Pharmacokinetics 1

Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distribution, metabolism, and excretion. The biodisposition ofa drug involves its permeation across cellular membrane barriers.

Drug administration (IM, PO, etc.)

Absorption into plasma

Plasma

Distribution to tissues

Bound drug

Free drug

Figure 1-1 -1 . Drug Biodisposition

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Chapter 1 • Pharmacokinetics

Bioavailability(t)

Measure ofthe fraction of a dose that reaches the systemic= circulation. By defini­ tion, intravascular doses have 100% bioavailability, f 1.

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Chapter 1 • Pharmacokinetics

Redistribution

In addition to crossing the blood-brain barrier (BBB), lipid-soluble drugs redis­ tribute into fat tissues prior to elimination.

In the case of CNS drugs, the duration of action of an initial dose may depend more on the redistribution rate than on the half-life. With a second dose, the blood/fat ratio is less; therefore, the rate of redistribution is less and the second dose has a longer duration of action.

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Drug (D)D 2 Slow

Inactive

Figure 1-1-7. Redistribution

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Chapter 1 • Pharmacokinetics

Nonmicrosomal metabolism

Hydrolysis

0Phase I reaction involving addition of a water molecule with sub- sequent bond breakage

0Includes esterases and amidases

0Genetic polymorphism exists with pseudocholinesterases

0Example: local anesthetics and succinylcholine

Monoamine oxidases

0Metabolism of endogenous amine neurotransmitters (dopamine, norepinephrine, and serotonin)

0Metabolism of exogenous compounds (tyramine)

Alcohol metabolism

0Alcohols are metabolized to aldehydes and then to acids by dehy­ drogenases (see CNS Pharmacology, section IV)

0Genetic polymorphisms exist

Phase II

•Definition: Conjugation with endogenous compounds via the activity of transferases

•May follow phase I or occur directly

•Types of conjugation:

Glucuronidation

-Inducible

-May undergo enterohepatic cycling (Drug: Glucuronide ---intestinal7 bacterial glucuronidases ---free7 drug)

Reduced activity in neonates

Examples: morphine and chloramphenicol

Acetylation

0Genotypic variations (fast and slow metabolizers)

0Drug-induced SLE by slow acetylators with hydralazine > procain­ amide > isoniazid (INH)

Glutathione (GSH) conjugation

0Depletion of GSH in the liver is associated with acetaminophen hepatotoxicity

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Section I • General Principles

ELIMINATION

Concerns the processes involved in the elimination of drugs from the body (and/ or plasma) and their kinetic characteristics. The major modes of drug elimina­ tion are:

•Biotransformation to inactive metabolites

•Excretion via the kidney

•Excretion via other modes, including the bile duct, lungs, and sweat

•Definition: Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level) is called the elimination half-life (tl/2).

Zero-Order Elimination Rate

• A constant amount of drug is eliminated per unit time; for example, if 80 mg is administered and 10 mg is eliminated every 4h, the time course of drug elimination is:

•Rate of elimination is independent of plasma concentration (or amount in the body).

•Drugswith zero-order elimination have no fixedhalf-life (t112 is a variable).

•Drugs with zero-order elimination include ethanol (except low blood levels), phenytoin (high therapeutic doses), and salicylates (toxic doses).

Figure l-1-9a. Plots of Zero-Order Kinetics

First-Order Elimination Rate

• A constant fraction of the drug is eliminated per unit time (t112 is a con­ stant). Graphically, first-order elimination follows an exponential decay versus time.

•For example, if 80mg of a drug is administered and its elii:nination half­ life = 4h, the time course of its elimination is:

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Rate of infusion Cko) does determine plasma level at steady state. If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled. A similar relationship can exist for other forms of drug administration (e.g., per oral)-doubling oral doses can double the average plasma levels of a drug. Plot­ ting dose against plasma concentration yields a straight line (linear kinetics).

•It takes 4-5 half-lives to achieve steady state.

•In some situations, it may be necessary to give a higher dose (loading dose) to more rapidly achieve effective blood levels (CP).

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Chapter 1 • Pharmacokinetics

Chapter Summary

•The pharmacokinetic characteristics of a drug are dependent upon the processes of absorption, distribution, metabolism, and excretion. An important element concerning drug biodistribution is permeation, which is the ability to cross membranes, cellular and otherwise.

•A drug's ability to permeate is dependent on its solubility, the concentration gradient, and the available surface area, which is influenced by the degree ofvascularity. Ionization affects permeation because unionized molecules are minimallywater soluble but do cross biomembranes, a feat beyond the capacity of ionized molecules. Figure 1-1-2 illustrates the principles associated with ionization; Table 1-1-1 summarizes the three basic modes oftransport across a membrane: passive, facilitated, and active.

•Absorption concerns the processes of entry into the systemic circulation. Exceptforthe intravascular route, some absorptive process is always involved. These have the same determinants as those of permeation. Because absorption may not be 100% efficient, less than the entire dose administered may get into the circulation.

•Any orally administered hydrophilic drug will be absorbed first into the portal vein and sent directly to the liver, where it may be partially deactivated. This is the first-pass effect.

•The distribution of a drug into the various compartments ofthe body is dependent upon its permeation properties and its tendency to bind to plasma

proteins. The placental and blood-brain barriers are of particular importance in considering distribution. The Vd is a kinetic parameter that correlates the dose given to the plasma level obtained: the greater the Vd value, the le$S the plasma concentration.

•Aswell as having the abilityto cross the blood-brain barrier, lipophilic drugs have a tendency to be deposited in fat tissue. As blood concentrations fall, some ofthis stored drug is released. This is called redistribution. Because with each administration more lipophilic drug is absorbed into the fat, the duration of action of such a drug increases with the number of doses until the lipid stores are saturated.

•Biotransformation is the metabolic conversion of drugs, generally to less active compounds but sometimes to iso-active or more active forms. Phase I biotransformation occurs via oxidation, reduction, or hydrolysis. Phase II metabolism occurs via conjugation.

•The cytochrome P-450 isozymes are a family of microsomal enzymes that collectively have the capacity to transform thousands of different molecules. The transformations include hydroxylations and dealkylations, as well as the promotion ofoxidation/reduction reactions. These enzymes have an absolute

requirement for NADPH and 02• The various isozymes have different substrate and inhibitor specificities.

•Other enzymes involved in phase I reactions are hydrolases (e.g., esterases and amidases) and the nonmicrosomal oxidases (e.g., monoamine oxidase and alcohol and aldehyde dehydrogenase).

(Continued)

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Section I • General Principles

Chapter Summary (confd)

•Phase II reactions involve conjugation, sometimes after a phase I hydroxylation. The conjugation may be glucuronidation, acetylation, sulfation, or addition of glutathione.

•Modes of drug elimination are biotransformation, renal excretion, and excretion by other routes (e.g., bile, sweat, lungs, etc.). Most drugs follow first-order elimination rates. Figures l-1-9a and l-1-9b compare zeroand

first-order elimination, and Figure 1-1-10 demonstrates howthe t112 and the theoretical zero time plasma concentration (C0) can be graphically determined. An important relationship is dose= Vdx c0.

•Renal clearance (CIR) represents the volume of blood cleared by the kidney per unit time and is a constant for drugs with first-order elimination kinetics.

Total body clearance equals renal plus non renal clearance. An important relationship is Cl= k x Vd.

•A steady state is achieved when the rate coming in equals the rate going out. The time to reach a steady state is dependent only on the elimination half-life. It is independent of dose and frequency of administration or rate of infusion (see Figures 1-1-11, -12, and -13).

•Other equations describing relationships important for calculation are those used to determine the loading dose, infusion rate, and maintenance dose.

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Section I • General Principles

Noncompetitive antagonists:

°Cause a nonparallel shift to the right

°Can be only partially reversed by i the dose of the agonist 0 Appear to l the efficacy of the agonist

•Physiologic antagonism (different receptor)

-Two agonists with opposing action antagonize each other

-Example: a vasoconstrictor with a vasodilator

•Chemical antagonism:

-Formation of a complexbetween effector drug and another compound

-Example: protamine binds to heparin to reverse its actions

•Potentiation

Causes a parallel shift to the left to the D-R curve - Appears to i the potency of the agonist

QUANTAL (CUMULATIVE) D-R CURVES

•These curves plot the percentage of a population responding to a speci­ fied drug effect versus dose or log dose. They permit estimations of the median effective dose, or effective dose in 50% of a population-EDSO.

•Quanta! curves can reveal the range of intersubject variability in drug response. Steep D-R curves reflect little variability; flat D-R curves indi­ cate great variability in patient sensitivity to the effects of a drug.

Toxicity and the Therapeutic Index (Tl)

•Comparisons between EDSO and TDSO values permit evaluation of the relative safety of a drug (the therapeutic index), as would comparison between EDSO and the lethal median dose (LDSO) if the latter is known.

mg/kg

Figure 1-2-5. Quantal D-R Curves of Therapeutic

and Toxic Effects of a Drug

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Chapter 2 • Pharmacodynamics

•As shown in Figure I-2-5, these D-R curves can also be used to show the relationship between dose and toxic effects of a drug. The median toxic

dose of a drug (TDSO) is the dose that causes toxicity in 50% of a popu­ lation. = =

• From the data shown, TI 10/2 5

•Such indices are of most value when toxicity represents an extension of the pharmacologic actions of a drug. They do not predict idiosyncratic reactions or drug hypersensitivity.

SIGNALING MECHANISMS: TYPES OF DRUG­

RESPONSIVE SIGNALING MECHANISMS

•Binding of an agonist drug to its receptor activates an effector or signal­ ing mechanism.

•Several different types of drug-responsive signaling mechanisms are known.

Intracellular Receptors

•These include receptors for steroids. Binding of hormones or drugs to such receptors releases regulatory proteins that permit activation and in some cases dimerization of the hormone-receptor complex. Such com­ plexes translocate to the nucleus, where they interact with response ele­ ments in spacer DNA. This interaction leads to changes in gene expres­ sion. For example, drugs interacting with glucocorticoid receptors lead to gene expression of proteins that inhibit the production of inflamma­ tory mediators.

•Other examples include intracellular receptors for thyroid hormones, gonadal steroids, and vitamin D.

•Pharmacologic responses elicited via modification of gene expression are usually slower in onset but longer in duration than many other drugs.

Membrane Receptors Directly Coupled to Ion Channels

•Many drugs act by mimicking or antagonizing the actions of endog­ enous ligands that regulate flow of ions through excitable membranes via their activation of receptors that are directly coupled (no second messengers) to ion channels.

•For example, the nicotinic receptor for ACh (present in autonomic ner­ vous system [ANS] ganglia, the skeletal myoneural junction, and the central nervous system [CNS] ) is coupled to a Na+/K+ ion channel. The receptor is a target for many drugs, including nicotine, choline esters, ganglion blockers, and skeletal muscle relaxants.

•Similarly, the GABAA receptor in the CNS, which is coupled to a chlo­ ride ion channel, can be modulated by anticonvulsants, benzodiazepines, and barbiturates.

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