Pharmacodynamics PDF

Pharmacodynamics Ewura Seidu Yahaya 1 Pharmacodynamics Intro Disposition Distribution Elimination Absorption Metabolism Blood +...

Pharmacodynamics Ewura Seidu Yahaya 1 Pharmacodynamics Intro Disposition Distribution Elimination Absorption Metabolism Blood + Excretion 2 Pharmacodynamics Intro 3  Principles of Drug action Drug effects are produced by altering the normal functions of cells and tissues in the body A. Interaction with receptors B. Alteration of the activity of enzymes C. Antimetabolite action D. Nonspecific chemical or physical interactions 4 Principles of Drug action A. Interaction with receptors I. Ligand-activated ion channels. 5 Principles of Drug action II. G-protein–coupled receptors The largest class of receptors; seven transmembrane segments - three intracellular loops + an intracellular carboxy-terminal tail. Biologic activity mediated via interaction with a number of G (GTP binding) proteins. 6 Principles of Drug action II. G-protein–coupled receptors ✓Gαs-coupled receptors. 7 Principles of Drug action II. G-protein–coupled receptors ✓Gαi-coupled receptors 8 Principles of Drug action II. G-protein–coupled receptors ✓Gq (and G11)-coupled receptors 9 Principles of Drug action III. Receptor-activated tyrosine kinases 10 Principles of Drug action IV. Intracellular nuclear receptors 11 Mechanism of Drug action Major categories of targeted proteins: A. Enzymes Stimulation Direct Via receptors & 2nd messengers Induction Inhibition Competitive Noncompetitive 12  Mechanism of Drug action Major categories of targeted proteins: A. Enzymes Stimulation Direct Via receptors & 2nd messengers Induction Inhibition Competitive Noncompetitive 13  Mechanism of Drug action Major categories of targeted proteins: B. Receptors Agonist: activates a receptor to produce a response similar to that of the physiological signal molecule Full agonists Partial agonists: produces submaximal effect and antagonises full agonist Inverse agonist: produces effect in the opposite direction to the agonist 14  Mechanism of Drug action Major categories of targeted proteins: B. Receptors Antagonist: prevents action of an agonist on a receptor or subsequent response Competitive Non-competitive 15  Mechanism of Drug action Major categories of targeted proteins: B. Receptors Ligand: any molecule which attaches selectively to particular receptors or sites Ability of a drug to initiate cellular effect = Efficacy Ability to bind with receptor = Affinity 16 Drug-Receptor Interactions Drugs mostly bind to receptors by forming reversible hydrogen, ionic or hydrophobic bonds with the receptor site D-R interaction is stereospecific Law of mass action: 𝑘2 A drug’s dissociation constant (KD) = = 50% occupancy 𝑘1 17 Receptor regulation and Drug Tolerance Receptors can undergo dynamic changes with respect to their density (down-regulate) affinity for drugs/ligands (desensitization) Continuous agonist exposure can desensitize receptors (tachyphylaxis) Repeated exposure to antagonist can initially increase receptor response (supersensitivity) Chronic exposure to antagonist can increase number of receptors (upregulation) 18 Receptor regulation and Drug Tolerance Tolerance: same dose of drug given loses effect Pharmacodynamic tolerance (receptor downregulation) Pharmacokinetic tolerance (upregulation of metabolising enzymes) Disease state can alter receptor number and function e.g. myasthenia graves 19 Dose-response relationships Graded (continuous) response Each response is described in terms of a percentage of the max response 20 Dose-response relationships Quantal (all or none) response 21 Describe the DRC below: 22 Synergism and Antagonism Synergism Additive (A+B = A+B) Aspirin + Paracetamol; Amlodipine + Atenolol; Glibenclamide + Metformin Supraadditive (potentiation); A+B > A+B Acetylcholine + Physostigmine Sulfamethoxazole + Trimethoprim Antagonism (A + B < A + B) Physical antagonism Charcoal in alkaloidal poisoning 23 Synergism and Antagonism Chemical antagonism Oxidation of alkaloids by KMnO4; Chelating agents and toxic metals; Reaction of drugs in syringe Physiological/Functional antagonism 2 drugs with opposite effects on same physiological fxn Glucagon and insulin Receptor antagonism 24 Clinical Pharmacokinetics Dr. ES Yahaya 25 Clinical Pharmacokinetics PK: Describes changes in plasma drug concentration with time Not practicable to determine amount of drug that reaches site of action with time, though ideal 26 Clinical Pharmacokinetics Distribution and Elimination One Compartment model IV dose Drug in body t1/2 Drug eliminated V 27 Clinical Pharmacokinetics Distribution and Elimination One Compartment model If mechanisms of elimination are not saturated, semilog plot of conc. Vrs T will be linear after a single IV dose Elimination is 1st order Plasma concentration at time t: In Ct = ln C0 –kt Plasma concentration at any two points: In C2 = ln C1 – k (t2-t1) 28 Clinical Pharmacokinetics Distribution and Elimination Two Compartment model Distribution phase Elimination phase Linear for 1st order elimination 29 Clinical Pharmacokinetics Distribution and Elimination Order of elimination First-order Most drugs Constant fraction eliminated per unit time Rate of elimination is a linear function of the plasma drug concentration Occurs when elimination systems are not saturated by drug 30 Clinical Pharmacokinetics Distribution and Elimination Order of elimination Zero-order Constant amount eliminated per unit time Concentration-time plot decreases in a concave upward manner Occur when therapeutic dose of drug exceeds capacity of elimination mechanisms 31 Clinical Pharmacokinetics Half-life (t1/2) Determined by Log-plasma drug concentration vrs time profile of drugs in a one compartment model Elimination phase of drugs in two compartment model Constant if dose does not exceed capacity of elimination system 32 Clinical Pharmacokinetics Half-life (t1/2) Applies only to drugs eliminated by first order kinetics t1/2 = 0.693/k = 0.693Vd/Cl NB: Vd = Cl/k Where first order applies, >95% of drug will be eliminated within 5 t1/2 33 Clinical Pharmacokinetics Multidose kinetics Infusion and multi-dose repeat administration 1st order kinetics + Continuous IV infusion at a constant dose rate; Constant steady-state plasma concentration will be reached when the rate of elimination becomes equal to the rate of administration 1st order kinetics + repeated administration; average plasma concentration of drug will increase until a mean steady-state level is reached The time required to reach steady state is equal to five half-lives. NB: Whenever a dose rate is changed it will take five half-lives for a new steady-state level to be reached for any route of administration. 34 Clinical Pharmacokinetics Multidose kinetics Steady state after repeat administration Some fluctuation in plasma concentration will occur even at steady state. The magnitude of fluctuations can be controlled by the dosing interval. A shorter dosing interval decreases fluctuations, and a longer dosing interval increases them. On cessation of multidose administration, >95% of the drug will be eliminated in a time interval equal to five half-lives if first-order kinetics applies. 35 Clinical Pharmacokinetics Multidose kinetics Maintenance dose rate Dose of a drug required per unit time to maintain a desired steady-state level in the plasma Maintenance dose rate = Desired [drug]plasma × Clearance (CL) If one administers a drug at the maintenance dose rate, a steady-state plasma concentration of the drug will be reached in four to five half-lives 36 Clinical Pharmacokinetics Multidose kinetics Loading dose To rapidly achieve therapeutic concentration of drug in plasma Loading dose = Desired [drug]plasma × Vd After administration of the loading dose one administers the drug at the maintenance dose rate to maintain the drug concentration at the desired steady-state level 37