PHARMCOKINETIC AND PHARMACODINAMIC PRINCPLES
Addiction medicine is the application of pharmacologic principles to drugs of abuse. Drugs of abuse are used to produce mood alterations which requires drug penetration into the brain. PHARMACOKINETIC
Pharmacokinetic describes Pharmacokinetic describes the time course of drug concentrations in blood and tissues (e.g., brain). Drug concentrations in blood and other sites are determined by absorption, distribution, metabolism, and elimination. Absorption
Absortion is Absortion is the process of drug movement from the site of drug delivery to the site of action. Figure (6.) illustrates the differences in drug concentrations over time for the various routes of administration. !he more rapidly a psychoactive drug is delivered to its site of action in the central nervous sistem, the greater is its mood"altering and reinforcing affects. !he more rapidly achieved and higher the pea# concentrations from intravenous and pulmonary (smo#ing) routes illustrate this point. Bioavailability Bioavailability is defined as the fraction of unchanged drug that reaches the system systemic ic circula circulatio tion n after after admini administra stratio tion n by any route. route. First" First"pass pass metab metabolis olism m is the metabolism that occurs before a drug reaches the systemic circulation and occurs most e$tensively for lipid"soluble drugs such as morphine, methylphenidate, and desipramine, and can significantly reduce bioavailability. %orphine, for e$ample, requires nearly twice the dose when administered orally orall y as compared to intravenously. Distribution
&nce absorbed, a drug is distributed to the various organs and tissues of the body. body. %ost psychoactive drugs enter the brain because the are highly lipid soluble. !he blood"brain barrier hinders the ability of non"lipid"soluble drugs to reach the brain tissue by diffusion. For some compounds, specific active transport system e$ist. !hese active transport systems enable glucose, amino acids, amines, purines, nucleosides, and organic acids to again access to the brain. 'n contrast, p"glycoprotein is an efflu$ carrier. Clearance
Elimination refers Elimination refers to disappearance of the parent andor active molecule from the bloodstream or body, which can occur by metabolism andor e$cretion. $cretion is the process of removing a compound from the body without chemically changing that compound. %etabolic capacity determines drug clearance in most cases. %ost drugs display first"order elimination #inetics* the fraction or percentage of the total amount of drug present in the body removed at any one time is constant and indepe independe ndent nt of dose. dose. Follow Following ing admini administra stratio tion n of a drug drug with first" first"ord order er #ineti #inetics, cs, concentrations show an e$ponential decline of drug concentrations. !he half-life (t half-life (t +) of 1
a drug is the amount of time it ta#es for a drug concentration to decrease by half, or conversely achieve half of steady"state concentrations. &ne half"life represents a - change, and +, /, 0, and half"lives represent 1, 21,, 3/,1, and 36,2 changes, respectively.
'n contrast, for drugs with zero-order elimination kinetics, the amount of drug removed (rather than the fraction of drug removed) at any one time is constant and dependent on dose. !he ma$imal rate of metabolism andor elimination is generally due to saturation of a #ey en4yme. Drug dosing becomes difficult in these cases* a small increase in dose can cause a large increase in concentration, in contrast to drugs with first"order clearance where there is proportionality between dose and concentration. Aspirin, phenytoin, and ethanol are e$amples of drugs with zero-order elimination. Drug metabolism is the process of chemical modification of drugs and other chemicals by the body, generally into less active and more hydrophilic compounds. !hese chemical modificationreaction are generally performed by en4ymatic system, such as the chytocrome 50- en4yme sistem. ot all metabolites are inactive or nonto$ic, and active metabolites need to be considerd when assessing a drug7s total activity. Pharmacoenomics
Pharmacogenomics is the study of the relationship between genetic variations and drug disposition and response. 8enetic variability in drug"metaboli4ing en4ymes can effect drug bioavailability and clearance. 9ingle nucleutide polymorphisms may alter :;5 activity. :;5 +D6, for e$ample, which metaboli4es codeine to morphine, is the best studied of the drug metaboli4ing en4ymes. 'ndividuals can be genotyped for +D6 en4yme function (with classification as poor (5%), intermediate ('%), e$tensive (%), and ultrarapid metaboli4ers (<%). !hose with poor metaboli4er genotypes generally do not receive
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adequate analgesia due to inability to metaboli4e codeine to the active morphine. hon7s wort speed the metabolism of methadone and decrease methadone levels. Awareness of potential interaction, clinical observation, and tailoring medication regimens and dosages are needed to optimi4e therapy and minimi4e potential to$icities. 8enetically defined differences in drug metabolism may influence ris# of addiction, with relative protection for persons who e$perience adverse drug reactions at lower drug doses. PHARMACOD!NAMICS
5harmacodynamics is the study of the dose"response phenomena, which are the biochemical and physiologic effects of drugs on the body, and the body7s homeostatic response. %ost drugs act on specific endogenous targets, or receptors, to modulate the rate and e$tent of the body7s endogenous functions. Potenc"# E$$icac"# an% Dose Response
?hen drug dose and response are plotted on a logarithmic scale, a sigmoidal curve often results. !he ma$imal efficacy of a drug occurs at ma$, and the concentration
of the drug needed to produce - of the ma$imal effect occurs at : -". 5otency denotes the amount of drug needed to produce a given effect@ the more potent the drug, the smaller the dose required to achieve ma$imal effect. 5otency is primarily determined by the affinity of the receptor for the drug. (Fig. 6.+)
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Antagonists have no effect upon response when used alone (Fig. 6./). Antagonists bind with equal affinity to the active and inactive conformations and prevent an agonist from inducing a respons. :ompetitive antagonists may be revered by adding e$cess agonist, but noncompetitive antagonists cannot be counteracted in this manner. =uprenorphine is an e$ample of a highly potent opioid receptor partial agonist. !he drug has a high affinity for receptors and displaces morphine, methadone, and other full opiate agonists from these receptors. 'n contrast to the full agonists, however, increases in buprenorphine dose may result in a longer duration of action but do not result in increased pharmacologic affects. igher doses of buprenorphine can be given without respiratory depression. !he partial agonist properties of buprenorphine may precipitate withdrawal in individuals who have a high level of physical dependence on opioids. 9ome drugs, depending on their concentrations, act as mi$ed agonists and antagonists. %i$ed opioid agonist"antagonists have been developed in an attempt to produce analgesia
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with drugs that have less addictive potential and less respiratory depression. For e$ample, nalbuphine and butorphanol are competitive µ receptor antagonists that e$ert their analgesic actions by acting as agonist at #B receptors. Tolerance# Sensiti&ation# an% ph"sical %epen%ence
!olerance and sensiti4ation reflect changes in the way the body responds to a drug when it is used repeatedly. !olerance is the reduction in response to a drug after its repeated adminisration. 9ensiti4ation indicates an increase in drug response after its repeated administration. !here are several mechanisms by which tolerance can occur. Pharmacokinetic tolerance most often occurs as a consequence of increased metabolism of a drug after its repeated administration, resulting in less drug being available at the receptor for drug activity. Pharacodynamic tolerance refers to the adaptive changes in receptor density, efficiency of receptor coupling, andor signal transduction pathways that occur after repeated drug e$posure. Cearned tolerance refers to a reductions in the effects of a drug because of compensatory mechanisms that are learned. Conditioned tolerance, which is a subset of learned tolerance, occurs when specific environmental cues such as sights, smells, or circumstances are paired with drug administration so that, when the drug is ta#en in the presence of the specifict environmental cue, a state of e$pectation occurs. A powerful e$ample of conditioned tolerance occurred in a study when rats died after being given a dose of opiates to which the rats previously had been tolerant. !he deaths occurred when the rats were put in an unusual environment instead of the home cage were they were used to receiving the drug. Cross-tolerance occurs when tolerance to the repeated use of a specific drug in a given category is generali4ed to other drugs in that same structural and mechanistic category. !he cross"tolerance that occurs between alcohol, barbiturates, and ben4odia4epines can be used to facilitate the smooth weaning of a patient from their drug of dependence during deto$ification. 5hysical dependence is a state that develops as a result of the adaptation produced by resetting homeostatic mechanisms after repeated drug use. ?ithdrawal sign and symtomps can occur in a physically dependent person when drug aministration suddenly ceases. ?ithdrawal symptoms may reflect the interactions of numerous neurocircuits and organ system. !he conclusions in this paper represent the views of the authors and do not necessarily represent the views of the Eunice Kennedy hriver !ational "nstitute of Child #ealth and #uman Development or the !ational "nstitutes of #ealth .
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!he authors wish to e$press their gratitude to linore %c:ance"#at4, %D, whose contributions to the pharmacogenomics portion of the last version of this chapter set the stage for this fifth edition.
KE! POINTS
. 5harmaco#inetics describes the time course of drug concentrations in the blood and tissues. Drug consentrations are determined by absorption, distribution, metabolism, and elimination. +. Drugs with high abuse liability are psychoactive and have rapid distribution into the central nervous system. /. 5harmacodynamics is the study of doseresponse phenomena, including both the activity of the drug and adaptive changes within the body. 5harmacodinamics of drugs of abuse is comple$ and determined by receptor interactions, tolerance, sensiti4ation, and withdrawal. 0. 5harmacogenomics is the study of the relationship between genetic variations and drug disposition and response, including both pharmaco#inetics and pharmacodynamics. RE'IE( )*ESTIONS
. =ioavailability is the fraction of unchanged drug that reaches the systemic circulation after administration by any route. !e bioavailability of drugs adminisered intravenously is * A. - =. 1- :. 2- D. 3- . -- +. Drugs with first"order elimination #inetics show an e$ponential decline ofdrug concentrations. !he time to reach steadly state of drugs with first" order elimination #inetics is dependent upon. A. Dose =. Frequency of drug administration :. alf"lif D. First"pass metabolism . n4yme saturation
/. Fluma4enil can be used to treat ben4odia4epine receptor as*
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A. An antagonist withou intrinsic activity =. A mi$ed agonist antagonist :. An inverse agonist with intrinsic activity D. A partial agonist . An agonist with intrinsic activity 0. 'ndividuals may have different isoforms of 50- +D6. !hose who are ultrarapid metaboli4ers of codeine* A. Are li#ely to have poor pain relief when they are prescribed a usual dose of codein =. %ay become hot and flushed when thy ta#e codeine :. ave increased safety when breast"fedding their infants D. Are more li#ely to overdose and die when they ta#e codein . Are less li#ely to becomeaddicted to codeine ANS(ER
. . --. First"pass metabolism is important for orally administered drugs. !he dose of orally administered drugs may need to be increased relative to its intravenus dose due to that drugs bioavailability. +. :. alf"life. Drugs with first"order elimination #inetics are felt to achieve steady state at three, four, or five half"lives representing 21,, 3/,1, an 36,2 of the steady"state consentration, respectively. alf"life for drugs with first"order elimination #inetics is independent of dose. For drugs with 4ero"order elimination #inetics, dug levels dependen upon dose. alf"lives and steady"state concentrations are less useful concepts in these circumstances. /. A. An antagonist without intrinsic activity antagonists have no effect when used alone. Antagonist bnd with equal affinity o the active and inactive conformations of receptors and prevent an agonist rom inducing a response. :ompetitive antagonist bind reversibly and ca be overcome by adding additional agonist, whereas noncompetitive antagonists bind irreversibly and cannot be overcome by adding additional agonist. 4. D. Are more li#ely to overdose and die when they ta#e codein.
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