Pharmacology Week #2 (Test 1)

What is intravenous administration? How fast is absorption? Ex. How quickly are IV drugs usually administered?

An injection given directly into the blood stream, bypassing the absorption process. Provides an almost immediate pharmacologic effect. Ex. Ativan Most IV drugs are administered slowly to help prevent adverse reactions.

What is intraosseous administration? Also used when? Ex. (6)

An injection given directly into the bone marrow cavity of pediatric patients through an IO infusion system. Also used in anyone that is coding, if you can't get an IV placed. Ex: Epinephrine (Adrenalin) Atropine Sodium bicarbonate Dexamethasone (Decadron) Dopamine (Intropin) Dobutamine (Dobutrex)

What is intradermal administration? How fast is absorption? Ex. What is the fluid limit for this?

An injection given into the dermal (2nd or middle) layer of the skin. Absorption doesn't usually take place or is extremely slow, usually used for skin testing. Ex. TB test Used only for small very small volumes of drugs (0.1 ml or less) primarily for diagnostic skin testing.

What is intramuscular administration? How fast is absorption? Ex. What is the fluid limit for this?

An injection given into the skeletal muscle. Absorption generally occurs more rapidly than SQ injection because of greater tissue blood flow. Ex.Diphenhydramine (Benadryl). 2-3 mL

As free drug is filtered from the blood, what happens to the bound drug? What does the rate of excretion depend on?

As free drug is filtered from the blood, bound drug is released from its binding sites into the plasma. 1. The speed of this reaction, thus giving the drug a longer half-life 2. Blood flow 3. Glomerular filtration rate (GFR) - Which is one way to estimate kidney function (GFR calculates the # of functioning glomerulus).

Short vs long half-life What can increase half-life?

Drugs with a short half-life (2-3 hours) need to be administered more often to maintain a therapeutic range than drugs with a long half-life (12 hours). A drug's half-life may be markedly lengthened in persons with hepatic dysfunction and renal disorders. This may require a reduction in drug dosage or an increased interval between doses.

How does tissue binding work with drugs that have an affinity for bones?

Drugs with an affinity for bones (e.g., tetracycline) accumulate in bone after being absorbed onto the bone crystal surface. This will do things like discolor teeth in the pediatric population, so you only want to use this as a last resort.

Why do genetic factors influence the actions of drugs?

Can alter the response of some people to a number of medications through: Inherited metabolic (enzymatic) deficiencies Altered receptor site sensitivities Abnormalities may manifest as idiosyncrasies or be mistaken for drug allergies.

What do phase II reactions involve? Phase I and phase II metabolites are usually what? Some drugs only go through what?

Phase I metabolite subsequently conjugated with endogenous groups, including glucuronides, sulfates and other hydrophilic conjugates. Phase I & II metabolites are usually inactive or at least less active. Some drugs only go through phase II metabolism.

Various disease factors (e.g., liver disease) alter the body's ability to handle many medications resulting from what? (2)

1. Decreased serum albumin levels 2. Decreased hepatic metabolism

What are two factors that affect the volume of distribution (Vd)?

1. Fat Solubility: if highly fat soluble, more drug in fat (therefore outside of plasma/central compartment), resulting in a higher Vd. 2. Protein Binding: if high degree of protein binding, more drug remains in plasma (central compartment) compared to rest of body, resulting in a lower Vd.

In order for a drug to be absorbed via passive diffusion in either the stomach or the small intestine, what three characteristics must it have?

1. Must be small. 2. Cannot have an electrical charge. 3. Must be fat soluble, or lipophilic.

What is excretion? How can a drug be excreted? Renal excretion consists of what three mechanisms?

A process that takes place in the kidneys, where toxic or inactive metabolites are excreted. A drug can be excreted in the urine unchanged or as a chemical metabolite of its previous form. 1. Passive glomerular filtration 2. Partial reabsorption 3. Active tubular secretion

For the most common cytochrome P450 enzyme <CYP3A4> , what does each letter mean?

CYP = Cytochrome P450 enzyme 3 = Family Must have > 40% identical amino acid sequence Major families in man: CYP1, 2, 3 A = Subfamily Must have > 55% identical amino acid sequence 4 = Individual enzyme in subfamily. Amino acid sequences > 97% identical.

What is cytochrome P450? How many enzymes are identified? Ex.

Cytochrome P450 is a group of isoenzymes which are involved in the metabolism of many commonly prescribed medications. Over 30, Approx. 10 used in the biotransformation process involving drugs categorized in "families". Ex. CYP3A4

What is Pharmacogenetics - Toxicology/Teratogenicity?

Decreased metabolism with increased drug levels. Use of alternate metabolic pathways with toxic metabolites. Drugs which are metabolized by enzymes with genetic variation may be two to eight times more likely to result in adverse reactions than drugs where clearance is not a function of genetics.

What type of reaction is Phase I metabolism? What does it usually involve What cell level does is mainly take place at? What type of metabolites does it form?

Degradative reaction. Introduction of a functional group. Mainly microsomal. Metabolites formed may be smaller, polar or non-polar, or active / inactive.

What does absorption involve? Absorption is faster with what? How long does absorption typically take for immediate release drugs? How does most absorption take place? What does this mean? (3)

Getting the drug from the Gut into Systemic Circulation. Faster on an empty stomach (especially if the drug is non-fat soluble), slower with food in stomach. Usually range of 20 minutes to an hour for Immediate Release drugs. Most absorption takes place via passive diffusion across a semi-permeable membrane. This means the molecules must be relatively small, neutral charge, and fairly lipid soluble.

Where does most absorption actually take place?

In the small intestine.

Why does body mass influence the actions of drugs?

Many drugs are given according to body mass (kilograms) There is an indirect relationship between body mass and the final concentration of a drug for any given dose The larger the patient, the lower the concentration The average adult dose Calculated on the basis of drug quantity that produces a particular effect in 50% of the population between the ages of 18 and 65 and who weigh approximately 150 pounds (68 kg) The administration of drugs in children is also based on body mass.

What is the pulmonary route? What is absorption like in this route? Drugs taken in this way usually produce what?

Medication administered by inhalation in the form of gas or fine mist (aerosol). Absorption into the blood stream is rapid due to large surface area and rich capillary network adjacent to alveolar membrane. Produces primarily local effects, occasionally results in unwanted systemic effects. Ex. Albuterol (local effect) Ex. Anestetic gas (systemic effect)

What is an example of a compound that can form a drug reservoir?

Phenytoin is an anti-epileptic drug that is lipid-soluble and can freely pass throughout the body. But, when bound to the plasma protein albumin, it cannot leave the bloodstream, 2/2 having a high molecular weight (creating a plasma protein binding drug reservoir). These drugs are not only a circulating drug reservoir, but they are also pharmacologically inactive. Only when these molecules detach is it possible for phenytoin to pass out of the blood and into the target tissues.

What are other barriers in patients that can occur?

Poor perfusion due to shock, PVD or ischemia (esp in diabetic patients). Abscesses.

What is the placental barrier? What are they not permeable to? What does it allow some of? What does this mean?

The membrane layers that separate the blood vessels of the mother and fetus. They are not permeable to many lipid-soluble drugs, which provides some protection to the fetus. Does allow passage of certain non-lipid-soluble drugs (steroids, narcotics, anesthetics, and some antibiotics). This means some of these drugs can affect the development of the embryo.

How does solubility effect absorption? Ex.

The more soluble the drug, the more rapidly it is absorbed. Ex. Tylenol pill will longer to break down than a liquid capsule.

Explain VOD using Vancomycin as an example

Vancomycin, has a VOD is the range of .8 L/kg. So, after we give drug, more in the blood than there is in the tissue (it's a little water soluble, doesn't like the cross membranes). This is only a population norm, so if someone weights 100 kg you expect then to have a .8 volume of distribution, but in reality everyone's composition is different, so it could be more like .4, .9 etc.

Why does pathological state influence the actions of drugs?

nausea, vomiting, anorexia, fever, dehydration, and diarrhea effects drug levels. Illness or injury and the severity of symptoms can affect the type and amount of drug needed to produce the desired effect Underlying disease processes (circulatory, hepatic, renal dysfunction) can interfere with the physiological processes of drug action and elimination

What can affect the pH of the stomach? (5)

pH of the stomach affected by stress, food, use of antacids, H2 blockers (like cimetidine - Tagamet®), or proton pump inhibitors (like omeprazole - Prilosec®).

What is the equation used to calculate the loading dose? (and define all 4 variables) What are the two variables that have been added?

(Vd)(Cp) Loading Dose = ------------------- (S)(f) Vd = Volume of Distribution Cp = Desired Concentration in Plasma after distribution S = Salt Factor (Usually 1.0) f = Bioavailability (Usually 1 for IV, < 1 for PO) 1. Bioavailability (usually 1 for IV drugs). 2. Salt Factor (which is also usually one, but can be less is part of the drug is made of salt for delivery).

In practice, what are normal serum creatinine levels? So, if showing this, makes you think what?

0.5 - 1.2. Issue: In practice, normal serum creatinine is 0.5 - 1.2. So, think kidney function is ok because the creatinine level is normal, when in reality their kidney function could be terrible.

What can a protein molecule act as? (3)

1. A carrier enzyme 2. A receptor 3. An antigenic site (a mechanism by which infectious agents alter their surface proteins to avoid the host's immune system).

List the four factors that are involved when talking about pharmacokinetics of a drug, along with a definition for each.

1. Absorption: Getting the drug into the body. 2. Distribution: How the drug moves around in the body. 3. Elimination: How to body gets rid of chemicals. 4. Metabolism: How the body chemically changes drugs to make them more water soluble or inactive.

What are four limitations of using the two previous equations to estimate renal function?

1. Assumes serum creatinine is at steady state, which isn't true all the time, like in people with acute kidney loss, their creatinine function lags behind kidney function. 2. Muscle trauma can increase creatinine. 3. Will usually overestimate with a patient such as an amputee who has decreased muscle mass. 4. Drug Interactions: Cephalosporins will show falsely elevated creatinine levels.

What are three barriers to drug distribution?

1. Blood-brain barrier: Issue for meningitic, and psyc drugs. 2. Placental barrier: Hoping something doesn't cross to fetus, so give heprin, which has a larger molecular weight, and is less likely to cross to the fetus (if the mother has had a DVT) 3. Poor perfusion

What are the three steps involved after a drug goes through first pass metabolism?

1. Drugs are eliminated by biliary excretion (via the liver, gall bladder, and bile ducts). 2. After liver metabolism, the metabolites are carried in bile and passed into the duodenum and then eliminated with the feces. 3. Some drugs are reabsorbed by the blood stream, returned to the liver, and later excreted by the kidneys.

Based on the concept of passive diffusion, explain how drugs are absorbed. (3)

1. Drugs will go down their concentration gradient, from high to low concentration, until it's even on both sides. 2. The more drug on one side of the bilayer, the faster it will cross (called concentration dependent transfer). As the concentration gradient on either side of the membrane becomes less and less, the rate of passive diffusion will also get less and less. 3. Also the more drug that is given, the faster it is going to get there.

What are the four major routes of administration?

1. Enteral - Nasogastric tubes, oral route, etc. Anything that gets into the lumen of the intestines. 2. Parenteral - IM, subcutaneous, IV, etc. Gets into the body while avoiding the digestive system. 3. Pulmonary - Given only for local effect, like respiratory meds that will only effect the pulmonary system. One of the only drugs that are the exception to this are anestetic gases that are lipid soluble. 4. Topical - Via the skin. Not absorded systemically usually, Ex. Calamine lotion for poision ivy. Can also use nicotine pathches which are made up of very small lipid soluble molecules, which will spread systemically, throughout the entire body.

What are three drugs that can be excreted by the lungs? Drugs excreted by the lungs may produce what? What are factors that can alter eliminated via the lungs? (2) Ex. (2)

1. General anesthetics 2. Volatile alcohols 3. Inhaled bronchodilators Drugs excreted by the lungs may produce an odor on the patient's breath (e.g. alcohol). Factors that can alter elimination via the lungs are rate and depth of respiration and cardiac output. Ex. Deep breathing and increased cardiac output increase pulmonary blood flow and promote excretion. Ex. Respiratory compromise and decreased cardiac output can prolong elimination of drugs through the lungs

What are the three specifc routes of administration, going from fastest to slowest acting?

1. IV is the fastest acting, but also lasts for the shortest period of time. 2. IM is the next fastest acting, but also only lasts for a relatively short period of time. 3. PO or by mouth takes much longer to absorb but is more practical in long run due to ease of ingestion and its slow release. Some drugs cannot be taken this way however due to high concentrations that may induce vomiting.

List the time it takes for each of the about routes to reach the systemic circulation, and how much of the drug will actually reach the circulation once it gets there. 1. IV 2. Endotracheal 3. IM 4. Oral

1. IV: a. Reaching systemic circulation: 100% active drug. b. Time to effect: immediate (if distributed to site of action) 2. Endotracheal: a. Reaching systemic circulation: varies usually 50%. b. Time to effect: varies, usually within a few minutes. 3. IM: a. Reaching systemic circulation: usually 100%. b. Time to effect: varies... usually 30-60 minutes. 4. Oral: a. Reaching systemic circulation: widely variable 0-100% b. Time to effect: varies... for I.R. usually 1-2 hrs.

List the order of 5 steps that take place when a drug goes through first-pass metabolism. After this process takes place, what does the drug become?

1. Ingest the drug 2. Drug goes through the digestive system 3. Drug goes through the hepatic portal system 4. Drug goes through the liver 5. Drug passes to the systemic circulation, and goes throughout the rest of the body. A metabolite.

What happens when you administer a drug sublingually? (2) Ex.

1. It rapidly dissolves in salivary secretions and is then absorbed via the oral mucosa. 2. The drug then enters the systemic circulation, initially bypassing GI fluid and the liver. (effect usually apparent within 2 minutes). Ex. Nitroglycerin for chest pain, [Nifedipine - NOT RECOMMENDED - due to causing an unsafe drop in BP]

What are the two general states the stomach can be in while taking a drug PO (by mouth)? What else will affect absorption time in the stomach?

1. Many drugs administered on an empty stomach with sufficient water (8 ounces) to ensure rapid passage into the small intestine. 2. Other drugs cause gastric irritation and are usually given with food which slows absorption. A liquid taken orally will absorb faster than a tablet that needs to first be broken down before it can be absorbed.

So, the BBB keeps what type of molecules out? (3)

1. Non lipid soluble (water soluble) 2. Too highly charged 3. Too large

What are some reasons why individuals metabolize drugs at different rates?

1. Patients with liver and renal disease and cardiovascular dysfunction are expected to have prolonged drug metabolism. 2. Infants with immature metabolic capacity and older adults with degenerative metabolic function experience delayed biotransformation. 3. May need to consider dosage reductions (particularly maintenance doses) in these patient groups. 4. If drug metabolism is delayed, drug accumulation and cumulative drug effects may occur

What are two ways that genetic can influence the cytochrome p-450 enzyme systems?

1. Reduced metabolism: Codeine is metabolized to morphine by cytochrome p-450 2D6. ~ 5 to 10% of the population does not obtain adequate analgesia with codeine. 2. Rapid metabolism Northern Europeans, multiple copies of the 2D6 gene are infrequently observed; East African populations, frequency has been reported as high as 29% of the population

What are two other factors that influence absorption?

1. The nature / thickness of the absorption surface. If a drug must only pass through a single layer of cells (intestinal epithelium) transport will be much faster, compared to if it must pass through several layers (skin). 2. The surface area. The greater the surface area of the absorbing site, the greater the absorption and the more rapid the drug effect. The small intestine offers the largest surface area, due to the presence of villi / microvilli. The stomach has a relatively small absorption surface area

What does it mean when the volume of distribution (Vd) is equal to, less than, and greater than 1.0 L/Kg?

1. Vd = 1.0 L/Kg, then concentration measured in blood shortly after IV administration = average concentration distributed throughout body (drug not overly represented in either blood/tissues/fat). 2. Vd < 1.0 L/Kg, then concentration measured in blood shortly after IV administration > average concentration distributed (more drug on average in blood than rest of body; example: gentamicin). Water soluble drugs. Too much in the blood, to little in the fat. 3. Vd > 1.0 L/Kg, then concentration measured in blood shortly after IV administration < average concentration throughout body (more drug on average in rest of body - example benzodiazepines like diazepam (Valium®)). Fat soluble drugs. To much in the fat, too little in the blood.

What is a drug reservoir? What happens as serum levels decline? What are the two general types of drug reservoirs?

A drug reservoir is when a drug may accumulate at certain locations that function as storage sites, forming reservoirs by binding to specific tissues. As serum levels decline, tissue-bound drug is released from its storage site into the blood stream. 1. Plasma protein binding drug reserviour: Hanging out in the blood. 2. Tissue binding drug reservior: Hanging out in muscle or fat tissue.

What is the "first-pass effect"?

A drug where most of it is metabolized the first time it's going through the liver has a "high first-pass effect". If little or none of it does, it has a low first-pass effect.

What is a loading dose? What would you give after a loading dose? What are loading doses based on? (2) Ex.

A large dose that temporarily exceeds the body's capacity for excretion, and rapidly establishes a therapeutic drug level at the receptor site. A smaller dose (maintenance dose) can then be administered to replace the amount of drug excreted. Loading doses are based more on the volume of distribution (of which body size is an important component) and less on capacity for excretion (e.g., renal failure). Maintenance doses are exactly the opposite. Ex. If someone is seizing, give a bolus dose of a drug to get enough of the drug into the system intrevenously, so the effect takes place ASAP.

Why do psychological factors influence the actions of drugs?

A patient's belief in the effects of a drug may influence and potentiate drug effects Tell the patient when to expect the onset of drug actions to enhance effects and to minimize frustration. For example, many IM analgesics will take 15-20 minutes to begin their actions. A placebo can have the same result as a drug if the patient believes in the desired effect Patient hostility and mistrust can diminish the perceived effects of a drug.

How does blood flow effect absorption? Ex. (2)

A rich blood supply enhances absorption (sublingual route), and a poor blood supply delays absorption (subcutaneous route). Ex. A patient in shock may not respond to IM administration, because diminished circulation decreases absorption. Ex. Also why nitroglycerine is given sublingually, in order to increase the rate of absorption.

What is passive glomerular filtration? What does the availability of a drug for glomerular filtration depend on? What isn't filtered out?

A simple process that can be measured as the glomerular filtration rate (GFR). It's the total quantity of glomerular filtrate (usually expressed in milliliters) formed each minute in all nephrons of both kidneys. The availability of a drug for glomerular filtration depends on its free concentration in plasma. Protein-bound drugs.

What is albumin manufactured by? What does this mean?

Albumin is manufactured in the liver. This means that hepatic dysfunction and other factors may result in more free drug being available for distribution to tissue sites. This can increase the free drug fraction, and cause an enhanced pharmacological response.

What is subcutaneous administration? How fast is absorption? Ex. What is the fluid limit for this?

An injection given beneath the skin into the connective tissue or fat immediately beneath the dermis. Absorption rate is usually slow and can provide a sustained effect. (slower than IM) Ex. Insulin Used only for small volumes of drugs (0.5 ml or less) that do not irritate tissue.

What is the stomach pH typically? How does this affect drug absorption? (2)

About 1.4. 1. Weakly acidic drugs (such as barbiturates) tend to remain un-ionized (uncharged) and are readily absorbed into the circulation. 2. Basic drugs (such as morphine) ionize in the stomach and are poorly absorbed.

Where does absorption begin? The rate and extent of absorption depends on what three factors?

Absorption begins at the site of administration. 1. Dosage 2. Dosage form 3. Route of administration

What are the advantages of giving a loading and a maintenance dose?

Advantage of loading and maintanence dose, get amount near the receptors very quickly, but still takes the same amount of time to get to the steady state (about 5x the half life).

After a drug has entered the circulatory system, what happens? What does the rate of distribution depend on? Lipid soluble vs lipid insoluble

After a drug has entered the circulatory system, it is rapidly distributed. The rate of distribution depends on the permeability of the capillaries to the drug molecules. Lipid-soluble drugs readily cross capillary membranes to enter most tissues and fluid compartments. Lipid-insoluble drugs require more time to arrive at their point of action.

What are 6 other factors that influence the actions of drugs?

Age Body mass Gender Pathological state Psychological factors Genetic factors

During an intraosseous administration, how are agents thought to circulate? How to fluids or drugs enter the central circulation? Time from injection to entry into the systemic circulation is though to be equal to what after giving an IO?

Agents are thought to circulate via the medullary cavity of the bone. Fluids or drugs rapidly enter the central circulation through numerous venous channels of long bones. Time from injection to entry into the systemic circulation is thought to equal that of the venous route.

What is the issue with mothers that are breast feeding?

Breast milk is acidic (pH 6.5) Basic compounds that ionize at this pH (e.g. narcotics) achieve high concentrations in this fluid Weak acids (e.g., diuretics and barbiturates) are less concentrated. Nursing mothers are cautioned against medication use Usually are advised to take prescribed medications immediately after breast feeding to diminish any risk to the infant.

What is the relationship between breastmilk and blood?????????? DOUBLE CHECK!!!!

Breastmilk is more acidic than the blood. So, basic drugs will pick up charges in the acidic breastmilk, and now they cannot leave the breast, 2/2 obtaining this charge and now not being able to cross the membrane (because the drug is no longer unionized).

What is the most common class of medications taken via the pulmonary route? What are three drugs that are given via various inhalation devices?

Bronchodilators are the most common inhalation medications. Drugs given by various inhalation devices (e.g., nebulizer) that propel agents into alveolar sacs include: a. Bronchodilators b. Steroids c. Antibiotics (tobramycin in a patient with TB) will not use for a patient that has an infection

What other 2 factors affect the rate and extent of distribution in body tissues? Generally speaking, what is the order of distribution?

Cardiac output and regional blood flow also affect rate and extent of distribution in body tissues. Generally, a drug is first distributed to organs that have a rich blood supply (heart, liver, kidneys, brain); then it enters tissue with a lesser blood supply (e.g., muscle and fat).

What is the equation for clearance? (which is how much drug is eliminated per unit time)

Clearance = Vd x Kel (units = L/hr) Represents the volume of plasma from which all drug is removed per unit time. Clt = Total Body Clearance Clt = Clrenal + Clhepatic + Clbiliary + Clother Relationship of t ½ to Vd, Kel, and Cl: T ½ = (0.693 x Vd)/Cl T ½ = (0.693 x Vd)/(Vd x Kel) T ½ = 0.693/Kel

How do you estimate renal function? (2 equations)

Cockcroft and Gault Formula in ml/min: Males = (140-age)(Lean Wgt in Kg) (72)(SrCr) Females=(0.85)x same eq as above Lean Body Wgt Estimate: Males: 50 + 2.3kg for each inch > 5 feet Females: 45 + 2.3kg for each inch > 5 feet Jelliffe Estimate (in ml/min): Males = (98 - (0.8 x (age - 20) (SrCr) Females = (0.9) x above equation Correction for Body Surface Area/Ideal Body Wgt: Patient BSA Correction for BSA: Patient BSA Result x ------------ 1.73 Correction for IBW: Patient BSA Result x ------------ 72 kg

What does the cell membrane consist of?

Consists of a lipid bilayer with protein molecules irregularly dispersed throughout

What is the biological half-life of a drug? A drug is considered gone when? When is the half-life of a drug important? Ex.

Defined as the time required to excrete half the amount of drug in the body at the time equilibrium is first established or the time required to excrete half of the total amount of the drug. A drug is considered gone from the body after 5 half-lives have passed. The half-life of a drug is important when determining the rate of administration Example: If a 1000-mg injection of ampicillin is administered and its half-life is 2 hours, 500 mg will be excreted in the first 2 hours, 250 mg (half of the remaining 500 mg) will be excreted in the second 2 hours, and so on.

What is passive reabsorption? Can be greatly influenced by what? How are weak acids excreted in alkaline vs acidic urine?

Describes reabsorption from the renal tubules by passive diffusion. Lipid soluble drugs move back into the blood, and polar and ionized drugs remain in the urine. Can be greatly influenced by the pH of the tubular urine (can vary between 5 and 8). Weak acids are excreted more readily in alkaline urine and more slowly in acidic urine. Weak acids are ionized (water soluble) in alkaline urine but non-ionized (lipid soluble) in acidic urine The reverse is true for weak bases.

Why does gender influence the actions of drugs?

Differences in drug effects on men and women result partially from size differences Women are usually smaller than men, so they may have a higher concentration of drugs administered without consideration of size Differences in the relative proportions of fat and water in the bodies of men and women can also produce variations in drug distribution.

What is distribution? What is it based on? Ex.

Distribution is the process of getting a drug from the blood stream to the various tissues of the body and ultimately to its site of action. It's based on lipid solubility of the drug and degree of protein binding, drugs may have a higher concentration in the plasma or in the peripheral tissues. Ex. Some drugs slowly distributed (water soluble), and some drugs quickly distributed (fat soluble).

When may drug effects be seen? Why would this take place?

Drug effects may be seen days after the last ingestion. The released drug maintains significant serum drug levels and may permit a sustained release, allowing continued pharmacological effect at the receptor site.

What is a drug protein complex? Ex. What does the free or unbound drug exist in? What happens as the free drug is eliminated from the body? What happens as the free drug is eliminated from the body? When measuring a drug, what are we measuring?

Drug protein complex = Free drug + protein. Ex. For example, if a patient taking warfarin (Coumadin) is given quinidine (Duraquin), the quinidine may displace the protein-bound warfarin, causing warfarin toxicity, manifested by severe hemorrhage. The free drug (unbound drug) exists in equilibrium with the protein bound fraction and is the only portion of the drug that has biological activity. As the free drug is eliminated from the body, the drug protein complex dissociates, so more drug is released to replace the free portion that was metabolized or excreted. The entire drug protein complex.

What is the enteral route? This route is both the ___(3)___, but also the ___(2)_____ due to ___________ including _____(3)____.

Drugs administered along any portion of the GI tract. Safest, most convenient, and economical route Least reliable and slowest route due to frequent changes of the GI environment Food contents Emotional state Physical activity

When tends to happen when drugs are administered in high concentrations?

Drugs administered in high concentrations tend to be absorbed more rapidly than those administered in low concentrations.

What is the topical route? What type of drugs are absorbed via this route? Why should you only apply topical drugs to intact skin? What promotes topical drug absorption?

Drugs applied topically to skin and mucous membranes that are rapidly absorbed to produce a local effect. Only lipid-soluble compounds are absorbed through the skin, and the skin acts as a barrier to most water-soluble compounds. Only intact skin surfaces should be used to prevent systemic effects. Massaging skin promotes drug absorption, due to capillary dilation and increased local blood flow.

How does the route of drug administration effect drug absorption?

Drugs are usually administered for local or systemic effects. Some drugs given locally produce local and systemic effects if they are partly or entirely absorbed. Other drugs are applied for local absorption yet are targeted solely for systemic effects, such as nitroglycerin (Nitrostat and others) and ointment hormones.

First order vs zero order elimination Ask Joe to clarify!!!!

First order elimination is when a constant amount of the drug is eliminated per unit time, and the drug concentration is important. The rate of elimination is proportional to the amount of drug in the body. So for every half life that passes, the drug concentration is halved. This takes place for about five half lives, until the drug is completely eliminated from the system. Usually this is the one that takes place. NOTE: The half-life is NOT dependent upon the drug dose. Happens more quickly, 2/2 metabolism now being concentration dependent. Zero order elimination is when a constant amount of the drug is eliminated per unit time. The elimination rate is still NOT concentration dependent, as this only takes place when you fully saturate the system. NOTE: Concentration/Time curve linear Usually observed at Very High serum levels for a limited number of drugs (phenytoin, aspirin, ethanol). Drops slowly, 2/2 every enzyme being saturated.

What direction do transporter proteins transport drugs? What is a genetic defect that effects this process?

From the intestinal lumen to the interstitial space. P glycoprotein. This is a genetic defect some individuals have where instead of pumping drugs / toxins out of the intestinal lumen into the interstitial space, the drugs are pumped from the interstitial space back into the intestinal lumen, increasing toxicity.

What is endotracheal administration? How fast is absorption? Ex. What is this usually reserved for? Used anymore?

Generally through an ET tube. Permits drug delivery into the pulmonary alveoli and systemic absorption via lung capillaries. Absorption rate is almost as rapid as IV administration due to large surface area of alveolar sacs. Ex. ET medications include Lidocaine (Xylocaine), Epinephrine (Adrenalin), Atropine, Naloxone (Narcan). Usually reserved for situations in which an IV line cannot be established. Not used that much anymore, largely replaced by IO administration.

What is the plasma level profile of a drug? What do the trough and the peak represent in this?

How much drug is in the blood plasma. Trough--The amount of drug in the bloodstream right before the next dose. Peak—The maximal amount of drug achieved in the bloodstream / that you would expect to see (varies with drug and route of administration, usually 30min-1 hour after intravenous administration).

What is the equation used to calculate the incremental loading dose (ILD)? (and define all 4 variables)

ILD = (Vd)(Cp desired -Cp initial) = --------------- (S)(f) Vd = Volume of Distribution Cp = Desired Concentration in Plasma after distribution S = Salt Factor (Usually 1.0) f = Bioavailability (Usually 1 for IV, < 1 for PO).

What delivery system immediately places the drug into the circulatory system?

IV administration immediately places the drug in the circulatory system. It is completely absorbed and must be delivered to target tissue

If an un-ionized drug is lipid soluble, then it will do what? Ex.

If an un-ionized drug is lipid-soluble, then it readily diffuses across the cell membrane. Ex. An acidic drug (e.g., aspirin) is relatively un-dissociated (un-ionized) in an acidic environment such as the stomach

Although most drugs are transported across the cell membrane via passive diffusion, how else can they cross the phospholipid bilayer?

If the molecule is lipophilic, too large, or has a charge, then is is transported via active transport, or a carrier-mediated mechanism.

What is the bioavailability area under a curve?

If you are looking at a bioavailability curve, the entire area under the curve is a bioavailability of 1 ( f = 1.0 ). If the drug is taken orally, the bioavailability is going to be much less ( like f = 0.3 ), and the curve will be u-shaped, and only occupy a small area under the curve.

What happens if you give two drugs at the same time that have the same binding site? What are four other factors that may affect a drug's binding ability to the drug-protein complex?

If you give two drugs at the same time that have the same binding sites, one can outcompete the other, which leads to more free levels of the drug, and is extremely problematic. 1. The concentration of plasma proteins 2. The number of binding sites on a protein 3. The drug's affinity for the protein 4. The acid-base balance of the patient

How does the pH of the drug environment effect absorption? In solution, what do most drugs exist as? The extent of this depends on what? (3)

In order to increase the likelihood of drug absorption, it needs to have a neutral charge. In solution, many drugs exist in an ionized (charged)and un-ionized (uncharged) form. How and to what extent a drug ionizes depends on: 1. Whether it is an acid or a base 2. Its relative strength 3. Measure of this degree of dissociation is referred to by the pKa

What is active tubular secretion? Drugs actively secreted by the renal tubules can be affected by what? What test is used to check this? So, active transport is what?

Involves the transport of free drug from the blood across the proximal tubular cell and into the tubular urine by an active process against a concentration gradient. Drugs actively secreted by the renal tubules can be affected by other drugs that compete for the same active transport process. Drug testing of urine checks for the presence of a drug—or its metabolites. A tubular pump for organic acids and bases that move drugs from the blood to the urine.

In order for something to be capable of glomerular filtration, what two characteristics must it have?

It must be fat soluble enough to cross the membrane but water soluble enough to get into the urine and be excreted.

What is the role of cystatin C? It may be what?

It's a protein biomarker of kidney function, that is found in all tissues, and is eliminated by glomerular filtration. May be more accurate predictor when renal function declines. (more accurate that creatinine) May be marker of early renal dysfunction.

What is the apparent volume of distribution? What is the volume not associated with? What is it a proportionality constant for?

It's the volume of sampled fluid needed to account for the total amount of drug in the body, at distribution equilibrium. It's not associated with a particular space, anatomical area or tissue. It's a proportionality constant constant related concentration and amount in the body.

What types of drugs have a large distribution and what types have a small or narrow distribution? (3) Ex.

Lipid soluble drugs bind to fat tissue, and tend to cross into blood brain barrier, so they go pretty much everywhere. Water soluble drugs only go certain places. But, at the same time if a drug is too fat soluble, it will stay in adipose tissue. Ex. DDT

What type of drugs can pass through the phospholipid membrane?

Lipid-soluble drugs can pass through the lipid membrane, but water-soluble drugs cannot Water-soluble substances, such as urea, alcohol, electrolytes, and water, must enter the cell through membrane pores.

Many disease have what? Effectiveness of drugs on many diseases may vary based on what? (3)

Many disease processes have a genetic basis. 1. Genetic variation in drug receptors 2. Genetic variation in enzyme function 3. Genetic variation in other cellular systems. Ex. Oncology: Tumor response to drug is in part genetically determined; Neurology: ~ One third of individuals with seizures do not respond adequately to pharmacotherapy.

For Phase I metabolism, how many drug interactions are involved, and what does it include? What does Phase I metabolism usually use for the oxidation reduction? Why can't you give Grapefruit juice at the same time as Lipitor for cholesterol?

Many drug interactions are involved, and this includes Theophylline and Charcoal/ burned foods. Cytochrome p-450 Enzymes Cannot give grapefruit (like liptor for cholesterol) at the same time, due to flavanoids in the peel of the grapefruit, so static drugs can accumulate and cause harm to the patient.

What is a memory aid to remember the 4 drugs that can be administered via endotracheal administration?

Memory aid: L--Lidocaine E--Epinephrine A--Atropine N—Naloxone

More than half of the P450 isoenzymes in drug elimination are part of the 3A4 group. Why is this significant for the development of new drugs?

More than half the enzymes using this P450 system uses 3A4 system. So, if a drug used the 3A4 system, you have lost an edge, because it's much more likely that another drug will compete with this drug.

Where does most drug absorption take place? What is the pH of intestinal fluid? What other factor (besides increased surface area) makes absorption in this organ favorable?

Most drug absorption occurs in the upper part of the small intestine, due to its rich blood supply and large absorption area. pH of intestinal fluid is alkaline (7.0-8.0), increasing the rate of absorption of basic drugs. Increased GI transit time, or prolonged exposure permits greater time for drug absorption in the small intestine. Because of this, increased intestinal motility (e.g., diarrhea) decreases exposure to intestinal membrane and diminishes absorption.

What is the summary for Inter-individual Variability?

Not all individuals will respond to drugs in the same way. Differences in levels achieved by different patients: Absorption, Distribution, Metabolism, Elimination. Drug Interactions Differences in pharmacologic response despite similar levels: Example: Individuals with history of ethanol or substance abuse often tolerant to lower levels.

Why does inter-individual variability influence the actions of drugs?

Not all individuals will respond to drugs in the same way. Differences in levels achieved by different patients: Absorption, Distribution, Metabolism, Elimination. Drug Interactions Differences in pharmacologic response despite similar levels: Example: Individuals with history of ethanol or substance abuse often tolerant to lower levels.

What are the two different volumes of distribution?

One based on population, and one based on your patient. If most of the drug goes to the tissue and little stays in the plasma, it's probably fat soluble and has a large volume of distribution (measured in milligrams). If most of the drug stays in the blood and doesn't go into the tissue, it's probably either water soluble or bound to albumin, and has a low volume of distribution (measured in micrograms).

What are phase I metabolic reactions? What do they create? What do they usually involve?

Oxidative transformations. Hydrophilic metabolites, that the body can eliminate. In some cases they are hydrophilic enough to be effectively eliminated by the kidneys. Cytochrome p450 enzyme systems.

Why does age influence the actions of drugs?

Pediatrics and older patients are highly responsive to drugs. Results in part from: Immature hepatic and renal systems of the infant Natural deterioration of these systems in the older adult. Older patients may have underlying disease processes that produce unexpected variations in response to drug therapy. Medication doses for children are usually modified on basis of body weight or surface area. Ex. Peds: Often have immature liver / kidney function, more % of their weight is water, which all effects volume of distribution of the drug. Older: imparied kidney function, which will effect the volume of distribution.

What is pharmacokinetics? What does it include? (4) These factors effect what?

Pharmacokinetics is the study of how the body handles a drug over a period of time. This includes absorption, distribution, biotransformation, and excretion These factors affect a patient's response to drug therapy.

When talking about bioavailability, what other factor do you have to include?

The salt content of the drug. Ex. Aminophylline is a drug that contains 160 mg of the drug theophylline and 40 mg of ethylene diamine (salt). So, even if given intravenously, the bioavailability would be less than 100% due to the salt content.

Why isn't endotracheal administration used that much anymore? How do some clinicians administer it? How should an ET drug be administered?

Possibly more erratic and less reliable than IV or IO delivery (not a first-line method). Some clinicians have used syringes without needles to prevent possible aspiration of a needle. ET drug dose should be 2 to 2 1/2 times the recommended IV dose, and diluted in 10 ml of normal saline.

Why would someone administer a drug rectally? Why wouldn't someone want to administer a drug rectally? Ex. (2)

Rectal administration is very effective for some medications, due to a small surface area that is very vascular and capable of drug absorption. Rectal medications also do not undergo hepatic alteration on first pass through the body, and the blood vessels that perfuse the rectal region bypass the liver. Although some drugs can be given rectally, if given via this route it's also difficult to predict absoption rates, which are likely to be erratic, due to rectal contents, local drug irritation, uncertainty of drug retention and variable blood supply to area. Ex. Diazepam (Valium) and lorazepam (Ativan) may be given rectally. Ex. So can aspirin, especially is someone that has just had a CVA.

What is the difference in fluid distribution between surgical and medical teams?

Surgical teams tend to give much more fluid, and are less dry. Medical teams avoid giving a lot of fluid (due to fear of heart failure), so they like to keep patients on the dryer side, which can adversely effect kidney function.

What is a relatively unimportant means of drug excretion? Side effects of this include what? Drugs excreted this way are taken how? What other category of drug delivery can be excreted in this way?

Sweat. Side effects include various skin reactions and sweat discoloration. Drugs excreted in saliva are usually swallowed and eliminated in the same manner as other orally administered drugs. Some IV drugs can be excreted into saliva, causing a person to complain about the taste of the drug.

What type of reaction is Phase II metabolism? What does it usually involve What cell level does is mainly take place at? What type of metabolites does it form?

Synthetic reaction. Conjugates phase I metabolite with glucuronic acid, sulfate, acetyl and methyl groups. Microsomal, mitochondrial and cytoplasmic. Metabolites formed are usually larger, polar, water soluble and inactive.

What is gastric absorption like? What does gastric absorption depend on?

The stomach has a rich blood supply, but is not considered an important site for drug absorption. This is due to the fact that the length of time the drug remains in the stomach varies, and because there are so many variables that affect gastric absorption, it is considered unpredictable. It depends on pH of the environment and gastric motility.

What is the blood-brain barrier (BBB)? This allows what type of drugs in, and keeps what type of drugs out? May also act as what?

The BBB is a single layer of endothelial cells that lines the blood vessels entering the CNS. Special anatomical arrangement permits only lipid-soluble drugs to be distributed into the brain and CSF (e.g., general anesthetics and barbiturates). Drugs that are poorly soluble in fat (e.g., many antibiotics) have trouble passing this barrier and cannot enter the brain This may be a protective device to prevent substances from affecting the brain (like protection against meningitis, which is an infection of the CNS).

What will happen to a weak acid drug in basic media?

The drug will dissociate into two charged particles, now making it so it cannot cross the phospholipid bilayer without a protein transporter.

What is bioavailability? (including variable) Ex. What about IV drugs? What is this effected by? (5)

The extent of absorption into the systemic circulation. It's represented as "f". Ex. Give 100mg of tables, 80 mg goes into the blood (or systemic circulation), 20mg doesn't due to liver and other factors. So this has 80% bioavailability, or an f of 0.8. Some IV drugs don't have 100% Bioavailability, but usually this specifically is 100%. Most IV drugs that 100% bioavalibility. 1. Degree of metabolism (First Pass) 2. Drug Properties 3. Drug Formulation 4. Drug Salt 5. Route of administration

When looking at a half life elimination curve with hours on the x axis and drug level on the y axis, what does the first, steep drop represent? What does the second drop represent?

The first half of the drop would be due to distribution from the blood to the tissues (steep), the second half of the drop would be due to elimination (more gradual).

What is pharmacogenetics? Each person differs in how drugs do what? (2) Toxic responses to drugs are usually based on what? What are 3 things influenced by genetics?

The impact of genetics on drug action. act at receptors how drugs are metabolized Toxic responses to drugs related to genetically based variation in drug metabolism. 1. Pharmacodynamics (receptors) 2. Drug metabolism 3. Drug toxicity

What is the primary site for drug metabolism? What can also be involved? (4) If taking a drug PO, where do they travel to first?

The liver is the primary site of drug metabolism. Plasma, kidneys, lungs, and intestinal mucosa may also be involved. Orally administered drugs absorbed through the GI tract normally travel to the liver before entering the general circulation.

What is the functional unit of the kidney? What will not end up this functional unit? What does this mean?

The nephron. Highly protein (albumin bound drug) will not end up in urine, 2/2 being too large. So, dialysis will not do these people any good, and it will be a long process before this gets out.

What happens after a drug exits the liver?

The new molecule (metabolite) enters the systemic circulation, and then is eliminated from the body via the renal system.

What is the pKa?

The pKa is a quantitative measure of the strength of a particular acid in solution. The lower the pKa (esp if negative) the stronger the acid (or the lower the pH).

What is elimination? How do drugs usually leave? What can happen to drug eliminated in the urine? What happens to individuals with kidney disease?

The process of drugs leaving the body. Usually drugs leave via the kidney in the urine. Drugs eliminated in the urine can often be tested for by a urine screen. Individuals with kidney disease hold on to drugs longer.

What is hemodialysis? What type of drug will this not effect? How often do they go? What is peritoneal dialysis? Common risk for both? (2)

The type of dialysis that is used when someone has kidney failure. Have a membrane, then some solution that draws toxins out of the blood, via passive diffusion, 2/2 concentration differences. This means if a drug is highly protein bound, it will not cross the membrane. Hemodialys: 3 days per week for 3-4 hours. Paroteneal dialysis: Pumped into abdominal cavity, have 5 bags of 1 L per day, which takes place every night. Infection and blood clots.

What is the volume of distribution? What is it trying to explain? What is the equation for Vd, and the description of the variables? What type of drug has a high Vd and what type of drug has a low Vd?

Theoretical Concept: a calculated value which represents the volume that would be required to contain the administered dose if that dose were evenly distributed at the concentration measured in the plasma. It's trying to explain the drug level after giving a specific amount. Ab Vd = --------------- Cp Vd = Volume of Distribution (L) Ab = Administered Dose Cp = Concentration in the Plasma If fat-soluble, will have a large volume of distribution (high Vd) If water-soluble, will have a small volume of distribution (low Vd)

For the last slide, what are both of these equations telling you? What is this number normally?

They're telling you that you have cleared the blood of a certain amount of creatinine, which is a toxic end product produced by muscle waste. Normally 110 (for cockcroft and gault formula). Once you get to 30 and below, concerned, below 10, very concerned.

What is oral absorption? Why is this so rapid? Ex. (2)

This is absorption either under the tongue (sublingual) or between the teeth and the cheek (buccal). Because the oral cavity has a rich blood supply. Ex. Dip - Buccal Ex. Nitroglycerin - Sublingual

What is first pass effect? What does this reduce? Medication affected by this can be given how? Ex. (2)

This is when a significant amount of a certain drug may be metabolized (first-pass metabolism) before the drug reaches the systemic circulation. This reduces the amount of drug available for distribution. Medications affected by this initial biotransformation can be given orally in high doses or administered parenterally to initially bypass the liver. Ex. Propranolol (Inderal) is an example. Ex. Morphine, when giving 15 mg IV, they will stop breathing, 2/2 none of it becoming inactive due to the first pass effect. When giving the same dosage orally, a good amount of it will become inactive 2/2 the first pass effect, and the patient will be fine.

When looking at the y axis (which tells you the drug concentration in serum) of a drug distribution curve, what is the first drop showing you? What is the bottom part of the curve showing you?

This shows there is a drop in blood level almost immediately, which is the distribution phase of the drug (when the drug is spreading throughout the body tissues). The bottom part of the curve, which is when the drug is already distributed throughout the body is the elimination phase, shown by a steady, predictable decline.

How do you reach a steady state?

With repeated dosing: Rate of input = Rate of output Concept only valid for first order elimination Takes 4-5 t ½ to reach steady state Important concept to realize when to draw levels.

What is tissue binding? Especially problematic in what class of drugs? Why? How long can these drugs remain in the body for? When can this be helpful?

Tissue binding is when a drug reservoir may occur in fat tissue and bone. Especially problematic in lipid-soluble drugs, which have a high affinity for adipose tissue, which is where these drugs are stored. Because the low blood flow in fat tissue serves as a stable reservoir for drugs. Some lipid-soluble drugs can remain in body fat for as long as 3 hours after administration. (can actually be helpful when sustained drug response is desired).

What is the goal of metabolism? What are the two types of metabolism?

To convert fat soluble drugs to more water soluble drugs so kidney can eliminate them. 1. Phase I: Oxidation Reduction reaction. Usually makes it more water soluble. Converts it into metabolytes, which can be more active, inactive, have increase toxicity, etc. 2. Phase II: Conjugation reaction. Simple process, takes water soluble molecule (usually a sugar), links it up to a fat soluble drug, which makes the entire thing more water soluble.

What does glomerular filtration do? What isn't filtered out? What happens to lipid soluble and water soluble compunds after filtration?

Unbound drugs and water-soluble metabolites are filtered by the glomeruli, moving drugs from the blood into the urine. Drugs highly bound to protein do not pass through this structure. After filtration, lipid-soluble compounds are reabsorbed by the renal tubules and reenter the circulation. Water-soluble compounds are not reabsorbed and are eliminated from the body.

How do you calculate the Vd (volume of distribution) for the following case: J.M. weighs 70kg and receives his first dose of 160mg gentamicin IV from 8AM until 8:30AM. At 9AM his gentamicin level is 7.2mg/L. What is the Vd? So, what was expected? What does this say about Gentamicin? What does this say about J.M.?

Vd = [dose administered]/[post distribution peak concentration measured in plasma] Vd = 160mg/7.2mg/L = 22.2L 22L/70kg = 0.31L/kg Vd = 0.25 L/kg Expected Vd of 0.25L/kg for most hospitalized patients, but many ICU patients, patients with fluid overload (ascites, CHF), have larger volumes of distribution in the range of 0.3 - 0.4L/kg. Vd < 1 L/kg, so more gentamicin is represented in the central compartment (either highly protein bound or very water soluble - in this case highly water soluble). He has a larger volume of distribution than would be expected for a healthy adult; as such, he may be "tanked up", having more fluid on board than otherwise expected.

What is the parenteral route of administration? What are the six different subtypes? (the first 4 are in order from deepest to most superficial, the last 2 are the most invasive)

Via injection. 1. Intramuscular Administration 2. Subcutaneous Administration 3. Intravenous Administration 4. Intradermal 5. Endotracheal Administration 6. Intraosseous Administration

Water vs Fat Soluble drugs

Water soluble drug will only stay in the blood stream, and have very little distribution throughout the body and into the tissues of the body. Fat soluble drugs like to go everywhere, especially in the CSF, making it so they have an extremely broad or wide area of distribution. So, by its very nature, any drug being used for neuro or psyc has to be fat soluble, so it will cross the BB into the CNS, which is the site that it needs to effect. The only exception to this is Lithium , which is non-fat soluble, and electrically charged.

What is the process of metabolism? What is the goal of metabolism? Most of this chemical conversion happens where? Why is variation in this process so varied?

Where many drugs are chemically converted to less active or inactive substances by enzymes. To covert Fat Soluble Drugs to Water Soluble Drugs. Most of this chemical conversion happens in the liver, GI. Great variation, 2/2 enzymes that metabolize drugs are specific the each individuals genes.