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 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 the process of drug movement from the site of drug delivery to the site of
action. Figure (6.1) illustrates the differences in drug concentrations over time for the
various routes of administration. The 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. The more rapidly achieved and higher the peak concentrations from intravenous
and pulmonary (smoking) routes illustrate this point.
Bioavailability is defined as the fraction of unchanged drug that reaches the
systemic circulation after administration by any route. First-pass metabolism is the
metabolism that occurs before a drug reaches the systemic circulation and occurs most
extensively for lipid-soluble drugs such as morphine, methylphenidate, and desipramine,
and can significantly reduce bioavailability. Morphine, for example, requires nearly twice
the dose when administered orally as compared to intravenously.
Distribution
Once absorbed, a drug is distributed to the various organs and tissues of the body.
Most psychoactive drugs enter the brain because the are highly lipid soluble. The
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 exist. These active
transport systems enable glucose, amino acids, amines, purines, nucleosides, and organic
acids to again access to the brain. In contrast, p-glycoprotein is an efflux carrier.
Clearance
Elimination refers to disappearance of the parent and/or active molecule from the
bloodstream or body, which can occur by metabolism and/or excretion. Excretion is the
process of removing a compound from the body without chemically changing that
compound. Metabolic capacity determines drug clearance in most cases.
Most drugs display first-order elimination kinetics: the fraction or percentage of
the total amount of drug present in the body removed at any one time is constant and
independent of dose. Following administration of a drug with first-order kinetics,
concentrations show an exponential decline of drug concentrations. The half-life (t 1/2) of
1

a drug is the amount of time it takes for a drug concentration to decrease by half, or
conversely achieve half of steady-state concentrations. One half-life represents a 50%
change, and 2, 3, 4, and 5 half-lives represent 75%, 87,5%, 93,7%, and 96,8% changes,
respectively.

In 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. The maximal rate of metabolism and/or elimination is generally due
to saturation of a key enzyme. 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 examples 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. These
chemical modification/reaction are generally performed by enzymatic system, such as the
chytocrome P450 enzyme sistem. Not all metabolites are inactive or nontoxic, and active
metabolites need to be considerd when assessing a drugs total activity.
Pharmacogenomics
Pharmacogenomics is the study of the relationship between genetic variations and drug
disposition and response.
Genetic variability in drug-metabolizing enzymes can effect drug bioavailability
and clearance. Single nucleutide polymorphisms may alter CYP activity. CYP 2D6, for
example, which metabolizes codeine to morphine, is the best studied of the drug
metabolizing enzymes. Individuals can be genotyped for 2D6 enzyme function (with
classification as poor (PM), intermediate (IM), extensive (EM), and ultrarapid
metabolizers (UM). Those with poor metabolizer genotypes generally do not receive

adequate analgesia due to inability to metabolize codeine to the active morphine.

Ultrarapid metabolizers, on the other hand, metabolize codeine significantly more rapidly
and exstensively than others, producing rare but life-threatening morphine intoxication.
Breast-feeding infants of mothers who are ultrarapid metabolizers have received
morphine overdoses from their mothers who are prescribed codein for postpartum pain
relief.
Drug interactions at the level of the cytochromes and other metabolizing systems
are often clinically significant. Methadone is metabolized primarily by CYP 3A4, with
contributions from CYP 2B6, 2C19, 3A4, and to a lesserextent CYP 26D. Inhibitors of
CYP 3A4, including erithromycine, diltiazem, ketoconazole, and saquinavir, slow the
metabolism of methadone and increase methadone levels. Inducers of CYP 3A4 such as
carbamezepine, phenobarbital, evavirenz, and st.Jhons 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 optimize
therapy and minimize potential toxicities.
Genetically defined differences in drug metabolism may influence risk of
addiction, with relative protection for persons who experience adverse drug reactions at
lower drug doses.
PHARMACODYNAMICS
Pharmacodynamics is the study of the dose-response phenomena, which are the
biochemical and physiologic effects of drugs on the body, and the bodys homeostatic
response. Most drugs act on specific endogenous targets, or receptors, to modulate the
rate and extent of the bodys endogenous functions.
Potency, Efficacy, and Dose Response
When drug dose and response are plotted on a logarithmic scale, a sigmoidal
curve often results. The maximal efficacy of a drug occurs at E max, and the concentration

of the drug needed to produce 50% of the maximal effect occurs at EC 50-. Potency
denotes the amount of drug needed to produce a given effect; the more potent the
drug, the smaller the dose required to achieve maximal effect. Potency is
primarily determined by the affinity of the receptor for the drug. (Fig. 6.2)

Antagonists have no effect upon response when used alone (Fig. 6.3).
Antagonists bind with equal affinity to the active and inactive conformations and
prevent an agonist from inducing a respons. Competitive antagonists may be
revered by adding excess agonist, but noncompetitive antagonists cannot be
counteracted in this manner. Buprenorphine is an example of a highly potent
opioid receptor partial agonist. The drug has a high affinity for receptors and
displaces morphine, methadone, and other full opiate agonists from these
receptors. In 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. Higher doses of buprenorphine can be given without
respiratory depression. The partial agonist properties of buprenorphine may
precipitate withdrawal in individuals who have a high level of physical
dependence on opioids.
Some drugs, depending on their concentrations, act as mixed agonists and
antagonists. Mixed opioid agonist-antagonists have been developed in an attempt
to produce analgesia

with drugs that have less addictive potential and less respiratory depression. For
example, nalbuphine and butorphanol are competitive receptor antagonists that
exert their analgesic actions by acting as agonist at k+ receptors.
Tolerance, Sensitization, and physical dependence
Tolerance and sensitization reflect changes in the way the body responds to a drug
when it is used repeatedly. Tolerance is the reduction in response to a drug after
its repeated adminisration. Sensitization indicates an increase in drug response
after its repeated administration.
There 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, and/or signal
transduction pathways that occur after repeated drug exposure. Learned 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 taken
in the presence of the specifict environmental cue, a state of expectation occurs. A
powerful example 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.
The 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 generalized to other drugs in that same structural and
mechanistic category. The cross-tolerance that occurs between alcohol,
barbiturates, and benzodiazepines can be used to facilitate the smooth weaning of
a patient from their drug of dependence during detoxification.
Physical dependence is a state that develops as a result of the adaptation
produced by resetting homeostatic mechanisms after repeated drug use.
Withdrawal sign and symtomps can occur in a physically dependent person when
drug aministration suddenly ceases. Withdrawal symptoms may reflect the
interactions of numerous neurocircuits and organ system.
The conclusions in this paper represent the views of the authors and do not
necessarily represent the views of the Eunice Kennedy Shriver National Institute
of Child Health and Human Development or the National Institutes of Health.

The authors wish to express their gratitude to Elinore McCance-katz, MD,

whose contributions to the pharmacogenomics portion of the last version of this
chapter set the stage for this fifth edition.

KEY POINTS
1. Pharmacokinetics describes the time course of drug concentrations in the
blood and tissues. Drug consentrations are determined by absorption,
distribution, metabolism, and elimination.
2. Drugs with high abuse liability are psychoactive and have rapid
distribution into the central nervous system.
3. Pharmacodynamics is the study of doseresponse phenomena, including
both the activity of the drug and adaptive changes within the body.
Pharmacodinamics of drugs of abuse is complex and determined by
receptor interactions, tolerance, sensitization, and withdrawal.
4. Pharmacogenomics is the study of the relationship between genetic
variations and drug disposition and response, including both
pharmacokinetics and pharmacodynamics.
REVIEW QUESTIONS
1. Bioavailability is the fraction of unchanged drug that reaches the systemic
circulation after administration by any route. Te bioavailability of drugs
adminisered intravenously is :
A. 50%
B. 70%
C. 80%
D. 90%
E. 100%
2. Drugs with first-order elimination kinetics show an exponential decline
ofdrug concentrations. The time to reach steadly state of drugs with firstorder elimination kinetics is dependent upon.
A. Dose
B. Frequency of drug administration
C. Half-lif
D. First-pass metabolism
E. Enzyme saturation

3. Flumazenil can be used to treat benzodiazepine receptor as:

A. An antagonist withou intrinsic activity

B. A mixed agonist antagonist
C. An inverse agonist with intrinsic activity
D. A partial agonist
E. An agonist with intrinsic activity
4. Individuals may have different isoforms of P450 2D6. Those who are
ultrarapid metabolizers of codeine:
A. Are likely to have poor pain relief when they are prescribed a usual
dose of codein
B. May become hot and flushed when thy take codeine
C. Have increased safety when breast-fedding their infants
D. Are more likely to overdose and die when they take codein
E. Are less likely to becomeaddicted to codeine
ANSWER
1. E. 100%. First-pass metabolism is important for orally administered
drugs. The dose of orally administered drugs may need to be increased
relative to its intravenus dose due to that drugs bioavailability.
2. C. Half-life. Drugs with first-order elimination kinetics are felt to achieve
steady state at three, four, or five half-lives representing 87,5%, 93,7%, an
96,8% of the steady-state consentration, respectively. Half-life for drugs
with first-order elimination kinetics is independent of dose. For drugs with
zero-order elimination kinetics, dug levels dependen upon dose. Half-lives
and steady-state concentrations are less useful concepts in these
circumstances.
3. 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. Competitive 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 likely to overdose and die when they take codein. Ultrarapid
metabolizers of codein metabolize codeine to morphine more readily.
Deaths have been reported in ultrarapid metabolizers of coein, due to the
rapid increase in their resultant morphine levels. Breast-feeding infants are
also susceptible to this problem if theirs mother is a rapid metabolizer of
codein.