CHAPTER 3 PHARMAKCOKINETICS PHARMACODYNAMICS INTRODUCTION

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Goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects Principles of pharmacokinetics and pharmacodynamics are combined to clarify the dose-effect relationship Pharmacodynamics Governs concentration-effect part of interaction Maximum response and sensitivity determine the magnitude of the effect at a particular concentration Pharmacokinetics Deals with dose-concentration part Absorption, distribution, and elimination determine how rapidly and for how long the drug will appear at the target organ

Measure of the apparent space in the body available to contain the drug Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma

(1) May be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = Cb, Cp, Cu) The V calculated from equation(1) is an apparent volume Can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogenously at the concentration found in blood, plasma, or water Drugs with very high volumes of distribution have much higher concentration in extravascular tissue than in the vascular compartment

Clearance Measure of the ability of the body to eliminate the drug Factor that predicts the rate of elimination in relation to the drug concentration

PHARMACOKINETICS standard dose Based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug Not suitable for all patients due to physiologic (ex. Maturation of organ function in infants) and pathologic (ex. Heart failure) processes that dictate the dosage adjustment

May be defined with respect to blood, plasma, or unbound in water Elimination of drug from the body may involve processes occurring in the kidney, lungs, liver and other organs Dividing the rate of elimination at each organ by the concentration of drug presented to its yields the respective clearance at that organ

Volume of Distribution

Major sites of drug elimination are kidneys and liver Clearance of unchanged drug in urine represents renal clearance Drug elimination in liver occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both For most drugs, clearance is constant over the concentration range encountered in clinical settings Rate of drug elimination is directly proportional to concentration

B. Flow-Dependent Elimination Some drugs are cleared very readily by the organ of elimination, so that any clinically realistic concentration of the drug, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it Elimination of drugs depend primarily on the rate of drug delivery to the organ of elimination These drugs can be called high-extraction drugs since they are almost completely extracted from the blood by the organ Blood flow to the organ is the main determinant of drug delivery, but plasma protein binding and blood cell partitioning may also be important for extensively bound drugs that are highly extracted

When clearance is first-order, it can be estimated by calculating the area under the curve of the time-concentration profile after a dose Clearance is calculated from the dose divided by the AUC

Half-Life Time required to change the amount of drug in the body by one-half during elimination Time course of drug in the body will depend on both the volume of distribution and the clearance

A. Capacity-Limited Elimination Phenytoin, aspirin and ethanol Clearance will vary depending on the concentration of drug that is achieved Also known as mixed-order, saturable, dose-dependent or concentrationdependent, nonlinear, and MichaelisMenten elimination When the blood flow to an organ does not limit elimination, the relation between elimination rate and concentration is expressed as

Twofold decrease can be shown to be proportional to the natural logarithm of 2; 0.7 is constant and is the approximation of the natural logarithm of 2

Vmax is the maximum elimination capacity Km is the drug concentration at which the rate of elimination is 50% of Vmax At concentrations that are high relative to the Km, the elimination rate is almost independent of concentration a state of pseudo zero order elimination If dosing rates exceeds elimination capacity, steady state cannot be achieved
Solid line: Plasma concentrations reflecting drug accumulation during a constant-rate infusion of a drug. Fifty percent of the steady-state concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives. Dashed line: Plasma concentrations reflecting drug elimination after a constant rate infusion of a drug had reached steady state. Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc.

Indicates the time required to attain 50% of steady state or to decay 50% from steadystate conditions Change in half-life will not necessarily reflect a change in drug elimination

Drug Accumulation Drug will accumulate in the body until dosing stops it takes an infinite time to eliminate all of a given dose; if dosing interval is shorter than four half-lives, accumulation will be detectable Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval Fraction lost is 1 minutes the fraction remaining just before the next dose Accumulation factor convenient index of accumulation

After oral administration, drug may be incompletely absorbed due to lack of absorption from gut Other drugs are too hydrophilic (atenolol) or too lipophilic (acyclovir) to be absorbed easily and their low bioavailability is also due to incomplete absorption Too hydrophilic, drug cannot cross lipid cell membrane Too lipophilic, drug is not soluble enough to cross the water layer adjacent to the cell

B. First-Pass Elimination After absorption at gut wall, portal blood delivers the drug to the liver prior to entry into systemic circulation Drug can be metabolized in the gut wall or portal blood, but liver is the most commonly responsible for the metabolism Liver can also excrete the drug into the bile This whole process is known as first-pass elimination

Accumulation factor predicts the ratio of the steady-state concentration to that seen at the same time following the first dose

Q is hepatic blood flow, normally about 90 L/h in a person weighing 70 kg Systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER)

Bioavailability Fraction of unchanged drug reaching the systemic circulation following administration by any route AUC is proportional to the extent of bioavailability for a drug if its elimination is first order For IV dose, bioavailability is assumed to be equal to unity For a drug administered orally, bioavailability may be less than 100% because of incomplete extent of absorption across the gut wall and first-pass elimination by the liver

*Bioavailability of morphine (f=1)

A. Extent of Absorption Bioavailability of morphine is 33%

C. Rate of Absorption Determined by the site of administration and drug formulation Rate of absorption and extent of input can influence clinical effectiveness of a drug Differences in rate of absorption may become important for drugs given as a single dose Drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut

Drugs that are poorly extracted by the liver shunting of blood past the liver will cause little change in availability

Alternative Routes of Administration & the FirstPass Effect *Reasons for different routes of administration Convenience oral To maximize concentration at the site of action and minimize elsewhere topical To prolong duration of drug absorption transdermal To avoid first-pass effect

*Ways to avoid hepatic first-pass effect A. Sublingual absorption Use of sublingual tablets Direct access to systemic veins

B. Transdermal route Extraction Ratio & the First-Pass Effect Systemic clearance is not affected by bioavailability; clearance can affect the extent of availability because it determines the extraction ratio Lidocaine Used for cardiac arrhythmias and has bioavailability of less than 40% Never given orally because metabolites are believed to contribute to CNS toxicity Other drugs highly extracted by liver Isoniazid, morphine, propranolol and several tricyclic antidepressants Drugs with high extraction ratios will show marked variation in bioavailability between subjects because of differences in hepatic function and blood flow Drugs that are highly extracted by the liver bypassing hepatic sites of elimination will result in substantial increases in drug availability Same advantage as sublingual

C. Rectal suppositories Drugs absorbed from suppositories in lower rectum enter vessels that drain into the inferior vena cava, thus bypassing liver Only about 50% of rectal dose can be assumed to bypass liver because suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate

D. Inhalation Lung may also serve as site of first-pass loss by excretion and metabolism for drugs administered by non-gastrointestinal (parenteral) routes

THE TIME COURSE OF DRUG EFFECT Immediate Effects Drug effects are directly related to plasma concentrations but this does not mean that effects simply parallel the time course of concentrations

Relationship between drug concentration effect is not linear Consider the effect of an angiotensinconverting enzyme (ACE) inhibitor, such as enalapril, on plasma ACE. The half-life of enalapril is about 3 hours. After an oral dose of 10 mg, the peak plasma concentration at 3 hours is about 64 ng/mL. Enalapril is usually given once a day, so seven halflives will elapse from the time of peak concentration to the end of the dosing interval. The concentration of enalapril after each half-life and the corresponding extent of ACE inhibition are shown in Figure 35

concentration is still half the C 50. This is very common for drugs that act on enzymes (eg, ACE inhibitors) or compete at receptors (eg, propranolol) When concentrations are in the range between four times and one fourth of the C 50, the time course of effect is essentially a linear function of time. It takes four half-lives for concentrations to drop from an effect of 80% to 20% of E max 15% of the effect is lost every half-life over this concentration range. At concentrations below one fourth the C 50, the effect becomes almost directly proportional to concentration and the time course of drug effect will follow the exponential decline of concentration. It is only when the concentration is low in relation to the C 50 that the concept of a half-life of drug effect has any meaning

Delayed Effects Changes in drug effects are often delayed in relation to changes in plasma concentration The delay reflects the time required for the drug to distribute from plasma to the site of action Distributional delay can account for the lag of effects after rapid intravenous injections of CNS active agents such as thiopental Reason for delayed effects is slow turnover of a physiologic substance that is involved in the expression of the drug effect

Example: warfarin Note that plasma concentrations of enalapril change by a factor of 16 over the first 12 hours (four half-lives) after the peak, but ACE inhibition has only decreased by 20%. Because the concentrations over this time are so high in relation to the C 50, the effect on ACE is almost constant. After 24 hours, ACE is still 33% inhibited. This explains why a drug with a short half-life can be given once a day and still maintains its effect throughout the day. The key factor is a high initial concentration in relation to the C 50. Even though the plasma concentration at 24 hours is less than 1% of its peak, this low Anticoagulant by inhibiting vitamin K epoxidase in the liver Reflects a decrease in the concentration of the prothrombin complex of clotting factors Inhibition of vitamin K epoxidase decreases the synthesis of these clotting factors, but the complex has a long half-life of about 14 hours Half-life determines how long it takes for the concentration of clotting factors to reach a new steady state and for a drug effect to reflect the average warfarin plasma concentration

Cumulative Effects Renal toxicity of aminoglycoside antibiotics is greater when administered as a constant infusion than with intermittent dosing; accumulation causes renal damage

Equation of maintenance intermittent doses are given

dose

when

THE TARGET CONCENTRATION APPROACH TO DESIGNING A RATIONAL DOSAGE REGIMEN Rational dosage regimen is based on the assumption that there is a target concentration that will produce the desired therapeutic effect

Maintenance Dose Drugs are administered as to maintain a steady state of drug in the body Clearance is the most important pharmacokinetic term to be considered in defining a rational steady-state drug dosage regimen At steady state, the dosing rate (rate in) must equal the rate of elimination (rate out) Substitution of the target concentration(TC) for concentration (C) predicts the maintenance dosing rate

Steady-state concentration achieved by continuous infusion or the average concentration following intermittent dosing depends only on clearance Example At different dosing intervals, the concentration-time curves will have different maximum and minimum values even though the average level will always be 10 mg/L

Loading Dose In theory, only the amount of the loading dose need be computed not the rate of administration and, to a first approximation, this is so Volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration

If desired target concentration is known; the clearance will determine the dosing rate Equation for oral dosing

If the rate absorption is rapid relative to distribution (always true for rapid IV), the concentration of drug in plasma that results from an appropriate loading dose calculated using the apparent volume distribution can initially be considerably higher than desired While the estimation of amount of a loading dose may be correct, the rate of administration can sometimes be crucial in preventing excessive drug concentrations, and slow administration of drug is almost always prudent practice Peak steady-state concentration

Apparent volume of distribution reflects a balance between binding to tissues, which decreases plasma concentration and makes the apparent volume larger, and binding to plasma proteins, which increases plasma concentration and makes the apparent volume smaller Changes in either tissue or plasma binding can change apparent volume of distribution Abnormal accumulation of fluid edema, ascites, pleural effusion can markedly increase the volume of distribution of drugs

D. Half-Life Differences between clearance and half-life are important in defining the underlying mechanisms for the effect of a disease state on drug disposition

TARGET CONCENTRATION INTERVENTION: APPLICATION OF PHARMACOKINETICS & PHARMACODYNAMICS TO DOSE INDIVIDUALIZATION Pharmacokinetic Variables A. Absorption Amount of drug that enters the body depends on the patients adherence to the prescribed regimen and on the rate and extent of transfer from the site of administration to the blood Variations in bioavailability are due to metabolism during absorption

*Example: Diazepam Half-life of the drug increases with patient age Clearance is related to age However, increasing half-life of the drug actually comes from changes in volume of distribution

Pharmacodynamic Variables A. Maximum Effect No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved Helps in avoiding toxicity

B. Clearance Abnormal clearance may be anticipated when there is major impairment of the function of the kidney, liver or heart Creatinine clearance is a useful quantitative indicator of renal function Drug clearance may be a useful indicator of the functional consequences of heart, kidney, or liver failure Hepatic disease does not always affect the hepatic intrinsic clearance

B. Sensitivity Sensitivity of target organ to drug concentration is reflected by the concentration required to produce 50% of maximum effect Increased sensitivity to a drug is usually signaled by exaggerated responses to small or moderate doses DRUG

C. Volume of Distribution

INTERPRETATION OF CONCENTRATION MEASUREMENTS

Clearance Clearance is the single most important factor determining drug concentrations Three factors that affect clearance Dose Organ blood flow Intrinsic function of the liver or kidney Factors affecting protein binding

1. Albumin concentration Phenytoin, salicylates, and disopyramide are extensively bound to plasma albumin Albumin levels are low in many disease states, resulting in lower total drug concentrations

Absorption usually occurs during the first 2 hours after a drug dose and varies according to food intake, posture, and activity Avoid drawing blood until absorption is complete (about 2 hours after an oral dose) Clearance is readily estimated from the dosing rate and mean steady-state concentration Blood samples should be appropriately timed to estimate steady-state concentration

Initial Predictions of Volume of Distribution & Clearance A. Volume of Distribution Commonly calculated for a particular patient using body weight (70 kg body weight is assumed) If a patient is obese, drugs that do not readily penetrate fat should have their volumes calculated from fat-free mass

2. Alpha1-acid glycoprotein concentration 1-Acid glycoprotein is an important binding protein with binding sites for drugs such as quinidine, lidocaine, and propranolol Increased in acute inflammatory disorders and causes major changes in total plasma concentration of these drugs

For women:

3. Capacity-limited protein binding For men: Binding of drugs to plasma proteins is capacity-limited Salicylates and prednisolone show concentration-dependent protein binding Increases in dosing rate will cause corresponding changes in the pharmacodynamically important unbound concentration Total drug concentration will increase less rapidly than the dosing rate would suggest as protein binding approaches saturation at higher concentrations

HTM is height in meters WT is total body weight in kilograms Patients with edema, ascites, or pleural effusions offer a larger volume of distribution to the aminoglycoside antibiotics than is predicted by body weight

B. Clearance Drugs cleared by the renal route often require adjustment of clearance in proportion to renal function Predicted creatinine production rate in women is 85% of the calculated value, because they have smaller muscle mass per kilogram and it is muscle mass that determines creatinine production

Dosing History Accurate dosing history is essential if one is to obtain maximum value from a drug concentration measurement Samples for Concentration

Timing of Measurement

Decrease of renal function with age is independent of decrease in creatinine production Fat-free mass should be considered rather than total body weight for obese patients and correction should be made for muscle wasting in severely ill patients

Revising Individual Estimates of Volume of Distribution & Clearance Interpretation of drug concentrations compares predictions of pharmacokinetic

parameters and expected concentrations to measure values If measured concentrations differ by more than 20% from predicted values, revised estimates of V or CL for that patient should be calculated using equation 1 or 2 (note: yun first 2 equations ito, go to start of reviewer) If the change calculated is more than a 100% increase or 50% decrease in either V or CL, the assumptions made about the timing of the sample and the dosing history should be critically examined