chapter 3. clinical pharmacokinetics clinical pharmacokinetics, which involves the mathematical...

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  • Chapter 3. Clinical Pharmacokinetics Clinical pharmacokinetics, which involves the mathematical description of the process of drug absorption, distribution, metabolism, and elimination, is useful to predict the serum drug concentration under various conditions.
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  • 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.
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  • C. Bioavailability (F) refers to the fraction of a drug administered that gains access to the systemic circulation: F= Bioavailability is 100% following an intravenous injection (F=1), but drugs are usually given orally and the proportion of the dose reaching the systemic circulation varies with different drugs and also from patient to patient.
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  • Bioavilability (F) = Area under curve (AUC) Time (h)
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  • 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 bioavailability 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- selling product Redesign the pill with a coating stable in acid but dissolves in the more basic pH of the small intestine.
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  • 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 (K e ) = 0.69/ t 1/2 K e is the fraction of drug present at any time that would be eliminated in unit time (e.g. K e = 0.02 min -1 means that 2% of the drug present is eliminated in 1 min)
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  • V d = = The V d can be very large, even larger than the total body volume, if a drug is highly bound to tissues. This makes the serum drug concentration very low and the V d very large. Apparent volume of distribution
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  • Volumes of body fluid compartments for a 70 kg man: total body (42 L), intracellular (28 L) + extracellular (14 L = plasma 4 L + interstital 10 L). [a value V d of 15 L) distribution throughout the total body water or concentration in certain tissues.
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  • 4. The loading dose for a drug by IV injection = V d x C where C is the serum drug concentration oral loading dose =
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  • 5. Clearance the 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) = V d x K e = V d x 0.69/ t 1/2
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  • 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.
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  • 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 crud 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.
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  • c. For drug treatment, a steady state plasma concentration (C ss ) 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 C ss. This equation could be applied to an IV infusion.
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  • During repeated administrations, it takes 4-5 t 1/2 to attain a steady state drug concentration.
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  • There is also a concentration at steady sate for repeated doses. Some textbooks call this an average concentration (C ss, av ). Repeated dosing is associated with peak and trough plasma concentrations.]
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  • Oral maintenance dose = For oral administration
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  • 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 concentration. 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.
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  • Elimination of some drugs follow the zero-order reactions e.g. alcohol, heparin, phenytoin and aspirin at high concentration.
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  • Part II. Fundamentals of Pharmacodynamics and Toxicodynamics A. Pharmacodynamics is a description of the properties of drug- receptor interactions. Chapter 4. Drug receptors
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  • 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
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  • 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 and can be composed of subunits. 4. Frequently glycosylated
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  • 5. K d of drug binding to receptor (1-100 nM); binding reversible and stereoselective. 6. Specificity of binding not absolute, leading to drug binding to several receptor types (a continuum) 7. Receptors saturable because of finite number.
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  • 8. Specific binding to receptors results in signal transduction to intracellular site. 9. May require more than one drug molecule to bind to receptor to generate signal. 10. Magnitude of signal depends on number of receptors occupies or on receptor occupancy rate; signal is amplified by intracellular mechanisms
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  • 11. By acting on receptor; drugs can enhance, diminish, or 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 transduction. 14. Receptors can be up-regulated or down-regulated.
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  • C. Drugs bind to specific receptors with: (1) ionic bonds electrostatic, r 2 (2) hydrogen bonds, r 4 (3) Van der Waals forces, r 7 (4) covalent bonds
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • Myasthenia gravis autoantibody to the receptors in the neuromucsular junction administration of ACh esterase inhibitors e.g. neostigmine, physostigmine Receptor function altered by disease
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  • Graves, disease antithyrotropin receptor agonist effect thyroid hormone , hyperthyroidism
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  • 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 R