has the proper molecular configuration to be transported, saturation is unlikely. There is some evidence that select therapeutic drugs (e.g., β-lactams such as ampicillin) may be absorbed by active transport systems in the small intestine. There are also transport systems (P-glycoprotein) that expel absorbed drug back into the intestinal lumen. This system is beginning to be studied more closely in veterinary species and will be discussed later in this chapter under distribution and elimination. After the drug is in solution, it must still be in a nonionized relatively lipid-soluble form to be absorbed across the lipid membranes comprising the intestinal mucosa. It must be stressed that absorption across any membrane is a fine balance between adequate solubility on the donor side of the membrane with sufficient permeability (or active transport capacity) to actually transit the membrane. For orally administered products, the pH of the gastrointestinal contents becomes very important, as is evident from the earlier discussion on pH partitioning. Specifically, a weak acid would tend to be preferentially absorbed in the more acidic environment of the stomach since a larger fraction would be in the nonionized form. However, the much larger surface area and blood flow available for absorption in the more alkaline intestine may override this effect. It is important to mention at this point why a weak acid such as aspirin is better absorbed in a bicarbonate buffered form, which would tend to increase the ionized fraction and thus decrease membrane passage. The paradox is that dissolution must first occur, a process favored by the ionized form of the drug. It is only the dissolved ionized aspirin that is available to the partitioning phenomenon described earlier. Thus, when more aspirin is dissolved in the buffered microenvironment, more is available for partitioning and diffusion across the mucosa. In contrast to the situation of a weak acid, a weak base would tend to be better absorbed in the more alkaline environment. However, it must be repeated that the very large surface area available in the intestines, coupled with high blood flow and a pH of approximately 5.3 in the immediate area of the mucosal surface makes it the primary site of absorption for most drugs (weak acids with pKa >3 and weak bases with pKa <7.8). Species differences in both gastric and intestinal pH further modulate this differential (e.g., canine gastric pH is much higher than humans). A further obstacle to absorption is that the compound must also be structurally stable against chemical or enzymatic attack. Finally, compounds with a fixed charge and/or very low (or very high) lipid solubility for the uncharged moiety, may not be significantly absorbed after oral administration. Examples include the polar aminoglycoside antibiotics, the so-called "enteric" sulfonamides, and quaternary ammonium drugs

Species Effects on Gastrointestinal Transit Time and Food Interactions

- there are 2 categories of antibiotics, if you administer them orally in a patients at the same time they are nursing are being body fed there will be a sticker on the bottle saying do not take with dairy products. Those drugs like to bond with monovalent dye and trivalent cations especially calcium and magnesium so when the antibiotics bind with the cations it's pretty strong, they do not disassociate, and they will be bound the entire time even get pooped out and won't be able to elicit its pharmacological effects this is called keylation Food may also interact with other aspects of oral drug absorption and have opposite effects for more hydrophilic drugs. Depending on the physicochemical properties of the specific drug, administration with food may significantly increase or decrease absorption. Such effects are not only drug dependent, but also are species dependent due to the continuous foraging behavior of ruminants and some other omnivores compared to the periodic feeding habits of predatory carnivores. These variables are difficult to incorporate into formal pharmacokinetic models yet they add to the variability in parameters derived from these studies or in drug response between species. The first potential interaction relates to the rate of drug delivery to the small intestine that is governed by the rate of drug release from the stomach, the gastric emptying time. This process is dependent upon the eating habits of the species, with continuous foraging animals (e.g., herbivores such as horses and ruminants) having a steady input of drug and a relatively stable gastric pH compared to periodic eaters (e.g., carnivores like dogs and cats and omnivores such as pigs) who have more variable eating patterns with large swings in gastric pH depending on the presence or absence of food. In addition, the drug may directly interact with the ingested food, as is the case of chelation of tetracyclines with divalent cations such as Mg++ in antacids or Ca++ in milk products. Thus, the decision to administer a compound with or without food is species and drug dependent and may significantly alter the bioavailability (rate and extent of absorption) of the drug. In contrast, for very-lipid-soluble drugs, food is necessary in order to have bile release, which allows solubilization and absorption to occur. The forestomachs of a ruminant provide a major obstacle to the delivery of an oral dosage form to the true stomach (abomasum) for ultimate release to the intestines, although a significant amount of drug absorption may occur from this site. The rumen is essentially a large fermentation vat (>50 liters in cattle, 5 liters in sheep) lined by stratified squamous epithelium, buffered at approximately a pH of 6 by extensive input of saliva, which maintains it in a fluid to soft consistency, designed primarily for the absorption of volatile fatty acids. If drugs dissolve in this medium and remain intact, they undergo tremendous dilution that decreases their rate of absorption. They then are pumped from the rumen and reticulum through the omasum for a rather steady input of drug into the true stomach. An understanding of the physiology of the ruminant has allowed for the development of some unique and innovative mechanical drug delivery technologies, which essentially are encapsulated pumps that "sink" to the bottom of the rumen and become trapped, much as many unwanted objects tend to when ingested by a ruminant (e.g., nails and wire in hardware disease). These "submarine-like" devices then slowly release drug into the ruminal fluid for a true sustained-release preparation. In preruminant calves, a drug may bypass the rumen entirely through the rumen-reticulo groove and essentially behave as if administered to a monogastric. In contrast, fermentation in the horse occurs after drug absorption by the small intestine and thus has less impact than in ruminants. However, a nonabsorbed drug that reaches the equine large intestines and cecum, the site of fermentation, may have disastrous effects (e.g., colic) if digestive flora or function is perturbed.

Absorption

- there is no absorption in IV administered drug since u put it directly in the blood stream. - you have sublingual( under the tongue) or buccal( pouch created by the gum line such as a buprenophine), rectal, topical, intramamory are certain routes of administration Absorption is the movement of the drug from the site of administration into the blood. There are a number of methods available for administering drugs to animals. The primary routes of drug absorption from environmental exposure in mammals are gastrointestinal, dermal, and respiratory. The first two are also used as routes of drug administration for systemic effects, with additional routes including intravenous, intramuscular, subcutaneous, or intraperitoneal injection. Other variations on gastrointestinal absorption include intrarumenal, sublingual, and rectal drug delivery. Many techniques are also used for localized therapy, which may also result in systemic drug absorption as a side effect. These include, among others: topical, intramammary, intraarticular, subconjunctival, and spinal fluid injections. Methods of utilizing these different routes of drug administration are also explored in Chapter 5

Sympathomimietic

- this means to mimic or like(mimicking the sympathetic nervous system -AKA adrenergic, it resembles effects caused by stimulation of adrenergic neurons. EX; direct acting alpha and beta receptor agonist -AKA adrenomimetic, it stimulates effects of epi and norepi. EX; indirect acting, release of endogenous stores of catecholamines

Plasma Protein Binding

- you can get albumin through the red cross( liquid gold is the name -highly plasma protein bound drugs will have a long duration of action to overcome that you have to administer more drug so that there's more unionized form. this will allow the drug to get to it specific organ to cause some affect. eventually drugs will unbind to albumin, but it takes time to do this. if there is also another drug that has a higher protein bond in comparison to the first drug that is attached to the plasma protein it can cause side affects Studies of plasma proteins have shown albumin to be particularly important in the binding of drugs. This is especially true for weak acids, with weak bases often binding to acid glycoproteins. For certain hormones, specific high-affinity transport proteins are present. Studies of toxicant binding have been more limited, but there is evidence of a significant binding/partitioning role for lipoproteins in carrying very lipophilic chemicals in the blood. In the case of most drug-protein interactions, reversible binding is established, which follows the Law of Mass Action and provides a remarkably efficient means whereby drugs can be transported to various tissues. The strength of this association may be quantitated through the use of the dissociation constant, Kdiss. Among a group of binding sites on proteins, those with the smallest Kdiss value for a given drug will bind it most tightly. In contrast to reversible binding seen with most therapeutic drugs, agents like cisplatin and some potentially carcinogenic metabolites that are formed from chlorinated hydrocarbons (such as CCl4 ) are covalently bound to tissue proteins. In this case, there is no true distribution of the drug as there is no opportunity for dissociation. Once a molecule binds to a plasma protein, it moves throughout the circulation until it dissociates, usuallyfor attachment to another large molecule. Dissociation occurs when the affinity for another biomolecule or tissue component is greater than that for the plasma protein to which the toxicant was originally bound. Thus, forces of association must be strong enough to establish an initial interaction, and they must also be weak enough such that a change in the physical or chemical environment can lead to dissociation. Dissociation could occur by binding to proteins of greater affinity (lower Kdiss values), binding with a higher concentration of proteins of lower affinity, or changes in Kdiss with changes in ionic strength, pH, temperature, or conformational changes in the binding site induced by binding of other molecules. As long as binding is reversible, redistribution will occur whenever the concentration of one pool (i.e., blood or tissue) is diminished. Redistribution must occur when the concentration is diminished in order to reestablish equilibrium.

define/describe protein binding

- you can get albumin through the red cross( liquid gold is the name -highly plasma protein bound drugs will have a long duration of action to overcome that you have to administer more drug so that there's more unionized form. this will allow the drug to get to it specific organ to cause some affect. eventually drugs will unbind to albumin, but it takes time to do this. if there is also another drug that has a higher protein bond in comparison to the first drug that is attached to the plasma protein it can cause side affects Studies of plasma proteins have shown albumin to be particularly important in the binding of drugs. This is especially true for weak acids, with weak bases often binding to acid glycoproteins. For certain hormones, specific high-affinity transport proteins are present. Studies of toxicant binding have been more limited, but there is evidence of a significant binding/partitioning role for lipoproteins in carrying very lipophilic chemicals in the blood. In the case of most drug-protein interactions, reversible binding is established, which follows the Law of Mass Action and provides a remarkably efficient means whereby drugs can be transported to various tissues. The strength of this association may be quantitated through the use of the dissociation constant, Kdiss. Among a group of binding sites on proteins, those with the smallest Kdiss value for a given drug will bind it most tightly. In contrast to reversible binding seen with most therapeutic drugs, agents like cisplatin and some potentially carcinogenic metabolites that are formed from chlorinated hydrocarbons (such as CCl4 ) are covalently bound to tissue proteins. In this case, there is no true distribution of the drug as there is no opportunity for dissociation. Once a molecule binds to a plasma protein, it moves throughout the circulation until it dissociates, usuallyfor attachment to another large molecule. Dissociation occurs when the affinity for another biomolecule or tissue component is greater than that for the plasma protein to which the toxicant was originally bound. Thus, forces of association must be strong enough to establish an initial interaction, and they must also be weak enough such that a change in the physical or chemical environment can lead to dissociation. Dissociation could occur by binding to proteins of greater affinity (lower Kdiss values), binding with a higher concentration of proteins of lower affinity, or changes in Kdiss with changes in ionic strength, pH, temperature, or conformational changes in the binding site induced by binding of other molecules. As long as binding is reversible, redistribution will occur whenever the concentration of one pool (i.e., blood or tissue) is diminished. Redistribution must occur when the concentration is diminished in order to reestablish equilibrium.

Signs of drug instability of compounded formulations

-Benzoalchohol helps to prevent intability in compound drugs but cats do not do well with benzoalchohol Liquid dose forms Color change (pink or amber) Signs of microbial growth Cloudiness, haze, flocculent, or film formation Separation of phases (e.g., oil and water, emulsion) Precipitation, clumping, crystal formation Droplets or fog forming on inside of container Gas or odor release Swelling of container Solid dose forms Odor (sulfur or vinegar odor) Excessive powder or crumbling Cracks or chips in tablets Swelling of tablets or capsules Sticking together of capsules or tablets Tackiness of the covering of tablets or capsules

Table . Pharmaceutical factors affecting absorption

-Disintegration Excipients Compaction pressure Enteric coatings, capsules Homogeneity -Dissolution Particle size/surface area Binding Local pH, buffers Boundary layers -Barrier diffusion Solubility Transit time

A Primer on the Language of Pharmacokinetics

-Most drugs are eliminated after the first order rate process the amount of drugs eliminated is directly proportional to the serum drug concentration, higher the serum drug concentration the more that will be eliminated -nonlinear or zero order process to metabolize a drug maybe you rely on a specific enzyme system and there's just so much enzymes in a patient body and once you saturate that enzyme system so now you are waiting for the body to produce more enzyme to metabolize drugs this is called zero nonlinear process As can again be appreciated by examining the equation for Fickian diffusion (Equation 2.1 in Chapter 2), compounds that are either absorbed, distributed, or eliminated in direct proportion to a concentration gradient are by definition first-order rate processes. The rate constants (Kn ) modeled in pharmacokinetics are actually aggregate constants reflecting all of the membrane diffusion and transfer processes involved in the disposition parameter being studied. This includes pH partitioning phenomena in the body, which exist when blood and a cellular or tissue compartment have a pH gradient that alters the fraction of drug available for diffusion. Recall that it is only the unionized fraction of a weak acid or base that diffuses down its gradient across a lipid membrane. The rate constant also reflects the degree of plasma protein binding since only the free fraction of drug is available for distribution. The actual value of a K in a pharmacokinetic model thus reflects all of these variables whose relationship defines the biological system that we are attempting to quantitate. In this scenario, the rate of excretion is fixed and thus independent of the amount of compound available, X. Although this would appear to simplify the situation, in reality nonlinear kinetics actually complicate most models. Nonlinear behavior becomes evident when saturation of a process occurs. The focus of most pharmacokinetic studies is on drugs with linear pharmacokinetics since the majority of therapeutically active compounds are described by these models

Know the definitions for; first order linear models

-Most drugs are eliminated after the first order rate process the amount of drugs eliminated is directly proportional to the serum drug concentration, higher the serum drug concentration the more that will be eliminated -nonlinear or zero order process to metabolize a drug maybe you rely on a specific enzyme system and there's just so much enzymes in a patient body and once you saturate that enzyme system so now you are waiting for the body to produce more enzyme to metabolize drugs this is called zero nonlinear process As can again be appreciated by examining the equation for Fickian diffusion (Equation 2.1 in Chapter 2), compounds that are either absorbed, distributed, or eliminated in direct proportion to a concentration gradient are by definition first-order rate processes. The rate constants (Kn ) modeled in pharmacokinetics are actually aggregate constants reflecting all of the membrane diffusion and transfer processes involved in the disposition parameter being studied. This includes pH partitioning phenomena in the body, which exist when blood and a cellular or tissue compartment have a pH gradient that alters the fraction of drug available for diffusion. Recall that it is only the unionized fraction of a weak acid or base that diffuses down its gradient across a lipid membrane. The rate constant also reflects the degree of plasma protein binding since only the free fraction of drug is available for distribution. The actual value of a K in a pharmacokinetic model thus reflects all of these variables whose relationship defines the biological system that we are attempting to quantitate. In this scenario, the rate of excretion is fixed and thus independent of the amount of compound available, X. Although this would appear to simplify the situation, in reality nonlinear kinetics actually complicate most models. Nonlinear behavior becomes evident when saturation of a process occurs. The focus of most pharmacokinetic studies is on drugs with linear pharmacokinetics since the majority of therapeutically active compounds are described by these models

Know what must be on the label of a drug you dispense

-Name and address of the prescribing veterinarian -Established name of the drug -Any specified directions for use including the class/species or identification of the animal or herd, flock, pen, lot, or other group; -the dosage frequency and route of administration; and the duration of therapy - Any cautionary statements: Your specified withdrawal, withholding, or discard time for meat, milk, eggs, or any other food

Define pharmacokinetics and its application to drugs used in food animals.

-Pharmacodynamics is what the drug is doing to the body (increase in heart rate, decrease in heart rate, causing sedation) Pharmacokinetics is best defined as the use of mathematical models to quantitate the time course of drug absorption and disposition in man and animals.

Pharmacokinetics

-Pharmacodynamics is what the drug is doing to the body (increase in heart rate, decrease in heart rate, causing sedation) Pharmacokinetics is best defined as the use of mathematical models to quantitate the time course of drug absorption and disposition in man and animals. With the tremendous advances in medicine and analytical chemistry, coupled with the almost universal availability of computers, what was once an arcane science has now entered the mainstream of most fields of human and veterinary medicine. This discipline has allowed dosages of drugs to be tailored to individuals or groups to optimize therapeutic effectiveness, minimize toxicity, and avoid violative tissue residues in the case of food-producing animals.

Compounded Transdermal Medications for Pets

-Popular in female cats, never compound transdermal medications with insulin and antibiotics it doesnt do well Because of convenience, ease of administration, and therapeutic success with some transdermal drugs (antiparasitic agents and fentanyl), there is considerable interest in formulating a wide range of other drugs for use by this route. Historically, transdermally administered drugs were formulated for single-dose delivery in a liquid preparation, or for continuous delivery out of a drug-releasing matrix or "patch." A compounding pharmacist (Marty Jones, PharmD) discovered a penetration-enhancing drug vehicle in the 1990s, and application of this delivery system to drugs used in animals rapidly caught on. A quick Internet search of "compounding pharmacy + transdermal" will reveal over 11,000 advertisements from compounding pharmacies who provide drugs in transdermal delivery gels. Noninvasive, nonstressful, palatable drug delivery is an attractive option for many veterinary patients, especially cats. Consequently, many veterinarians are eager to try this dosage form on fractious or fragile patients who should not be (or do not want to be) stressed during medication. While transdermal drug delivery is appealing, there is only one drug (methimazole) that was shown to produce therapeutic benefits when compounded and administered via the transdermal route in cats. The skin is a formidable barrier to drug penetration, and drug absorption into systemic circulation is difficult (Riviere and Papich, 2001)(see Chapter 47 of this book). In order to facilitate drug transport across skin, drugs need to be small in molecular weight and placed in a biphasic vehicle that can propel the drug across the various lipophilic and hydrophilic layers of the skin. Passage of the drug across the skin relies on the thickness of the skin, the partition coefficient of the drug, the diffusion coefficient of the skin, and the concentration of drug in solution. The partition coefficient, the diffusion coefficient, and the thickness of the skin are not alterable; therefore, transdermally applied drugs must be placed in high concentrations in vehicles that accommodate the various coefficients of diffusion. There are few drugs that can meet these criteria to be successfully absorbed by this route. One commonly used penetration enhancer is pleuronic lecithin organogel (PLO), which is lecithin (derived from eggs or soybeans) mixed with isopropyl palmitate and a poloxamer (Pluronic). The ingredients in PLO act as surfactants, emulsifiers, and solubilizing agents to escort drug across the skin into systemic vasculature. There are many other penetration-enhancing vehicles (e.g., Lipoderm, Van Penn) utilized to compound transdermal preparations, but at the time of writing, there are no FDA-approved formulations that utilize these penetration-enhancing vehicles to deliver systemic drugs. Most FDA-approved transdermal drugs for people are available as patch delivery systems (e.g., patches containing fentanyl, lidocaine, or buprenorphine), or are single-dose applications of parasiticides for animals. Compounded transdermal preparations are formulated in high concentrations so that a therapeutic dose may be delivered in 0.1-0.2 ml, which is applied to a hairless area and rubbed in until no residue remains on the skin surface. Because the drug must be in solution in order to penetrate skin, many drugs are logically precluded from transdermal administration because they are not soluble in concentrations high enough to deliver a dose in 0.1- 0.2 ml (e.g., any drug dosed at 10 mg/kg requires a transdermal concentration of at least 500 mg/ml to deliver a 0.1-ml dose to a 5-kg cat). The majority of drugs are not soluble at these high concentrations. Single-dose pharmacokinetic studies for transdermally administered drugs have demonstrated that absorption was incomplete, nonexistent, or highly inconsistent among study cats, and that after single doses, bioavailability was low compared to a single oral dose. There have been an even smaller number of chronic dosing safety and efficacy studies for transdermally administered drugs, and few of those demonstrated positive evidence of efficacy. Transdermally administered drugs examined so far have included methimazole, amlodipine, glipizide, dexamethasone, buspirone, amitriptyline, metoclopramide, atenolol, fentanyl, morphine, fluoxetine, ondansetron, theophylline, and diltiazem. Methimazole was not absorbed well according to a pharmacokinetic study (Hoffman et al., 2002; Trepanier, 2002), but produced clinical efficacy with repeated transdermal application in other studies (Hoffman et al., 2001). It is suspected that efficacy from repeated doses of transdermal methimazole is attributed to the cat rubbing their paw on the ear, then licking the medication from the paw producing oral absorption. Transdermal amlodipine produced a change in blood pressure in a small study in hypertensive cats (Helms, 2007), but it is known that blood pressure response from amlodipine in cats can be highly variable. Absorption of atenolol from a transdermal preparation in cats was low and inconsistent and did not produce therapeutic blood levels of atenolol after a week of chronic dosing at an equivalent oral dose (MacGregor et al., 2008). The remaining drugs were examined as single-dose pharmacokinetic studies and showed poor bioavailability as compared to oral dosing and a high degree of intrasubject variation in drug absorption.A major concern for use of transdermally administered drugs, for which there is no safety, efficacy, or strength evidence, is the risk of poor absorption or decreased stability of the formulated drug. For example, unstable or poorly absorbed transdermal antibiotics may result in therapeutic failure or increase the risk of antimicrobial drug resistance. Misinterpretation of single-dose pharmacokinetic studies might lead prescribers to increase transdermally administered drug doses, leading to accumulation of drug and severe toxicity. For example, the transdermal bioavailability of amitriptyline was 10% compared to oral dosing in a single dose pharmacokinetic study. Several veterinarians erroneously interpreted these results to mean that transdermal amitriptyline should effectively be administered at 10 times the oral dose. Other poor candidates for transdermal administration include drugs that are known to be contact irritants or phototoxins. In addition to bioavailability rationale, veterinarians evaluating drugs for transdermal application should also consider the local damage caused by these drugs (e.g. clopidogrel, doxycycline, fluoxetine, enrofloxacin) when applied to thin, hairless skin (e.g. pinnae). Obviously, there also is considerable risk for absorption by the human caregiver. Drugs toxic to humans (e.g., chloramphenicol, diethylstilbestrol, carprofen, digoxin anticancer agents) are extremely poor candidates for transdermal drug administration. Similarly, caregiver health and lifestyle must also be considered when prescribing transdermal drugs for pets. For example, a hypothyroid owner is a poor candidate to administer transdermal methimazole to her hyperthyroid cat, and a long-distance truck driver subject to periodic drug testing is a poor candidate for administration of transdermal opiates to his pet in pain.

Know the definitions for; half-life, number of half-life's where 99% of drug is depleted

-T1/2 is the abbreviation of half life being the time required for the amount of drug to decrease by one-half or 50%. The concept of T1/2 is applicable only to first-order rate processes. What does T1/2 really mean? Assume that we start with X, decrease it by half, and repeat this process 10 times. Table 3.1 compiles this data and lists how much drug is remaining and how much has been excreted over each Δt corresponding to one T1/2. For therapeutic drugs, most workers assume that after five T1/2s, the drug has been depleted or the process is over since 97% of the depletion has occurred

The Concept of Half-Life

-T1/2 is the abbreviation of half life being the time required for the amount of drug to decrease by one-half or 50%. The concept of T1/2 is applicable only to first-order rate processes. What does T1/2 really mean? Assume that we start with X, decrease it by half, and repeat this process 10 times. Table 3.1 compiles this data and lists how much drug is remaining and how much has been excreted over each Δt corresponding to one T1/2. For therapeutic drugs, most workers assume that after five T1/2s, the drug has been depleted or the process is over since 97% of the depletion has occurred

define T 1/2

-T1/2 is the abbreviation of half life being the time required for the amount of drug to decrease by one-half or 50%. The concept of T1/2 is applicable only to first-order rate processes. What does T1/2 really mean? Assume that we start with X, decrease it by half, and repeat this process 10 times. Table 3.1 compiles this data and lists how much drug is remaining and how much has been excreted over each Δt corresponding to one T1/2. For therapeutic drugs, most workers assume that after five T1/2s, the drug has been depleted or the process is over since 97% of the depletion has occurred

- it is illegal to use adulterated drugs -it is legal to purchase/use/store C.S with an expired DEA license - you are not responsible for the accuracy of your C.S drug inventory ( taken every 2 years) or your daily C.S drug administration records TRUE OR FALSE?

-True -false -false

Unclear Abbreviations

-When outsources medication for a patient do not say SID because pharmacist do not use that term and it can be mistaken for 4 times a day which can cause an overdose Unclear medical abbreviations are one cause of medication errors. There are different reasons why practitioners use abbreviations, including what they were taught in school and training. Using abbreviations is also a way to save time when writing prescriptions and documenting what was prescribed in patient records. However, experience with marketed drugs shows many medication mix-ups occur because abbreviations are misinterpreted. Not all practitioners interpret abbreviations in the same way. Abbreviations can be vague and unfamiliar, causing the intended meaning to be improperly conveyed. Poor penmanship is not the only culprit - abbreviations are prone to misinterpretation even when prescriptions are typed. In June 2006, FDA and the Institute for Safe Medication Practices (ISMP) launched a nationwide education campaign aimed at reducing medication errors caused by unclear abbreviations (http://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/2006/ucm108671.htm). Although the campaign targeted human drugs, a review of ISMP's list of error-prone abbreviations shows that the same mistakes may easily cross over to animal drugs.1 In fact, FDA's CVM is learning that medication errors caused by unclear medical abbreviations do occur with animal drugs. After reviewing reports of problems with animal drugs, CVM found that the abbreviation "SID" (once daily) in prescriptions was misinterpreted as "BID" (twice daily) and "QID" (four times daily), resulting in drug overdoses for the patients. For a drug where there is a strong correlation between the dose and the severity of side effects, an overdose can be serious. Medication errors in animals occur not only in veterinary clinics, but also in pharmacies where pharmacists and pharmacy technicians may be unfamiliar with veterinary abbreviations.

Two-Compartment Models

-antibiotics is a common drug -example, propofol first goes into the brain and then it goes into the muscles Many drugs are not described by a simple one compartment model since the plasma concentration time profile is not a straight line. This reflects the biological reality that for many drugs, the body is not a single homogeneous compartment, but instead is composed of regions that are defined by having different rates of Figure . Generalized open two-compartment pharmacokinetic model after intravenous administration with elimination (Kel) from the central compartment. K12 and K21 represent intercompartmental micro-rate constants. drug distribution. Such a situation is reflected in the two compartment model depicted in Figure 3.10. The drug initially is distributed in the central compartment and by definition is eliminated from this compartment. The difference comes because now the drug also distributes into other body regions at a rate that is different from that of the central compartment. As presented in Chapter 2, there are many factors that determine the rate and extent of drug distribution into a tissue (e.g., blood flow, tissue mass, blood/tissue partition coefficient, etc.). When the composite rates of these flow and diffusion processes are significantly different than Kel, then the C-T profile will reflect this by assuming a biexponential nature. For many drugs, the central compartment may consist of blood plasma and the extracellular fluid of highly perfused organs such as the heart, lung, kidneys, and liver. Distribution to the remainder of the body occurs more slowly, which provides the physiological basis for a two-compartment model. Such a peripheral compartment is defined by a distribution rate constant (K12) out of the central compartment and a redistribution rate constant (K21) from the peripheral back into the central compartment. As discussed in the distribution chapter, depots or sinks may also occur. This is a pharmacokinetic concept where the distribution rate constants are significantly slower than Kel and thus become the rate-limiting factor defining the terminal slope of a biexponential C-T profile, a situation analogous to flip-flop in absorption studies.

Most drugs follow a 2 compartment model

-antibiotics is a common two compartment model -example propofol will first go to the brain and then will go to the muscles Many drugs are not described by a simple one compartment model since the plasma concentration time profile is not a straight line. This reflects the biological reality that for many drugs, the body is not a single homogeneous compartment, but instead is composed of regions that are defined by having different rates of drug distribution. Such a situation is reflected in the two-compartment model depicted in Figure 3.10. The drug initially is distributed in the central compartment and by definition is eliminated from this compartment. The difference comes because now the drug also distributes into other body regions at a rate that is different from that of the central compartment.

two compartment model

-antibiotics is a common two compartment model -example propofol will first go to the brain and then will go to the muscles Many drugs are not described by a simple one compartment model since the plasma concentration time profile is not a straight line. This reflects the biological reality that for many drugs, the body is not a single homogeneous compartment, but instead is composed of regions that are defined by having different rates of drug distribution. Such a situation is reflected in the two-compartment model depicted in Figure 3.10. The drug initially is distributed in the central compartment and by definition is eliminated from this compartment. The difference comes because now the drug also distributes into other body regions at a rate that is different from that of the central compartment.

Define/describe; the concept of clearance (no calculations).

-clearance is not how much drug is being removed rather it represent a theoretical volume of blood that is cleared of a substance per unit time Clearance is a concept widely used to measure the efficiency of drug elimination from an organ or the whole body. The concept was developed for use in assessing kidney function by renal physiologists. The problem with simply measuring the concentration of drug in urine as an index of its renal excretion is that the kidney also modulates the volume of urine produced in association with its primary mission of regulating fluid balance. Thus, the concentration of drug alone may be higher or lower depending on the ultimate urine volume. To accurately assess how much drug is eliminated, the product of volume of urine produced and the concentration of drug in urine (mass/volume) must be determined to provide the amount excreted (mass). If timed urine samples are collected, an excretion rate (mass/time) is determined. Similarly, to assess how efficient this process is, one must know how much drug is actually presented to the kidney for excretion. There are two definitions of renal clearance that are used to define equations to calculate this parameter from real data. The first is the volume of blood cleared of a substance by the kidney per unit of time, that is, the volume of blood required to contain the quantity of drug removed by the kidney during a specific time interval. This will be derived when we have developed pharmacokinetic parameters in Chapter 3 to quantitate Vd and fractional excretion rates. The second definition is the rate of drug excretion relative to its plasma concentration. In both cases, the actual value for a drug's renal clearance is the vectorial sum of {filtration + tubular secretion − tubular reabsorption}, making it a parameter that estimates the entire contribution of the kidney to drug elimination. Similarly, any change in renal drug processing will be reflected in renal clearance if it is not compensated for by more distal components of the renal tubules

The Concept of Clearance and its Calculation

-clearance is not how much drug is being removed rather it represent a theoretical volume of blood that is cleared of a substance per unit time Clearance is a concept widely used to measure the efficiency of drug elimination from an organ or the whole body. The concept was developed for use in assessing kidney function by renal physiologists. The problem with simply measuring the concentration of drug in urine as an index of its renal excretion is that the kidney also modulates the volume of urine produced in association with its primary mission of regulating fluid balance. Thus, the concentration of drug alone may be higher or lower depending on the ultimate urine volume. To accurately assess how much drug is eliminated, the product of volume of urine produced and the concentration of drug in urine (mass/volume) must be determined to provide the amount excreted (mass). If timed urine samples are collected, an excretion rate (mass/time) is determined. Similarly, to assess how efficient this process is, one must know how much drug is actually presented to the kidney for excretion. There are two definitions of renal clearance that are used to define equations to calculate this parameter from real data. The first is the volume of blood cleared of a substance by the kidney per unit of time, that is, the volume of blood required to contain the quantity of drug removed by the kidney during a specific time interval. This will be derived when we have developed pharmacokinetic parameters in Chapter 3 to quantitate Vd and fractional excretion rates. The second definition is the rate of drug excretion relative to its plasma concentration. In both cases, the actual value for a drug's renal clearance is the vectorial sum of {filtration + tubular secretion − tubular reabsorption}, making it a parameter that estimates the entire contribution of the kidney to drug elimination. Similarly, any change in renal drug processing will be reflected in renal clearance if it is not compensated for by more distal components of the renal tubules

Know the definitions for; one-compartment model

-comparative meaning it's the same as human side -VD is the shorthand for volume and distribution -polar drugs will have a small volume of distribution while lipophilic drugs will have a large volume of distribution -VD estimates the extend of drugs distribution to the tissues also its a term to describe the volume of fluids that would be required to account for all the fluid in the body -VD you can calculate, and it will always be in litters/kilogram. -1 litter/killigram is the base line so anything below that is considered a small volume of distribution while anything above that is considered a high level of distribution. A small volume of distribution means that drug is confined to the vascular system and a really large volume of distribution means that most of the drug is in the tissues specifically the adipose tissue so very little of the drug is in the circulatory system The most widely used modeling paradigm in comparative and veterinary medicine is the compartmental approach. In this analysis, the body is viewed as being composed of a number of so-called equilibrium compartments, each defined as representing nonspecific body regions where the rates of compound disappearance are of a similar order of magnitude. Specifically, the fraction or percent of drug eliminated per unit of time from such a defined compartment is constant. Such compartments are classified and grouped on the basis of similar rates of drug movement within a kinetically homogeneous but anatomically and physiologically heterogeneous group of tissues. These compartments are theoretical entities that allow formulation of mathematical models to describe a drug's behavior over time with respect to movement within and between compartments. Since pharmacologists and clinicians sample blood as a common and accessible biological matrix for assessing drug fate, most pharmacokinetic models are constructed with blood or plasma drug concentrations as the central reference to which other processes are related. The simplest compartment model is when one considers the body as consisting of a single homogeneous compartment; that is, the entire dose X of drug is assumed to move out of the body at a single rate. This model, depicted in Figure 3.4, is best conceptualized as instantly dissolving and homogeneously mixing the drug in a beaker from which it is eliminated by a single rate process described by the rate constant K, now termed Kel. Since the drug leaves the system, the model is termed open. Equation 3.6 is the pharmacokinetic equation for the one-compartment open model. Although expressed in terms of the amount of drug remaining in the compartment, most experiments measure concentrations. This requires the development of the volume of distribution (Vd) (recall Equation 2.5 when distribution was discussed). In terms of the one-compartment model, this would be the volume of the compartment into which the dose of drug (D) instantaneously distributes. Vd thus becomes a proportionality factor relating D to the observed concentration Cp by Vd (ml) = X (mg)∕Cp (mg∕ml) = D∕Cp (3.12) Using this relation, we can now rewrite Equation 3.6 in terms of concentrations, which are experimentally accessible by sampling blood, instead of the total amount of drug remaining in the body. Cp = X0∕Vd e−Kelt = Cp0 e −Kelt (3.13) A semilogarithmic plot seen after intravenous administration using this model is depicted in Figure 3.5. Vd quantitates the apparent volume into which a drug is dissolved**************************************(important), since, recalling the discussion in Chapter 2, the true volume is determined by the physiology of the animal, the relative transmembrane diffusion coefficients, and the chemical properties of the drug being studied. A drug that is restricted to the vascular system will have a very small Vd; one which distributes to total body water will have a very large Vd. In fact, it is this technique that is used to calculate the plasma and interstitial spaces - almost as fast as you are putting the drug in the body the kidney is kicking the drug back out of the body, so the drug has not metabolized, and it is not really interacting with a receptor its staying in one compartment, the circulatory volume The analysis above assumes that the drug was injected into the body, which behaves as a single space into which the drug is uniformly dissolved. The first real-world complication is when the drug is administered by one of the extravascular routes discussed in Chapter 2. In this case, the drug must be absorbed from the dosing site into the bloodstream. The resulting semilogarithmic concentration-time profile, depicted in Figure 3.7, now is characterized by an initial rising component that peaks and then undergoes the same log-linear decline. The proper pharmacokinetic model for this scenario is depicted in Figure 3.8. The rate of the drug's absorption is governed by the rate constant Ka . When the absorption process is finally complete, elimination is still described by Kel as depicted in Figure 3.5. The overall elimination half-life can still be calculated using Kel if this terminal slope is taken after the peak (Cmax) in the linear portion of the semilogarithmic plot (providing Ka ≫ Kel).

One-Compartment Open Model

-comparative meaning it's the same as human side -VD is the shorthand for volume and distribution -polar drugs will have a small volume of distribution while lipophilic drugs will have a large volume of distribution -VD estimates the extend of drugs distribution to the tissues also its a term to describe the volume of fluids that would be required to account for all the fluid in the body -VD you can calculate, and it will always be in litters/kilogram. -1 litter/killigram is the base line so anything below that is considered a small volume of distribution while anything above that is considered a high level of distribution. A small volume of distribution means that drug is confined to the vascular system and a really large volume of distribution means that most of the drug is in the tissues specifically the adipose tissue so very little of the drug is in the circulatory system The most widely used modeling paradigm in comparative and veterinary medicine is the compartmental approach. In this analysis, the body is viewed as being composed of a number of so-called equilibrium compartments, each defined as representing nonspecific body regions where the rates of compound disappearance are of a similar order of magnitude. Specifically, the fraction or percent of drug eliminated per unit of time from such a defined compartment is constant. Such compartments are classified and grouped on the basis of similar rates of drug movement within a kinetically homogeneous but anatomically and physiologically heterogeneous group of tissues. These compartments are theoretical entities that allow formulation of mathematical models to describe a drug's behavior over time with respect to movement within and between compartments. Since pharmacologists and clinicians sample blood as a common and accessible biological matrix for assessing drug fate, most pharmacokinetic models are constructed with blood or plasma drug concentrations as the central reference to which other processes are related. The simplest compartment model is when one considers the body as consisting of a single homogeneous compartment; that is, the entire dose X of drug is assumed to move out of the body at a single rate. This model, depicted in Figure 3.4, is best conceptualized as instantly dissolving and homogeneously mixing the drug in a beaker from which it is eliminated by a single rate process described by the rate constant K, now termed Kel. Since the drug leaves the system, the model is termed open. Equation 3.6 is the pharmacokinetic equation for the one-compartment open model. Although expressed in terms of the amount of drug remaining in the compartment, most experiments measure concentrations. This requires the development of the volume of distribution (Vd) (recall Equation 2.5 when distribution was discussed). In terms of the one-compartment model, this would be the volume of the compartment into which the dose of drug (D) instantaneously distributes. Vd thus becomes a proportionality factor relating D to the observed concentration Cp by Vd (ml) = X (mg)∕Cp (mg∕ml) = D∕Cp (3.12) Using this relation, we can now rewrite Equation 3.6 in terms of concentrations, which are experimentally accessible by sampling blood, instead of the total amount of drug remaining in the body. Cp = X0∕Vd e−Kelt = Cp0 e −Kelt (3.13) A semilogarithmic plot seen after intravenous administration using this model is depicted in Figure 3.5. Vd quantitates the apparent volume into which a drug is dissolved**************************************(important), since, recalling the discussion in Chapter 2, the true volume is determined by the physiology of the animal, the relative transmembrane diffusion coefficients, and the chemical properties of the drug being studied. A drug that is restricted to the vascular system will have a very small Vd; one which distributes to total body water will have a very large Vd. In fact, it is this technique that is used to calculate the plasma and interstitial spaces.

-A lay-person can use an OTC drug in an extra label manner without DVM oversight -A lay-person can use a VFD drug in food animals without DVM oversight -I will not be able to call Dr. Blythe from jail because I failed to pay attention while covering regulatory topics in pharm 1

-false -false -false

Inventory Records

-keep your schedule 2,3,4 drugs all in separate files so that it is easier to find when needed All DEA 222 order forms for Schedule II orders as well as other commercial invoices accompanying controlled drugs must be signed and dated, and items must be counted, noted, and stored in a readily retrievable file for 2 years. Schedule II records must be stored separately from Schedule III-V records. A complete and accurate inventory of all stocks of all controlled substances must be taken every 2 years on the anniversary of the practitioner's initial DEA registration. The written inventory should contain the following information: the name, address, and DEA registration number of the registrant; the date and time the inventory is taken; the signature of the person taking inventory; an indication that the inventory is maintained for at least 2 years at the location appearing on the registration; an indication that inventory and other records of Schedule II drugs are maintained separately from other drugs

What is considered a schedule Class -11 drug?

-morphine -hydrophorphone -fentanyl -Methadone -Hydrocodone -pentobarbital -Etorphine

Respiratory Absorption

-nebulizer is a type of respiratory drug - The third major route for systemic exposure to drugs and toxicants is the respiratory system. Since this system's primary function is gas exchange (O2 , CO2 ), it is always in direct contact with environmental air as an unavoidable part of breathing. A number of toxicants are in gaseous (CO, NO2 , formaldehyde), vapor (benzene, CCl4 ), or aerosol (lead from automobile exhaust, silica, asbestos) forms and are potential candidates for entry via the respiratory system. There are no approved inhalational drugs for use in veterinary medicine. Each mode of inhalational exposure results in a different mechanism of compound absorption and for the purposes of this text, a different definition of dose. These concepts are also discussed In Chapters 11 and 48 of this text. Opportunities for systemic absorption are excellent through the respiratory route since the cells lining the alveoli are very thin and profusely bathed by capillaries. The surface area of the lung is large (50−100 m2 ), some 50 times the area of the skin. Based on these properties and the diffusion equation presented earlier (Equation 2.1), the large surface area, the small diffusion distance, and high level of blood perfusion maximize the rate and extent of passive absorption driven by gaseous diffusion. The process of respiration involves the movement and exchange of air through several interrelated passages including the nose, mouth, pharynx, trachea, bronchi, and successive smaller airways terminating in the alveoli where gaseous exchange occurs. All of these anatomical modifications protect the internal environment of the air passages from the harsh outside environment by warming and humidifying the inspired air. The passages also provide numerous obstacles and baffles to prevent the inhalation of particulate and aerosol droplets. Thus the absorption of particulate and aerosolized liquids, such as those employed in nebulized drug therapy, is fundamentally different from that of gases. The absorption of such impacted solids and liquids along the respiratory tract has much more in common with oral and topical absorption, with the critical caveat that the precise dose of compound finally available for absorption is very difficult to determine. Great strides have been made in developing aerosol drug delivery devices for human use that take advantage of this mechanism of impaction; however, these may not be transferable to veterinary species since their efficacy is closely related to the geometry and physiology of the human respiratory tract. Another unique aspect of respiratory exposure is the fact that the pulmonary blood circulation is in series with the systemic circulation. Thus, in contrast to cutaneous or oral exposure, compounds absorbed in the lung will enter the oxygenated pulmonary veins that drain to the systemic arterial circulation. Compared to oral administration, this reduces first-pass hepatic metabolism. However, the pulmonary circulation is adept at metabolizing peptides secondary to its role in inactivating peptide hormones.

Recall the Delaney anti-cancer clause.

-no food additive will be deemed to be safe if it is found to induce cancer (carcinogenic) I.e. metronidazole

Requirements for writing a prescription for controlled substances

-no refills are allowed on prescription particularly schedule 2 drugs. (They have the highest level for abuse) -schedule drugs 3,4,5 Prescriptions will expire 6 or after 5 refills months no matter what - noncontrolled prescription expire after 1 year after the day is given The elements listed below are required by law to be included on the written prescription document: Printed or stamped name, address, and telephone number of the licensed practitioner DEA registration number of the licensed practitioner Legal signature of the licensed practitioner followed by printed name of the practitioner Name and strength of drug Directions for use Full name and address of client Animal identification (name and/or species) Cautionary statements including, if applicable, withdrawal times for food animals No refills are allowed on Schedule II prescriptions and refills are limited to 5 times or 6 months (whichever comes first) on prescriptions for drugs in Schedules III-V.

Drug Receptor and Ligand as Agonist or Antagonist

-opioids are a good example of this A full agonist produces a maximal effect under a given set of conditions whereas a partial agonist produces only a submaximal effect regardless

Name the various routes of absorption

-oral -SQ -IM

Other Routes of Administration

-parenteral drug route is any drug that goes through the skin with a needle must always be sterile such as im, iv etc. TPN is a sterile mix into a bag of fluids it's a way to feed a patient similar to a nasogastric tube but its known for developing bacteria it has to be extremely sterile discontinue it if needed In order to complete this discussion of absorption, it is important to realize that there are other extravascular drug administration routes that are often encountered. Relative to pharmacokinetic analysis, these are dealt with in the same fashion as the primary routes discussed above. The important difference is that in all cases, the barrier to absorption is less than that encountered in oral or topical delivery. Second, all of these routes involve an invasive procedure to inject drug into an internal body tissue, thereby bypassing the epithelial barriers of the skin and gastrointestinal tract. The primary therapeutic routes of drug administration are subcutaneous (SC or SQ) and intramuscular (IM). In these cases, the total dose of drug is known and injected into tissue that is well perfused by systemic capillaries that drain into the central venous circulation. Both of these routes as well as intravenous administration are termed parenteral to contrast primarily with oral (enteral) and topical dosing, which are classified as nonparenteral routes of drug administration. A primary difference between these two classes is that parenteral routes bypass all of the body's defensive mechanisms. Parenteral dosage forms are manufactured under strict guidelines that eliminate microbial and particulate contamination resulting in sterile preparations that must be administered using aseptic techniques. This restriction does apply to oral or topical dosage forms. As with all methods of drug administration, there are numerous variables associated with SC and IM dosing that can be conveniently classified into pharmaceutical and biological categories. Finally, there are other occasional routes of drug administration employed that require absorption for activity. Administration of drugs by intraperitoneal injection is often used in toxicology studies in rodents since larger volumes can be administered. Peritoneal absorption is very efficient, provided adequate "mixing" of the injection with the peritoneal fluid is achieved. The majority of drug absorbed after interperitoneal administration enters the portal vein and thus may undergo first-pass hepatic metabolism. The disposition of intraperitoneal drug thus mirrors oral administration. Some drugs are administered by conjunctival, intravaginal, or intramammary routes. In these cases achievement of effective systemic concentrations are often not required for what is an essentially local therapeutic effect. Prolonged absorption from these sites may result in persistent tissue residues in food-producing animals if the analytical sensitivity of the monitoring assay is sufficiently low. The systemic absorption of these dosage forms is quantitated using procedures identical to those employed for other routes of administration. conveniently classified into pharmaceutical and biological categories. Finally, there are other occasional routes of drug administration employed that require absorption for activity. Administration of drugs by intraperitoneal injection is often used in toxicology studies in rodents since larger volumes can be administered. Peritoneal absorption is very efficient, provided adequate "mixing" of the injection with the peritoneal fluid is achieved. The majority of drug absorbed after interperitoneal administration enters the portal vein and thus may undergo first-pass hepatic metabolism. The disposition of intraperitoneal drug thus mirrors oral administration. Some drugs are administered by conjunctival, intravaginal, or intramammary routes. In these cases achievement of effective systemic concentrations are often not required for what is an essentially local therapeutic effect. Prolonged absorption from these sites may result in persistent tissue residues in food-producing animals if the analytical sensitivity of the monitoring assay is sufficiently low. The systemic absorption of these dosage forms is quantitated using procedures identical to those employed for other routes of administration.

Define/describe phase I and II reactions

-phase 1 and phase 2 metabolic process you take a lipid soluble drug or a toxicant to metabolize it into something water soluble so it can be excreted into the urine since the urine is largely water - cats do not have some of the phase 2 metabolic enzymes to metabolize them and detoxify them such as glucuronidation -paracetamol is tylenol Various metabolic pathways are involved in drug metabolism including oxidation, reduction, hydrolysis, hydration, and conjunction. These processes can be divided into Phase I and Phase II reactions (Table 2.2). Phase I includes reactions introducing functional groups to drug molecules necessary for the Phase II reactions, which primarily involve conjugation. In other words, Phase I products act as substrates for Phase II processes, resulting in conjugation with endogenous compounds, which further increase their water solubility and polarity, thus retarding tissue distribution and facilitating drug excretion from the body. Specific examples of drug metabolism are included in chapters throughout this text. The focus of this introduction will be to briefly overview the general processes involved in drug metabolism relative to how they might affect pharmacokinetic parameters and the disposition of drugs in the body. Interested readers should consult standard texts in drug metabolism or biochemical pharmacology/toxicology for specific detailed examples illustrating the chemistry and genetic control of these processes Phase I metabolism includes four major pathways: oxidation, reduction, hydrolysis, and hydration, among which oxidation is the most important. Attention is usually focused on oxidation mediated by the microsomal mixed-function oxidase system (e.g., cytochrome P450, etc.) due to its central role and significance in governing the metabolic disposition of many drugs and xenobiotics. An understanding of this pathway is often critical to making interspecies extrapolations. Phase II conjugating enzymes play a very important role in the deactivation of the Phase I metabolites of many drugs as well as in direct deactivation of some parent compounds when their specific structure doesn't require Phase I modification. For example, the analgesic drug paracetamol can be deactivated directly by Phase II reactions using glutathione, glucuronide, and sulfate conjugation mechanisms. Phase II deactivation can be achieved by both gross chemical modification of the drug thereby decreasing their receptor affinity, and by enhancement of excretion from the body, often via the kidney. In summary, Phase I metabolism is primarily responsible for drug deactivation, although Phase II plays an important role in deactivation of some drugs. Phase I reactions prepare drugs or toxicants for Phase II metabolism; that is Phase I modifies the drug molecule by introducing a chemically reactive group on which the Phase II reactions can be carried out for the final deactivation and excretion. This increased water solubility after metabolism restricts a drug's metabolite distribution to extracellular fluids, thereby enhancing excretion. Specific pathways for drug metabolism and transport are discussed in the individual drug chapters as well as their pharmacogenomics in Chapter 50

Phase I and Phase II Reactions

-phase 1 and phase 2 metabolic process you take a lipid soluble drug or a toxicant to metabolize it into something water soluble so it can be excreted into the urine since the urine is largely water - cats do not have some of the phase 2 metabolic enzymes to metabolize them and detoxify them such as glucuronidation -paracetamol is tylenol Various metabolic pathways are involved in drug metabolism including oxidation, reduction, hydrolysis, hydration, and conjunction. These processes can be divided into Phase I and Phase II reactions (Table 2.2). Phase I includes reactions introducing functional groups to drug molecules necessary for the Phase II reactions, which primarily involve conjugation. In other words, Phase I products act as substrates for Phase II processes, resulting in conjugation with endogenous compounds, which further increase their water solubility and polarity, thus retarding tissue distribution and facilitating drug excretion from the body. Specific examples of drug metabolism are included in chapters throughout this text. The focus of this introduction will be to briefly overview the general processes involved in drug metabolism relative to how they might affect pharmacokinetic parameters and the disposition of drugs in the body. Interested readers should consult standard texts in drug metabolism or biochemical pharmacology/toxicology for specific detailed examples illustrating the chemistry and genetic control of these processes Phase I metabolism includes four major pathways: oxidation, reduction, hydrolysis, and hydration, among which oxidation is the most important. Attention is usually focused on oxidation mediated by the microsomal mixed-function oxidase system (e.g., cytochrome P450, etc.) due to its central role and significance in governing the metabolic disposition of many drugs and xenobiotics. An understanding of this pathway is often critical to making interspecies extrapolations. Phase II conjugating enzymes play a very important role in the deactivation of the Phase I metabolites of many drugs as well as in direct deactivation of some parent compounds when their specific structure doesn't require Phase I modification. For example, the analgesic drug paracetamol can be deactivated directly by Phase II reactions using glutathione, glucuronide, and sulfate conjugation mechanisms. Phase II deactivation can be achieved by both gross chemical modification of the drug thereby decreasing their receptor affinity, and by enhancement of excretion from the body, often via the kidney. In summary, Phase I metabolism is primarily responsible for drug deactivation, although Phase II plays an important role in deactivation of some drugs. Phase I reactions prepare drugs or toxicants for Phase II metabolism; that is Phase I modifies the drug molecule by introducing a chemically reactive group on which the Phase II reactions can be carried out for the final deactivation and excretion. This increased water solubility after metabolism restricts a drug's metabolite distribution to extracellular fluids, thereby enhancing excretion. Specific pathways for drug metabolism and transport are discussed in the individual drug chapters as well as their pharmacogenomics in Chapter 50

Define/describe hepatic biotransformation and biliary excretion

-pro drug is something you administer, and you rely on the liver to metabolize it to its active form Hepatic disposition is one of the final keys in the ADME scheme needed to describe the disposition of many drugs and chemicals in the body. The liver is responsible for both biotransformation and biliary excretion. In many ways, the liver should be considered as two separate organs, one encompassing metabolism and the other biliary excretion Drug metabolism may often result in metabolite(s) with altered chemical structures, which change the receptor type affected, drug-receptor affinity, or pharmacological effect. . Most parent drugs can be deactivated to inactive metabolites. In contrast, some drugs can also be activated either from an inactive form (prodrug) to an active drug, or from an active form (e.g., meperidine) to an active metabolite (normeperidine) with similar activity/toxicity Therefore, drug metabolism can either reduce or enhance parent drug's effect, create another activity, or even elicit toxicity, depending on both the drug and the biological system in question.

Hepatic Biotransformation and Biliary Excretion

-pro drug is something you administer, and you rely on the liver to metabolize it to its active form Hepatic disposition is one of the final keys in the ADME scheme needed to describe the disposition of many drugs and chemicals in the body. The liver is responsible for both biotransformation and biliary excretion. In many ways, the liver should be considered as two separate organs, one encompassing metabolism and the other biliary excretion Drug metabolism may often result in metabolite(s) with altered chemical structures, which change the receptor type affected, drug-receptor affinity, or pharmacological effect. . Most parent drugs can be deactivated to inactive metabolites. In contrast, some drugs can also be activated either from an inactive form (prodrug) to an active drug, or from an active form (e.g., meperidine) to an active metabolite (normeperidine) with similar activity/toxicity Therefore, drug metabolism can either reduce or enhance parent drug's effect, create another activity, or even elicit toxicity, depending on both the drug and the biological system in question.

define clearance

-renal clearance= -hepatic clearance= As presented in our discussion on renal excretion, clearance of a drug by an organ (Clorg) can be ultimately defined as a function of its blood flow (Qorg) and its extraction ratio (Eorg) expressed in Equation 2.6 as Clorg = Qorg Eorg. The ability of the liver to remove drug from the blood, defined as hepatic clearance, is related to two variables: intrinsic hepatic clearance (Clint) and rate of hepatic blood flow (Qh ), as defined in Equation 2.13: whereClh is the hepatic clearance, Qh is the hepatic blood flow, and Clint/(Qh+Clint) is the hepatic extraction ratio or Eh . Intrinsic clearance (Clint) is conceptualized as the maximal ability of the liver to extract/metabolize drug when hepatic blood flow is not limiting. It represents the inherent metabolic function of all enzyme systems in the liver to metabolize the drug in question. As seen in Equation 2.13, when Clint ≫ Qh , hepatic extraction ratio ≈1.0 (flow limited or high extraction, usually seen with Eh > 0.8), Clh is dependent only on the blood perfusion rate Qh . The more blood passing through the liver, the more drug molecules will be extracted by the liver for metabolic elimination. A hepatic blood perfusion dependent hepatic clearance will then be seen. Drugs with such high extraction ratios will show significant first-pass metabolism after oral administration to the extent that this route of administration may not produce effective systemic drug concentrations.

Parasympathetic Nervous System

-rest and digest Parasympathetic nerves originate from cell bodies in the brainstem and sacral sections of the spinal cord, and synapse in ganglia (more anatomical detail is presented later in this chapter). The level of activity in parasympathetic nerves is regulated by multiple areas in the br. Parasympathetic nerves innervating many target organs are tonically active and changing the level of activity in peripheral parasympathetic nerves in response to specific physiological stimuli is a primary mechanism by which the PSNS regulates physiological function. Figure 6.4 shows directly recorded cardiac vagal parasympathetic nerve discharge under basal conditions, and in response to an experimentally induced activation of the baroreceptor reflex, which produced an increase in the level of cardiac vagal nerve activity and an associated reduction in heart rate (Simms et al., 2007). The primary functional profile elicited by activation of the PSNS includes initiating and sustaining energy conservation and homeostasis during periods of relative physiological quiescence. In general, increasing the level of activity in parasympathetic nerves reduces heart rate, stimulates gastrointestinal secretions and peristalsis, contracts the body of the urinary bladder, and modulates immune function. Physiological responses of selected organs and effector tissues elicited by activation of efferent parasympathetic nerves are summarized in Table 6.1. Specific receptor classes and types involved in mediating PSNS-induced physiological responses are included in Table 6.1, and are introduced later in this chapter and considered in more detail in Chapter 7 ACh is also the primary neurotransmitter released from postganglionic PSNS neurons at target organ sites, and at these sites ACh primarily binds to and activates muscarinic receptors (designated as M2 receptors, as in Figure 6.5). As stated previously, nerve fibers that synthesize and release ACh are classified as cholinergic fibers, therefore both preganglionic and postganglionic parasympathetic neurons are cholinergic.

First-Pass Metabolism

-sublingual, buccal, rectal bypass first pass metabolism but any drugs that is highly predisposed to first pass metabolism like some oral drugs zero percent of the drug will not make it to the blood stream since the liver already destroyed it. -Most opiates are highly predisposed to first-pass metabolism that's why there will never be oral fentanyl that's why people who are addicted to drugs they either snort it or use needs and put it iv - fluids can go rectally, if a patient needs to be warmed you can administer warm fluids, seizure meds can go rectally =, things that go through the rectum goes to the circulation it does not go through the liver Another unique aspect of oral drug absorption is the fate of the absorbed drug once it enters the submucosal capillaries. Drug absorbed distal to the oral cavity and proximal to the rectum in most species enters the portal circulation and is transported directly to the liver where biotransformation(metabolized) may occur. This is a major cause for differences in a drug's ultimate disposition compared to all other routes of administration. This may result in a significant first-pass biotransformation of the absorbed compound. For a drug that is extensively metabolized by the liver, this first-pass effect significantly reduces absorption of the active drug even when it is absorbed across the mucosa. This occurs for many opiate medications in dogs, reducing their efficacy after oral administration. Finally, some drugs that are too polar to be absorbed across the gastrointestinal wall are formulated as ester conjugates to increase lipid solubility and enhance absorption. Once the drug crosses the gastrointestinal epithelium in this form, subsequent firstpass hepatic biotransformation enzymes and circulating blood and mucosal esterases cleave off the ester moiety releasing free drug into the systemic circulation. There are selected drug administration sites that avoid first-pass hepatic metabolism by allowing absorption through gastrointestinal tract segments not drained by the portal vein. These include the oral cavity buccal and rectal routes of drug administration in some species, although this assumption hasn't been tested in many veterinary species.

Define/Describe; first pass effect

-sublingual, buccal, rectal bypass first pass metabolism, but any drugs that are highly predisposed to first pass metabolism, like some oral drugs, the drug will not make it to the blood stream since the liver already destroyed it. -Most opiates are highly predisposed to first-pass metabolism that's why there will never be oral fentanyl that's why people who are addicted to drugs they either snort it or use needles to inj IV - fluids can go rectally, if a patient needs to be warmed you can administer warm fluids, seizure meds can go rectally =, things that go through the rectum goes to the circulation it does not go through the liver — Another unique aspect of oral drug absorption is the fate of the absorbed drug once it enters the submucosal capillaries. — Drugs absorbed distal to the oral cavity and proximal to the rectum in most species enters the portal circulation and is transported directly to the liver where biotransformation(metabolized) may occur. - This is a major cause for differences in a drug's ultimate disposition compared to all other routes of administration. - May result in a significant first-pass biotransformation of the absorbed compound. — For a drug that is extensively metabolized by the liver, this first-pass effect significantly reduces absorption of the active drug even when it is absorbed across the mucosa. This occurs for many opiate medications in dogs, reducing their efficacy after oral administration. — Finally, some drugs that are too polar to be absorbed across the gastrointestinal wall are formulated as ester conjugates to increase lipid solubility and enhance absorption. Once the drug crosses the gastrointestinal epithelium in this form, subsequent firstpass hepatic biotransformation enzymes and circulating blood and mucosal esterases cleave off the ester moiety releasing free drug into the systemic circulation. There are selected drug administration sites that avoid first-pass hepatic metabolism by allowing absorption through gastrointestinal tract segments not drained by the portal vein. These include the oral cavity buccal and rectal routes of drug administration in some species, although this assumption hasn't been tested in many veterinary species.

Sympatholytic

-this means to lyse or break -receptros blocking effects+ adrenergic blocking drugs., inhibit responses causes by stim of adrenergic neurons. EX; alpha or beta blockers (phenoxybenzamine, propranolol) - Neuronal blocking effects= adrenolytic, inhibit responses caused by adrenergic neurons EX; deplete endogenous catacholamines

Bioavailability

-this will always be in percent, and it starts with a IV dose (IV is the only route where the drug is 100% is systemically available) -bioavailability is the proportion of the drug that reaches the systemic circulation - so, you want a drug with high bioavailability such as 95% or 99% The final topic to consider with absorption is the assessment of the extent and rate of absorption after oral, topical, or inhalational drug administration. The extent of drug absorption is defined as absolute systemic availability and is denoted in pharmacokinetic equations as the fraction of an applied dose absorbed into the body (F). Although this topic will also be discussed extensively in Chapter 3, it is important and convenient at this juncture to introduce the basic concepts so as to complete the discussion of drug absorption. If one is estimating the extent of drug absorption by measuring the resultant concentrations in either blood or excreta, one must have an estimate of how much drug normally would be found if the entire dose were absorbed. To estimate this, an intravenous dose is required since this is the only route of administration that guarantees that 100% of the dose is systemically available (F = 1.0) and the pattern of disposition and metabolism can be quantitated. Parameters used to measure systemic availability are thus calculated as a ratio relative to the intravenous dose. For most therapeutic drug studies, systemic absorption is assessed by measuring blood concentrations. The amount of drug collected after administration by the route under study is divided by that collected after intravenous administration. When drug concentrations in blood (or serum or plasma) are assayed, total absorption is assessed by measuring the area under the concentration-time curve (AUC) using the trapezoidal method. This is a geometrical technique that breaks the AUC into corresponding trapezoids based on the number of samples assayed. The terminal area beyond the last data point (a triangle) is estimated and added together with the previous trapezoidal areas. Absolute systemic availability then is calculated as in Equation 2.4: F (%) = AUCroute Doseiv AUCiv Doseroute Calculation of F provides only an estimate of the extent, and not rate, of drug absorption. To calculate rate, pharmacokinetic techniques are required and presented in Chapter 3. Finally, so-called relative systemic availability may be calculated for two nonintravenous formulations where the data for the reference product is in the denominator and the test formulation in the numerator.

Adrenoceptors

-α1 -A Vascular smooth muscle; urogenital smooth muscle; reproductive organs; CNS, AND THE KIDNEYS - α1B Vascular smooth muscle; spleen; liver; -α1D Platelets; CNS (they are found in ruminates in compared to small animals and people) -α2A Presynaptic adrenergic nerve terminals; CNS; brainstem and spinal cord sites; postganglionic SNS neurons; autonomic ganglia; platelets -β1 Heart; kidney; juxtaglomerular cells; CNS; presynaptic sites on adrenergic and cholinergic nerve terminals -β2 Smooth muscle (bronchial, vascular, bladder); heart; liver; skeletal muscle -β3 Adipose tissue -D1 (DA1 ), D5 CNS; kidney; vascular smooth muscle - D2 smooth muscle; presynaptic nerve terminals

As of this writing, which of the drugs has the Agency prohibited the extralabel use of the following drugs in food-producing animals:

1) Chloramphenicol; ( if you touch it, inhale it, it can cause aplastic anemia in people, which can be fatal) 2) Clenbuterol;( use this in horses with asthma, reactive airway disease, it is a beta agonist which causes bronchodilation vasodilation it is a reprotissioning agent it alters the animal metabolism to take all the carbs they are being fed to lay it down as more of muscles but less in fat 3) Diethylstilbestrol (DES); (it is a known carcinogen; it is good to treat uriniary continence in a female spayed dog) 4) Dimetridazole; 5) Ipronidazole; 6) Other nitroimidazoles; ( known carcinogen known to teat Trichomoniasis) 7) Furazolidone; ( known carcinogen) 8) Nitrofurazone; 9) Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine( only one used in America, sulfabromomethazine, and sulfaethoxypyridazine); 10) Fluoroquinolones; ( you can only use this per lable) 11) Glycopeptides;( used for to treat MRSA infection in people, it is illegal to use because it is effective and currently fighting resistance in people to we have to preserve the efficacy in people) 12) Phenylbutazone in female dairy cattle 20 months of age or older; ( NSAID we tend to have inappropriate use which causes residue in milk 13) Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys: a) for disease prevention purposes; b) at unapproved doses, frequencies, durations, or routes of administration; or c) if the drug is not approved for that species and production class. (you can use per label but not in a extra use label because there has been resistance in this drug with humans) 14) The following drugs, or classes of drugs, that are approved for treating or preventing influenza A, are prohibited from extralabel use in chickens, turkeys, and ducks: a) Adamantanes you can use this in small animal patients for nerve pain particularly in chemo patients same with gabapentin b)Neuraminidase inhibitors. Tama flu is a oral capsule from the human side so if someoen gets seasonal flu you can perscribe someone with Tama flu and you can use this in dogs to treat parvovirus

Know the drugs that are prohibited for ELDU in food animals in AMDUCA

1) Chloramphenicol; ( if you touch it, inhale it, it can cause aplastic anemia in people, which can be fatal) 2) Clenbuterol;( use this in horses with asthma, reactive airway disease, it is a beta agonist which causes bronchodilation vasodilation it is a reprotissioning agent it alters the animal metabolism to take all the carbs they are being fed to lay it down as more of muscles but less in fat 3) Diethylstilbestrol (DES); (it is a known carcinogen; it is good to treat uriniary continence in a female spayed dog) 4) Dimetridazole; 5) Ipronidazole; 6) Other nitroimidazoles; ( known carcinogen known to teat Trichomoniasis) 7) Furazolidone; ( known carcinogen) 8) Nitrofurazone; 9) Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine( only one used in America, sulfabromomethazine, and sulfaethoxypyridazine); 10) Fluoroquinolones; ( you can only use this per lable) 11) Glycopeptides;( used for to treat MRSA infection in people, it is illegal to use because it is effective and currently fighting resistance in people to we have to preserve the efficacy in people) 12) Phenylbutazone in female dairy cattle 20 months of age or older; ( NSAID we tend to have inappropriate use which causes residue in milk 13) Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys: a) for disease prevention purposes; b) at unapproved doses, frequencies, durations, or routes of administration; or c) if the drug is not approved for that species and production class. (you can use per label but not in a extra use label because there has been resistance in this drug with humans) 14) The following drugs, or classes of drugs, that are approved for treating or preventing influenza A, are prohibited from extralabel use in chickens, turkeys, and ducks: a) Adamantanes you can use this in small animal patients for nerve pain particularly in chemo patients same with gabapentin b)Neuraminidase inhibitors. Tama flu is a oral capsule from the human side so if someoen gets seasonal flu you can perscribe someone with Tama flu and you can use this in dogs to treat parvovirus

Designation

: This legislation provides incentives for approvals, such as grants to support safety and effectiveness testing. Sponsors must apply for designation prior to filing a new animal drug application for FDA approval. At the time that a designated drug gains approval or conditional approval, it is awarded 7 years of exclusive marketing rights. This means that FDA will not approve another application for the same drug in the same dosage form for the same intended use until after the 7 years have elapsed. This is 2- 4 years longer than the protection provided from generic copying of nondesignated drugs. The MUMS marketing exclusivity also protects against approval of another pioneer (nongeneric) application for the same drug, in the same dosage form, for the same intended use.

What is a phase 2 RXN?

???????glugoronidation, this makes something that is lipid bound into something that is hydrophilic -phase 1 and phase 2 metabolic process you take a lipid soluble drug or a toxicant to metabolize it into something water soluble so it can be excreted into the urine since the urine is largely water - cats do not have some of the phase 2 metabolic enzymes to metabolize them and detoxify them such as glucuronidation -paracetamol is tylenol Various metabolic pathways are involved in drug metabolism including oxidation, reduction, hydrolysis, hydration, and conjunction. These processes can be divided into Phase I and Phase II reactions (Table 2.2). Phase I includes reactions introducing functional groups to drug molecules necessary for the Phase II reactions, which primarily involve conjugation. In other words, Phase I products act as substrates for Phase II processes, resulting in conjugation with endogenous compounds, which further increase their water solubility and polarity, thus retarding tissue distribution and facilitating drug excretion from the body. Specific examples of drug metabolism are included in chapters throughout this text. The focus of this introduction will be to briefly overview the general processes involved in drug metabolism relative to how they might affect pharmacokinetic parameters and the disposition of drugs in the body. Interested readers should consult standard texts in drug metabolism or biochemical pharmacology/toxicology for specific detailed examples illustrating the chemistry and genetic control of these processes Phase I metabolism includes four major pathways: oxidation, reduction, hydrolysis, and hydration, among which oxidation is the most important. Attention is usually focused on oxidation mediated by the microsomal mixed-function oxidase system (e.g., cytochrome P450, etc.) due to its central role and significance in governing the metabolic disposition of many drugs and xenobiotics. An understanding of this pathway is often critical to making interspecies extrapolations. Phase II conjugating enzymes play a very important role in the deactivation of the Phase I metabolites of many drugs as well as in direct deactivation of some parent compounds when their specific structure doesn't require Phase I modification. For example, the analgesic drug paracetamol can be deactivated directly by Phase II reactions using glutathione, glucuronide, and sulfate conjugation mechanisms. Phase II deactivation can be achieved by both gross chemical modification of the drug thereby decreasing their receptor affinity, and by enhancement of excretion from the body, often via the kidney. In summary, Phase I metabolism is primarily responsible for drug deactivation, although Phase II plays an important role in deactivation of some drugs. Phase I reactions prepare drugs or toxicants for Phase II metabolism; that is Phase I modifies the drug molecule by introducing a chemically reactive group on which the Phase II reactions can be carried out for the final deactivation and excretion. This increased water solubility after metabolism restricts a drug's metabolite distribution to extracellular fluids, thereby enhancing excretion. Specific pathways for drug metabolism and transport are discussed in the individual drug chapters as well as their pharmacogenomics in Chapter 50

Drug

A chemical can be considered a drug if it meets one of the following criteria: (Chapter 5 of this book covers special considerations on pharmaceutics.) 1) It is an article recognized in one of the official compendia, i.e., the United States Pharmacopoeia/National Formulary or the official Homeopathic Pharmacopoeia of the United States or their supplements. 2) It is an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals. 3) It is an article other than food intended to affect the structure or any function of the body of man or other animals.

Veterinary pharmacy introduction

A pharmacist's responsibility for providing patients with high-quality pharmaceutical care extends beyond the human species. Although colleges of pharmacy and licensing boards have focused almost exclusively on human pharmacotherapy, society expects an equally competent quality of pharmaceutical care and products to be provided for nonhuman family members. Veterinarians are trained to provide quality care and products for animal patients, but few pharmacists receive training in pharmacy school about veterinary medicine. Pharmacists may be asked more frequently to dispense medications for animals in their day-to-day practice and they must familiarize themselves with veterinary pharmacotherapy and develop a clinically and legally sound algorithm for processing veterinary prescriptions. Pharmacists who dispense medications for animals have an obligation to become familiar with important species differences with respect to pharmacotherapy and susceptibility to drug adverse reactions (Table 56.1). Because this process is very slowly evolving in the pharmacy profession, veterinarians should be well versed in pharmacy issues related to veterinary medical therapy. Although several of these issues have been introduced or discussed in other chapters of this book, this chapter describes a variety of pharmacy-related topics of which all veterinarians should be aware.

Prescription Writing controlled substances

A prescription is a written order or other order, which is promptly reduced to writing for a controlled substance or for a preparation, combination, or mixture thereof, issued by a practitioner who is licensed in his state to administer and prescribe drugs in the course of his professional practice. A prescription does not include an order entered in a chart or other medical record for drugs administered. Always store blank prescription pads in a secure place with access limited to minimal personnel. The elements required in a valid prescription are provide in Tables 56.9 and 56.10. When writing a prescription, abbreviations are allowed. Some commonly accepted and recognized abbreviations are listed in Table 56.11. When in doubt about an abbreviation, spell it out.

Recognize that FDA approved animal drugs for use in food animals have to meet the FDA drug standards as well as the FDA food/additive standards. Major public health task of the FDA.

A separate and unique category of drugs are those that fall under the Veterinary Feed Directive (VFD). - A "VFD drug" : drug intended for use in or on animal feed, which is limited to use under the professional supervision of a licensed veterinarian. - A VFD drug is not a prescription drug, but is a written (nonverbal) statement issued by a licensed veterinarian in the course of the veterinarian's professional practice that authorizes the use of a VFD drug or combination VFD drug in or on an animal feed. Because there are new regulations that pertain to the VFD taking effect on January 1, 2017, this topic is discussed in more detail in Chapter 55 and 59 in the regulatory section of this book.

VFD Drugs

A separate and unique category of drugs are those that fall under the Veterinary Feed Directive (VFD). A "VFD drug" is a drug intended for use in or on animal feed, which is limited to use under the professional supervision of a licensed veterinarian. A VFD drug is not a prescription drug, but is a written (nonverbal) statement issuedby a licensed veterinarian in the course of the veterinarian's professional practice that authorizes the use of a VFD drug or combination VFD drug in or on an animal feed. Because there are new regulations that pertain to the VFD taking effect on January 1, 2017, this topic is discussed in more detail in Chapter 55 and 59 in the regulatory section of this book.

Establishment of a tolerance

A tolerance (the FDA maximum concentration of the marker residues within the target tissue) or the European version of a tolerance, the maximum residue limit (MRL) is determined based on the marker residue. The target tissue for the tolerance is generally the edible tissue from which residues most slowly deplete.

what neurotransmitter is released from all parasympathetic outflow tracts?

ACH

Have a clear understanding what AMDUCA restricts and what it allows. Know what records a DVM must keep for ELDU (extra label drug use)

AMDUCA- (Animal medicinal drug use clarification Act) to prescribe extra label use of veterinary and human drugs for animals under specific circumstances and also codified compounding for animal patients provided the starting ingredients were FDA approved drug products. Restrict: -the use must not result in violative residues in food-producing animals; and certain listed compounds are prohibited from extra label use in food-producing animals -ELDU (extra label drug use) in feed is prohibited. -is not permitted if it results in a violative food residue, or any residue that may present a risk to public health. Allows: -is permitted only by or under the supervision of a veterinarian. -is allowed only for FDA-approved animal and human drugs. -is for therapeutic purposes only -what records the DVM must keep-VCPR (Vet -client Patient relationship)

Recall the definition of adulterated and misbranded drugs.

Adulterated drugs a recognized drug but it does not meet the quality standard set by the FDA ex: anything that is counterfeit, contaminated drugs, drugs coming from outside of America (FDA does not approve drugs outside of America) Misbranded drugs the label of the drug does not accurately reflect the content of the bottle ex: expired drugs

Regulatory Discretion for Extralabel Use

Advances in medical knowledge occur at a much faster rate than do drug product approvals. Since it is impossible for a drug company to test marketed drugs in all species at all doses and for all indications, it is difficult for veterinarians to adhere to the strict limitations of approved drug labels. Passage of the Animal Drug Amendment in 1968 significantly restricted use of drugs in animals to use only in those species for which the product was labeled with strict adherence to the labeled indication, dose, route of administration, and duration of therapy. Any use of a human-labeled drug in animals, for example, was considered illegal under the 1968 Amendment. Pursuant to enactment of this legislation, veterinarians were forced to break the law most of the time when using drugs in their patients. Physicians, on the other hand, were still allowed to use any drug at any dose for any indication in human patients. Realizing the impracticality of strict interpretation of this law for veterinarians, the Food and Drug Administration published compliance policy guidelines (CPGs) in 1993 to show veterinarians the boundaries for regulatory discretion by FDA inspectors. Four main CPGs provided the boundaries for drug use by veterinarians: Extralabel Drug Use, Human Label Drug Use, Use of Drugs in Food Producing Animals, and Compounding for Animals (see www.fda.gov for summaries of these CPGs); however, the CPG for Compounding for Animals was rescinded in May 2015 and replaced with Guidance For Industry #230, Use of Bulk Drug Substances in Compounding For Animals. Chapter 55 of this book provides a background on the drug approval process by regulatory authorities and a summary of the legal control of veterinary drugs.

What is affinity

Affinity is determined by the chemical structure of the drug and minimal modification of the drug structure may result in a major change in affinity The concept of drug efficacy and potency is also used in a clinical context. Drug efficacy is the property of most interest to clinicians who are looking for the most efficacious drug. For example, it was shown using an inflammatory model in horses that flunixin was more efficacious than phenylbutazone in induced lameness (Toutain et al., 1994). For some drugs such as loop diuretics, there is actually a maximum possible effect that can be obtained regardless of how large a dose is administered and this is termed the high ceiling effect. When different drugs within a series are compared, the most potent drug is not necessarily the most clinically efficacious (Figure 4.6). For example, butorphanol is more potent but less efficacious than morphine for analgesia. Another example is glucocorticoids.

What is considered a schedule Class - 1V (4)

All benzodiazepines, midazolam, Alprazolam, diazepam Also, phenovarbital, Butorphanol, tramadol, alfaxalone

Device

All devices must be FDA approved ex: you need to be licensed to sell or resell needles or syringes because they are regulated by the state is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its principal intended purposes. Currently, there are no FDA premarketing approval requirements for medical devices intended for animal use. However, veterinary medical devices are subject to the general provisions of the Act that relate to misbranding and adulteration.

Population Pharmacokinetics

All of the models discussed to this point have been focused on predicting drug concentrations in the individual animal. However, in many cases populations are of interest. For example in dogs, it would be ideal to know the basic pharmacokinetic parameters for a drug in the population at large that would apply to all breeds, ages, and gender. More important would be knowledge of which subpopulation had significantly different parameters. This is normally achieved by collecting a large number of plasma samples in individual animals and averaging resulting pharmacokinetic data from small (4-6 animals) studies. Recently, techniques have been developed that allow one to conduct studies in large numbers of individuals with less individual sampling. The approach uses very simple pharmacokinetic models (e.g., Equation 3.13) or SHAM approaches, and collect more physiological data (body weight, age, creatinine) to solve the models. For example, instead of estimating ClB only from C-T data, one establishes a relation between GFR and ClB , and through statistical approaches, uses both data sets. The mathematics and statistical approaches in these so-called "mixed-effect" models (called mixed because kinetic and statistical models are combined) are beyond the scope of the present text. However, their adoption by scientists in drug development areas coupled with commercial software platforms that facilitates their use will ensure that better estimates of pharmacokinetic parameters, applicable to populations, will be available.

Need for Legal Extralabel use — AMDUCA

Although these CPGs provided veterinarians with a higher comfort level for using drugs in animal patients, extralabel use of drugs in animals was still illegal. The law did not change; CPGs only informed veterinarians of occasions when FDA inspectors would exercise regulatory discretion with respect to interpreting and enforcing extralabel drug use. In 1993, veterinarians, increasingly frustrated by being forced to break the law, demanded the same legal right physicians had in treating their patients. On October 22, 1994, the Animal Medicinal Drug Use Clarification Act (AMDUCA) was passed allowing veterinarians to legally use drugs extralabel under certain circumstances. AMDUCA went into effect December 9, 1996. Concurrently, Congress passed the Animal Drug Availability Act, significantly expediting the process by which FDA approved products intended for use in animals. Passage of both laws was intended to significantly improve the ability of veterinarians to best treat nonfood-producing animal patients.

History of the FDA and its Relationship to Veterinary Medicine

Although veterinarians have been a part of the FDA since it was formed in 1927, regulation of veterinary pharmaceuticals was not initiated until the 1950s.When the FDA was divided into five Bureaus in 1954, a branch dedicated to the evaluation of veterinary medicine was created within the Bureau of Medicine. This branch became a bureau of its own in 1965, and, in 1984, the Bureau of Veterinary Medicine became the current Center for Veterinary Medicine (CVM).

Other Factors Affecting Distribution

Among the factors that affect distribution, apart from binding to blood macromolecules per se, are the route of administration, molecular weight, rate of metabolism, polarity, and stereochemistry of the parent compound or metabolic products, and rate of excretion. Molecular weight, charge, and/or polarity have been previously discussed. Stereoselectivity in the disposition of a drug is an often ignored phenomenon which could influence many studies. Its impact on metabolism is obvious; however, any receptor-mediated binding or transport process, including high-specificity protein binding could be affected. Propranolol and ibuprofen have been shown to demonstrate stereoselective distribution.

Reporting ADEs

An adverse drug event, also called an adverse drug experience or ADE, is an undesired side effect associated with the use of a drug, or a lack of a desired effect (the drug does not do what it is supposed to do). A medication error may result in an ADE. Veterinarians and pet owners are encouraged to report to CVM all ADEs, including those caused by medication errors. ADE reports help CVM determine the frequency and severity of medication errors in animals. The information collected from ADE reports can also help CVM develop education outreach programs aimed at preventing medication mistakes in animals. Instructions on how to report an ADE can be found on CVM's Web site at: http://www.fda.gov/ AnimalVeterinary/SafetyHealth/ReportaProblem/ ucm055305.htm.

What is a New Animal Drug?

An animal drug is a product intended for use in animals for the diagnosis, cure, mitigation, treatment or prevention of disease, or a product other than food, intended to affect the structure or any function of the body of animals. This includes any drug intended for use in animal feed but not including the animal feed. If the animal drug's composition is such that the drug is not generally recognized as safe and effective for the use under the conditions prescribed, recommended, or suggest in the labeling of the drug (21 U.S.C. § 321(v)) and some other criteria, it is deemed to be a new animal drug. Virtually all animal drugs are "new animal drugs" within the meaning of the FFDCA As mandated by the FFDCA (the Act), a new animal drug may not be introduced into interstate commerce unless it is: -the subject of an approved new animal drug application (NADA), or -the subject of an abbreviated NADA (ANADA), or -the subject of a conditional approval (CNADA) pursuant to 21U.S.C. §360ccc or -there is an index listing in effect pursuant to 21 USC § 360ccc-1 (21 U.S.C. §§ 331(a) and 360b(a)). A new animal drugs may be exempt from the approval requirements of the act if they are intended solely for investigational use to evaluate the safety and effectiveness of the drug.

What is considered a schedule Class -111 (3)

Anabolic steroids (unless elevated at state level) Also, Buprenorphine, pentobarbital and lidocaine/phenytoin, ketamine, telazol(tiletamine and zolazepam

Drugs versus Biologics versus Pesticides

Animal products that are regulated by agencies work together to determine which regulatory authority is the best fit for a particular animal product. The intent of this cooperation is to ensure consistency and equity in the regulation of animal products and to avoid animal products being regulated by multiple authorities and under different laws. FDA/CVM regulates the manufacture and distribution of drugs, food additives, and medical devices used in veterinary species. This includes both product approval and postapproval monitoring to ensure continued product safety and effectiveness.

Apomorphine

Apomorphine is in a class of medications called dopamine agonists. It works by acting in place of dopamine, a natural substance produced in the brain that is needed to control movement. Apomorphine injection is used to treat ''off'' episodes (times of difficulty moving, walking, and speaking that may happen as medication wears off or at random) in people with advanced Parkinson's disease (PD; a disorder of the nervous system that causes difficulties with movement, muscle control, and balance)

Hepatic Clearance

As presented in our discussion on renal excretion, clearance of a drug by an organ (Clorg) can be ultimately defined as a function of its blood flow (Qorg) and its extraction ratio (Eorg) expressed in Equation 2.6 as Clorg = Qorg Eorg. The ability of the liver to remove drug from the blood, defined as hepatic clearance, is related to two variables: intrinsic hepatic clearance (Clint) and rate of hepatic blood flow (Qh ), as defined in Equation 2.13: whereClh is the hepatic clearance, Qh is the hepatic blood flow, and Clint/(Qh+Clint) is the hepatic extraction ratio or Eh . Intrinsic clearance (Clint) is conceptualized as the maximal ability of the liver to extract/metabolize drug when hepatic blood flow is not limiting. It represents the inherent metabolic function of all enzyme systems in the liver to metabolize the drug in question. As seen in Equation 2.13, when Clint ≫ Qh , hepatic extraction ratio ≈1.0 (flow limited or high extraction, usually seen with Eh > 0.8), Clh is dependent only on the blood perfusion rate Qh . The more blood passing through the liver, the more drug molecules will be extracted by the liver for metabolic elimination. A hepatic blood perfusion dependent hepatic clearance will then be seen. Drugs with such high extraction ratios will show significant first-pass metabolism after oral administration to the extent that this route of administration may not produce effective systemic drug concentrations.

Define/describe biliary drug elimination

As presented in our discussion on renal excretion, clearance of a drug by an organ (Clorg) can be ultimately defined as a function of its blood flow (Qorg) and its extraction ratio (Eorg) expressed in Equation 2.6 as Clorg = Qorg Eorg. The ability of the liver to remove drug from the blood, defined as hepatic clearance, is related to two variables: intrinsic hepatic clearance (Clint) and rate of hepatic blood flow (Qh ), as defined in Equation 2.13: whereClh is the hepatic clearance, Qh is the hepatic blood flow, and Clint/(Qh+Clint) is the hepatic extraction ratio or Eh . Intrinsic clearance (Clint) is conceptualized as the maximal ability of the liver to extract/metabolize drug when hepatic blood flow is not limiting. It represents the inherent metabolic function of all enzyme systems in the liver to metabolize the drug in question. As seen in Equation 2.13, when Clint ≫ Qh , hepatic extraction ratio ≈1.0 (flow limited or high extraction, usually seen with Eh > 0.8), Clh is dependent only on the blood perfusion rate Qh . The more blood passing through the liver, the more drug molecules will be extracted by the liver for metabolic elimination. A hepatic blood perfusion dependent hepatic clearance will then be seen. Drugs with such high extraction ratios will show significant first-pass metabolism after oral administration to the extent that this route of administration may not produce effective systemic drug concentrations. -pro drug is something you administer, and you rely on the liver to metabolize it to its active form Hepatic disposition is one of the final keys in the ADME scheme needed to describe the disposition of many drugs and chemicals in the body. The liver is responsible for both biotransformation and biliary excretion. In many ways, the liver should be considered as two separate organs, one encompassing metabolism and the other biliary excretion Drug metabolism may often result in metabolite(s) with altered chemical structures, which change the receptor type affected, drug-receptor affinity, or pharmacological effect. . Most parent drugs can be deactivated to inactive metabolites. In contrast, some drugs can also be activated either from an inactive form (prodrug) to an active drug, or from an active form (e.g., meperidine) to an active metabolite (normeperidine) with similar activity/toxicity Therefore, drug metabolism can either reduce or enhance parent drug's effect, create another activity, or even elicit toxicity, depending on both the drug and the biological system in question.

Potential Problems from Compounded Drugs

Because many drugs are not in a form that is ideal for the species being treated, either due to body size, taste preferences, or species-specific metabolic intolerances, commercially available drug products have been altered to make a more convenient and palatable oral dose form. However, when protective coatings on tablets or capsules are disrupted, and suspending or solubilizing vehicles are diluted or changed, the bioavailability and stability of the product may be compromised. (See Chapter 5 of this book for more detailed information on pharmaceutics.) In some instances, the only change is a slight alteration of pH. However, according to the USP (2015c), "improper pH ranks with exposure to elevated temperature as a factor most likely to cause a clinically significant loss of drug. A drug solution or suspension may be stable for days, weeks, or even years in its original formulation, but when mixed with another liquid that changes the pH, it degrades in minutes or days. It is possible that a pH change of only one unit could decrease drug stability by a factor of ten or greater." Addition of a water-based solution to a product to make a liquid solution or suspension can hydrolyze some drugs (beta-lactams, esters). Some drugs undergo epimerization (steric rearrangement) when exposed to a pH range higher than what is optimum for the drug (for example, this occurs with tetracycline at a pH higher than 3). Other drugs are oxidized, catalyzed by high pH, which renders the drug inactive. Drugs most likely to be subject to oxidation are those with a hydroxyl group bonded to an aromatic ring structure. Oxidation may occur from exposure to light and oxygen during reformulation and mixing. Oxidation is catalyzed by high pH and usually leads to drug inactivation. Other factors contributing to instability and decrease in bioavailability may be through the addition of sugars and starches to an oral suspension. For example, it is well documented that the presence of sugar significantly decreases the stability of oral suspensions of atenolol and pyrimethamine, and the addition of methylcellulose to solutions of pyridostigmine will significantly decrease the oral bioavailability of pyridostigmine resulting in potential harm to the patient receiving these medications. Veterinarians and pharmacists are obligated to be cognizant of the potential for interactions and interference with stability (Table 56.7). Oxidation is often visible through a color change (color change to pink or amber, for example). Loss of solubility may be observed through precipitation. Some drugs are prone to hydrolysis from moisture. A rule-of-thumb for veterinarians is that if a drug is packaged in blister packs or moisture-proof barrier, it is probably subject to loss of stability and strength if mixed with aqueous vehicles. If compounded formulations of solid dose forms show cracking or "caking," or swelling, the formulation has probably accumulated moisture and may have lost strength over time. Another rule-of-thumb is that if the original packaging of a drug is in a light-resistant or amber container it is probably prone to inactivation by light. Vitamins, cardiovascular drugs, and phenothiazines are labile to oxidation from light during compounding. Also, as a general rule, if an antibiotic is available in a powder that must be reconstituted in a vial or oral dispensing bottle prior to administration, it is probably unstable for long periods of time and should also not be mixed with other drugs.

Know the neurotransmitters at the ganglion and neuroeffector junctions. Additionally; receptor types at the ganglion and neuroeffector junctions. Know these very, very well!

CNS(SNS) pre and post ganglion pre-cholinergic and releases ach on to nicotinic receptors post - adrenergic which releases nor epi on alpha and beta receptors CNS(PSNS) pre and post pre- cholinergic and releases ach on to nicotinic receptors post- cholinergic with ach being the neurotransmitter gets released on to the receptors of M2

Drugs prohibited for extralabel use in food animals

Chloramphenicol Clenbuterol Diethylstilbestrol (DES) Dimetridazole Ipronidazole Other Nitroimidazoles Furazolidone (except for approved topical use) Nitrofurazone (except for approved topical use) Sulfonamide drugs in lactating dairy cows (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine) Fluoroquinolones Glycopeptides (example: vancomycin) Phenylbutazone for female dairy cattle over 20 months of age

Compounded Drugs

Compounded drugs are mixtures of approved dosage forms or drugs formulated from bulk chemicals that are not approved by FDA for use as drugs in the United States. Veterinarians may compound items for their own use or write prescriptions for their patients for some of these active pharmaceutical ingredients to be used in preparing compounds by licensed pharmacists. These active pharmaceutical ingredients (e.g., potassium bromide, cisapride, diethylstilbestrol) are considered as drugs when used for therapeutic purposes and are recognized by FDA to be essential in the treatment of some companion, nonfood animals. As many of these drugs have been withdrawn from the market because of human safety hazards, the FDA has published a "negative" list (Drugs Withdrawn for Safety or Efficacy Reasons) for human compounding describing the drugs that are either prohibited for use in humans or are restricted to small dosages. Note that some of the drugs (e.g., cisapride and diethylstilbestrol) may still be compounded for nonfood animals such as companion animal pets but never for food animals or humans.

Controlled Substances

Controlled substances ("narcotics") are defined and monitored by the Drug Enforcement Authority (under jurisdiction of the Controlled Substances Act of 1970) and are divided into five schedules according to potential for abuse. An example of the schedules used for opiate drugs is provided in Chapter 13. Other controlled drugs are anesthetics and sedatives listed in Chapters 12 and 14. These drugs are strictly controlled by federal and state law and specific requirements for administering, dispensing, and prescribing are addressed in Section Prescribing Controlled Substances. Individual states are allowed to have more strict requirements than the federal (DEA) scheduling.

T.A.L.K. Before You Treat

Correctly medicating animals is sometimes tricky. It requires a proper diagnosis and responsible veterinary treatment. Correctly medicating food-producing animals, such as cows, pigs, and chickens, is especially tricky. These animals provide us with food products like meat, milk, and eggs, and as the saying goes, "We are what we eat." When a food-producing animal is treated with a drug, chemical residues of the drug may be present in or on food products made from that animal. Chemical residues include small amounts of leftover drug, or parts of the drug that are not completely broken down by the animal's body. FDA's CVM makes sure the chemical residues that may be present in or on food products made from treated animals pose little risk to people. By looking at information about the drug, CVM toxicologists determine the "acceptable daily intake," or "ADI." The ADI is the largest amount of the drug that will not harm people if they ingest that amount every day. Using the ADI, CVM residue chemists set the tolerance for the drug, which is the level of chemical residues allowed to be in or on food products made from treated animals. Eating food that contains even the full amount of chemical residues allowed by the tolerance will not exceed the ADI. Based on the tolerance, the residue chemists set the withdrawal time. The withdrawal time is the time from when the animal was last treated with the drug to when the animal can be slaughtered for food or the animal's milk can go to market. The withdrawal time allows for the drug (or parts of the drug) in the edible tissue of the treated animal to get to levels that are at or below the tolerance. If the withdrawal time is followed, food products made from a treated animal are safe for people to eat. A drug that takes longer to get to the tolerance has a longer withdrawal period. Also, while there is only one tolerance for a given drug in a specific animal tissue (for example, cattle liver), the same drug may have different withdrawal times depending on how the drug is used, how it is given, or what type of food the treated animal produces. For example, the withdrawal time for a drug given to beef cattle (which provide us with meat) may be longer or shorter than the withdrawal time for the same drug given to dairy cattle (which provide us with both meat and milk). Similarly, an injectable form of a drug may have a different withdrawal time than the same drug given in another form, such as orally in medicated feed. If a drug is used in an extra-label ("off-label") manner in a food-producing animal, a veterinarian must be involved and is responsible for establishing an appropriate withdrawal time. Selling food products containing levels of chemical residues above the set tolerances is illegal because such levels may harm people who eat that food. Both over-the-counter and prescription drugs can cause chemical residue levels to be above the set tolerances. To avoid illegal residues and to keep food products safe, CVM reminds veterinarians and animal producers to follow the withdrawal time for every drug they use in food-producing animals. CVM also asks animal producers to "T.A.L.K. before you treat."

Amduca defines which of the following? A) VFD (veterinary feed directive) B) MUMS C) Policy on frugs use in teaching hospitals D) ELDU (extra label drug use) E) Controlled substance drug use F) Veterinary Drug Approvals G) Outsourcing of Rx's to human pharmacies

D) ELDU (extra label drug use)

Define/describe; mechanisms of renal drug excretion

Drugs are normally excreted by the kidney through the processes of (i) glomerular filtration, (ii) active tubular secretion and/or reabsorption, and/or (iii) passive, flow dependent, nonionic back diffusion. These processes can be considered as vectorial quantities, each possessing magnitude and direction relative to transport between tubular fluid and blood. Their sum determines the ultimate elimination of a specific drug by the kidney as illustrated in Figure 2.9. The total renal excretion of a drug equals its rate of filtration plus secretion minus reabsorption. If a drug is reabsorbed back from the tubular fluid

Mechanisms of Renal Drug Excretion

Drugs are normally excreted by the kidney through the processes of (i) glomerular filtration, (ii) active tubular secretion and/or reabsorption, and/or (iii) passive, flow dependent, nonionic back diffusion. These processes can be considered as vectorial quantities, each possessing magnitude and direction relative to transport between tubular fluid and blood. Their sum determines the ultimate elimination of a specific drug by the kidney as illustrated in Figure 2.9. The total renal excretion of a drug equals its rate of filtration plus secretion minus reabsorption. If a drug is reabsorbed back from the tubular fluid

Requirements for extralabel drug use (ELDU) in animals

ELDU is permitted only by or under the supervision of a veterinarian. ELDU is allowed only for FDA-approved animal and human drugs. A valid veterinarian/client/patient relationship is a prerequisite for all ELDU. ELDU is for therapeutic purposes only (animal's health is suffering or threatened), not for production use. Rules apply to dosage for drugs and drugs administered in water. ELDU in feed is prohibited. ELDU is not permitted if it results in a violative food residue, or any residue that may present a risk to public health. FDA prohibition of a specific ELDU precludes such use (Table 56.3).

what is efficacy?

Efficacy is the drug's ability, once bound, to initiate changes that lead to the production of responses. The concept of drug efficacy and potency is also used in a clinical context. Drug efficacy is the property of most interest to clinicians who are looking for the most efficacious drug. For example, it was shown using an inflammatory model in horses that flunixin was more efficacious than phenylbutazone in induced lameness (Toutain et al., 1994). For some drugs such as loop diuretics, there is actually a maximum possible effect that can be obtained regardless of how large a dose is administered and this is termed the high ceiling effect. When different drugs within a series are compared, the most potent drug is not necessarily the most clinically efficacious (Figure 4.6). For example, butorphanol is more potent but less efficacious than morphine for analgesia. Another example is glucocorticoids.

Organs/effector tissues sympathetic

Eye -Pupillary dilation(α1) Lungs Bronchiolar dilation(β2) Heart -↑ Heart rate (β1 > β2) -Blood vessels (arteries and arterioles) Gastrointestinal tract-↓ Motility(α1 , α2 , β1 , β2) Blood vessels (arteries and arterioles) -Coronary Constriction; dilation α1 , α2 ; β2 -Pulmonary Constriction; dilation α1 ; β2 -Skin and mucosa Constriction α1 , α2 -Skeletal muscle Constriction; dilation Urinary bladder -Detrusor muscle(relaxes,β2) -Sphincters( constriction, α1) skin -pilomotor muscles( erection) -Adrenal medulla (Secretion of EPI) -uterus serves relaxation (if you want to stop pre labor you would administer a beta agonist)

Organs/effector tissues parasympathetic

Eye Pupillary constriction(M3 , M2) Glands of head -lacrimal(increase in secretion -salivary ( increase in secretion Lungs Contraction(M2 = M3) Heart ↓ Heart rate (M2 >> M3) Gastrointestinal tract -↑ Motility(M2 = M3) Urinary bladder -Detrusor muscle(contraction, M3 and M2) -sphincters(relaxation, M2 and M3)

Classifying Prescription, Over-the-Counter and Veterinary Feed Directive Animal Drugs

FDA is responsible for determining the marketing status (Rx, OTC, or VFD) of animal drug products based on whether or not it is possible to prepare "adequate directions for use" under which a layperson can use the drugs safely and effectively. Prescription (Rx) products can be dispensed only by or upon the lawful written order of a licensed veterinarian. Considerations include the potential toxicity or other harmful effects of the product, its method of administration, collateral measures necessary for its use (e.g., accurate diagnosis of a disease with reasonable certainty), and that the course of therapy can be followed for other potential safety risks or lack of success of the product. The same drug substances can be marketed in a number of different dosage forms, intended for use by different routes of administration, and in different species of animals. Thus, these drug products may be appropriately labeled Rx in some cases and OTC in others. Veterinary prescription drugs must bear the legend: "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian." Before the passage of the ADAA, the FFDCA provided FDA only two options for regulating the distribution of animal drugs: OTC and Rx. The prescription legend invoked the application of State pharmacy laws, and the pharmacy laws in a significant number of States prohibited feed manufacturers from possessing and dispensing prescription animal drugs and medicated feed containing those drugs. Pharmacy laws in other States required the presence of a pharmacist at the feed manufacturing facility that uses prescription drugs in the manufacture of medicated feeds. As a practical matter, the application of State pharmacy laws to medicated feeds would burden State pharmacy boards and impose costs on animal feed manufacturers to such an extent that it would be impractical to make these critically needed new animal drugs available for animal therapy. For this reason, through the ADAA, Congress enacted legislation to create the VFD, providing a new class of restricted feed use drugs that may be distributed without invoking State pharmacy laws. Although statutory controls on the distribution and use of VFD drugs are similar to those for prescription animal drugs regulated under section 503(f ) of the FFDCA (21 U.S.C. 353(f )), the VFD regulations are tailored to the unique circumstances relating to the distribution of animal feeds containing a VFD drug. Unlike prescription drugs, VFD drugs are not regulated by State pharmacy bodies. No extralabel use of a VFD drug is permitted and a veterinarian may issue a VFD only if a valid veterinarian-client-patient relationship exists, as defined in 21 CFR §530.11(b).

What are FDA's enforcement priorities regarding animal drugs compounded from bulk drug substances?

FDA's priorities generally include compounded drugs: That present human or animal health concerns; for instance, because of contamination or formulation errors (e.g., potency issues) For food-producing animals, because of the risk of drug residues in the meat, milk, or eggs consumed by people. When FDA evaluates a drug for a food-producing animal, the agency reviews human food safety data to establish residue tolerance levels, withdrawal times, and other conditions of use to prevent illegal drug residues in the edible products from those animals. Drugs compounded for food-producing animals have not been subject to this thorough evaluation by FDA. That are copies of FDA-approved or indexed products, because they have not undergone the same rigorous evaluation as the approved drug and undermine incentives for firms to invest in getting drugs approved or indexed. This can reduce the availability of animal drugs that the FDA evaluation process has established as safe and effective. Distributed as office stock without a patient-specific prescription, because office stock exposes larger numbers of animals to drugs of unproven quality and undermines incentives to seek FDA evaluation and approval.

A valid VCPR is not required for prescribing drugs for the pets of immediate family members Violating the definition of a valid VCPR has never gotten a DVM in trouble TRUE OR FALSE?!??!?!?

False

When is a New animal drugs considered to be unsafe

Federal Food Drug and Cosmetic Act (FFDCA) Through this act, a new animal drug is considered to be unsafe unless there is in effect an approval of a New Animal Drug Application (NADA) and unless the use of a drug and its labeling conform to the approved application. Any drug that is deemed unsafe is considered to be adulterated within the meaning of the FFDCA.

The Phased Review Process

For a sponsor to market a new animal drug in the United States, the sponsor must obtain an approval for their product through an NADA. Traditionally, a sponsor would generate all of the necessary data and information and file a complete NADA. Because of the complexity of an NADA, the likelihood of each component of the NADA being acceptable without working closely with CVM is small. This means that the sponsor has probably spent a significant amount of effort and resources developing an application that will need to be rehabilitated. This is not only inefficient but is also costly. For this reason CVM developed a Phased Review process where a sponsor could work with CVM to develop the components or technical sections of their NADA prior to filing their NADA. This higher level of interaction enables the sponsor to have each piece of their application reviewed under the investigational phase and receive feedback on the acceptability of their submission. Sponsors may submit study protocols, final study reports, and other information for review as they are produced.

Know the autonomic receptors (alpha and betas) on nerve terminals, general concepts of nitric oxide and its pharmacologic modulation and physiologic roles

For example, nitric oxide (NO), synthesized and released from NANC nerves and endothelial cells, is an important contributor to penile erection (Burnett, 2006; Lasker et al., 2013). nitric oxide causes vasodilation and relaxation of the blood vessels.NO is considered a primary vasoactive neurotransmitter and chemical mediator, and after binding to an intracellular receptor results in the conversion of GTP to cGMP -you will use Viagra phosphodiesterase inhibitors to treat a couple of things such as pulmonary hypertension, you can use this to help with laminitis use this drug for dialation

Nonadrenergic-Noncholinergic Neurons

For example, nitric oxide (NO), synthesized and released from NANC nerves and endothelial cells, is an important contributor to penile erection (Burnett, 2006; Lasker et al., 2013). nitric oxide causes vasodilation and relaxation of the blood vessels.NO is considered a primary vasoactive neurotransmitter and chemical mediator, and after binding to an intracellular receptor results in the conversion of GTP to cGMP -you will use Viagra phosphodiesterase inhibitors to treat a couple of things such as pulmonary hypertension, you can use this to help with laminitis use this drug for dialation

What is considered a schedule Class -V (5)

Gabapentin-state specific Pseudoephedrine PPA-phenylpropanolamine and they are also list 1 chemicals: Pseudoephedrine PPA-phenylpropanolamine tinctures and solutions of iodine 2.2% and stronger

Recall the definitions of; steady-state.

However, the more likely scenario is that depicted in Figure 3.19 where a second dose is administered before the first dose is completely eliminated from the body. In this case, the drug concentrations will accumulate with continued dosing. This accumulation will stop or reach a steady-state when the amount of drug administered at the start of each dosing interval is equal to the amount eliminated during that interval. This can be appreciated since the AUC under one dosing interval is equal to that after a single dose administration. In fact, steady-state could be defined as the dosing interval where the AUC for that interval is equal to the single dose AUC. Administering repeated doses at a τ defined in this manner will continuously produce a C-T profile with the same peak and trough plasma concentrations.

steady dosage

However, the more likely scenario is that depicted in Figure 3.19 where a second dose is administered before the first dose is completely eliminated from the body. In this case, the drug concentrations will accumulate with continued dosing. This accumulation will stop or reach a steady-state when the amount of drug administered at the start of each dosing interval is equal to the amount eliminated during that interval. This can be appreciated since the AUC under one dosing interval is equal to that after a single dose administration. In fact, steady-state could be defined as the dosing interval where the AUC for that interval is equal to the single dose AUC. Administering repeated doses at a τ defined in this manner will continuously produce a C-T profile with the same peak and trough plasma concentrations.

Record requirements for drugs dispensed for animals

Identify the animals, either as individuals or a group Animal species treated Numbers of animals treated Condition being treated The established name of the drug and active ingredient Dosage prescribed or used Duration of treatment Specified withdrawal, withholding, or discard time(s), if applicable, for meat, milk, eggs, or animal-derived food Keep records for 2 years FDA may have access to these records to estimate risk to public health

Are compounded animal drugs legal?

It depends. Animal drugs compounded from bulk drug substances violate the Federal Food, Drug, and Cosmetic Act (FD&C Act) because they are not approved or indexed, are not made in accordance with current good manufacturing practice (CGMP) requirements, and cannot satisfy the FD&C Act provision for adequate directions for use. The FD&C Act gives FDA the authority to regulate animal drugs, which includes animal drugs compounded from bulk drug substances. On the other hand, compounding animal drugs from FDA-approved, conditionally approved, or indexed drugs is generally permissible under certain conditions (/animal-veterinary/guidance-regulations/animal-medicinaldrug-use-clarification-act-1994-amduca). Although the resulting compounded drug is not considered FDAapproved, the process starts with a substance that has been evaluated by FDA, which provides some assurance of safety and effectiveness.

Dispensing Medications Intended to Go Home with a Patient

Many state and federal legal requirements exist for the act of dispensing a drug to go home with a patient. Any prescription medications that leave a practice to go home with a patient must be labeled with the information indicated in Table 56.8. Any medications that leave a practice to go home with a patient should be packaged in a child-resistant container as described by the Poison Prevention Packaging ActThe Act applies only to drug dispensed for human use, but should be followed to prevent unintentional human poisonings from animal drugs. Medications dispensed in nonchild-resistant containers should be adequately labeled with auxiliary labels indicating "Caution: Package not child resistant" and "Keep out of reach of children." Other auxiliary labels detailing important information such as "shake well," "refrigerate," "not for injection," etc. should also be affixed to the container.

Recognize the dangers of trailing zero's and lack of leading zero's and how such strengths should be written in order to prevent errors

Medication errors are also caused by using trailing zeros and not using leading zeros when writing out doses. FDA has well-documented evidence of tenfold drug overdoses occurring in both people and animals from practitioners either using a trailing zero or not using a leading zero in a written dose. For example, a "5 mg" dose written with the trailing zero as "5.0 mg" can be misread as "50 mg," resulting in a tenfold overdose. Similarly, a "0.5 mg" dose written without the leading zero as ".5 mg" can easily be mistaken for "5 mg," also resulting in a tenfold overdose.

Trailing and Leading Zeros

Medication errors are also caused by using trailing zeros and not using leading zeros when writing out doses. FDA has well-documented evidence of tenfold drug overdoses occurring in both people and animals from practitioners either using a trailing zero or not using a leading zero in a written dose. For example, a "5 mg" dose written with the trailing zero as "5.0 mg" can be misread as "50 mg," resulting in a tenfold overdose. Similarly, a "0.5 mg" dose written without the leading zero as ".5 mg" can easily be mistaken for "5 mg," also resulting in a tenfold overdose.

Types of Drug Targets

Most drugs act via an interaction with certain proteins either of the host or of the pathogen (Figure 4.2). Detailed discussions of drug mechanism of action are discussed in the specific chapters of this text. Exceptions are drugs in which the activity is based on physical properties, such as osmotic diuretics (e.g., mannitol) and antacids. Protamine that can be injected as an antidote of heparin acts as a physical antagonist by binding to it. Tiludronic acid is a biphosphonate used to prevent or to treat a variety of bone conditions. It binds to hydroxyapatite crystals and inhibits hydroxyapatite breakdown, suppressing bone resorption (Drake et al., 2008). General anesthetics were previously thought to produce their effect by simply dissolving in the lipid bilayer of the nerve membrane. It is currently acknowledged that all anesthetics act by either enhancing inhibitory signals or by blocking excitatory signals (for a review see Garcia et al., 2010). For intravenous anesthetics such as propofol and inhaled anesthetic as isoflurane, the target has been identified as the GABAA receptor (GABAR ), the most abundant fast inhibitory neurotransmitter receptor in the central nervous system. Ketamine and nitrous oxide inhibit ionotropic glutamate receptors, with the strongest effects being seen on the NMDA receptor subtype. Four types of protein are targeted by drugs: enzymes, carriers, ion channels, and receptors (Figure 4.2). The term receptor should be reserved for regulatory proteins that play a role in intercellular communication. Thus, enzymes, ion channels, and carriers are not usually classified as receptors. Enzymes such as cyclooxygenases are the target site for NSAIDs, and their inhibition leads to the suppression of proinflammatory prostaglandins. Acetylcholine esterase, an enzyme that metabolizes acetylcholine at the receptor site, is a target site for cholinesterase inhibitors (neostigmine, physostigmine, etc.). Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing acetylcholine. Other examples of enzymes serving as drug targets are dihydrofolate reductase for trimethoprim (an antibacterial) and angiotensin converting enzyme (ACE) for ACE inhibitors such as benazepril and enalapril. Antibiotics may act by inhibiting enzymes involved in cell wall biosynthesis, nucleic acid metabolism and repair, or protein synthesis, which is why antibiotics are generally more efficacious on multiplying bacteria. Carriers (also termed membrane transport proteins) are target sites for many drugs. The Na+/K+/2Cl− symport in the nephron is the site of action of furosemide and other loop diuretics such as torasemide. Furosemide acts at the luminal surface of the thick ascending limb of the loop of Henle to prevent sodium chloride reabsorption. For all diuretics other than spironolactone, the biophase is urine, not plasma, and they need to gain access to the lumen of the nephron to develop their diuretic action. This explains why in renal failure, the dose often needs to be substantially increased, not decreased as for other drugs. ATP-powered ion pumps such as the sodium pump (Na+/K+ ATPase) are the target sites for cardioactive digitalis and the Na+/H+ pump in the gastric parietal cell is the target site for proton pump inhibitors such as omeprazole. Some drugs, such as local anesthetics, produce their effects in the nervous system and in the heart (Grace and Camm, 2000; Sills, 2011) by directly interacting with ion channels. They inhibit voltage-gated Na+ channels in sensory neurons by binding to specific sites within the Na+ channel and produce a direct effect by incapacitating the protein molecule. Their affinity varies with the gating state of the channel, with a high affinity when the channels are opened and inactivated during action potentials at high frequency, as occurs during pain or a cardiac arrhythmia. Most antiepileptic drugs act on voltage-gated Na+ channels and voltage-dependent gated calcium channels are the main target of most calcium-channel blockers, such as the antiarrhythmic drugs verapamil and amlodipine. This mechanism of drug action on ion channels should not be confused with that of ligand-gated ion channels, which function as ionotropic receptors (see Section Macromolecular Nature of Drug Receptors). Other nonreceptor/nonprotein targets as sites of action are nucleic acids for drugs such as actinomycin D, an antineoplastic antibiotic. DNA is also the target for a number of antibiotics (quinolones) as well as mutagenic and carcinogenic agents.

Nonlinear Models

Most pharmacokinetic models incorporate the common assumption that drug elimination from the body is a firstorder process, and the rate constant for elimination is assumed to be a true constant, independent of drug concentration. In such cases, the amount of drug cleared from the body per unit time is directly dose or concentration dependent, the percentage of body drug load that is cleared per unit time is constant, and the drug has a single constant elimination half-life. Fortunately, firstorder elimination (at least apparent first-order elimination) is typical in drug studies. First-order linear systems application greatly simplifies dosage design, bioavailability assessment, dose-response relationships, prediction of drug distribution and disposition, and virtually all quantitative aspects of pharmacokinetic simulation. However, drugs most often are not eliminated from the body by mechanisms that are truly first-order by nature. Actual first-order elimination across all concentrations applies only to compounds that are eliminated exclusively by mechanisms not involving enzymatic or active transport processes (i.e., processes involving energy). As presented in Chapter 2, they are primarily driven by diffusion and obey Fick's Law. The subset of drugs not requiring a transfer of energy in their elimination is restricted to those that are cleared from the body by urinary and biliary excretion and, among those, only drugs that enter the renal tubules by glomerular filtration or passive tubular diffusion. All other important elimination processes require some form of energy-consumptive metabolic activity or transport mechanism. What is the impact of this on pharmacokinetic parameters? The reason energy-involved processes are not strictly first-order is that they are generally saturable, or more specifically are capacity-limited. At clinical dosages, the majority of drugs do not reach saturation concentrations at the reaction sites and follow first-order linear kinetics. Recalling for first-order processes, a constant percentage of remaining drug is cleared per unit time, and the drug has a discrete, concentration-independent elimination rate constant (K) and thus half-life. For drugs eliminated by zero-order kinetics or saturated pathways, however, a constant quantity of drug is eliminated per unit of time, and this quantity is drug concentration independent, and the drug does not have a constant, characteristic elimination half-life. The potential impact of saturable, leading to zero-order (versus first-order) elimination, can be profound, and its effects include altered drug concentration profiles, scope and duration of drug activity, and distribution and disposition among tissues. Saturable hepatic metabolism may markedly affect drug absorption due to reduced clearance (lower hepatic extraction) and altered first-pass activity after oral administration. Nonlinearity is associated with a nonconstant T1/2 at different doses or when a plot of dose versus AUC is not linear, indicating that Cl is reduced as dose increases.

nonlinear models (saturation, capacity limited)

Most pharmacokinetic models incorporate the common assumption that drug elimination from the body is a firstorder process, and the rate constant for elimination is assumed to be a true constant, independent of drug concentration. In such cases, the amount of drug cleared from the body per unit time is directly dose or concentration dependent, the percentage of body drug load that is cleared per unit time is constant, and the drug has a single constant elimination half-life. Fortunately, firstorder elimination (at least apparent first-order elimination) is typical in drug studies. First-order linear systems application greatly simplifies dosage design, bioavailability assessment, dose-response relationships, prediction of drug distribution and disposition, and virtually all quantitative aspects of pharmacokinetic simulation. However, drugs most often are not eliminated from the body by mechanisms that are truly first-order by nature. Actual first-order elimination across all concentrations applies only to compounds that are eliminated exclusively by mechanisms not involving enzymatic or active transport processes (i.e., processes involving energy). As presented in Chapter 2, they are primarily driven by diffusion and obey Fick's Law. The subset of drugs not requiring a transfer of energy in their elimination is restricted to those that are cleared from the body by urinary and biliary excretion and, among those, only drugs that enter the renal tubules by glomerular filtration or passive tubular diffusion. All other important elimination processes require some form of energy-consumptive metabolic activity or transport mechanism. What is the impact of this on pharmacokinetic parameters? The reason energy-involved processes are not strictly first-order is that they are generally saturable, or more specifically are capacity-limited. At clinical dosages, the majority of drugs do not reach saturation concentrations at the reaction sites and follow first-order linear kinetics. Recalling for first-order processes, a constant percentage of remaining drug is cleared per unit time, and the drug has a discrete, concentration-independent elimination rate constant (K) and thus half-life. For drugs eliminated by zero-order kinetics or saturated pathways, however, a constant quantity of drug is eliminated per unit of time, and this quantity is drug concentration independent, and the drug does not have a constant, characteristic elimination half-life. The potential impact of saturable, leading to zero-order (versus first-order) elimination, can be profound, and its effects include altered drug concentration profiles, scope and duration of drug activity, and distribution and disposition among tissues. Saturable hepatic metabolism may markedly affect drug absorption due to reduced clearance (lower hepatic extraction) and altered first-pass activity after oral administration. Nonlinearity is associated with a nonconstant T1/2 at different doses or when a plot of dose versus AUC is not linear, indicating that Cl is reduced as dose increases.

Muscarinic Receptors: Anatomical Location, Receptor Subtypes, and Signal Transduction

Muscarinic receptors are located predominately at postsynaptic target sites innervated by postganglionic parasympathetic nerves such as the heart, glands, urinary bladder, and gastrointestinal tract, thereby establishing a pivotal role for these receptors in the functionality of the PSNS. Five subtypes of muscarinic receptors have been identified, each associated with a different gene, and many of the physiological functions associated with PSNS activation are mediated by muscarinic2 (M2 ) and muscarinic4 (M4 ) receptors. Muscarinic receptor subtypes are located in distinct peripheral anatomic locations (Table 6.2) and demonstrate differential specificities to various agonists and antagonists. Muscarinic receptors are G protein-coupled receptors (GPCRs), and activation of these receptors may elicit an excitatory or inhibitory response (Calebiro et al., 2010; Jalink and Moolenaar, 2010; Ambrosio et al., 2011; Vischer et al., 2011; Latek et al., 2012; Duc et al., 2015). A fundamental mechanism mediating the capability of the PSNS to produce an assortment of physiological response profiles arises from the fact that specific muscarinic receptors couple primarily to specific G proteins. Muscarinic receptor subtypes M1 , M3 , and M5 couple through Gq/11, whereas M2 and M4 receptors couple to Gi and G0. Specificity in the intracellular response profiles following activation of specific muscarinic receptors are the result of G protein-mediated effects on the generation of second messengers and on the activity of ion channels (Table 6.2).

What neurotransmitter is released from the postganglionic axon of the sympathetic outflow tract

NOR EPI

Label requirements for drugs prescribed for animals

Name and address of the prescribing veterinarian Established name of the drug Any specified directions for use including the class/species or identification of the animal or herd, flock, pen, lot, or other group; the dosage frequency and route of administration; and the duration of therapy Any cautionary statements Your specified withdrawal, withholding, or discard time for meat, milk, eggs, or any other food

Drug dispensing labeling requirements

Name, address, and phone number of the dispensing facility Name of client Animal identification (name and species) Date dispensed Full directions for use Name, strength, and quantity of drug dispensed Name of prescribing veterinarian For controlled substances, the label must also contain the message "Caution: Federal law prohibits transfer of this drug to any person other than the patient for whom it was prescribed.

what must be on the face of prescriptions that you outsource to a pharmacy?

Name, address, phone number, refills amount veterinary signature, dea #, patient address, quantity, drug name, number of refills

Non-linear zero order kinetics involves energy and are saturable. Think about your drunk friend

Nonlinear zero order kinetics involve energy and are saturable. Think about your drunk friend.

introduction to the Autonomic Nervous System and Autonomic Pharmacology

Numerous physiological functions are regulated by the ANS including, but not limited to: regulation of heart rate and cardiac contractility; visceral and cutaneous blood flow distribution; gastrointestinal motility and digestion; and urogenital processesIt is virtually impossible to consider physiological regulation without integrating the roles of sympathetic and parasympathetic neural mechanisms into a functional overview, as summarized in the Primer on the Autonomic Nervous System (Hamill and Shapiro, 2004):

Generic Animal Drug and Patent Term Restoration Act

On November 16, 1988, the President signed into law the Generic Animal Drug and Patent Term Restoration Act. The new law, known as GADPTRA, amends the Federal Food, Drug, and Cosmetic Act to provide for the approval of generic copies of animal drug products that have been previously approved and shown to be safe and effective when used in accordance with their labeling. Under GADPTRA, a generic animal drug product may be approved by providing evidence that it has the same active ingredients, in the same concentration, as the approved animal drug product, and that it is bioequivalent to the approved animal drug product. The GADPTRA provides for a period of 3 years of marketing exclusivity for a new use of an animal drug (a use that required reports of new clinical or field investigations for its approval), during which time no abbreviated application for a generic copy may be approved for the new use. The law also provides for a period of 5 years of marketing exclusivity for an animal drug that has not been previously approved in any new animal drug application. During this period, no abbreviated application may be submitted. (Exception: An abbreviated application may be submitted after 4 years if the generic applicant claims noninfringement of a listed patent that is claimed for the approved product or its use.) The law also provides for another form of marketing exclusivity, known as patent term restoration. This type of exclusivity extends the period of protection by US patent for an animal drug, or its method of use, that was approved after November 16, 1988, to compensate for the time that was required for investigation and regulatory review of the animal drug prior to its approval. Patent term restoration is not related to the exclusivity periods described above and may overlap those exclusivity periods. The information necessary to obtain approval to market a generic animal drug is submitted to FDA in the form of an Abbreviated New Animal Drug Application (ANADA). The application must provide certification by the applicant that a patent does not exist, that a patent has expired or will soon expire, or that a patent claimed for the approved product is invalid or will not be infringed upon by approval of the abbreviated application. In the latter case, the generic applicant or sponsor must then notify the sponsor of the approved product application and the owner of the patent that he or she has filed an abbreviated application claiming invalidity or noninfringement of the patent. All animal drugs that were approved for safety and effectiveness on November 16, 1988, or have been approved since that date, and are not protected by patent or exclusivity are eligible for copying under the provisions of the GADPTRA, unless the animal drug has been subsequently withdrawn from the market for safety or effectiveness reasons, or unless it is the subject of a Notice of Hearing that has been published in the Federal Register.

Animal Medicinal Drug Use Clarification Act

On October 22, 1996, the Animal Medicinal Drug Use Clarification Act of 1994 was enacted into law, allowing veterinarians to prescribe extralabel use of veterinary and human drugs for animals under specific circumstances and also codified compounding for animal patients provided the starting ingredients were FDAapproved drug products. The key extralabel provisions of the Animal Medicinal Drug Use Clarification Act are provided in Table 56.2. (A copy of the AMDUCA Extra Label Drug Use Guidelines Brochure is available in the February 15, 1998, issue of the Journal of the American Veterinary Medical Association (JAVMA) or may be obtained from the AVMA website: www.avma.org.) Some drugs are strictly prohibited from administration to food animals because a safe level of residue in food products cannot be identified (Table 56.3). Additional provisions of the AMDUCA legislation require proper dispensing and labeling of prescribed drugs for animals (Tables 56.4 and 56.5).

Adjusting for Disease

One of the primary and most common factors that affects the disposition of a drug in the body is diseaseinduced changes in renal function. It is no surprise that renal disease has a profound impact on the disposition of a drug in the clinical setting. Many drugs are excreted primarily in urine as unchanged pharmacologically active drug. Drugs excreted in this manner accumulate in the body during renal insufficiency as a direct result of decreased renal clearance and is the primary manifestation of renal disease, which is compensated for in clinical dosage adjustment regimens. Renal disease can also influence other aspects of drug disposition, including altered protein binding, volume of distribution, and hepatic biotransformation. All of these effects complicate the establishment of safe and efficacious regimens for drug therapy. The chapters on specific drugs should be consulted when considering their use in such patients. Of course, the obvious choice for selecting a drug for a patient with renal disease is to use a drug not cleared by the kidney. If this is not possible, current approaches for constructing adjusted dosage regimens for renal insufficiency or failure compensate only for decreased renal clearance of the parent drug and are based upon the principles of dosage regimen construction discussed above. In this approach, we assume (1) a standard loading dose is administered; (2) drug absorption, volume of distribution, protein binding, nonrenal elimination, and tissue sensitivity (dose-response relation) are unchanged; (3) creatinine clearance is directly correlated to drug clearance; and (4) there is a relatively constant renal function over time.

Know the organization of the ANS, Sympathetic and Parasympathetic nervous system, and organ responses to the ANS.

Organs/effector tissues sympathetic Eye -Pupillary dilation(α1) Lungs Bronchiolar dilation(β2) Heart -↑ Heart rate (β1 > β2) -Blood vessels (arteries and arterioles) Gastrointestinal tract-↓ Motility(α1 , α2 , β1 , β2) Blood vessels (arteries and arterioles) -Coronary Constriction; dilation α1 , α2 ; β2 -Pulmonary Constriction; dilation α1 ; β2 -Skin and mucosa Constriction α1 , α2 -Skeletal muscle Constriction; dilation Urinary bladder -Detrusor muscle(relaxes,β2) -Sphincters( constriction, α1) skin -pilomotor muscles( erection) -Adrenal medulla (Secretion of EPI) -uterus serves relaxation (if you want to stop pre labor you would administer a beta agonist) Organs/effector tissues parasympathetic Eye Pupillary constriction(M3 , M2) Glands of head -lacrimal(increase in secretion -salivary ( increase in secretion Lungs Contraction(M2 = M3) Heart ↓ Heart rate (M2 >> M3) Gastrointestinal tract -↑ Motility(M2 = M3) Urinary bladder -Detrusor muscle(contraction, M3 and M2) -sphincters(relaxation, M2 and M3)

FDA's Initiative

Over the last decade, FDA reviewed many cases of medication errors in people in an effort to prevent these mistakes. CVM's Division of Surveillance recently began a similar initiative to prevent medication errors in animals. As a result of this initiative, the Division of Surveillance has identified reports of medication errors in animals that are similar to the medication errors in people. Fortunately, medication errors are preventable. By applying the lessons learned from human medicine to veterinary medicine, veterinarians can avoid making similar mistakes in animals.

Over-The-Counter ("Nonprescription") Drugs

Over-the-counter (OTC) drugs are also considered "nonprescription" drugs. These are familiar to veterinarians and pet owners because they are available for human use in retail outlets such as pharmacies, markets, and grocery stores. Such OTC products can also be found for animals in the same retail outlets as for humans as well as in pet and feed stores. These drugs have been recognized by experts as safe and effective and bear extensive labeling that renders them safe for use by laypersons and are sold "over the counter," without a prescription. All OTC products must be used precisely as labeled just as legend drugs. Use outside of these specifications constitutes extralabel use and the aforementioned guidelines should govern this use. Pharmacists must not make recommendations for use of human OTC drugs in animals unless so directed by a veterinarian. Veterinarians should avoid repackaging OTC medications for dispensing because reproducing the required labeling that is comprehensive enough for safe use by a layperson is difficult and dangerous

What does pharmacokinetics and pharmacodynamics mean?

Pharmacokinetics This is what the body does to the drug, does it absorb it? does it metabolize it? does it distributed it? does it excrete it ? Pharmacodynamics What the drug does to the body, is it agonizing a receptor, is it antagonizing a receptor, is it lowering blood pressure, is it providing analgesia, is it knocking back a viral infection

Postapproval Monitoring of Animal Drugs

Postapproval monitoring of animal drugs is a very important function, necessary to ensure that the approved new animal drugs continue to be manufactured in accordance with their approval specifications and continue to perform as expected. In addition, CVM monitors the advertising and promotional material used by pharmaceutical sponsors to ensure that the product is represented in accordance with the conditions of its approved application. CVM uses Drug Experiencing Reports (DERs), Adverse Drug Experience Reports, and continued manufacturing facility inspections to conduct this monitoring

what is potency?

Potency corresponds to the concentration of drug required to achieve a given effect. The concept of drug efficacy and potency is also used in a clinical context. Drug efficacy is the property of most interest to clinicians who are looking for the most efficacious drug. For example, it was shown using an inflammatory model in horses that flunixin was more efficacious than phenylbutazone in induced lameness (Toutain et al., 1994). For some drugs such as loop diuretics, there is actually a maximum possible effect that can be obtained regardless of how large a dose is administered and this is termed the high ceiling effect. When different drugs within a series are compared, the most potent drug is not necessarily the most clinically efficacious (Figure 4.6). For example, butorphanol is more potent but less efficacious than morphine for analgesia. Another example is glucocorticoids.

Prescribing Records controlled substances

Practitioners are not required to keep records of prescriptions written for controlled substances, but it is in the best interest of the veterinarian to make a note of such prescriptions in the patient's medical record to provide for a complete patient medical profile.

Legend ("Prescription") Drugs

Prescription drugs are limited to dispensing by or upon the order of a licensed prescriber ("prescription") because they are habit forming, are toxic, or have potential for harm. These drug labels contain the following warnings identifying them as legend drugs: Veterinary Legend: "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian." Human Legend: "Rx only." Legend (prescription) drugs cannot be dispensed without a prescription and may only be prescribed and dispensed within the confines of a valid veterinarian-client- patient relationship (VCPR) (Table 56.6). Because of the requirement of a valid VCPR, if a veterinarian has not examined the animal, he/she cannot prescribe legend

Abbreviated New Animal Drug Applications

Prior to GADPTRA, the FDA could approve abbreviated applications only for copies of animal drugs approved prior to 1962 and found to be effective under the DESI (drug efficacy study implementation) program. The intent of GADPTRA was to encourage competition and lower animal drug prices by allowing abbreviated applications for copies of previously approved drugs, without the generic drug sponsor duplicating the safety and efficacy studies that were required for the original NADA approval. GADPTRA permits an ANADA for an animal drug product that is the same as an animal drug product listed in the approved animal drug product list published by the Agency (listed new animal drug) with respect to conditions of use recommended in the product labeling, active ingredient(s), dosage form, strength, and route of administration. An ANADA applicant may petition the Agency under Section 512(n)(3) of the FFDCA for permission to file an ANADA for a new animal drug product with certain defined changes from an approved pioneer product. The changes are limited to the following: a change of one active ingredient in an approved combination product; a change in dosage form; a change in dosage strength; a change in route of administration; a change in one active ingredient in a feed mixed combination. A generic sponsor may file a suitability petition to request that the specific change in the pioneer product be allowed. The petition must follow the format and content described for a Citizen Petition (21 CFR §10.20) which is a public document filed with the FDA. The FDA response to the petition is also a public document. The Agency determines whether to deny or approve the petition. ANADAs need to address all of the technical sections applicable to NADAs, but, in some cases, the information needed to fulfill these requirements is different. For example, target animal safety and effectiveness are evaluated through the demonstration of product bioequivalence between the pioneer and generic products. The focus of bioequivalence studies is to determine whether or not differences in product manufacturing and formulation will affect the rate and extent of drug absorption. The fundamental assumption of all bioequivalence testing is if the rate and extent of drug absorption are comparable, then the products will be medically indistinguishable and therefore interchangeable. Bioequivalence studies (i.e., blood level, pharmacological end-point, and clinical end-point studies) and tissue residue depletion studies are conducted in accordance with GLP regulations (21 CFR Part 58). When absorption of the drug is sufficient to enable the quantification of drug concentrations in the blood (or other appropriate biological fluid or tissue) and if systemic absorption is relevant to drug action, a blood (or other biological fluid or tissue) level bioequivalence study should be conducted. For certain generic drug products, the Agency may waive the requirement for demonstration of bioequivalence to the pioneer product. In general, the bioequivalence between solutions is considered to be self-evident for solutions with the same active and inactive ingredients in the same concentrations and with the same pH and physicochemical characteristics as the pioneer product. Categories of products that may be eligible for waivers include parenteral solutions intended for injection by the intravenous, subcutaneous, or intramuscular routes of administration, oral solutions or other solubilized forms, topically applied solutions intended to produce local therapeutic effects, and inhalant volatile anesthetic solutions. When using serum or blood concentrations of drug in the evaluation of product bioequivalence, the principles underlying this assessment reflect a blending of pharmacokinetics and biostatistics. It is founded upon the principle that two formulations containing the identical active ingredient will exhibit the same safety and effectiveness if the two formulations exhibit the same rate and extent of absorption. In addition to its use in generic drug product applications, bioequivalence studies may be used to support the approval of proposed changes in the manufacturing of a generic version of an approved off-patent product or to cover the safety and/or effectiveness of a sponsor's own drug. Blood level bioequivalence studies compare a test formulation to a reference formulation using parameters derived from the concentrations of the drug moiety and/or its metabolites (as a function of time) in the plasma, serum, or other appropriate biological fluid. This approach is applicable to dosage forms intended to deliver the active drug ingredient(s) to the site of action by way of the systemic circulation. Although usually conducted as a comparison of blood levels following single dose administration, a multiple dose study may be appropriate when there are concerns regarding poorly predictable drug accumulation. For details regarding the assessment of product bioequivalence, readers are referred to CVM Guidance #35 (Bioequivalence Guidance) as well as Chapter 3 of the present textbook. Since veterinary generic drug products must contain all of the same indications, warnings, cautions, directions for use, etc. that are associated with the approved pioneer product (except as deemed appropriate on the basis of the Suitability Petition (21 CFR §512(n)(1)(F)), a bioequivalence study is generally needed for each species for which the pioneer product is approved (with the exception of "minor" species). When the product in question is a generic product intended for use in a food-producing animal, sponsors are required to conduct both bioequivalence and tissue residue studies unless blood concentrations of the active drug can be measured out to the withdrawal time of the pioneer product. The requirement is based upon the conclusion that tissue residue depletion of generic products is not adequately addressed through blood level bioequivalence studies. Differences that may go undetected in a blood level study (and which would be without clinical significance) could impact the withdrawal time because the latter is based upon extremely low drug concentrations in the tissue (see section Human Food Safety). A tissue residue study should generally accompany clinical end-point and pharmacological end-point bioequivalence studies (21 USC 360b(n)(1)(A)(ii)). The sponsor of the generic product application uses the existing tolerance, marker residue, target tissue, and analytical method (as contained within the pioneer product's approved NADA) to determine the withdrawal time for the generic product (FDA/CVM Guidance For Industry #35). Accordingly, generic sponsors need only monitor the depletion of the unlabelled marker residue in the target tissue to establish a withdrawal time for the generic product. However, for reasons explained above, there is a risk that the generic formulation will be associated with a withdrawal time that differs (longer or shorter) than that of the pioneer product. For this reason, the end-users of generic products should carefully read each product label to avoid the potential for incurring violative residues.

Recall the challenges and concerns when using compounded drugs (legal, chemical, lack of testing, etc...).

Recall that compounded drugs are not FDA approved In a commercial formulation, the inactive ingredients and excipients are added to drug formulations to ensure the stability of the drug; provide an optimum chemical environment, pH; or increase the ease of packaging or handling. However, adding other chemicals, flavorings, or vehicles, or interfering with protective coatings of tablets may affect the stability of the drug, decreasing strength, oral absorption, and efficacy. There are published formulas in compounding journals, and texts, but few of these formulations have been tested for safety, efficacy, bioavailability, stability, strength, and purity for use in the target species.

Clearance

Recalling the development of clearance concepts in Chapter 2, we now can easily determine ClB using this information. Clearance was defined as the volume of blood cleared of a substance by the kidney per unit of time. If one considers the whole body, this would read as the volume of distribution of drug in the body cleared of a substance per unit of time.

Establishment of a withdrawal time

The withdrawal time is the time between the last administered dose and when the drug residues drop below the safe concentration. The regulatory objective of the FDA is to predict a time when we can be 95% certain that the tissue residue concentrations in 99% of the animal population receiving the drug product (when dosed in accordance to the approved product label) will be at or below tolerance. Generally, multiple animals are sampled across at least four time points and regression methods with tolerance limits are used to set the withdrawal time. Concentrations of the marker residue must be measured with the same FDA-approved analytical method that will be used for the regulatory inspections. These topics are also discussed in Chapter 61 of this text. For antibacterial drugs, additional information is assessed as part of the human food safety section. Two types of potential effects of the new animal drug on bacteria of human health concern are considered (see Section Microbiological Effects on Bacteria of Human Health Concern).

Examples of Potential Problems of compound drugs

There are published studies in which drugs for veterinary patients have been tested for strength over time or stability under the conditions used during compounding. In a commercial formulation, the inactive ingredients and excipients are added to drug formulations to ensure the stability of the drug; provide an optimum chemical environment, pH; or increase the ease of packaging or handling. However, adding other chemicals, flavorings, or vehicles, or interfering with protective coatings of tablets may affect the stability of the drug, decreasing strength, oral absorption, and efficacy. There are published formulas in compounding journals, and texts, but few of these formulations have been tested for safety, efficacy, bioavailability, stability, strength, and purity for use in the target species. Veterinarians are responsible for the risk to an animal, or person handling the medication, when they prescribe compounded preparations. Pharmacists and veterinarians preparing compounds for animal patients are obligated to be in compliance with USP compounding standards. They have an obligation to request evidence from compounding pharmacists about the stability and strength of formulations prepared for their patients. When veterinarians compound formulations in their own practices, they should be cognizant of the potential interactions and alterations that may compromise the stability and strength of the active ingredient and should not attempt compounding without proper training, equipment, and quality assurance techniques There are published examples in which drug stability and efficacy have been compromised through compounding. For example, when omeprazole was compounded for oral use in horses, it was not as effective for treating gastric ulcers as the commercial formulation registered for horses (GastroGard) (Nieto et al., 2002). Systemic bioavailability and strength of the compounded formulation was not as high as for the proprietary product. Omeprazole is known for its instability unless administered in the original formulation intended for horses or people. On the other hand, when the FDAapproved equine paste (GastroGard ® ) was compounded in oil for dogs and cats, it retained the original strength for 6 months (unpublished data from laboratory of MG Papich). Fluoroquinolone antibiotics are frequently modified for administration to exotic animals and horses. The compatibility of enrofloxacin and orbifloxacin with flavorings, vehicles, and other ingredients has been evaluated. With few exceptions, this class of drugs is compatible with most mixtures and remarkably stable. Enrofloxacin retained strength when the FDA-approved product was mixed with various vehicles and flavorings for exotic animals (Petritz et al., 2013). A notable exception is the chelation of enrofloxacin with iron and aluminum-containing products (e.g., antacids, sucralfate, mineral supplements, iron-containing molasses), in which a significant portion of the medication may become unavailable for absorption. It has also been observed that certain mixtures and flavorings may be incompatible with fluoroquinolones if they contain metal ions that are known to cause chelation. For example, when crushed orbifloxacin tablets were mixed with a vitamin and mineral supplement (Lixotinic) that is sometimes used as a flavored vehicle for oral administration of drugs, the strength of orbifloxacin was decreased from its original concentration by 50%. (Lixotinic contains 2.5 mg/ml iron.) Other flavorings and vehicles (for example, corn syrup, regular molasses, fish sauce, and Syrpalta) had no effect. Antifungal drugs are subject to instability if not maintained at an optimum pH and formulation conditions. Itraconazole is frequently compounded from the bulk chemical or the proprietary capsules. However, itraconazole must be complexed onto cyclodextran in order to be orally bioavailable, and as bulk chemical preparations of itraconazole are not complexed in this fashion, they have not been found to be orally bioavailable in animal patients (Mawby et al., 2014). Itraconazole may also adsorb to plastic and glassware during compounding, decreasing the predicted strength of the finished preparation. When doxycycline hyclate was compounded from FDA-approved tablets in an aqueous vehicle, it retained strength for only 7 days. After 7 days it degraded and showed a change in color and consistency (Papich et al., 2013). Aminoglycoside antibiotics (gentamicin, tobramycin, kanamycin) are inactivated when admixed with other antibiotics, particularly beta-lactams. This interaction is greatest from carbenicillin, followed by ticarcillin, penicillin G, and ampicillin. Loss of strength by as much as 50% can occur within 4 to 6 hours. This interaction is a potential problem when antibiotic mixtures are prepared in a vial or fluid administration set and dispensed to be used several hours later. This interaction does not occur intravascularly at therapeutic concentrations in the patient because the drugs are diluted out in plasma and body fluids (Bowman et al., 1986), but visual precipitation of these agents in IV administration sets is commonly reported when they are mixed. Drugs formulated as acids - such as the hydrochloride form of basic drugs - are formulated to maintain their solubility in aqueous solutions. However, when these formulations are mixed with other drugs that are more basic, or added to basic vehicles, drug precipitation may occur. Several drugs are not soluble in aqueous vehicles. Therefore they are dissolved in organic solvents (propylene or ethylene glycol, for example) or alcohols. These are notoriously unpalatable to some animals, particularly cats. However, if these formulations are diluted in aqueous fluids, precipitation may occur. When these are stored at home by the pet owner, precipitation of the drug to the bottom of the container results in dilute oral dosing when the container is sampled from the top, and highly concentrated formulation when the containeris sampled from the bottom (assuming that the precipitate at the bottom can be resuspended). This also may be observed when mixing some drugs in aqueous fluids. For example, if diazepam solution (which contains propylene glycol and alcohols) is diluted in saline solution or Lactated Ringer's solution, precipitation occurs.

Why are animal drugs compounded?

There are thousands of FDA-approved medications, including low-cost generic options, that veterinarians can prescribe for their patients. But, due to the wide variety of animal species, each with their own conditions, diseases, and specific needs, there may not always be an FDA-approved, conditionally approved, or indexed product that can be safely used to treat a particular animal in the finished dosage form. Some reasons for choosing a compounded drug over an FDA-approved, conditionally approved, or indexed drug include the need for flavoring (to encourage the patient to take the drug), a different route of administration (such as a capsule instead of a liquid), or a particular dosage that is not approved (such as for a very large or very small animal).

Unapproved Drugs Available by Importation

There was a mechanism in the past whereby a veterinarian could obtain an unapproved drug or dosage formthrough importation from other countries by filing a Medically Necessary Personal Veterinary Import form with FDA-CVM. This mechanism is no longer sanctioned by the FDA-CVM

What is DEA 222

This is a form where you log in drugs specifically controlled drugs

what is significance of reselling needles and syringes

This is very important because many viruses can be passed through the needles, and it is a public health concern

-You must keep complete records of ELDU (extra label drug use), for at least 2 years and FDA has the right to inspect said records - FDA can restrict the use of a currently approved drug if there is a perceived threat to public health TRUE OR FALSE?

True

USP-797 Usp-778 USP-800

USP-797 If you compound anything sterile, you will have to be compliant to USP-797 you have to be trained, and its a long long list and expensive Usp-795 allows you to compound non sterile, this method is a lot safer, there is still training a a list you have to complete but its not as intense as the USP- ex: tablets,something topical, capsules USP-800 this applies to working safety, teaching of vet med if you use compound drugs you have to use precaution and protect your team such as chemo therapy or any other drugs that is a human health Hassard, there's a lot that will terminate pregnacy

What are the risks associated with compounded drugs?

Unlike with approved drugs, animal drug compounders do not submit any data to FDA about the safety or effectiveness of their products before marketing them. FDA does not receive information about how compounded animal drugs are produced, nor does the agency inspect the compounding site to verify how these products are made. And, while sponsors of FDA-approved animal drugs must regularly report to FDA any adverse events and side effects associated with their products, animal drug compounders face no such requirement. This means that safety or effectiveness issues with compounded animal drugs could go undetected. FDA is especially concerned about the potential risk of widespread harm when office stock is compounded under "insanitary" (unsanitary) conditions. Poor compounding practices can result in serious drug quality problems, such as bacterial or fungal contamination of a drug that is intended to be sterile, or a drug that has either too much or too little of the active ingredient(s). These problems can and have led to serious injury or death (/animal-veterinary/animal-drug-compounding/inspections-recalls-and-other-actions-respect-firmsengage-animal-drug-compounding) of the patient. FDA also has concerns about the stability of compounded drugs, especially when they are retained in inventory as office stock for an extended period of time.

Study Documentation and Submission

Using the protocol, a sponsor will conduct the study. Effectiveness studies are conducted in accordance with GCP Guidance, and safety studies are conducted in accordance with GLP regulations. When the study is completed and the final study report written, the sponsor will provide CVM with a study submission that contains the final study report and supporting documentation including the raw data for review. CVM will review the study for data integrity and for scientific merit. If the study is accepted, it will be used to support either a portion of or the complete technical section.When the entire technical section is complete, CVM will send the sponsor a technical section complete letter

NPI number

Veterinarian do not need it; vets cannot legally get NPI number it is only for physician you can give pharmacist your state licenses number instead

Administrative New Animal Drug Application

When a sponsor has received technical section complete letters for each of the required technical sections submitted to support approval of a new animal drug, the sponsor may file an Administrative NADA. The Administrative NADA contains a number for critical documents including the complete facsimile labeling, copies of all the technical section complete letters, and a signed FDA Form 356V. Upon receipt of an Administrative NADA, CVM will review and process the application to approval within 60 days.

What is the significance of "When in doubt, write it out"?

When you call in a verbal RX's to a pharmacist, always have them repeat back to you the drug elements-name, strength, route, directions for use. That is your opportunity to catch errors -C.S.-#5 Xanax tabs(five) -Avoid SID on outsourced Rx's, write out "daily"

Interpretation of Pharmacokinetic Parameters

With these equations, we now have the three so-called primary pharmacokinetic parameters describing drug disposition in the body: T1/2, ClB , and Vd. The data required to calculate them is a knowledge of dose and an experimental derivation of either Kel or T1/2. This is a good place to discuss the limits of calculating parameters from such simple concentration-time profiles. Only two parameters are actually being "measured" from this analysis: the slope Kel and intercept Cp0 of the semilogarithmic plot, which - using Equation 3.12 directly - determines Vd. The third parameter Cl is "calculated" from the two measured parameters. Based on the mathematical method used to calculate these, some workers suggested that Kel and Vd are the independent parameters in a pharmacokinetic analysis and Cl is a derived parameter. This assertion is usually made when the statistical properties of the parameters are being defined since errors for these can be easily obtained. However, this belief is an artifact of the use of a compartmental model as a tool to get at values for these physiological parameters. Biologically, the truly independent parameters are the Vd and Cl, with Kel and thus T1/2 becoming the dependent variables. From this biological perspective, the true relationship is T1∕2 = (0.693 × Vd)∕Cl (3.18) The observed half-life of a drug is dependent upon both the extent of a drug's distribution in the body and its rate of clearance. If the clearance of a drug is high (e.g., rapidly eliminated by the kidney), the T1/2 is relatively short. Logically, a slowly eliminated drug will have a prolonged T1/2. Not obvious at first is that if a drug is extensively distributed in the body (e.g., lipid-soluble drug distributed to fat), Vd will be large and the T1/2 will also be relatively prolonged. In contrast, if a drug has restricted distribution in the body (e.g., only the vascular system), the Vd will be small, a large fraction of the drug will be available for elimination, and thus the T1/2 relatively short. In a disease state, T1/2 may be prolonged by either a diseased kidney, a reduced capacity for hepatic drug metabolism, or an inflammatory state, which increases capillary perfusion and permeability, thus allowing drug access to normally excluded tissue sites. Therefore, T1/2 is physiologically dependent on both the volume of distribution and clearance of the drug. ClB is the sum of clearances from all routes of administration: ClB = ClRenal + ClHepatic + Clother (3.19) There is another strategy that can be used to estimate clearance in an intravenous study. This is based on the basic principle of mass balance. The strategy is to infuse a drug into the body at a constant rate Ro (mass/time) and then measure plasma drug concentrations. By definition, when a steady-state plasma concentration is achieved, C ss (mass/volume), the rate of drug input must equal the rate of clearance from the body,

adulterated drug means what?

a recognize drug but it does not meet the quality standard set by the FDA ex: anything that is counterfeit, contaminated drugs, drugs coming from outside of America (FDA does not approve drugs outside of America)

Officially recognized Latin abbreviations used in prescription writing

a.c. before meals ml milliliter a.d. right ear o.d. right eye a.s. left ear o.s. left eye a.u. both ears o.u. both eyes amp ampoule p.c. after meals b.i.d. twice daily p.o. by mouth cc cubic centimeter p.r.n. as needed c with q. every cap capsule q4h every 4 hours, etc. disp dispense q.i.d. four times daily g or gm gram q.s. a sufficient quantity gtt(s) drop(s) Sig. directions to patient h hour SQ subcutaneously h.s. at bedtime stat immediately IM intramuscularly susp suspension IP intraperitoneally tab tablet IV intravenous TBSP tablespoonful (15 ml) kg kilogram t.i.d. three times daily lb pound tsp teaspoonful (5 ml) m2 meter squared Ut. dict as directed mg milligram

DEA 41 form

allows you to destroy controlled drugs in house make sure you list all the information means date, dosage. 2 people need to be witnessed and 2 people need to sign off on it

mobility act

allows you to take controlled substances away from adresses but it has to be locked up and keep the secure and keep records on them

Small Vd(i.e. 0.6 L/kg) means the drug is confined to the intravascular fluid

anything less then 1 litter/kilogram means the drug is confined to the intravascular fluid

large Vd(VD=distribution) (i.e 16 l/kg) means the drug accumulated in tissues such as adipose

anything more than 1 litter/killogram means the drug accumulated somewhere in a tissue space specifically in adipose tissue

How the Product is Supplied

can include a description of the delivery device, the number of units per package, and the dosage strengths.

Current Status of Compounded Veterinary Drugs

compounded drugs are not FDA approved Drug compounding has always been an important component of veterinary medicine. Historically, veterinarians have prepared concoctions, mixtures, and remedies for their patients because there were few approved formulations on the market for animals. Now, there are more available drugs for animals, and pharmaceutical science has provided for a better understanding of the factors contributing to poor drug bioavailability, instability, and physical incompatibility. Over the last several years, questions concerning the practice of compounding have been raised, particularly with respect to stability, purity, and strength when the original dosage form of the drug is altered. (Note that the term "potency" used in some publications has been replaced by "strength" in this chapter because it is a more accurate term. Potency is used to describe the biological activity of a medication in a patient, and is not a measure of drug concentration.) Compounding is the alteration of the original drug dosage form for the purposes of ease of administration or because the original dosage form is unsuitable for the purpose intended. According to the United States Pharmacopeia (USP), compounding involves the preparation, mixing, assembling, packaging, and labeling of a drug or device in accordance with a licensed practitioner's prescription. The USP chapter on pharmacy compounding (Chapter <795>: Pharmaceutical Compounding— Nonsterile Preparations) states that "compounding is an integral part of pharmacy practice and is essential to the provision of health care" (USP-NF, 2015a). Compounding does not include the preparation of a drug by reconstitution or mixing that is according to the manufacturer's instructions on an approved human or veterinary drug product. The FDA issued a Compliance Policy Guide (CPG) for compounding drugs for use in animals in 2003 (FDACVM, 2003b). The 2003 version of the CPG provided guidance to FDA's staff with regard to the compounding of animal drugs by veterinarians and pharmacists for use in animals. However, in 2015 the agency withdrew Compliance Policy Guide Section 608.400 "Compounding of Drugs for Use in Animals" because it is no longer consistent with the FDA's current thinking on these issues. The FDA has prepared new guidance, referred to as "Guidance for Industry, or GFI #230". (Available at: http://www. fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ ucm446846.htm). At the time of this writing, the draft has not yet been finalized; therefore, it is not possible to indicate in this chapter how compounding will be regulated in the future. However, from the draft guidance, it is clear that the FDA intends to demonstrate regulatory discretion for use of bulk drug substances for compounding and intends to place stronger limits on the compounding from bulk sources. Bulk drug substances are defined as active ingredients used in the manufacture of finished dosage forms of the drug. Bulk drug substances are also referred to as active pharmaceutical ingredients (APIs). Current law does not permit compounding of animal drugs from bulk drug substances, but the FDA recognizes that there are limited circumstances when an animal drug compounded from bulk drug substances may be an appropriate treatment option. FDA's GFI #230 outlines specific conditions under which the agency generally does not intend to take action against state-licensed pharmacies, veterinarians, and facilities registered as outsourcing facilities when drugs are compounded for animals from bulk drug substances. It is anticipated that the new FDA Guidance on compounding from bulk drug substances will allow outsourcing facilities to prepare compounds from a limited list of bulk drug substances. Compounding from such a list by outsourcing facilities may be allowed in the absence of a prescription for an individual animal in instances such as drug shortages, or for when emergent use precludes waiting for a compound to be prepared pursuant to an individual prescription for an individual animal. Outsourcing Facilities are defined in The Drug Quality and Security Act, signed into law on November 27, 2013. This law created a new section 503B in the Food Drug and Cosmetic Act (FDCA). Under section 503B, a compounder can become an "outsourcing facility." The law defines an "outsourcing facility" as a facility at one geographic location or address that is engaged in the compounding of sterile drugs; has elected to register as an outsourcing facility; and complies with all of the requirements of section 503B. The FDA recognizes the importance of compounding in veterinary practice, but also must ensure that compounded drugs do not cause harm to the treated animals or their caregivers, that compounded preparations are bioavailable, effective, stable, and potent, and that compounded preparations do not cause drug residues in food animals. The proposed guidance mentioned above specifically refers to compounding from unapproved bulk drug substances. FDA regulations permit the compounding of formulations from approved animal or human drugs under the current federal code: 21 CFR 530.13 (AMDUCA). The FDA is concerned that some compounding by veterinarians and pharmacists from bulk drug substances is performed to circumvent the usual drug approval process. Some activities performed under the guise of compounding (e.g., mass preparation of compounds that are wholesaled to veterinarians with no patient identified at the time of compounding, dispensing of compounds intended only for administration by the veterinarian in the office, or compounding less expensive copies of commercially available approved drugs) mimics exactly the manufacturing and distribution of what FDA defines as "new animal drugs." A court ruling by the 5th Circuit of Appeals (Medical Center Pharmacy vs. Mukasey, July 2008) reasserted that compounds prepared for animals outside of the provisions of AMUDCA fit the description of new animal drugs. New animal drugs must undergo the long and arduous FDA approval process to ensure the safety of the public health. Compounded products have not been subject to this scrutiny to determine the safety, efficacy, strength, purity, and stability required of drug manufacturers in order to receive FDA approval for marketing. Pharmacies are held to relevant USP Compounding standards by their state boards of pharmacy; however, under no circumstances can compounded products be manufactured or wholesaled. Licensed veterinary distributors who wholesale compounds from compounding pharmacies are in direct violation with licensure as granted by state licensing agencies (usually the Department of Revenue). Compounds must be prepared by pharmacists pursuant to a valid prescription order for an individual patient or prepared by outsourcing facilities for use in a veterinary practice ("office use")

federal label

contains all the information required to be on the drug per the federal government and the package insert is also the federal label

What will an anticholinergic agent do to salivary secretions

decrease

What would an beta blocker do to heart rate

decrease

What will an anti-cholinergic do to GI motility

decrease atropine is a good anticholingergic drug

What would an alpha blocker do to BP?

decrease BP

what will a cholinergic drug do to heart rate?

decrease it

The Contraindications section

defines the known circumstances under which a product should not be used because the risk associated with drug use clearly outweighs the possible benefit. Contraindications are based upon reasonable evidence that a drug caused a specific adverse reaction. Use of the drug in the situations described in the Contraindications section is likely to result in a serious adverse event that is fatal, or life-threatening, or requires professional intervention, or causes an abortion, or stillbirth, or infertility, or congenital anomaly, or prolonged or permanent disability or disfigurement to the treated animal.

What are the 3 catecholamines?

dopamine, norepinephrine, epinephrine

-Compounded drugs are the same as generic drugs - compounding a copy of an FDA approved drug for use in beef cattle is a good idea -the safety of compounded drugs is no big deal because we are just giving them to animals, not people TRUE OR FALSE?

false

Cats are deficient in what?

glucoronidation(phase 2 reaction) thus metabolize drugs very different from other species

What is the T1/2? In theory how many half-lives have to pass for -99% of a drug to be eliminated?

half-life is the time required for half of the drug to be eliminated you will never see a drug get to zero 99.9 percent of the drug being eliminated is about 10 or 11 half life. any type of renal disfunction will change half life. in geriatric drugs do you sometimes have to change the amount of drugs or the duration of the drug based upon disease state? =yes.

B-1 receptors are found mainly?

heart

What is about the only way to kill a patient with a stand alone benzodiazepine?

hit them repeatedly over the head with a bottle because they are extremely safe, sometimes can cause problems when it is mixed with an opioid.

Contrast dyes and mannitol display classic 1 compartment kinetics. What does that mean?

if something has compartment classic 1 kinetics it is homogenously everything is dispersed everywhere in the body

poison prevention act

if you use human label drugs you have to make the container child proof, you can despense meds in non child dispence containers do to difficukty of the owner being able to open it but it must be documented at all times

DEA forms 41 what does its document

if you want to destroy controlled substances then you must use this form. — There must always be 2 people there to witness you destroy the drug and to sign off on that

PMO law

if you work with dairy there is something out there called pasteurized milk ordentents (PMO) stake holders got together and said if you are going to work with dairy everyone should do the same thing to help with the quality of that milk. there is grade A milk and grade B milk and you need to produce grade A milk producers have a long list to make sure everything goes back to quality like testing, education of employs, prevent of cross contamination. grade b milk goes into the making of powdered milk, grade B milk does not make as much money as grade A. I you as a veterinarian prescribes pastured milk to a lactating cow you cant use drugs in a extra label, drugs that can be use per label you have to physically label them with your clinic information, and you have to keep record of all this. you have to store lactating drugs separately in non-lactating female drugs

What is a cubex machine?

importance is to dispense drugs they can come as much larger " supply bank"

Where are M2 and M3 receptors found?

in the heart, you find a lot more of M2 in the haeart then M3

The Precautions section

includes additional information to enhance the safe use of the product by the practitioner. The Precautions section includes any additional information that is important for the safe use of the product that has not been included in the Contraindications or Warnings sections. The Precautions section may include recommendations for screening or diagnostic tests, information about drug to drug interactions, carcinogenesis, reproductive safety, adverse reactions in species other than the target species, or use in particular subpopulations of the target species, such as pediatric, geriatric, or animals with a particular disease.

What would a beta agonist do to lungs function?

increase lung function

Mobility Act of 2014- what does it allow you to do?

it allows you to take controlled drugs off your premise to another location, you have to make sure you keep records on all the drugs just like it was in the clinic

Draxxinn a macrolide abx displays classic 2 compartment kinetics. what does that mean?

it has 2 compartment kinetics; you administer the drug it gets absorbed in the systemic circulation and then it concentrates in the lungs and that's why it is good to treat pneumonia

Topical drug distribution

it has to make its way through the dermis, the epidermis and get all the way down to the capillary bed which is how topical medications get absorbed

Farad, food animal residue avoidance database

it is funded by our tax dollars, they will help with assigning withdrawal time

Delaney anticancer amendment

it is illegal to have and carcinogen in our foods, you can't treat an animal with any carcinogen and then feed it to people because it is illegal. cannot use it in food producing animals many of the

What is a phase 1 RXN?

it will detoxify anything, it can be a toxicant or a poison or a drug so it typically undergoing some initial chemical reactions, oxidation,reduction, hydrolysis -phase 1 and phase 2 metabolic process you take a lipid soluble drug or a toxicant to metabolize it into something water soluble so it can be excreted into the urine since the urine is largely water - cats do not have some of the phase 2 metabolic enzymes to metabolize them and detoxify them such as glucuronidation -paracetamol is tylenol Various metabolic pathways are involved in drug metabolism including oxidation, reduction, hydrolysis, hydration, and conjunction. These processes can be divided into Phase I and Phase II reactions (Table 2.2). Phase I includes reactions introducing functional groups to drug molecules necessary for the Phase II reactions, which primarily involve conjugation. In other words, Phase I products act as substrates for Phase II processes, resulting in conjugation with endogenous compounds, which further increase their water solubility and polarity, thus retarding tissue distribution and facilitating drug excretion from the body. Specific examples of drug metabolism are included in chapters throughout this text. The focus of this introduction will be to briefly overview the general processes involved in drug metabolism relative to how they might affect pharmacokinetic parameters and the disposition of drugs in the body. Interested readers should consult standard texts in drug metabolism or biochemical pharmacology/toxicology for specific detailed examples illustrating the chemistry and genetic control of these processes Phase I metabolism includes four major pathways: oxidation, reduction, hydrolysis, and hydration, among which oxidation is the most important. Attention is usually focused on oxidation mediated by the microsomal mixed-function oxidase system (e.g., cytochrome P450, etc.) due to its central role and significance in governing the metabolic disposition of many drugs and xenobiotics. An understanding of this pathway is often critical to making interspecies extrapolations. Phase II conjugating enzymes play a very important role in the deactivation of the Phase I metabolites of many drugs as well as in direct deactivation of some parent compounds when their specific structure doesn't require Phase I modification. For example, the analgesic drug paracetamol can be deactivated directly by Phase II reactions using glutathione, glucuronide, and sulfate conjugation mechanisms. Phase II deactivation can be achieved by both gross chemical modification of the drug thereby decreasing their receptor affinity, and by enhancement of excretion from the body, often via the kidney. In summary, Phase I metabolism is primarily responsible for drug deactivation, although Phase II plays an important role in deactivation of some drugs. Phase I reactions prepare drugs or toxicants for Phase II metabolism; that is Phase I modifies the drug molecule by introducing a chemically reactive group on which the Phase II reactions can be carried out for the final deactivation and excretion. This increased water solubility after metabolism restricts a drug's metabolite distribution to extracellular fluids, thereby enhancing excretion. Specific pathways for drug metabolism and transport are discussed in the individual drug chapters as well as their pharmacogenomics in Chapter 50

What will a beta agonist do to uterine function in a pregnant, pre-term, labor female

it will relax the uterus and stop preterm labor

butorphanol(torbugesic) is an antagonist at mu and agonist at kappa receptors

its the opposite to buprenorphine

Define/describe; renal physiology relevant to clearance

kidneys are highly vascular and highly reliant on the heart For a perspective of drug excretion from the body, the kidney will be considered only as an excretory organ designed to remove foreign compounds (e.g., drugs) and metabolic by-products (e.g., creatinine, urea) from the blood. As will become evident, the major clinical indices of renal function such as blood urea nitrogen, serum creatinine, and creatinine clearance are actually pharmacokinetic parameters of creatinine and urea excretion! The kidney receives approximately 25% of the cardiac output and thus processes a prodigious amount of blood. The kidney functions in a two-step manner to accomplish its function. The first step is passage through a filtering unit to retain formed cellular elements (e.g., erythrocytes, white blood cells) and proteins in the blood, only allowing the passage of plasma fluid into the remainder of the kidney. The second step utilizes a system of anatomically and physiologically segmented tubules to further modify the contents of the filtered fluid depending on a host of physiological needs including but not limited to fluid, electrolyte, and acid-base balance and the regulation of systemic blood pressure. The primary functional unit of the kidney is the nephron depicted in Figure 2.8. Depending on the species, there may be 500,000 nephrons per kidney. The sum of their individual function is the observed organ function. Their specific anatomical arrangement is species dependent, often determined by the evolutionary adaptation of the animal to its environment relative to the need to conserve body fluids. The filtration unit is the glomerulus, while the remainder of the fluid processing is accomplished by the extensive tubular system, whose segments are named in relation to their relative distance(proximal versus distal) measured through the tubules from the glomerulus. The junction between these is a unique anatomical adaptation called the loop of Henle that is designed to use countercurrent exchangers to efficiently produce a concentrated urine since most of the water that is filtered by the glomerulus must be reabsorbed back into the body. The loop of Henle also forces the distal tubules to return toward the surface of the kidney to interact with the glomeruli. Grossly, the region of the kidney containing the glomeruli as well as the proximal and returning distal tubules are on the outside toward the surface and comprise the renal cortex. This region of the kidney is very well perfused by blood and is primarily characterized by oxidative metabolic processes.

Renal Physiology Relevant to Clearance of Drugs

kidneys are highly vascular and highly reliant on the heart For a perspective of drug excretion from the body, the kidney will be considered only as an excretory organ designed to remove foreign compounds (e.g., drugs) and metabolic by-products (e.g., creatinine, urea) from the blood. As will become evident, the major clinical indices of renal function such as blood urea nitrogen, serum creatinine, and creatinine clearance are actually pharmacokinetic parameters of creatinine and urea excretion! The kidney receives approximately 25% of the cardiac output and thus processes a prodigious amount of blood. The kidney functions in a two-step manner to accomplish its function. The first step is passage through a filtering unit to retain formed cellular elements (e.g., erythrocytes, white blood cells) and proteins in the blood, only allowing the passage of plasma fluid into the remainder of the kidney. The second step utilizes a system of anatomically and physiologically segmented tubules to further modify the contents of the filtered fluid depending on a host of physiological needs including but not limited to fluid, electrolyte, and acid-base balance and the regulation of systemic blood pressure. The primary functional unit of the kidney is the nephron depicted in Figure 2.8. Depending on the species, there may be 500,000 nephrons per kidney. The sum of their individual function is the observed organ function. Their specific anatomical arrangement is species dependent, often determined by the evolutionary adaptation of the animal to its environment relative to the need to conserve body fluids. The filtration unit is the glomerulus, while the remainder of the fluid processing is accomplished by the extensive tubular system, whose segments are named in relation to their relative distance(proximal versus distal) measured through the tubules from the glomerulus. The junction between these is a unique anatomical adaptation called the loop of Henle that is designed to use countercurrent exchangers to efficiently produce a concentrated urine since most of the water that is filtered by the glomerulus must be reabsorbed back into the body. The loop of Henle also forces the distal tubules to return toward the surface of the kidney to interact with the glomeruli. Grossly, the region of the kidney containing the glomeruli as well as the proximal and returning distal tubules are on the outside toward the surface and comprise the renal cortex. This region of the kidney is very well perfused by blood and is primarily characterized by oxidative metabolic processes.

B-2 receptors are mainly found?

lungs/ skeletal muscles

The Information for Owner or Person Treating Animal section

n contains specific information for the owner or person treating the animal regarding the safe and effective use of the product. This information is designed to be conveyed by the prescribing veterinarian to the animal owner. Some products have a separate client information sheet (CIS) in addition to the package insert. The CIS sheet is designed to be given to the animal owner every time the product is dispensed. The CIS is typically required by the FDA when there is a need to give the animal owner detailed information about the potential for serious adverse reactions from the drug. The CIS may include information to help the animal owner recognize and report to the veterinarian any early signs of problems following the use of the product in the individual patient.

Clinical Pharmacology section

n is a concise summary of the pharmacology, pharmacokinetics, and pharmacodynamics of the drug in the target species. This section may also provide information about the drug class, potential drug-drug interactions, and the effect of food on product bioavailability. For an antimicrobial agent, this section often includes a microbiology section with susceptibility data for the specific pathogens for which the product is approved

The Indications section

n of the labeling lists the specific disease(s) or conditions(s) for which a particular drug product is approved. The specific wording in this section depends upon the data contained in the effectiveness technical section of the approved new animal drug application.

Do IV administered drugs undergo absorption?

no

The Adverse Reactions section

of the labeling lists undesirable effects reasonably associated with the use of the drug that may occur as part of the pharmacological action of the drug or that may be unpredictable in their occurrence. The Adverse Reactions section is developed from the field effectiveness studies conducted by the pharmaceutical sponsor to support new animal drug approval. This section may also include a postapproval experience section, reporting any additional undesirable effects reported from the postapproval surveillance of the product in the larger population. The Adverse Reactions section includes a toll-free number for the practitioner to call for technical assistance from the pharmaceutical sponsor

Effectiveness section

of the package insert contains an abstract of the results from the effectiveness studies published in the FOI Summary. The abstract provides a concise summary of the pivotal effectiveness studies and includes information such as the number and geographic location of study sites, the age, sex, and total number, etc. of animals in the study, a brief description of the study design, and the study results. The abstract describes how the effectiveness studies were conducted and how well the treated animals fared as compared to the control animals. This information can be considered from the perspective of the similarity between the study population versus the potential patient undergoing treatment (where the "patient" can represent an individual animal or a group of animals). For example, relevant questions may include whether or not the patient and the study population are of a similar age, class, and level of morbidity. This kind of information may be particularly useful when choosing between similar products that are approved and available for the same indications. With regard to the database supporting product approvals, more detailed information than provided by the abstract can be obtained in the FOI summary. These summaries are easily accessed from CVM's website by simply inserting the NADA or ANADA number (another piece of information found on the package insert) for that product.

Drug Passage Across Membranes

p-glycoprtein is a transporter for drugs P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells - animals that lack p-glycoprotiens ( there job is to keep a lot of things out of the nervous system)drugs can get into the central nervous system and they can then become toxic this is what happens in coli crossed dogs with ivermectin - you can have residue for example if a lactating cow gets mastitis the PH will change and will a basic drug will then go to a basic place such as the udder and can cause residue -hydrochloride, acid, penicillin is a weakly acidic drug ( it can get trapped in basic drugs and vs versa) -if a dog ends in sulphate, phosphate it is a weakly basic drug -in response to fix drugs-if an oral drug is large and fixed, they won't be able to go through the mucus membrane in the small intestines, since it is too large it can't go through the membrane and since it is positively charged it repels which doesn't allow it to make its way to the mucus membrane - some drugs are very acidic while some drugs are very basic, so you put them in various tissues that might be a different type of polarity. Drugs can get trapped there Evidence also exists that membranes are more permeable to the nonionized ( lipid soluble) than the ionized(hydrophilic) form of weak organic acids and bases. If the nonionized moiety has a lipid : water partition coefficient favorable for membrane penetration, it will ultimately reach equilibrium on both sides of the membrane. The ionized form of the drug is completely prevented from crossing the membrane because of its low lipid solubility. The amount of the drug in the ionized or nonionized form depends upon the pKa (negative logarithm of the acidic dissociation constant) of the drug and the pH of the medium on either side of the membrane (e.g., intracellular versus extracellular fluid; gastrointestinal versus extracellular fluid). Protonated weak acids are nonionized (e.g., COOH) while protonated weak bases are ionized (e.g., NH3 +). If the drug has a fixed charge at all pHs (positive charge) encountered inside and outside of the body (e.g., quarternary amines, aminoglycoside antibiotics), they will never cross lipid membranes by diffusion. This would restrict both their absorption and distribution and generally lead to an enhanced rate of elimination. It is the nonionized form of the drug that is governed by Fick's Law of Diffusion and described by Equation 2.1 above. For this equation to predict the movement of a drug across membrane systems in vivo, the relevant pH of each compartment must be considered relative to the compound's pKa; otherwise, erroneous predictions will be made Such a gradient would greatly favor the absorption of this weak acid across the gastrointestinal tract into plasma. This is the situation that exists for weak acids such as penicillin, aspirin, and phenylbutazone. In contrast, a weak base would tend to be trapped in this environment and thus minimal absorption would occur. Examples of such weak bases are morphine, phenothiazine, and ketamine. Specific active transport systems may counter these predictions (e.g., β-lactam transporters in intestines), as well as the extreme surface area of the small intestines compared to gastric mucosa, which generally favors absorption of most drugs in the small intestines. With the weakly basic strychnine, pHdependent absorption is toxicologically significant. If strychnine were placed into the strongly acidic stomach, no systemic toxicity would be observed. However, if the stomach were then infused with alkali, most of this base would become nonionized, readily absorbed, and lethal. In summary, weak acids are readily absorbed from an acid environment and sequestered in an alkaline medium. In contrast, weak bases are absorbed in an alkaline environment and trapped in an acidic environment Thus weakly acidic drugs will tend not to distribute into the milk after systemic distribution (e.g., penicillin), while weakly basic drugs (e.g., erythromycin) will. If a disease process alters the pH of one compartment (e.g., mastitis), the normal equilibrium ratio will also be perturbed. In mastitis, where pH may increase almost one unit, this preferential distribution of basic antibiotics will be lost. The relatively acidic pH of cells relative to plasma is responsible for the relatively large tissue distribution seen with many weakly basic drugs (e.g., morphine, amphetamine). Similarly, in the ruminant, many basic drugs tend to distribute into the rumen, resulting in distribution volumes much larger than those in monogastrics. In fact, a drug that distributes into this organ may then undergo microbial degradation resulting in its elimination from the body Finally, active transport may also occur in the opposite direction to remove a drug after it has been absorbed into specific cells or tissue sites. This is called the P-glycoprotein system, a class of drug transporters originally associated with multiple drug resistance (MDR) encountered in cancer chemotherapy. MDR transporters have been identified in intestinal epithelial cells, the placenta, kidney tubules, brain endothelial cells, and liver bile canaliculus. These will be addressed throughout this text for specific drug classes

CNS(PSNS) pre and post

pre- cholinergic and releases ach on to nicotinic receptors post- cholinergic with ach being the neurotransmitter gets released on to the receptors of M2

CNS(SNS) pre and post ganglion

pre-cholinergic and releases ach on to nicotinic receptors post - adrenergic which releases nor epi on alpha and beta receptors

The Animal Safety section

provides an abstract of the results from the TAS studies that are required for FDA approval of the new animal drug. This information demonstrates the margin of safety for the drug. It also allows the reader to see what types of signs were observed in animals that received the drug at higher doses and for longer times than the intended dosage. It should help the practitioner decide whether or not to use the drug in animals that may be old, young, or have compromised organ function. If adverse signs in a treated animal are observed, the package insert provides information regarding whether or not similar signs were noted during the safety testing of this application.

Product Identification, Description and Prescription Legend

provides the product's brand name (often indicated by "® "), the generic name (the name given to the chemical entity), the dosage form (e.g., tablet, sterile solution, oral suspension, etc.), and if designated as a prescription or VFD drug, the prescription or VFD legend. The labeling for all veterinary prescription products contains the following statement: "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian." The prescription (Rx), over-the-counter (OTC), and VFD classification is discussed later in this chapter.

"Office stock

refers to compounded drugs kept on hand by veterinarians for patients. Office stock is generally compounded by a veterinarian, or by a pharmacist and sold to a veterinarian to have on hand, without a patient-specific prescription

DEA form 22 is used for what?

schedule 2 drugs to track the movement of all of them ex: if there is a clinic down the street what wants to use some opioid drug as the veterinarian you are allowed to give them the medication, but you must fill out this form first to document it.

The Storage Information

section describes the recommended storage conditions that are needed to maintain the potency of the drug within acceptable limits before the established expiration date. When applicable, this includes practical information for shipping, warehouse storage, and storage by the user. Any mandatory storage conditions are described (e.g., Store at controlled room temperature, 20-25◦C (68-77◦F)). When the drug is to be mixed with a diluent before use, this section describes the storage conditions for the diluted drug and also the time limitations for use of the diluted drug.

What would an alpha agonist do to receptors in the CNS?

sedation

The Warnings section describes

serious adverse reactions and potential safety hazards to the animal being treated. Although the adverse reactions may be serious, FDA has determined that the benefit of using the drug outweighs the risk of the adverse event. The Warnings section may also describe potential actions that could be taken by the veterinarian to mitigate the adverse reaction should it occur, or to decrease the likelihood of the adverse reaction occurring, such as avoiding use in a predefined high-risk population. Warning statements are based upon evidence indicating an association of a serious hazard with a drug, but not necessarily proof that the drug caused the reaction. Significant problems that may lead to death or serious injury may require a "boxed warning" on the package insert. The Warnings section may also include a user safety (Human Warnings) or human food safety section. The user safety section provides information regarding hazards to human health by contact, inhalation, ingestion, injection, or by other exposure to the product. The human food safety (Residue Warnings) section states the withdrawal time for use of the product in a food animal species. The withdrawal time is the time interval between the last administration of the drug to the food animal and the time when the animal can be slaughtered, or products, such as milk or eggs, can be used for food, without incurring violative drug residues in the food product. This section also warns against use of the drug in animals for which a withdrawal time has not been determined.

oral distribution of drugs

some drugs are never absorbed through the GI tract it goes right to the poop. Other drugs such as gabapentin it eventually makes it way to the systemic circulation, most of the absorption or orally administered drugs occurs in the small intestines.

state law controlled drug

state law requires you to document all controlled substance use, just like the federal law. federal law and state law very for how long to keep documents. federal law is a minimum of 2 years

horse with sweating

sweating in horses is mediated by the adrenergic mechanism so if you give them a alpha agonist like xylazine, dexmedetomidine you will see CNS sedation and sweating

PH pertitsioning phenomina

tendicy for acids to accumulate or get trapped in basic environments and vs versa. This happens becuase acids become negativley charged in basic fluids and they will lose a proton compared to bases they become positively charged in acidic envirponment because they excepting a proton. Which mean you will have residues and they wont be able to leave those comparments

misbranded drug

the label of the drug does not accurately reflect the content of the bottle ex: expired drugs

Methylxanthines (caffeine, theobromine, theophylline) elicit changes similar to activation of B receptors in the heart but B blockers do not prevent their actions

theobromine is found in chocolate you try to get them to throw it up but if it is too late you give them charcoal maybe orally or maybe rectally, it is toxic

phosphodiesterase 5 inhibitors (PDE-5) -ED drugs can be used to treat pulmonary hypertension or navicular disease. how?

these are you erectile dysfunction drugs

sweat glands in horses are regulated by adrenergic mechanism. What happens when administer an alpha agonist such as xylazine

they are regulated by adrenergic mechanism like a alpha agonist to a horse like xylazine, sedation will occur, and they will start sweating because sweating is regulated by adrenergic mechanism

IM/SQ drug distribution

they will eventually be absorbed into the systemic circulation once they get in the systemic circulation, they make their way to the tissue and make their pharmacologic effects, then goes by the liver extracted and metabolized and then excreted. Most of the drugs are excreted in the urine, some is excreted in the stool, but the majority is in the urine

IV drug distribution

this goes directly into the systemic circulation since you use a needle to put it directly there, there is no absorption with IV administer drugs

USPNF

this has quality standards so make sure you buy a drug with this type of label on it

A drug is 95% plasma protein bound. What does that mean to you?

this is a good thing and a bad thing. this is a good thing like medication like NSAIDS. in general, if a drug is highly plasma protein bound it is a bad thing because the drug is bound to albumin means it can't elicit its pharmacological effect. Eventually it will dissociate but it will take time, they tend to have a long duration of action so you can give an additional dose to counteract with the binding of the initial dose since the additional dose it unbound it can go elicit its pharmacological effect, its also a positive thing ti ensure the drug gets to its designated tissue do to the bind of albumin

The Animal Medicinal Drug Use Clarification Act of 1994

this is federal and state requirements as well The Animal Medicinal Drug Use Clarification Act (AMDUCA) enabled veterinarians for the first time to use a human or animal drug in an extralabel manner under certain conditions. Prior to the enactment of the AMDUCA of 1994, the FFDCA prohibited veterinarians from prescribing new animal drugs for any indications other than the specific conditions of use on the approved labeling. This extralabel use restriction precluded veterinarians from using an approved new animal drug for an unapproved animal species, for an unapproved indication, or for an approved species at dosage levels higher than that stated on the label. Prior to 1994, the use of human drugs for treating animals was also illegal. In 1996, Title 21 of the CFR was amended to add part 530, entitled Extra-label Drug Use in Animals. This action served to implement AMDUCA to permit veterinarians to prescribe extra label uses of certain approved animal and human drugs to treat animals under certain conditions. These regulations gave veterinarians the flexibility to meet patient needs in the practice of veterinary medicine. Under AMDUCA, the key constraints are that any extralabel use must be by or on the order of a veterinarian within the context of a veterinarian-client-patient relationship; the use must not result in violative residues in food-producing animals; and certain listed compounds are prohibited from extralabel use in food-producing animals. The Agency may establish safe and violative levels for residues for extralabel use and may require development of analytical methods for residue detection. If, after affording an opportunity for public comment, FDA finds that an extralabel animal drug use presents a risk to public health or that no analytical method has been developed and submitted, the Agency may prohibit the extralabel use. Neither AMDUCA nor the implementing regulations lessen the responsibility of the manufacturer, the veterinarian, and the FOOD PRODUCING to prevent risks to public health from drug residues in animal-derived foods. THERE ARE CERTAIN FOOD YOU CAN NEVER USE IN FOOD PRODUCING ANIMALS

-Trailing zeros are not acceptable in clinical writing/documents - leading zeros are acceptable in clinical writing/documents

true

EPI,NE and dopamine are endogenous catecholamines

true

true/false; patients with renal failure/dysfunction will have changes to PK parameters of T 1/2, clearance and Vd resulting in the need to change drug dosing/intervals

true

morphine, hydromorphone and fentanyl are full mu agonist

true they bind the receptors very tightly

true/ false; patients can develop tolerance to; opiates or albuterol as well as other drugs

true they can develop tolerance to other drugs

Atropine blocks muscarinic receptors

true this is a typical muscarinic blocker it is an antidote to organophosphate poisoning

Epi is a mixed a-B receptor agonist

true when patient is having a anaphylactic shock they are having a profound histamine which is a potent bronchoconstrictor and a vasodilator in the periphery, they can pass out dur to this since blood pressure is low and they are having trouble breathing

buprenorphine is a partial agonist at mu receptors

true, it is about 25 times potent then morphine but less efficacious because it is only partially binded

Acepromazine( a phenothiazine can decrease BP by blocking the interaction of NE with adrenergic receptor sites in blood vessels.

true, some vets won't use this because of the significant decrease in blood presser, heart rate etc you can use atropine to increase the heart rate

true/false; pentobarbital solution can be administered intraperitoneal when needed

true, you can use this route when a animal is dehydrated another route is intracardiac

DEA forms 106 when do you use it?

use this to report any type of theft of drugs — must also file a police report

thalidomide disaster

used in pregnant women to help with anxiety and given to women in first trimester. focal milia which is the absence of long bone formation it caused deformed babies

what is first pass metabolism. when is it clinically significant? how do you by-pass it?

when the drug goes straight to the liver, and it get destroyed so it doesn't get absorbed through the body. (The liver enzymes quickly start to degrade the drug) you can get around that but putting the drug sublingual, buccal, 1 inch of the rectum

state label

when you put a label on something, you are dispensing on a drug you are labeling it a state label

Recall the definitions of; loading dose, maintenance dose

with some patients you have to give a patient a loading dose meaning a much higher dose, more frequently and even earlier on in a therapeutic plan to get a high enough therapeutic concentration to start eliciting pharmacologic reaction, for example you need to control some seizures, so you give the patient potassium bromide at a higher dose in that dog for the first 5 days the I will back off to a maintenance dose, you can also do this with antibiotics. so, you use loading dose to rapidly achieve an affective an effective plasma concentration then you back off to a maintaining dose to maintain that

loading dose (DL) and Maintenace dose

with some patients you have to give a patient a loading dose meaning a much higher dose, more frequently and even earlier on in a therapeutic plan to get a high enough therapeutic concentration to start eliciting pharmacologic reaction, for example you need to control some seizures, so you give the patient potassium bromide at a higher dose in that dog for the first 5 days the I will back off to a maintenance dose, you can also do this with antibiotics. so, you use loading dose to rapidly achieve an affective an effective plasma concentration then you back off to a maintaining dose to maintain that

what is the only reason you would give a food animal compounds drug in food animals

you can compound drugs in Food animals to treat toxic tosis only such as lead poisoning, copper poising, it is common in cattle to get lead poising by paint, eating batteries, getting hardware disease etc. EDTA (Ethylenediamine tetraacetic acid) you can compound for this particular toxic tosis such as lead poisoning

Prescribing Controlled Substances

you must keep records and it is also prescription drugs A veterinarian who administers, dispenses, or prescribes controlled substances in the course of his practice MUST register with the Drug Enforcement Authority (DEA). This requires submission of an application, which may be obtained from the DEA. Practitioners must have a separate registration for every practice site employed. State regulations also must be followed, and practitioners must contact their state authorities to determine the requirements. Some states have stricter regulations that the Federal drug schedules. Veterinarians can find out more about the DEA drug schedules and handling of controlled substances in their practice by viewing the DEA web site (see: http://www.deadiversion.usdoj.gov/schedules/). Prescribing controlled substances requires submission of appropriate forms and maintaining records for controlled substances. Documentation must be made in the patient's medical record of all controlled substances administered, and such records must be stored in a readily retrievable fashion for 3 years. Appropriate entries must be made for waste or disposal of unused portions of controlled substance and witness is required for disposal. Records must be kept of all controlled substances dispensed, and such records must be stored in a readily retrievable fashion for 3 years. While the law does not specifically require a dispensing record separate from the medical record, a separate recordkeeping system provides more readily retrievable dispensing records than does the patient's medical record. A separate dispensing log does NOT replace the need to document dispensing of drugs in the medical record because these drugs are still restricted to the order of a licensed practitioner. It is also recommended that Schedule II dispensing records be maintained separately from other records.

Chemical Forces and Drug Binding

Several chemical intermolecular forces such as ionic bonds, hydrogen bonds, and Van der Waals forces may be involved in reversible binding of the drug to the receptor. In contrast, drug-receptor interactions involving covalent bond formation (very tight) are generally irreversible. Covalent binding to receptors is relatively rare. However, covalent binding is more frequent for drugs acting on enzymes. COX-1 inhibitors are generally reversible, although aspirin acts as a noncompetitive inhibitor of platelet COX-1 through a covalent binding mechanism. This is achieved by irreversible acetylation and explains the duration of the action of aspirin on blood coagulation. As platelets have no nucleus, the effect of aspirin is reversed by the production of new platelets. Omeprazole (a proton pump inhibitor) is another example of irreversible binding to an enzyme (H+,K+- ATPase). Drugs that bind covalently to DNA (alkylating agents) are extensively used as anticancer drugs. Since many drugs contain acid or amine functional groups that are ionized at physiological pH, ionic bonds are formed by the attraction of opposite charges in the receptor site. Ionic bonds are the strongest noncovalent bonds. The attraction of opposite charges is brought about by polar-polar interactions as in hydrogen bonding. Although this electrostatic interaction is weaker than the ionic bond, an important feature of hydrogen bonding is the structural constraint. Thus the formation of hydrogen bonds between a drug and its receptor provides some information about the three-dimensional structure of the resulting complex. The same forces are responsible for the shape of the protein and for its binding properties, so shape influences binding and, in turn, binding can influence protein shape. The ability of protein to change shape is called allostery

Other Problematic Abbreviations

Some drugs, such as insulin, are measured in units, abbreviated "U." One unit equals 0.01 milliliter, or said another way, there are 100 units in 1 milliliter. Many people have died from tenfold insulin overdoses when the abbreviation "U" (for units) was misread as a zero in a prescription, especially when the "U" closely followed a number. For example, "10U" for "10 units" can easily be misread as "100 units," resulting in a patient receiving ten times the intended dose. Also, the abbreviations "mcg" or "µg" (for microgram, or 1/1000 of a milligram) can be mistaken for "mg" (for milligram), creating a 1000-fold overdose. Despite the under-reporting of medication errors to CVM, it is known that similar mistakes also occur in veterinary medicine.

Define/ describe determinants of distribution

Some organs have unique anatomic barriers to xenobiotic penetration. The classic and most studied example is the blood-brain barrier, which has a glial cell layer interposed between the capillary endothelium and the nervous tissue (illustrated nicely in Figure 9.4). In the schematic membrane scheme depicted in Figure 2.2, this amounts to an additional lipid membrane between the capillary and target tissue. Only nonionized lipid-soluble compounds can penetrate this barrier. Similar considerations apply to ocular, prostatic, testicular, synovial, mammary gland, and placental drug or toxicant distribution. In addition, pH partitioning phenomenon also may occur since the protected tissue (e.g., cerebrospinal fluid) may have a lower pH than the circulating blood plasma. Chemicals may also distribute into transcellular fluid compartments, which are also demarcated by an epithelial cell layer. These include cerebrospinal, intraocular, synovial, pericardial, pleural, peritoneal, and cochlear perilymph fluid compartments. A few tissues possess selective transport mechanisms that accumulate specific chemicals against concentration gradients. For example, the blood-brain barrier possesses glucose, l-amino acid, and transferrin transporters. If the toxicant resembles an endogenous transport substrate, it may preferentially concentrate in a particular tissue. Recent work with the blood-brain barrier has demonstrated that some of these tissues also possess drug efflux transport processes that remove drug from the protected sites. Two such processes are P-glycoprotein associated with multidrug resistance (MDR) and the weak organic acid cell-to-blood efflux systems. P-glycoprotein is a member of the so-called ATPbinding cassette proteins that include the cystic fibrosis transmembrane regulator and the sulfonyurea-sensitive ATP-dependent potassium channel. Drugs such as vinblastine, vincristine, or cyclosporine, which have the proper physiochemical characteristics (high lipophilicity) to enter the brain, do not achieve effective concentrations because of this active efflux mechanisms. This transport system has recently been shown to cause the unique breed sensitivity of Collies to ivermectin toxicity. These transporters are also responsible for decreased bioavailability of some drugs due to active pumping of absorbed drug back into the intestinal lumen. A number of drugs also inhibit P-glycoprotein transport (e.g., ketoconazole, cyclosporine), which forms the basis for some complex drug-drug interactions. Similar processes and transport systems for peptides and other compounds are also found in other organs (e.g., liver). Chapter 50 in this text should be consulted for further details on Pglycoprotein.

Physiological Determinants of Distribution

Some organs have unique anatomic barriers to xenobiotic penetration. The classic and most studied example is the blood-brain barrier, which has a glial cell layer interposed between the capillary endothelium and the nervous tissue (illustrated nicely in Figure 9.4). In the schematic membrane scheme depicted in Figure 2.2, this amounts to an additional lipid membrane between the capillary and target tissue. Only nonionized lipid-soluble compounds can penetrate this barrier. Similar considerations apply to ocular, prostatic, testicular, synovial, mammary gland, and placental drug or toxicant distribution. In addition, pH partitioning phenomenon also may occur since the protected tissue (e.g., cerebrospinal fluid) may have a lower pH than the circulating blood plasma. Chemicals may also distribute into transcellular fluid compartments, which are also demarcated by an epithelial cell layer. These include cerebrospinal, intraocular, synovial, pericardial, pleural, peritoneal, and cochlear perilymph fluid compartments. A few tissues possess selective transport mechanisms that accumulate specific chemicals against concentration gradients. For example, the blood-brain barrier possesses glucose, l-amino acid, and transferrin transporters. If the toxicant resembles an endogenous transport substrate, it may preferentially concentrate in a particular tissue. Recent work with the blood-brain barrier has demonstrated that some of these tissues also possess drug efflux transport processes that remove drug from the protected sites. Two such processes are P-glycoprotein associated with multidrug resistance (MDR) and the weak organic acid cell-to-blood efflux systems. P-glycoprotein is a member of the so-called ATPbinding cassette proteins that include the cystic fibrosis transmembrane regulator and the sulfonyurea-sensitive ATP-dependent potassium channel. Drugs such as vinblastine, vincristine, or cyclosporine, which have the proper physiochemical characteristics (high lipophilicity) to enter the brain, do not achieve effective concentrations because of this active efflux mechanisms. This transport system has recently been shown to cause the unique breed sensitivity of Collies to ivermectin toxicity. These transporters are also responsible for decreased bioavailability of some drugs due to active pumping of absorbed drug back into the intestinal lumen. A number of drugs also inhibit P-glycoprotein transport (e.g., ketoconazole, cyclosporine), which forms the basis for some complex drug-drug interactions. Similar processes and transport systems for peptides and other compounds are also found in other organs (e.g., liver). Chapter 50 in this text should be consulted for further details on Pglycoprotein.

Tissue Barriers to Distribution

Some organs have unique anatomic barriers to xenobiotic penetration. The classic and most studied example is the blood-brain barrier, which has a glial cell layer interposed between the capillary endothelium and the nervous tissue (illustrated nicely in Figure 9.4). In the schematic membrane scheme depicted in Figure 2.2, this amounts to an additional lipid membrane between the capillary and target tissue. Only nonionized lipid-soluble compounds can penetrate this barrier. Similar considerations apply to ocular, prostatic, testicular, synovial, mammary gland, and placental drug or toxicant distribution. In addition, pH partitioning phenomenon also may occur since the protected tissue (e.g., cerebrospinal fluid) may have a lower pH than the circulating blood plasma. Chemicals may also distribute into transcellular fluid compartments, which are also demarcated by an epithelial cell layer. These include cerebrospinal, intraocular, synovial, pericardial, pleural, peritoneal, and cochlear perilymph fluid compartments. A few tissues possess selective transport mechanisms that accumulate specific chemicals against concentration gradients. For example, the blood-brain barrier possesses glucose, l-amino acid, and transferrin transporters. If the toxicant resembles an endogenous transport substrate, it may preferentially concentrate in a particular tissue. Recent work with the blood-brain barrier has demonstrated that some of these tissues also possess drug efflux transport processes that remove drug from the protected sites. Two such processes are P-glycoprotein associated with multidrug resistance (MDR) and the weak organic acid cell-to-blood efflux systems. P-glycoprotein is a member of the so-called ATPbinding cassette proteins that include the cystic fibrosis transmembrane regulator and the sulfonyurea-sensitive ATP-dependent potassium channel. Drugs such as vinblastine, vincristine, or cyclosporine, which have the proper physiochemical characteristics (high lipophilicity) to enter the brain, do not achieve effective concentrations because of this active efflux mechanisms. This transport system has recently been shown to cause the unique breed sensitivity of Collies to ivermectin toxicity. These transporters are also responsible for decreased bioavailability of some drugs due to active pumping of absorbed drug back into the intestinal lumen. A number of drugs also inhibit P-glycoprotein transport (e.g., ketoconazole, cyclosporine), which forms the basis for some complex drug-drug interactions. Similar processes and transport systems for peptides and other compounds are also found in other organs (e.g., liver). Chapter 50 in this text should be consulted for further details on Pglycoprotein.

Submissions

Sponsors are not required to submit study protocols for review but do so voluntarily. If CVM concurs with the submitted protocol CVM is agreeing that the protocol design, execution plans, and data analyses are adequate to achieve the objectives of the study. If CVM does not concur, a letter will be given to the sponsor with as much detail as possible considering the quality and level of detail of the protocol submission to include a succinct assessment of the protocol. This response will also state whether the Agency agrees, disagrees, or lacks sufficient information to reach a decision. Protocols should be well-written, clear, concise, and consistent across all sections so the investigator has a document outlining the study methodology and procedures. Data collection forms (e.g., case report forms, owner consent forms) should be included with the protocol and referenced in the section of the protocol where they are discussed. Relevant standard operating procedures (SOPs) for laboratory studies related to the collection of data should be appended to the protocol or an adequate description of the procedure should be incorporated into the protocol (for example, SOPs for describing parasite collection for anthelmintic studies or SOPs for culture and sensitivity microbiological procedures). If unsure, the sponsor should contact CVM to discuss which, if any, SOPs should be included with the protocol.

Protocol Development Meetings

Sponsors can request the scheduling of a protocol development meeting to discuss the specific details of a protocol. CVM strongly encourages a protocol development meeting for novel indication(s), novel products, and complex study designs. When requesting a protocol development meeting, sponsors should consider the timing of the meeting in relation to the submission of the protocol and any additional supportive information that may be needed.

Drug Experience Reports

Sponsors holding approved new animal drug applications are responsible for establishing and maintaining records concerning experience with the drug and Type A Medicated Articles containing the drug and for making reports of those experiences (21 CFR 514.80). Sponsors must file DERs within 30 days of the reporting period. After the initial approval, the first two reporting periods are at 6-month intervals, after which the reports are to be filed on an annual basis on the anniversary date of the approval. The DER submission includes: unpublished reports of clinical or other animal experience, studies, investigations or tests conducted or reported to the applicant; experience, investigations, or studies involving the physical or chemical properties of the animal drug;copies of labeling that accompany the drug and copies of promotional labeling; advertising for drugs that are labeled for use by or on the order of a licensed veterinarian; quantities of the drug distributed to facilitate assessment of adverse effects; summary of reports of increased frequency of adverse drug experience (ADE)(See Section Adverse Drug Experience Reports); mix-ups with the new animal drug or its labeling; changes or deterioration of the new animal drug or failure of a batch to meet specifications; unexpected side effects, injury, toxicity, sensitivity reaction, or unexpected incidence or severity of side effects associated with chemical use irrespective of attribution to the new animal drug; failure of new animal drug to exhibit expected pharmacological action.

All Other Information (AOI)

The All Other Information technical section includes all information pertinent to the review of safety and effectiveness received or otherwise obtained by the applicant from any source (see 21 CFR § 514.1(b)(8)(iv)). The AOI technical section is usually submitted to the CVM ONADE Target Animal Division when the last major technical section is submitted for review and contains information from any investigations, foreign marketing, and scientific literature, and any other data that were not already submitted by the sponsor as part of a major technical section. This information should be comprehensive and balanced and include favorable and any unfavorable literature. Although this technical section is submitted towards the end of the drug approval process, the sponsor should also submit AOI with each technical section. For example, the effectiveness technical section would include not only dosage characterization and substantial evidence data but also any AOI available at that time. Then when the final AOI technical section is submitted, it would contain only new information identified since the Effectiveness technical section was considered complete.

Chemistry, Manufacturing, and Controls technical sections

The Chemistry, Manufacturing, and Controls technical section is one of the most important as it establishes the identity, strength, and purity of the product as well as the safeguards, unique to approved drugs, that the product will remain the same batch to batch when in commercial production. This enables the user of the product to be able to rely on the data generated in the development of the product to continue to represent the established safety and effectiveness of the marketed product. Several pivotal considerations go into the evaluation of the chemistry and manufacturing of a new animal drug product. These considerations are intended to ensure the quality and performance of the product, both prior to and subsequent to marketing. CVM requires that sponsors provide the information needed to ensure that each lot of the product released to consumers performs in a consistent manner, and that consumers have the necessary information with regard to product storage conditions so that product quality and performance are maintained (21 CFR §514.1). A full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packaging of the new animal drug must be provided in the new animal drug application. This description should include full information with respect to any new animal drug in sufficient detail to permit an evaluation of the adequacy of the described methods of manufacture, processing, and packing, and the described facilities and controls. This information is evaluated by CVM's Division of Manufacturing Technologies to determine the identity, strength, quality, and purity of the new animal drug. Information is also needed with regard to the methods used in the synthesis, extraction, isolation, or purification of any new animal drug and the precautions being taken to ensure proper identity, strength, quality, and purity of the raw materials, whether active or not. Sponsors must provide CVM with the instructions used in the manufacturing, processing, packaging, and labeling of each dosage form of the new animal drug, and precautions being taken to ensure batch-to-batch product uniformity. To ensure adequate performance as the product ages, the sponsor also must conduct studies of the stability of the new animal drug in the final dosage form. Expiry dates represent the duration of time for which product quality and performance can be assured if the product is stored in accordance with label recommendations. The time for expiry is based upon extensive stability testing that is conducted by the drug sponsor on the product intended for marketing, and these data are evaluated by the Division of Manufacturing Technologies at CVM.

Pesticides

The Environmental Protection Agency regulates pesticides (including preparations for use on inanimate objects, rodenticides, and most insecticides) are regulated by the EPA under the authority of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The FDA and EPA work together through an informal agreement to determine whether a product will be regulated as an animal drug or a pesticide.

Laws, Regulations, and Guidance

The FDA is authorized by the US Congress to implement certain laws. For example, the predominant statutory authority for FDA to regulate animal drugs is the Federal Food, Drug, and Cosmetic Act. Other laws, such as the Environmental Policy Act, are also used by the FDA. The FDA further interprets these laws by promulgating(promote or make widely known) federal regulations. These regulations have the force of law and are used to further ensure that the intent of Congress is followed. These regulations are published in the Code of Federal Regulations (CFR). The FDA will often issue other documents, known as guidance, that provide the Agency's current thinking on a particular subject. These guidance documents are not legally binding on the Agency or a drug sponsor but are helpful in describing to a sponsor how to approach addressing a statutory(required) requirement.

Animal Drugs Intended for Minor Use/ Minor Species

The Minor Use and Minor Species Animal Health Act of 2004 (the MUMS Act) was enacted to increase the availability of new animal drugs for minor species and for minor uses, while still ensuring appropriate safeguards for animal and human health. The MUMS Act provided for the establishment of the Office of Minor Use and Minor Species Animal Drug Development (OMUMS). OMUMS is responsible for overseeing the development and legal marketing of new animal drugs for minor uses (disease conditions that are rare) in major species (cattle, swine, chickens, turkeys, dogs, cats, and horses) and for minor species that fall under the category of "all other animals", including sheep, goats, game birds, emus, ranched deer, alpacas, llamas, deer, elk, rabbits, guinea pigs, pet birds, reptiles, ornamental and other fish, shellfish, wildlife, zoo animals, aquarium animals, and bees. Because the markets are small and profit margins low for new animal drugs intended for minor uses in major species or for minor species, there are often insufficient economic incentives to motivate sponsors to develop the data necessary to support FDA approvals. In addition, some minor species populations are too small or their management systems too diverse to make it practical to conduct traditional studies to demonstrate safety and effectiveness. Consequently, manufacturers have not, in many cases, been willing to fund research to collect these data. Accordingly, very few new animal drugs intended for minor uses or for minor species have been approved and are legally marketed. The limited availability of approved new animal drugs intended for minor uses or minor species, has limited the availability of options for treating these sick animals. In many cases, the choices are to leave a sick animal untreated or to treat the animal with an unapproved drug. Failure to treat sick animals appropriately may increase public health hazards. For example, the transmission of disease from animals to humans or the shedding of disease-producing organisms by untreated animals into the environment may increase health risks to humans as well as other animals. Treating an animal with an unapproved drug introduces questions of effectiveness and safety to the animal, to the environment, and to the public (e.g., human food safety). The MUMS legislation modifies provisions of the FFDCA in three key ways, providing for:

The NADA or ANADA Number and FDA Approval Statement:

The NADA or ANADA number can be used for searching the FDA/CVM website or for reporting product-specific adverse reactions. The presence of this section ensures the practitioner that they are using an approved new animal drug.

Presubmission Conference

The Phased Review process starts with a meeting or series of meetings known as the presubmission conference. This meeting is very important for the success of the product development. During this meeting the sponsor provides scientific and technical information about their product and the proposed intended use(s) for their product. The sponsor outlines the safety and effectiveness issues that they perceive need to be addressed and how they intend to address them. CVM discusses these development plans with the sponsor leading to an understanding of the items that must be addressed for a successful development plan. After the presubmission conference, a sponsor will work on each of the parts of the application or technical sections. The technical sections are target animal safety, effectiveness, human food safety, manufacturing chemistry, environmental impact, labeling, and all other information. Outcomes of this conference will be documented in a memorandum of conference (MOC) as specified in 21 CFR 514.5.

Veterinary Biologics

The US Department of Agriculture, Animal and Plant Health Inspection Service, Veterinary Services, Veterinary Biologics regulates veterinary biologics (such as vaccines, antitoxins, and diagnostics that are used to prevent, treat, or diagnose animal diseases) under authority of the Virus Serum Toxin Act of March 4, 1913. The FDA and USDA work together through a Memorandum of Understanding to determine whether a product will be regulated as an animal drug or as a veterinary biologic. this is not regulated by the FDA becuase they are not considered drugs

Product Labeling

The ability to interpret and understand drug labels is essential in ensuring that use of a particular drug achieves the intended outcome and minimizes unintended effects. The product labeling is the avenue through which CVM communicates instructions about product use and storage conditions to veterinarians, as well as communicating the benefits and risks associated with the use of a drug product. Section 201K of the FFDCA defines "label" as a display of written, printed, or graphic matter upon the immediate container of any article. A drug's "labeling" includes all labels and other written, printed, or graphic matter, such as package inserts, on the drug, its containers or wrappers or accompanying the drug. Labeling information is derived from studies submitted by the pharmaceutical sponsor to the FDA to support new animal drug approval and is developed as a collaboration between FDA and the drug sponsor. Throughout the product label, the FDA provides the practitioner with a thorough understanding of the benefits and risks associated with the use of a drug product in the animal patient. The concept of "safe use" includes safety to the animal patient, safety to the person administering the product, the safety of food derived from the treated animal, and environmental safety issues associated with use or disposal of the product. Safety information on the labeling can be derived from studies conducted by the pharmaceutical sponsor, studies from peer reviewed scientific literature, or from extrapolation from human drug labeling information that reasonably applies to the target species. Safety information is provided throughout the package insert under several different headings, including Contraindications, Warnings, Precautions, Adverse Reactions, and Animal Safety. The labeling is evidencedbased information, and does not represent opinions or conjecture. Therefore, for the practitioner to fully understand how the animal drug will perform, the practitioner should become familiar with all sections of the package insert to better understand both the risks and benefits associated with use of the product. The safety information can be viewed from the perspective of a hierarchy of severity, with Contraindications being the most serious, followed by Warnings and Precautions. The Animal Safety section is generally derived directly from laboratory target animal safety studies. The Adverse Reactions section is developed directly from the preapproval field effectiveness studies and the postapproval experience after the drug is marketed to the larger population. The Contraindications, Warnings, and Precautions statements can be modified by new findings from the postapproval surveillance of product use. Typical sections/information found on a package insert

Aerosols and Particulates

The absorption of aerosols and particulates is affected by a number of physiological factors specifically designed to preclude access to the alveoli. The upper respiratory tract, beginning with the nose and continuing down its tubular elements, is a very efficient filtering system for excluding particulate matter (solids, liquid droplets). The parameters of air velocity and directional air changes favor impaction of particles in the upper respiratory system. Particle characteristics such as size, coagulation, sedimentation, electrical charge, and diffusion are important to retention, absorption, or expulsion of airborne particles. In addition to these characteristics, a mucous blanket propelled by ciliary action clears the tract of particles by directing them to the gastrointestinal system (via the glottis) or to the mouth for expectoration. This system is responsible for 80% of toxicant lung clearance. In addition to this mechanism, phagocytosis is very active in the respiratory tract, both coupled to the directed mucosal route and via penetration through interstitial tissues of the lung and migration to the lymph, where phagocytes may remain stored for long periods in lymph nodes. Compared to absorption in the alveoli, absorption through the upper respiratory tract is quantitatively of less importance. However, inhaled toxicants that become deposited on the mucous layer can be absorbed into the myriad of cells lining the respiratory tract and exert a direct toxicological response. This route of exposure is often used to deliver pharmaceutics by aerosol. If a compound is extremely potent, systemic effects may occur. The end result of this extremely efficient filtering mechanism is that most inhaled drugs deposited in nasal or buccal mucous ultimately enter the gastrointestinal tract. This can best be appreciated by examining the respiratory drainages depicted in Figure 2.1. Therefore, the disposition of aerosols and particulates largely mirrors that of orally administered drugs Nasal administration is a preferred route for many inhalant medications in humans. In these cases, great care is made to deliver aerosols of the specific size for deposition on the nasal mucosa and upper respiratory tract. The bioavailability of these compounds is assessed using the techniques developed for other routes, although a local effect is often desired. The problems with this strategy are the attainment of an accurately delivered dose and the inactivation and binding of administered drug by the thick mucous blanket. Drugs delivered by this route usually have a wide therapeutic window and large safety index. The final point to consider relates to some specific peculiarities of nasal absorption. In the region of the olfactory epithelium, there exists a direct path for inhaled compounds to be absorbed directly into the olfactory neural tissue and central nervous system, thereby bypassing both the systemic circulation and the blood-brain barrier. The mass of drugs involved in this uptake process is very small and thus would not affect a pharmacokinetic analysis. However, this route has obvious toxicological significance and unfortunately has not been carefully studied in veterinary species.

Drug Affinity, Efficacy and Potency

The concentration-effect relationship is determined by two features of the drug-receptor interaction, namely drug affinity and drug efficacy. The affinity of a drug is its ability to bind to a receptor. Affinity is determined by the chemical structure of the drug and minimal modification of the drug structure may result in a major change in affinity. This is exploited to discover new drugs. Affinity determines the concentration of drug required to form a significant number of drug-receptor complexes that in turn are responsible for drug action. The numerical representation of affinity for both an agonist and an antagonist is the constant of affinity, denoted by Ka (dimension M−1 , i.e., liter per mole). A Ka of 107M−1 means that one mole of the ligand must be diluted in 107 liters of solvent to obtain a concentration of the free ligand able to saturate half the maximal binding capacity of the system. The reciprocal of Ka is the equilibrium dissociation constant of the ligand-receptor complex, denoted by Kd (dimension M i.e., mole per liter). A Kd of 10−7M means that a free ligand concentration of 10−7 mole per liter is required to saturate half the maximal binding capacity of the system. The lower the Kd value of a drug, the higher the affinity for its receptor. The generation of a response for the drug-receptor complex is governed by a property named efficacy. Efficacy is the drug's ability, once bound, to initiate changes that lead to the production of responses. It is a property of the ligand/receptor pair. This term is used to characterize the level of maximal response (Emax) induced by an agonist. In contrast, a pure antagonist has no intrinsic efficacy because it does not initiate a change in cell functions. This concept of efficacy is not to be confused with the drug's clinical efficacy whereby an antagonist may be fully efficacious. This is because blocking the binding of an endogenous agonist to the receptor by an antagonist may be clinically useful. Potency corresponds to the concentration of drug required to achieve a given effect. It is expressed by the EC50 (or the IC50 if the effect is an inhibition), that is the concentration of an agonist which produces 50% of the maximum possible response for that agonist (Figure 4.5). Potencies of drugs vary inversely with the numerical value of their EC50 and the most potent drug is the one with the lowest EC50. The concept of drug efficacy and potency is also used in a clinical context. Drug efficacy is the property of most interest to clinicians who are looking for the most efficacious drug. For example, it was shown using an inflammatory model in horses that flunixin was more efficacious than phenylbutazone in induced lameness (Toutain et al., 1994). For some drugs such as loop diuretics, there is actually a maximum possible effect that can be obtained regardless of how large a dose is administered and this is termed the high ceiling effect. When different drugs within a series are compared, the most potent drug is not necessarily the most clinically efficacious (Figure 4.6). For example, butorphanol is more potent but less efficacious than morphine for analgesia. Another example is glucocorticoids.

Adrenergic Receptors: Anatomical Location, Receptor Subtypes, and Signal Transduction

The concept of distinct adrenergic receptors (α and β) as determined by their relative responsiveness to specific receptor agonists was first proposed in a classic paper authored by Ahlquist (1948). There are two types of αadrenergic receptors; α1 and α2 . Each type contains specific receptor subtypes, designated as α1A, α1B, and α1D; and α2A, α2B, and α2C. There are three primary types of β-adrenergic receptors, β1 , β2, and β3, and two primary types of dopaminergic receptors, dopamine1 , D1 , and dopamine2 , D2 . α- and β-adrenergic receptors are expressed predominately at target sites innervated by postganglionic sympathetic nerves, and their placement is characterized by a substantial degree of anatomical specificity (adrenergic types and designated tissue locations are summarized in Table 6.2). β-adrenergic receptors are expressed in the heart (primarily β1 ), urinary bladder (primarily β2 and β3 ), liver (primarily β2 ), kidney (primarily β1 ); and in bronchial (primarily β2 ), uterine (primarily β2 and β3 ), and vascular (primarily β2 ) smooth muscle. It is often considered that vascular smooth muscle β2 -adrenergic receptors are not innervated by postganglionic sympathetic nerve fibers and circulating catecholamines released from the adrenal medulla are the primary endogenous agonists for these receptors. β-adrenergic receptors regulate many physiological functions including: heart rate and cardiac contractility; renin release; smooth muscle relaxation; and numerous metabolic events in adipose, skeletal muscle, and hepatic cells (see Table 6.1). α1 -adrenergic receptors are expressed in numerous tissues and organs including vascular smooth muscle, radial muscle of the iris, and smooth muscle in the genitourinary system. It is generally considered that α1 -adrenergic receptors are in close proximity to postganglionic sympathetic nerve endings, and NE released from these neurons is a primary endogenous agonist for these receptors. α2 -adrenergic receptors are expressed in a variety of cells and tissues including vascular smooth muscle; thrombocytes; endothelial cells that synthesize and release nitric oxide; CNS sites; and on the terminals of postganglionic sympathetic nerve fibers

Drug Specificity and Selectivity

The drug receptor interaction is responsible for the specificity and selectivity of drug action. When the drug acts only on a single target (enzyme, receptor, etc.), it is said to be specific. Specificity is linked to the nature of the drug- receptor interaction and more precisely to the macromolecular structure of the receptors (or enzymes). As receptors are generally proteins, the diversity in three dimensional shape required for ligand specificity is provided by the polypeptide structure. The recognition of specific ligands by receptors is based on the complementarity of the three-dimensional structure of the ligand and a binding pocket on the macromolecular target. The shapes and actions of receptors are currently being investigated by X-ray crystallography and computer modeling. Specificity is rare. Most drugs can display activity towards a variety of receptors and are more often selective than specific. For example histamine antagonists produce several effects, such as sedation and prevention of vomiting, which do not depend on histamine antagonism. Selectivity is related to the concentration range. The drug may be specific at a low concentration if it activates only one type of target, whereas several targets may be involved simultaneously (activated, inhibited, etc.) if the drug concentration is increased. This is the case with NSAIDs and inhibition of the different subtypes of cyclooxygenases (COX-1 vs. COX-2 isoenzymes) (Figure 4.7). Cortisol possesses both glucocorticoid and mineralocorticoid properties and cortisol at pharmacological dose causes unwanted side effects, such as fluid- electrolyte imbalance, which is the reason why it cannot be used as an antiinflammatory drug. This is due to the close structural relationship of the nuclear glucoreceptor (GR) and the mineralocorticoid receptor (MR). The in vivo natural ligand of the MR is aldosterone. A biological paradox is that the affinity for the MR is similar for aldosterone and cortisol, while cortisol concentration in epithelial tissues is much higher (100-1000 fold) than aldosterone concentration, raising the issue of a possible unwanted binding of cortisol to the MR. Actually, the in vivo selectivity of aldosterone for the MR exists despite its much lower concentration and is of enzymatic origin; it is determined by the intracellular metabolism of cortisol into cortisone, an inactive metabolite with a low affinity for the MR. This inactivation of cortisol is carried out by the unidirectional 11β-hydroxysteroid dehydrogenase (11βHSD) of type 2, an enzyme expressed in the epithelial aldosterone target cell. 11βHSD can be inhibited by various substances, such as furosemide and licorice. For synthetic glucocorticoids, it was desirable to separate the gluco- from the mineralocorticoid effect and selectivity for the GR (associated to the antiinflammatory effect) was obtained by structural modification of the cortisol; first an increase of the selectivity was obtained by the introduction of Δ1-dehydro configuration (as for prednisolone) and then by adding a hydrophobic residue in position 16 as a 16-α-methyl group for dexamethasone or a 16-β-methyl group for betamethasone and beclomethasone(Farman and Bocchi, 2000).

Down- and Up-Regulation

The effect of a drug often diminishes when it is given repeatedly. The term used to describe a gradual decrease in responsiveness to chronic drug administration (days, months) is tolerance. Tachyphylaxis is an acute form of tolerance. Several pharmacodynamic mechanisms (desensitization, loss of receptor, exhaustion of mediator, etc.) and pharmacokinetic mechanisms (metabolism induction, active extrusion of the drug, etc.) may explain tachyphylaxis and tolerance. For loop diuretics such as furosemide, it was observed during a chronic treatment a progressive diminution of maximal natriuretic effect. This tolerance phenomenon is known for diuretics as the braking phenomenon and results from activation of the renin-angiotensin-aldosterone system and sympathetic nervous system. Chronic stimulation of receptors with a drug results in a state of long-term desensitization, also termed down-regulation. This is often due to a decrease in the number of receptors, whereas under-stimulation leads to up-regulation due to an increase in the number of receptors and a functional supersensitivity. Receptor expression is a dynamic process with equilibrium between the synthesis and destruction of receptors. For example, the binding of a hormone such as insulin to its receptors on the surface of a cell initiates endocytosis of the hormone-receptor complex and its destruction by intracellular lysosomal enzymes. This internalization regulates the number of sites that are available for binding on the cell surface. Although receptor desensitization is generally an unwanted effect, it can provide a way of controlling certain physiological systems. For example, long-term contraception by means of gonadotropin releasing hormone (GnRH) agonist-induced downregulation of pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as deslorelin acetate is now used in dogs and cats. The advantage of this nonsurgical method is its reversibility when the treatment is discontinued.

Requirements for writing a prescription for noncontrolled substances

The elements listed below are required by law to be included on the written prescription document: Printed or stamped name, address, and telephone number of the licensed practitioner Legal signature of the licensed practitioner Name and strength of drug Directions for use Full name and address of the client Animal identification (name and/or species) Cautionary statements including, if applicable, withdrawal times for food animals Number of refills, if any

Environmental Impact

The environmental impact section must contain either an environmental assessment (EA) under 21 CFR § 25.40, or a request for categorical exclusion under 21 CFR § 25.33 (21 CFR § 514.1(b)(14)). Environmental information is submitted to comply with the National Environmental Policy Act (NEPA). Before approving a new animal drug, the agency must consider potential effects on the environment. In many cases, including those for many intended uses for minor species, a categorical exclusion from the need to provide an EA can be granted. In other cases, such as new chemical entities, and almost always in the case of a drug for an aquatic species approval, some type of EA will be necessary to support a "finding of no significant impact" (FONSI). The environmental assessment may include information on the introduction of the drug into the environment through manufacture, use, and disposal, the fate of the drug in the environment, and the effects of the drug in the environment. Environmental documentation addresses the potential impact of the manufacturing and use of the product if the application were approved. The FDA Environmental Assessment Technical Handbook is available through the National Technical Information Service to assist in determining the contents of environmental documents. GLP compliance is required for all environmental laboratory studies. Preapproval GMP inspections are used to confirm the contents of environmental documents that apply to manufacturing environmental permits and controls. The overall target of the assessment is the protection of ecosystems. The field of ecotoxicology is a complex science and gaps in data and knowledge exist. Nevertheless, CVM and the International Veterinary Cooperative and Harmonization (VICH) have developed guidance (CVM Guidance #166 dated 1/09/2006) that describes the kinds of information needed as part of the Environmental Impact Assessment (EIA) of veterinary medicinal products (VMPs). The goal of the EIA is to assess the potential for VMPs to affect nontarget species in the environment, including both aquatic and terrestrial species. It is not possible to evaluate the effects of VMPs on every species in the environment that may be exposed to the VMP following its administration to the target species. The taxonomic levels tested are intended to serve as surrogates or indicators for the range of species present in the environment. Impacts of greatest potential concern are usually those at community and ecosystem function levels, with the aim being to protect most species. However, it may be important to distinguish between local and landscape effects. There may be some instances where the impact of a VMP at a single location may be of significant concern, for example, for endangered species or a species with key ecosystem functions. These issues are handled by risk management at that specific location, which may even include restriction or prohibition of use of the product of concern in that specific local area. Additionally, issues associated with cumulative impact of some VMPs may be appropriate at a landscape level. The route and quantity of a VMP entering the environment determines the risk assessment scenarios that are applicable and the extent of the risk assessment. The EIA is based on the accepted principle that risk is a function of the exposure, fate, and effects assessments of the VMP for the environmental compartments of concern. While emission can occur at various stages in the life cycle of the product, with the exception of certain topicals or those added directly to water, most VMPs first pass through the animal to which it is administered. Generally, the most significant environmental exposure results from excretion of the active substance(s).

Compounding Guidelines for Veterinarians and Veterinary Pharmacists

The future FDA-CVM guidance on compounding (GFI #230) will define the extent of compounding from bulk substances that will be allowed after this guidance if finalized. In the meantime, there are restrictions that apply to compounding in general, and each state may have more restrictive requirements than federal law. In the meantime, compounded therapies should be prepared from a commercially available formulation, if a suitable approved product exists, and compounding pharmacies should follow existing standards and guidelines. The United States Pharmacopeia (USP), a national standard-setting organization for pharmaceuticals, lists specific standards for pharmaceutical compounding in Chapters <795> Pharmaceutical Compounding— Non-Sterile Preparations, and <797> Pharmaceutical Compounding—Sterile Preparations, (USP-NF, 2015a). One important standard for compounded preparationsis that the final strength of the finished preparation is not less than 90.0% and not more than 110% of the theoretically calculated and labeled quantity of active ingredient per unit weight or volume. There are also guidelines available for stability considerations in the chapter on Observing Products for Evidence of Instability (Chapter <1191>) (USP-NF, 2015b). Generally, the beyond-use dating (BUD) for a nonaqueous solid compounded dosage form should not be later than the time remaining until the expiration date of the shortest-dated ingredient or 6 months, which ever is shorter. For watercontaining oral formulations the beyond-use date is not later than 14 days stored at controlled cold temperatures, and for nonaqueous liquid formulations USP Chapter <795> allows for the beyond-use date to be no later than 180 days. For water-containing topical formulations, the beyond use date is 30 days at controlled room temperature. These limits may be exceeded when there is supporting valid scientific data that applies to the specific compounded formulation. The Society of Veterinary Hospital Pharmacists, an organization of academic veterinary teaching hospital pharmacists, has published a position statement on Compounding For Animal Patients that may be consulted by pharmacists or veterinarians for further guidance (http://svhp.org). Finally, veterinarians should seek the services of a Pharmacy Compounding Accreditation Board (PCAB) accredited pharmacy when prescribing compounds. Formed in 2004 by eight national pharmacy organizations, the nonprofit PCAB runs a voluntary accreditation program to ensure quality standards for compounding pharmacies. Once a pharmacy applies for PCAB accreditation, they must undergo a rigorous standards evaluation that is then validated by multiple site visits and inspections by PCAB surveyors. If a pharmacy meets the incredibly rigorous accreditation standards, a veterinarian can be assured that the pharmacy is legally and ethically impeccable and that its compounds are of the highest possible quality. At the time of this writing, PCAB has accredited more than 300 pharmacies in the United States. PCAB maintains an interactive map of accredited pharmacies in each state, list of accredited compounding pharmacies on their website, or veterinarians can contact PCAB's executive director to find an accredited pharmacy in their state. Further information regarding PCAB can be reached at: http://www.achc.org/compounding-pharmacy.html.

Indexing

The implementation of this regulation allows the FDA to add a minor species drug to an index of unapproved new animal drugs that may be legally marketed when the potential market for the drug is too small to support the costs of the drug approval process, even under a conditional approval. This provision is especially helpful to veterinarians treating zoo or endangered animals, and to owners of minor pet species such as ornamental fish or caged reptiles, birds, or mammals.

Grants:

The legislation also includes a provision that will allow Congress to appropriate funds for grants to defray the costs of safety and effectiveness testing for designated drugs.

Microbiological Effects on Bacteria of Human Health Concern:

The level of antimicrobial residues present in food should not have clinically relevant effects on the human intestinal microflora. Consideration is given to potential microbiological effects on food-borne bacteria of human health concern (FDA/CVM Guidance for Industry #144, Pre-Approval Information for Registration of New Veterinary Medicinal Products for Food-Producing Animals with Respect to Antimicrobial Resistance VICH GL27 and FDA/CVM Guidance for Industry #159 Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: General Approach to establish a Microbiological ADI VICH GL36R). FDA/CVM Guidance for Industry #152 Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern provides guidance for characterization of antimicrobial resistance selection in bacteria of human health concern associated with the use of antimicrobials in food-producing animals. FDA/CVM then uses the resulting risk estimation ranking, along with other data and information submitted in support of the NADA, to determine if the drug is approvable under specific risk management conditions.

Adverse Drug Experience Reports

The primary purpose for maintaining the FDA/CVM ADE database is to provide an early warning or signaling system for adverse effects not detected during premarket testing of FDA-approved animal drugs and for monitoring the performance of drugs not approved for use in animals. The FDA/CVM ADE reporting system depends upon the detection of an adverse clinical event by veterinarians and animal owners, the attribution of the clinical event to the use of a particular drug ("suspect" drug), and the reporting of the ADE to the manufacturer of the suspected drug or directly to FDA. Data from these ADE reports are coded and entered into the computerized FDA/CVM ADE database. The reader should consult Chapter 58 for additional discussion of these topics. It is important to remember certain caveats when using data from the FDA/CVM ADE database: For any given ADE report, there is no certainty that the suspected drug caused the adverse event. This is because veterinarians and animal owners are encouraged to report all suspected ADEs, not just those that are already known to be caused by the drug. The adverse event may have been related primarily to an underlying disease for which the drug was given, to other concomitant drugs, or may have occurred by chance at the same time the suspect drug was administered. Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk. The Division of Surveillance is responsible for consolidation of all drug experience reports, necessary referrals and consultations, and preparation of the summary reports. The Divisions' ADE scoring system uses a modified Kramer scoring system (Bataller and Keller, 1999). In this system, each sign is separated from the other signs and scored according to previous experience with the drug, alternative etiological candidates (other causes), timing of the event, whether there was an overdose, whether the reaction continued or subsided with withdrawal of the drug, and whether a reaction recurred on reintroduction of a drug. Additional information on the criteria and responsibilities for the consolidation, screening, review, and evaluation of drug experience reports is further detailed in the CVM Program Policy and Procedures Manual section 1240.3522, Review and Evaluation of Drug Experience Reports (www.fda.gov/downloads/AnimalVeterinary/ GuidanceComplianceEnforcement/PoliciesProcedures Manual/ucm046832.pdf ).) Veterinarians and animal owners are encouraged to report adverse experiences and product failures to the government Agency that regulates the product in question. To access the FDA/CVM web site for information and forms that are needed to report adverse experience with veterinary drugs, the reader is referred to: www.fda.gov. Pretesting by the manufacturer and review of the data by the government does not guarantee absolute safety and effectiveness due to the inherent limitation imposed by testing the product on a limited population of animals. CVM encourages veterinarians and animal owners to contact the manufacturer of a suspect product. Withdrawal of an approved drug may be recommended if it is determined to be unsafe or ineffective. The drug company marketing the drug product in question should be notified of the need to report an ADE for an FDA-approved animal drug. Drug company phone numbers can usually be obtained from product labeling. Technical services will ask a series of questions about the event, complete the FDA 1932 form, and forward the report to CVM. Alternatively, the report may be submitted directly to the FDA on Form 1932a. Reports should preferably include a good medical history, all concomitant drugs the animal has been given, any recent surgical procedures, and as much in the way of clinical findings as is possible. Clinical findings may include veterinary exam, clinical chemistries, complete blood counts, urinalysis, fecal exams, radiographic results, and hemodynamic data such as blood pressure, any other pressure measurements in or around the heart, and neurological assessments. "Veterinary Adverse Experience, Lack of Effectiveness or Product Defect Report" form FDA 1932a is a preaddressed, prepaid postage form that can be completed and dropped in the mail. This form may be obtained at: https://www.fda.gov/opacom/morechoices/fdaforms/ FDA-1932a.pdf or by writing to: ADE Reporting System Center for Veterinary Medicine US Food & Drug Administration 7500 Standish Place Rockville, MD 20855-2773 The CVM can also be reached by phone at 1-888-FDAVETS. The Center may occasionally need more detailed information about an incident and the reporter may be called by a CVM staff veterinarian. The identities of all persons and animals is held in strict confidence by FDA and protected to the fullest extent of the law. The reporter's identity may be shared with the manufacturer or distributor unless requested otherwise. However, FDA will not disclose the reporter's identity to a request from the public, pursuant to the Freedom of Information Act. Information requested includes the reporter's name, address, phone number, and the brand name of the drug involved. For information regarding CVM's surveillance program, the reader is referred to Chapter 58 of this textbook. Additional contact information includes: Animal biologics: vaccines, bacterins, and diagnostic kits: US Department of Agriculture 800-752-6255. Pesticides: topically applied external parasiticides: US Environmental Protection Agency 800-858-PEST

Physiological-Based Pharmacokinetic (PBPK) Modeling

The second approach to studying pharmacokinetics in animals and humans is PBPK modeling. This approach is fundamentally different than discussed above as models are constructed by defining the body as a series of anatomical organs and tissues connected by the vascular system (Figure 3.18). Data is collected in plasma as well as tissue compartments, which are defined both on the basis of overall effect on drug disposition as well as sites of action or toxicity. Data input consists of blood flows into tissues as well as the partitioning coefficients for drug between blood and tissues. The model is solved in terms of a series of mass-balance equations defining input and output from each organ, very similar to that discussed when clearance was introduced in the last chapter (Equation 2.6). Advanced software packages facilitate solving these complex equations. These models are extensively employed in the field of toxicology where data collected in laboratory animals are used to extrapolate to humans. In these cases, models may be defined in mice or rats, and then human physiological parameters inputted to estimate human disposition. The models are well suited to integrate in vitro laboratory data on toxicity or effect, as well as being able to simultaneously model parent drug and metabolite disposition. They would be ideal to model the so-called pharmacodynamic effect compartment introduced in Chapter 4. They have recently been used to study tissue residue depletion in food animals because they allow for predictions in the target tissues monitored by veterinary regulatory authorities. Similar to the ability of population models to analyze data across diverse sets of data, PBPK models can do the same in addition to detailing more physiologically realistic absorption models and incorporating in vitro data (see recent examples by Leavens et al., 2014; Lin et al., 2015). A comprehensive review detailing how PBPK models work and applications to veterinary medicine has recently been published (Lin et al., 2016).

Conditional Approval

The sponsor of a veterinary drug can ask CVM for "conditional approval," which allows the sponsor to market the drug after proving the drug is safe and establishing a reasonable expectation of effectiveness, but before collecting all of the effectiveness data needed to support a full approval. The drug sponsor can keep the product on the market for up to 5 years, through annual reviews, while gathering the required effectiveness data.

Interspecies Extrapolations

The ultimate aim of any interspecies extrapolation would be to predict drug activity or toxicity in a new species not previously studied. There are two sources of error inherent to such an extrapolation. The first is that a drug's pharmacokinetic profile (especially excretion, metabolism, and distribution) does not extrapolate across species without adjusting for some individual species characteristics. The second, which will always be problematic, is that the pharmacodynamic response of a drug may be very different between species and not at all related to pharmacokinetics. This latter concern may not be important for antimicrobial drugs since the pathogenic organisms being treated should have susceptibilities that are pathogen dependent and host independent. However, for drugs that interact with physiological functions that have species-specific receptor types and distributions, an estimate of pharmacokinetic parameters may not be sufficient to predict pharmacodynamic response. There is a wealth of empirical observations that suggest that physiological functions such as O2 consumption, renal glomerular filtration, cardiac output, etc., are not linearly correlated to the mass of an individual animal, both within and between species. That is, if one expresses any physiological function on a per kg body weight basis (e.g., GFR/kg), an isometric relationship would suggest that the parameter is constant. However, in the case of these physiological functions, such a relationship does not hold since the parameter on a mg/kg basis still is species dependent and not constant. A knowledge of body weight does not allow one to determine the value of the parameter across species with different body weights. However, if these parameters are expressed on a per unit surface area basis, many parameters such as GFR will be equivalent across species. More refined analyses suggest that the optimal scaling factor would be to a species' Basal Metabolic Rate (BMR). Empirical observations suggest that BMR is a function of (body weight in Kg) raised to the 0.75 power [GFR = ∫ −(BWkg) 0.75]; when expressed on body surface area, the exponent is 0.67. An exponent of 0.75 is also theoretically predicted if metabolic functions are based on a model where substances in the body are transported through space-occupying fractal networks of branching tubes (e.g., the vascular system) that minimize energy dissipation and share the same size at the smallest level of structure (e.g., capillaries). Whatever the mechanism, these approaches are well suited for extrapolating drug disposition across species. Equations where a parameter is related to a mathematical function (in this case, a power function) of a metric such as body weight is termed an allometric relationship. The extensive literature surrounding this question of how one "collapses" physiological parameters between species has created a field of study called allometry. Since most drug pharmacokinetic parameters are dependent upon some physiological function, they may also be scaled across species using these strategies. The method for doing this is to correlate the parameter of concern (e.g., GFR, ClB , T1/2 = most common) with body weight (BW) using the following allometric equation: Y = a (BW) b (3.83) where Y is the parameter of concern, a is the allometric coefficient and b the allometric exponent. The data is obtained using simple linear regression on log10 Y versus log10 BW, as depicted in Figure 3.23. The slope is the allometric exponent b and the intercept a. There is uniform agreement that for most physiological processes, the allometric exponent b ranges from 0.67 to 1.0. Note that if the parameter being modeled is an inverse function of a physiological process (e.g., T1/2), the exponent will be 1 − b for that process. The coefficient a is actually the value of Y for a 1.0 kg BW animal (b = 0). Numerous texts and research manuscripts deal with this topic in greater depth. There is an issue in human medicine where data is often extrapolated from small laboratory animals and dogs to larger humans, thus extrapolation error may be large. However, in veterinary medicine, one often interpolates because data are available in species of very different body masses. We recently published a large analysis of 85 drugs across multiple species that confirmed many of the factors just discussed (Huang et al., 2015). The important clinical takehome message to the veterinarian is that for equivalent effects, the dose may be greater in a smaller animal on a body weight basis. In cancer chemotherapeutics, doses are often expressed on the basis of body surface area, an adjustment that essentially compensates for the allometric exponent.

Define/describe; renal elimination

The ultimate route for drug elimination from the body is the kidney. Drugs can also be eliminated in bile, sweat, saliva, tears, milk, and expired air; however, for most therapeutic drugs these routes are generally not quantitatively important as mechanisms for reducing total body burden of drug.

Renal Elimination

The ultimate route for drug elimination from the body is the kidney. Drugs can also be eliminated in bile, sweat, saliva, tears, milk, and expired air; however, for most therapeutic drugs these routes are generally not quantitatively important as mechanisms for reducing total body burden of drug.

A valid veterinarian-client-patient relationship (VCPR)

The veterinarian has assumed the responsibility of making medical judgments regarding the health of the animal(s) and the need for medical treatment, and the client (owner or other caretaker) has agreed to follow the instructions of the veterinarian. There is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s), and/or by medically appropriate and timely visits to the premises where the animal(s) are kept. The practicing veterinarian is readily available for follow-up in case of adverse reactions or failure of the regimen of therapy.

Have a clear understanding of the VCPR definition and be able to evaluate if a short veterinary care scenario meets all 3 components of the definition.

The veterinarian has assumed the responsibility of making medical judgments regarding the health of the animal(s) and the need for medical treatment. - the client (owner or other caretaker) has agreed to follow the instructions of the veterinarian. - There is sufficient knowledge of the animal(s) by the veterinarian to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). -The veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s), and/or by medically appropriate and timely visits to the premises where the animal(s) are kept. - The practicing veterinarian is readily available for follow-up in case of adverse reactions or failure of the regimen of therapy.