Chapter 3. Clinical Pharmacokinetics

Clinical pharmacokinetics, which involves the mathematical de

scription of the process of drug absorption, distribution, metabo

lism, and elimination, is useful to predict the serum drug conce

ntration under various conditions.

A. Absorption of a drug is usually fast, as compared to the elimination; thus, it is

often ignored in kinetic calculations.

B. Elimination usually follows the principles of first order kinetics, which means

that a constant fraction of the drug is eliminated per unit of time.

C. Bioavailability (F) refers to the fraction of a drug administered that gains a

ccess to the systemic circulation:

F= concentration of drug in the systemic circulation after oral administration

concentration of drug in the systemic circulation after IV administration

Bioavailability is 100% following an intravenous injection (F=1), but drugs are

usually given orally and the proportion of the dose reaching the systemic circul

ation varies with different drugs and also from patient to patient.

Bioavilability (F) = oral

IV

AUC

AUC Area under curve (AUC)

Time (h)

Example: Testing a compound (Newdrug) in clinical trials.

Newdrug is administered orally; plasma levels is determined;

only 75% of the oral dose reaches the circulation. the bioa

vailability of Newdrug is 0.75 or 75%.

Discover some of the drug is inactivated by the acid in the

stomach.

The bioavailability to 95%.

Newdrug becomes a best-sell

ing product

Redesign the pill with a coating stable in acid but dissolves in the more basic pH of the small intestine.

The half-life of a drug (t 1/2 ) the time required for the serum drug

concentration to be reduced by 50%

Elimination rate constant (Ke ) = 0.69/ t 1/2

Ke is the fraction of drug present at any time that would be elimin

ated in unit time (e.g. Ke = 0.02 min-1 means that 2% of the drug p

resent is eliminated in 1 min)

Vd = =total drug dose (mg)

plasma concentration at equilibrium (mg/ml)0

dose

C

The Vd can be very large, even larger than the total body

volume, if a drug is highly bound to tissues. This makes t

he serum drug concentration very low and the Vd very lar

ge.

Apparent volume of distribution

Volumes of body fluid compartments for a 70 kg man: total body (4

2 L), intracellular (28 L) + extracellular (14 L = plasma 4 L + interst

ital 10 L).

[a value Vd of < 5 L the drug is retained within the vascular comp

artment. a value Vd of < 15 L the drug is restricted to the extracellu

lar fluid, while (Vd > 15 L) distribution throughout the total body

water or concentration in certain tissues.

4. The loading dose for a drug by IV injection = Vd x C

where C is the serum drug concentration

dV x C

Foral loading dose =

5. Clearancethe rate at which a drug is cleared from the body.(Definition) the volume of plasma from which all drug is removed in a given time.

a. Clearance is measured as a volume per unit of time (or

ml/min)

b. Rate of drug elimination (mg/min) = Cl x C

(Cl) = Vd x Ke = Vd x 0.69/ t 1/2

a l0-liter aquarium; contains 10,000 mg of crud.concentration = 1 mg/ml. Clearance is 1 l/h. the aquarium filter and pump clear I liter of water in an hour.

At the end or the first hour, 1000 mg of crud has been removed

from the aquarium (1000 ml of 1 mg/ml). The aquarium thus has

9000 mg of crud remaining, for a concentration of mg/ml.At

the end of the second hour, mg of crud has been removed

(1000 ml of 0.9 mg/ml). The aquarium now has mg of cru

d remaining, for a concentration of mg/ml

a l0-liter aquarium; contains 10,000 mg of crud.concentration = 1 mg/ml. Clearance is 1 l/h. the aquarium filter and pump clear I liter of water in an hour.

c. For drug treatment, a steady –state plasma concentra

tion (Css) is required within a known therapeutic range.

A steady state will be achieved when the rate of drug entering the systemic circulation (dosage rate) equals the rate of elimination.

Thus, the dosing rate = Rate of drug elimination (mg/min) = Cl x Css. This equation could be applied to an IV infusion.

During repeated administrations, it takes 4-5 t 1/2 to at

tain a steady state drug concentration.

There is also a concentration at steady sate for repeated doses. So

me textbooks call this an average concentration (Css, av). Repeated

dosing is associated with peak and trough plasma concentrations.]

Oral maintenance dose = Cl x C x T

F

For oral administration

The above equations do not apply to drugs that have zero order elimination kinetics

They saturate the routes of elimination and will disappear from

plasma in a non-concentration dependent manner.

Thus, (1) a constant amount of drug is cleared per unit time;

(2) the half-life is not constant, but depends on the drug concent

ration.

e.g. clearance rate of ethanol is 10 ml/h, if one consumes 60 ml, 3 h is needed to clear half of it; however, if 80 ml is consumed, then 4 h is required.

Elimination of some drugs follow the zero-order reactions e.g. al

cohol, heparin, phenytoin and aspirin at high concentration.

Part II. Fundamentals of Pharmacodynamics and Toxicodynamics

A. Pharmacodynamics is a description of the properties of drug-receptor interactions.

Chapter 4. Drug receptors

P. Ehrlich, immunochemistry [toxin-antitoxin], chemotherapy [treatment of infectious disease with drugs derived from dyes]

Drug can have a therapeutic effect only if it “ has the right sort of affinity… combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor.”

Receptor concept

B. Nature of receptors

1. Protein; lipoprotein or glycoprotein

2. Usually located in cell membrane

3. Molecular mass in the range of 45-200 kd a

nd can be composed of subunits.

4. Frequently glycosylated

5. Kd of drug binding to receptor (1-100 nM); binding reversible and stereoselective.

6. Specificity of binding not absolute, leading to dru

g binding to several receptor types (a continuum)

7. Receptors saturable because of finite number.

8. Specific binding to receptors results in signal transdu

ction to intracellular site.

9. May require more than one drug molecule to bind to r

eceptor to generate signal.

10. Magnitude of signal depends on number of receptors

occupies or on receptor occupancy rate; signal is amplifi

ed by intracellular mechanisms

11. By acting on receptor; drugs can enhance, diminish, o

r block generation or transmission of signal

12. Drugs are receptor modulators and do not confer new

properties on cells or tissues

13. Receptors must have properties of recognition and tra

nsduction.

14. Receptors can be up-regulated or down-regulated.

C. Drugs bind to specific receptors with:

(1) ionic bonds –electrostatic, r2

(2) hydrogen bonds, r4

(3) Van der Waals forces, r7

(4) covalent bonds

D. Receptor classes:

1. Ligand-gated ion-channel receptors

2. Voltage-dependent ion channel receptors

3. G-protein-coupled second messenger receptors

4. Receptors with tyrosine kinase activity

Ligand-gated ion-channel receptors

• Nicotinic acetylcholine (Ach) receptor

– skeletal muscle end plate of the neuromuscular junction, autonomic ganglia and CNS

– Ach binding causes electric signal via Na + and K + influx

• GABA receptor

– A type inhibitory Cl- influx, e.g. benzodiazepane

Voltage-dependent ion channel receptors

• membrane bound, excitable nerve, cardiac and skeletal muscle

• membrane deplorization conformational change, channel open, Na+ and Ca++ ion influx

• blockade of the receptors, the mechanism of local anesthetics and some anti-hypertensive agents

G-protein-coupled second messenger receptors

• cAMP, IP3 (inositol triphosphate), DAG (diacyl glycerol) cascade

– binding of the receptor

– activation of membrane bound G protein

– activation of membrane bound enzyme

– activation of intracellular kinases

• GTP(GDP) binding protein, subunit activate or inhibit adenylcyclase and phospholipase C

Receptors with tyrosine kinase activity

• Growth factors receptors e.g. insulin, EGF, PDGF

– extracellular domain and intracellular

• domain, autophosphorylation

– exclusive on OH- group tyrosine residues

E. Receptor dynamism

- Desensitization

(1) uncoupling of receptor

(2) internationalization and sequestration

(3) down-regulation enzymatic degradation

- Sensitization

thyroid hormone, myocardial receptor , heart

rate elevated

Myasthenia gravis

autoantibody to the receptors in the neuromucsular junction

administration of ACh esterase inhibitors e.g. neostigmine,

physostigmine

Receptor function altered by disease

Graves, disease

antithyrotropin receptor

agonist effect

thyroid hormone , hyperthyroidism

1. the drug-receptor interaction follows the laws of mass

action.

a. drug molecules bind to receptors at a rate that is

dependent on the drug concentration

b. the number of drug-receptor interactions determines

the magnitude of the drug effect.

Chapter 5. Dose-Response Relationship

Simple occupancy theory by A.J. Clark

Law of mass actionadsorption of gas -metal surface, hyperbolic curve,

[X] + [R] [XR] E(effect)

Kd = [X][R]/[XR]

Langmuir adsorption isotherm

Assumptions in simple occupancy theory of A.J. Clark :

(1) magnitude of pharmacological effect (E) directly pr

oportional to XR

(2) Emax when all receptors are bound with X

Discrepancy to the simple occupancy theory by A.J. Clark

• “Some experimental data indicates that maximal effect can be achieved with <100% occupancy; leaving ‘spare receptors’ ”

2. Representation of the dose-response curves

a. graded (e.g. blood pressure)

b.quantal (all or none) [e.g. death]

Graded representation

quantal (all or none) representation

Agonists - compounds that activate receptor-mediated processes vi

a reversible interactions based upon the laws of mass action.

3. Agonists and Antagonists

Fig 6-4 shows a series of agon

ists with various affinity to the

same receptor

ED50 tells the relative potency

e.g. A is 20-30 times more

potent than D.

Efficacy is the maximal response a drug can produce. Potencyis a measure of the dose (for a drug ) to produce a response (e.g. ED50 )

But, all four drugs have same efficacy.

Exception of Clark occupancy model: Non-linear relation

ship between occupancy and response

[X] + [R] [XR] E(effect)

Intrinsic activity or efficacy introduced by Ariens and Ste

phenson (1956): inherent qualities of the drug, independe

nt of concentration, that modulate the effect.

Intrinsic activity or efficacy

Fig 6-5: same affinity (i.e. same ED50), efficacy differs, A is 2.5 tim

es more efficacious than C (partial agonist) dual effect (antagonist al

so).

Antagonists are compounds that diminish or prevent agonistic effects

and are usually classified as competitive or noncompetitive.

1. competitive - for same binding site; the efficacy of agonist m

ay be regained if concentration high, Fig 6-6,

2. noncompetitive, allosteric inhibition, Fig 6-7, this effect can’t be reversed by increasing concentration of agonist

Without anatgonist

With less or more anatgonist

Other types of antagonisms:

Physiological antagonism - compensatory mechanism

to maintain homeostasis

Chemical antagonism -forming complex

Phamacokinetic antagonism - enzyme induction to inc

rease metabolism or elimination