Pharmacokinetics

how does manipulating urine pH effect diffusion and renal clearance of certain drugs?

a. Weak acids reabsorbed at low pH -Increasing urinary pH leads to increased drug excretion b. Weak bases reabsorbed at high pH -Decreasing urinary pH leads to increased drug excretion c. Example: Phenobarbital (weak acid) overdose - Give bicarbonate, alkalinizes urine, keeps drug ionized 1. reabsorption is decreased and excretion is increased

Drugs binding to albumin are usually...

acidic drugs such as ASA, dilantin, barbiturates keep in mind patient lab levels! do they have hypoalbuminemia?? dose drug according to levels (would have to reduce the dose is albumin is abnormally low)

Why do you apply a scopolamine patch behind the ear? Other drug examples?

aka post auricular area it is put there because the external carotid provides good blood flow Clonidine (alpha 2 antagonist like precede) ,scopolamine (anti-cholinergic- like atropine tertiary drugs, cross the lipid barrier), nitro, fentanyl

describe the function of plasma protiens

albumin is the main one acidic drugs bind to albumin and basic drugs bind AAG while bound to proteins drugs can not be metabolized, excreted or cause effect

Drugs binding to alpha-acid glycoproteins (AAG) are usually...

basic drugs such as diazepam, midazolam, opioids, local anesthetics

Describe what the cell wall membrane (CWM) is composed of

bilipid layer composed of cholesterol and phospholipids.

How is bioavailability calculated?

bioavailability = (area under the curve ORAL/AUC IV) expressed as a percentage

mercapturic acid conjugation

conjugates formed when drug or metabolite combines with sulfyhydryl groups glutathione important pathway for detox "mop up" toxic and high reactive intermediates sometimes produced during drug metabolism ex) acetaminophen metabolized to metabolite that is toxic normal dose- these toxic metabolites react with glutathione to form mercapturic acid conjugates overdose: glutathione in liver is depleted and toxic metabolites = hepatic necrosis *importance of clearing free radicles mitochondrai

first order kinetics

constant fraction of the drug is eliminated per unit time %/hour most drugs alpha phase- distribution- rapid curvilinear decline in plasma concentration- drug from central compartment to the peripheral beta phase- elimination- linear decline in concentration- elimination from central compartment in the 2 compartment model- the rate at which is drug is eliminated is proportional (usually) to the concentration of the drug

What are some examples of highly protein-bound drugs?

coumadin, phenytoin, propanolol, propofol, fentanyl, diazepam, midazolam

what happens if drug accumulates in bones, muscle, fat

does not exert effect, potential to be released into blood stream and exert effect- creates reservoir why we see residual effects of anesthesia days later

Explain a pro-drug

drug given is not in its active form until it undergoes phase 1 metabolism Examples - dolasetron - heroin There are some drugs that have undesirable metabolites that are active after phase 1 metabolism- NOT a prodrug 1. Meperidein or Demerol 2. Enalapril --. enalaprilat Has a 1/3 effect of analgesic activity- metabolite can lead to potent central nervous system irritant that can lead to tremors myoclonus and seizures

name 4 factors that influence volume distribution

drug pka extent of drug-plasma protein binding lipid solubility of the drug regional blood flow patient gender, age, body composition (fat), disease,abnormal accumulation of fluid (edema, ascites, pleural effusion)

How and when do drug-protein bonds dissociate?

drug-protein complex is maintained by a weak bond (ionic, hydrogen, van der Waals), easily reversible. - dissociates when plasma conc is low after hepatic or renal clearance of unbound drug. essentially serves as a storage reservoir.

What is the first pass effect?

drugs absorbed from the GI tract enter the portal vein and pass through the liver before entering circulation. accounts for the larger difference between oral and IV dosages.

What effect does adding bicarb to a local anesthetic have?

hastens absorption and speed of onset. non-ionized

Vessel Rich Groups (VRG)

heart, brain lungs, liver, etc major organs of the body get a disproportionately large amount of the drug compared to the other areas of the body

Factors that effect IM/subQ absorption include

i. Blood flow to the area of injection ii. Solubility of the carrier vehicle iii. Solutions are absorbed faster than suspensions

How does Vd in infants and elderly?

infants- expanded extracellular fluid volume and high total body water content- expanded distribution and diminished blood levels in water soluble drugs. Low body fat resulting in increased blood levels of highly lipid soluble drugs elderly-decreased lean body mass- decreased water content, increased fat

pH compared to pKa determines...

ionization

What happens if you put ASA into the small bowel?

it will ionize and not be effective. it is an acidic drug, going into an alkaline environment (small bowel)

What is pinocytosis?

large molecule engulfed by CWM.

Define toxicology

looks at adverse effects and toxicities of drugs

Define the apparent volume of distribution

lots of drugs distribute into several compartments: extracellular fluids intracellular fluid fat can bind to cellular components lipids-cell CM, adipocytes protiens- plasma and in cells nucleic acids- nuclei of cell actual volume in which drug molecules are distributed can not be measured calculate: amount of drug injected/plasma concentration that would be obtained if the drug immediately distributed into the body upon injection Vd = Q/Cp Q = amount of drug or dose Cp = plasma concentration

clearance

measure of the ability of the body to eliminate the drug volume of blood or plasma freed of drug/unit time estimates organ function (elimination organs) dependent on: 1) blood flow to the organ 2) fraction of drug extracted from the blood important for long term dosing and steady stage drug concentrations -constant for therapeutic concentrations when a drug reaches a steady state- it follows first order kinetics and is eliminated at a constant fraction- for a constant state this remains the same/unit time ehtanol- zero order kinetics- eliminated at a constant amount - clearance is variable Cl = rate of elimination (mg/hr) / concentration (mg/L) =volume/time

volume of distribution

measure of the apparent space in the body available to contain the drug not an actual number but a proportionality factor not an actual compartment in the body if a drug has a large volume of distribution- widely distributed in tissues small Vd- may never leave extracellular fluid (plasma and interstitial) might be charge/water soluble- smaller Vd Lipid soluble drugs bigger Vd- dissolve into adipose

Glucuronic Acid Conjugation

most common major route of metabolism reduces renal absorption derived from glucose conjugation catalyzed by glycuronsyl transferase drug-glucuronide conjugate eliminated by excretion in urine/bile renders from or metabolite more water soluble, less liposoluble, more highly ionized at 7.4pH

Vessel Poor Groups (VPG)

muscle fat skin bone etc eventually equilibrium will occur but initial the vessel rich get more

What is carrier mediated diffusion?

occurs via transmembrane protein carrier. glucose is transported this way

pH is equal to...(equation)

pH = -log10 [H+] pH is equal to the negative log to the base ten of the molar hydrogen ion concentration. example: pH decrease from 3 to 2, causes ten fold increase in hydrogen ions

Disadvantage of topical administration

potential for systemic toxicity, example: benzocaine

Define pharmacology

preparation and dispensing of drugs

Acids and drug examples

proton donors Examples Not all inclusive Barbiturates, Dilantin, diuretics, NSAIDS, warfarin, pcns, cephalosporins, sulfonamides Easier to use since there are few of them

uptake of drugs across the cell membrane is influenced by...

regional blood flow and concentration gradient

list factors affecting renal clearance of a drug

renal disease filtration rate -volume filtered in glomeruli and the unbound drug concentration in plasma Drug secretion rate -depends on extent of drug-plasma protein binding carrier saturation drug transfer rates across tubular membranes, and rate of delivery to secretory sites -changes in plasma protein concentration -blood flow -functional nephrons

What is active transport? What is passive transport?

requires ATP. can move against concentration gradient. uses specific carrier proteins example: Na+/K+ pump passive-i. Requires no energy Moves only with a concentration gradient (membranes separating two body compartments high --> low) Lipophilicity of a compound is important- move readily across membranes water soluble- have to penetrate CMW through aqueous channels

Define posolgy

science of dosages

What should you consider when applying a transdermal patch?

skin conditions: hydration, body temp, excoriation/thickness, also infants and elderly have thinner skin and greater permeability has to pass the 1st layer of epidermis the stratum corneum so the drug has to be a small molecular size and lipid soluble

Describe what occurs after a bolus dose of an inducing agent

the drug is given, the patient goes to sleep, in a short period of time, the patient wakes up. They wake up because of redistribution, NOT metabolism . Drug is in vessel rich group (including the brain- on GABA receptors in the brain) occupies these receptors After a period of time the big bolus redistributes from the brain to other VPG THEN the drug is eliminated over time He draws the curve for this see rapid sleep decline on Y then slow decrease of y / x

Functional unit for the kidney

the nephron kidney- the major organ of exretion

What is Fick's law? and What is distribution?

there is a concentration gradient, and molecules attempt to create equilibrium on both sides Depends on organ perfusion, protein binding, and lipid solubility of the drug from 2 groups (vessel rich (VRG) and vessel poor (VPG)

Define half life (T1/2) for a drug

time required for the plasma concentration of the drug to be reduced by 50% and indicates the time required for drug elimination from the body. to set these problems up: T = 0 half life = 0 amount of drug = given work from there

What are the advantages of IV administration?

- 100% bioavailability - rapid and accurate delivery of drug (titrated to pt response) - route of choice for anesthesia

Four principles of pharmacokinetics

- Absorption - Distribution - Metabolism *now known as biotransformation - Excretion drugs either stimulate or depress 2 key concepts: Volume of distribution Clearance

Define bioavailability

- The fraction of unchanged drug that reaches the systemic circulation. - The amount of free drug that binds to target site and produces effect.

Advantages of intranasal admin

- avoids first apss effect - better bioavailability - rate of absorption + plasma concentration comparable to IV admin

describe protein binding's selectivity and competition

- binding of drugs to protein is nonselective - drugs with similar characteristics can compete for same binding site - when two drugs are competing for same binding site then this can increase the amount of free drug leading to potential toxicity

Describe the absorption of drugs administered subQ

- constant and slow absorption - sustained effect - use of vasoconstrictors with local anesthetics can prolong effect and slow absorption further

Describe ion trapping

- degree of ionization varies across membranes that separates fluids with different pH. non-ionized portion traverses CWM, ionized portion becomes trapped. can happen with pregnancy, and drugs cross the placenta and become trapped fetus ii. Fetal pH is lower than maternal pH iii. If a weak base is given to the mother the unionzed portion of the drug crosses from the mother into the fetus iv. If it becomes MORE ionized it can't cross back over v. The more drug the mom gets- the more the fetus gets stuck with all the ions vi. Toxic levels of the drug vii. In the more acidic environment of the fetus, the drug (which is a base in this instance) becomes more ionized. Now it is very difficult for the drug to leave the fetus. Toxic doss can rapidly accumulate posing a threat to the fetus 1. The gold standard for induction of general anesthesia in pregnancy is thiogental 2. Because it's an acid

Advantages of inhalational administration

- lungs provide large surface area for absorption - thin alveolar membrane between pulmonary capillaries and alveoli, allowing rapid blood-brain equilibration - highly lipid soluble and diffusable (also low molecular weight)

Describe the first pass effect of the lungs

- percentage of drug taken up by the lungs after IV admin - serves as a temporary reservoir --> drug released back into blood circ as plasma conc decreases.

What are the disadvantages of IV administration?

- possible adverse reaction due to high drug level (narrow therapeutic window) - requires vigilance - need for patient IV access

Describe the CWM role in drug administration

- selectively inhibits passage of certain drugs - lipid soluble drugs easily dissolve in CWM - relatively impermeable to water soluble drugs

What are some patient-related factors that impact protein-binding?

- severe hepatic or renal disease - pregnancy - aging (decreased albumin, less binding sites = more free drug) - acute/chronic inflammatory diseases (trauma, surgery, burns, acute MI, RA, crohns, cancer)

How does protein binding influence drug clearance?

- unbound fraction is subject to hepatic metabolism. - unbound fraction undergoes glomerular filtration. - highly bound drugs are metabolized and excreted slower -if a drug is bound to plasma proteins it is unavailable for uptake even in the vessel rich groups -in general the more soluble a drug is the more readily available it is for uptake

What is the degree of ionization determined by?

- whether the drug is an acid or a base - pH of the environment - pKa of agent Ionized portions of a drug are not re-absorbed in the renal tubules and are eliminated as unchanged drug Amount of the drug in the un-ionzed form is determined by the drugs pka and the pH of the environment that the drug is introduced in

What drugs are an exception to typical redistribution

. Muscle relaxants Redistribution does not occur Non-polarized muscle relaxant Drug in, hits receptor like Acetylcholine receptors on skeletal muscle, LOCKS onto receptor until it's metabolized

Oxidation

1 of 3 stages of biotransformation Addition of oxygen or removal of a hydrogen Drug oxidation carried out by a series of enzymes located in the sooth endoplasmic reticulum of the liver, kidney, and other tissues Principal site of metabolism of many drugs is the liver Cytochrome p-450 system is central to the oxidation pathway Examples a. Dealkylation b. Desulfuration c. Deamination d. N-oxidation e. Sulfide formation f. Hydroxylation g. Dehalogenation

Name the 6 factors that decrease bioavailability

1) ****first pass effect**** 2) incomplete absorption from GI tract 3) degree of blood flow to area 4) lipid solubility 5) pulmonary uptake of drug 6) degree of ionization also disease process and albumin levels

Advantages of oral route of administration

1) Convenient 2) Economical 3) fairly tolerant to errors

Disadvantages of oral route of administration

1) Emesis 2) Enzymatic destruction 3) ****Patient compliance**** 4) Irregular absorption (Influence of food or medications, ****First pass effect****) 5) Size of surface area for absorption and degree of blood flow (Stomach (acid) vs. small intestines (alkaline))

Characteristics of transdermal drugs

1) combo water and lipid soluble form 2) low molecular weight 3) absence of histamine release 4) low daily dose 5) can not give a half dose by cutting the patch- opens reservoir can give way more than intended this way

Drug characteristics that determine crossing a cell membrane

1) molecular size 2) degree of ionization 3) relative lipid solubility of ionized and nonionized forms 4) binding to tissue proteins (only unbound can cross cell membranes)

Factors affecting transfer of drugs across cell membranes

1) molecular size - smaller agents traverse easier. molecule wt < 200 transfers easily. >1000 do not readily diffuse 2) ***lipid solubility - high lipid solubility (lipiphilic/hydrophobic) 3) degree of ionization - influences the extent that a drug can cross cell membranes. ionized = H2O soluble = repelled by CWM + excreted by kidneys Ionized drugs are WATER soluble Unionized drugs are LIPID soluble 1) Acid + acid unionized 2) Base + base = unionzed 3) acid + base = ionized

Describe Systemic effects that decrease albumin production

1) renal disease -are they on dialysis? - Are you giving acidic drugs (proposal) -How will this effect their uptake? Propofol may not be the best choice- OR reduce dose significantly 2) liver disease 3) chronic CHF 4) malignancies

5 Factors that impact the degree of drug absorption

1) route of administration -IV no obstacles -inhalation- fast also pulmonary circulation large SA 2) solubility of drug administered -(lipid soluble?) 3) conditions at site of absorption -blood flow -area of absorbing surface (large more rapid) 4) degree of ionization of the drug non-ionized 5) bioavailability -hepatic first pass effect 6) concentration- highly concentrated solutions absorb more rapidly

Advantages of transdermal administration

1) sustained release provides steady plasma concentration- prolonged and continuous 2) low incidence of side effects and fewer dosing intervals (high patient compliance) 3) avoids first pass effect

Disadvantages of rectal administration

1) unpredictable absorption- erratic - if inserted into proximal rectum, drug undergoes first pass effect - if inserted into distal rectum, no metabolism occurs 2) mucosal irritation

Advantages of intramuscular administration

1) used when IV access is difficult (pediatrics, mentally challenged 2) rapid absorption - disadvantage pain at site or necrosis

proximal tubular secretion steps

1. Drug not transferred into glomerular filtrate leaves glomeruli via efferent arterioles that divide to form a capillary plexus surrounding nephric lumen 2. In proximal tubule water is reabsorbed and active secretion of some weak electrolyte, especially weak acids, occurs 3. Process is active and requires carrier and supply of energy

Discuss globular filtration

1. Drugs enter kidney via renal arteries, which divide to form a glomerular capillary plexus 2. Free drug not bound to protein flows through capillary slits into Bowman's space as part of glomerular filtrate 3. Lipid solubility and pH do not influence passage of drug into glomerular filtrate 4. Fraction of drug bound to protein and the glomerular filtration rate (GFR) impact amount of drug passing into renal tubular lumen 5. GFR depends

What processes are involved in renal excretion of a drug?

1. Glomerular filtration 2. Proximal Tubular secretion 3. Distal Tubular Reabsorption

distal tubular reabsorption steps

1. Passive excretion and reabsorption of lipid soluble drug 2. As drug moves toward distal convoluted tubule, concentration increases and exceeds that of the perivascular space. 7 3. If drug is uncharged, may diffuse out of nephric lumen

Describe conditions that increase AAG-alpha acid glycoprotein production

1. Trauma 2. Infection 3. Surgery 4. Recent MI 5. Chronic pain patients 6. Drugs that are basic will be more bound and less available for uptake You will have to give MORE drug Most of the drugs we give are BASIS FAR fewer acids than bases

zero order kinetics

A constant amount of drug is eliminated per unit of time (e.g. 5mg/min) when represented graphically the plasma concentration fall is linear with time The amount of drug eliminated per unit time is independent of the drug concentration Examples i. Alcohol ii. Phenytoin iii. Aspirin

define Tachyphylaxis

A diminished response to later increments of a physiological active drug

Reduction

Addition of a hydrogen or loss of an oxygen Cytochrome p-450 system also involved in reduction pathway Important in the metabolism and toxicity of halothane. Under conditions of low oxygen tension, halothane can be reduced by the p-450 system to transfer electrons not to oxygen as it usually does but directly to halothane, allowing reduction of halothane. Only occurs with low oxygen tension i. Can have halothane hepatitis

Describe the phases of redistribution and the curve related to this

Alpha portion -majority of redistribution -steep initial Y decline Beta portion -

What is biotransformation?

Changing a compound into something more usable by the body "The alteration of substances by metabolic processes end products are usually inactive and water soluble" - Liver is the primary organ for biotransformation -Phase I :The parent drug is converted into a more polar metabolite through one of the 3 processes 1. Oxidation 2. Reduction 3. Hydrolysis - in most cases these processes decrease the pharmacological activity of the drug and allow it to be eliminated by the kidneys

Three Compartment Model

Consists of a central compartment and two peripheral compartments. A shallow and deep peripheral compartment. In this model, when redistribution occurs, is is slower from the deep compartment than from the shallow. This distribution and redistribution continues over time until the drug is eliminated - Shallow and deep only difference - Again MOST drugs are 2 compartment mode - many anesthetic drugs conform to 3 compartment model (Fentanyl, methohexital, diazepam, propofol, pancuronium, vecuronium, thiopental (no longer here in US)

What is pKa?

Dissociation constant of an agent. ratio of ionized to non-ionized substance (drug) in a solution. - rate that substance will dissociate into its ion form when placed in a solution. - expressed as log of equilibration constant for the dissociation of an acid or base. -pKa of a drug is the pH at which 50% of the drug is ionized and 50% is unionzed

What effect does ionization have on drug absorption?

Drug absorption is greater if the drug is in non-ionized, lipid soluble form. The ionized form is water soluble and possesses an electrical charge which is repelled by the cell membrane. Equilibrium between ionized and non-ionized based on chemical make up of the drug and local pH where drug molecules are

Why is it important to know if a drug is an acid or base?

Drug molecules can either be ionized (charged) or un-ionized (uncharged, neutral) - Most drugs weak acids or weak bases are in solution as both ionized and unionized - Most of the time, the unionized portion of the drug exerts pharmacological effect undergoes reabsorption across renal tubules and is susceptible to hepatic biotransformation - Not ALWAYS the unionized there are exceptions but mostly the unionized

What happens to drug absorption when a patient is acidotic?

Drugs are more likely to ionized and can be less effective. example pKa of thiopental (a barbiturate- an acid) is 7.6 If given a pH of 7.6 then 50% is ionized and 50 % is unionzed if given in pH of 7.2 then more of the drug will be unionzed in the case of an acid Drugs that are weak bases are more unionized a pH increases. Base + base = unionzed

Routes of administration: name the shortest to the longest route in terms of duration

Duration (shortest to longest) : IV>IM>SC>oral

What has the greatest effect on bioavailability?

First-pass effect

What environment favors the absorption of weak acids? or Acidic environments favor absorption of acidic drugs? WHY?

Gastric fluids. pH 1.5-2.5 examples: ASA, barbiturates -More unionized (non-ionized), more lipid soluble i-Acid plus acid more unionized If it's the same it's unionized Base + acid is MORE ionized and can NOT pass the lipid barrier -Non ionized passes the lipid barrier and creates MORE effect

Define excretion and where it occurs in the body

Hepatic clearance: Rate of elimination of a drug to liver biotransformation - Depends on hepatic blood flow and the fraction of the drug removed from the blood by the liver hepatic extraction ration - Drugs that are efficiently removed by the liver have high hepatic extraction rations and their clearance is proportionate to hepatic blood flow - Drugs with low hepatic extraction rations rely on enzyme function - Disease processes that decrease hepatic blood flow have adverse effects on the clearance of drugs with high hepatic extraction rations - Disease processes that damage the liver have adverse effects on drugs with low hepatic extraction ratios

Why are most drugs formed as salts?

Increases solubility and absorption

Cytochrome p-450

Involves both oxidation and reduction Also called mixed function oxidase system Result of cytochromes p-450 reaction is the formation of substance that is polar and can be excreted in the urine

What is the Henderson-Hasselbalch equation used to calculate?

It is used to calculate the ratio of non-ionized to ionized drug at each pH. Used to estimate degree of drug absorption pH = pKa + log acid/base

describe acid/base response to changes in urine pH

Manipulate pH of the urine can be used to minimize the amount of back diffusion and increase the clearance of undesirable drug -Increasing urine pH increases -Weak bases are absorbed when the urine pH is high -Weak acids are absorbed when the urine pH is low -Give bicarb to a weak acid overdose- like phenobarbital- urine more alkaline- keeps the drug ionized- reabsorption is decreased and the excretion is increased

Why does the solubility of a drug matter in relation to drug absorption?

More lipid soluble, aka lipophilic (lipid LOVING) can pass through cell membranes easily (remember cell membranes are composed of a lipid bilayer).

Hydrolysis

NO involvement of cytochrome p-450 Only esters and amides metabolized by hydrolysis of esterases and amidases Circulating phosphodiesterases hydrolyze a non-polar drug by hydrolysis Amide- most amides 2 "I" in generic name Ester- 1 "I" in generic name Examples i. Drugs metabolized by hydrolysis include 1. Local anesthetics- procaine 2. Locals are either esters or amides both classes are metabolized by hydrolysis 3. Succinylcholine- ester hydrolysis 4. Esmolol

Routes of administration: name the fastest to the slowest route in terms of onset

Onset (quickest - slowest) : IV>IM>SC>oral also we discuss nasal, sublingual, rectal, transdermal- varied response due to many factors

Where are oral drugs mostly absorbed, regardless of ionization, and why?

Oral drugs are mostly absorbed in the small intestine d/t larger surface area and better blood flow.

Discuss acetylation rates

People are either fast acetylators or slow acetylators. fast can conjugate drugs that undergo acetylation faster. Slow acetylators can possible become toxic from the same dose of the drug that a fast acetylator had no problem with to - test for this give caffeine 6 hours later a urine sample taken if chemicals from the breakdown of caffeine are few the person is a slow acetylator b. Generally 60% of people of European and African ancestry are considered slow acetylators c. Most Asians are considered fast d. Percentages who are slow i. Indian- 60% ii. Italians/Spanish - 55% iii. African, German- 50% iv. Thai- 23% v. Chinese's 20-% vi. Japanese 10% vii. Koreans 10%

what drugs are broken down using accetylation?

Procainamide - Antiarrythmic -acetylated to N-acetyl procainamide (NAPA) eliminated half-time in rapid acetylators 2.5 hours compared to 5 hours in slow acetylation -slow acetylators tend to develop antinuclear antibodies resulting in lupus-like syndrome Hydralazine - Works on arterial smooth muscle by inhibiting intracellular calcium - takes 10 minutes to work - Mild compared to things like nitro is have low BP or HR might be better choice Isoniazid - Tb- antibacterial

bases and drug examples

Proton acceptors MOST drugs we give are bases Drugs that end with -ine -Morphine -Meperidine

Advantage of sublingual administration

Rapid onset of drug effect. Direct drainage into superior vena cava from veins in mouth. it bypasses the liver, and avoids first pass effect.

Extraction ration

Reflect Organ Function! - fraction of drug removed in a simple pass through the organ of elimination measured in single organ- sample arterial blood (Cin) and venous blood (Cout) ER = [Cin- Cout] / Cin ER is then converted to % which is the drug in the plasma removed as it passes through an organ 0-1.0 varies with functional capacity of organ (disease changes it or blood flow) Renal-shut down due to hypovolemia can alter drug elimination (why we give fluids to increase renal perfusion and aide in elimination) if saturated NO longer 1st order kinetics

What environment favors the absorption of weak bases?

Small intestines. pH 7-8 examples: Local anesthetics, benzodiazepines

Inhibitors

Some drugs effect the action of cytochrome p-450 These are classified as either enzyme inducers of enzyme inhibitors a. Erythromycin - Antibiotic b. Cimetidine - H2 blocker c. Amiodarone - Antiarrhythmic d. Grapefruit juice e. MAO inhibitor drugs f. allopurinol g. ketoconazole -protease inhibitors toxic levels of drug with normal dose??

Inducers

Some drugs effect the action of cytochrome p-450 These are classified as either enzyme inducers of enzyme inhibitors a. Phenobarbital - Barbiturate b. Phenytoin - Anti-elliptic c. Rifampin - antibiotic d. Troglitazone - Oral hypoglycemic e. Grisofulvin - antifungal f. Nicotine g. Alcohol (this is why they require more drugs is you are an alcoholic) h. st. john's wart i. isoniazid quinadine BCGPQRST remember! they will be sub therapeutic levels if they are taking one of these and another drug that is being eliminated by this metabolism pathway

What happens during Phase 2 of metabolism?

The drug is polarized to increase its excretion rate, basically the parent drug or metabolite reacts with and endogenous substance such a glucuronic acid, carbs or amino acids to form a water soluble conjugate this is a conjugation reaction these are the possible processes - Glucoronidtaion - Sulfuration - Transsulfuration - Methylation - Acetylation - Hippuric acid formation - Mercapturic acid formation Conjugation occurs when the drug contains a reactive group: -carboxyl (-COOH) -primary amine (-NH2) sulfhydryl (-SH) hydroxyl (-OH) if the reactive group is not in the drug itself it must under go metabolism and insert a reactive group in phase 1 before conjugation and thus elimination can occur

What is the relationship between lipid solubility and protein binding?

The more lipid soluble a drug, the more likely it is to bind to protein

What is volume of distribution?

Theoretical volume that drugs have to distribute in body Vd = dose/concentration If you gave 12 g of a drug and its concentration was 2 mg/cc then the Vd would be 6cc

Advantage of rectal administration

Useful for pediatrics, vomiting, or unconscious patients

Describe the 2 compartment model of distribution and elimination

View the body as having two compartment central compartment (smaller volume/greatest perfusion) which includes the plasma and vessel rich group peripheral compartment (larger volume) muscle, fat, skin, bones (2 areas where uptake is relatively the same in each) Theoretical construct to help in understanding and describing plasmas concentration of a drug as a function of time redistribution- as drug levels fall in the central drug from peripheral redistributes to central to crease equilibrium- decrease over all concentration as it is cleared faster from the central compartment

What is pharmacokinetics?

What the body does to the drug dose-concentration relationship of a drug molecular interactions between drug and body constituents it describes the time-dependent changes of : 1) plasma drug concentration and total amount of drug in the body

Define Redistribution

When a drug is fist injected IV, the VRG get a large concentration of the drug, redistribution refers to the time when the drug is moving from the VRG back to the central circulation