P harmacology RHPT-365 By M ajid A hmad G anaie M. Pharm., P h.D. Assistant Professor Department of Pharmacology E mail: Chapter 3: P HARMACODYNAMICS

Overview Drug(Ligand) + Receptor ⇋ Drug-receptor complex  Biologic effect “A drug doesn’t work unless it is bound” Drugs only modify underlying biochemical and physiological processes, they do not create effects de novo (anew)

DRUG RECEPTOR INTERACTION DRUG DOSE-RESPONSE RELATIONSHIP THERAPEUTIC INDEX Topics of Discussion

Receptor mechanisms:  Most drugs exert their effects by binding to receptors  This has the effect of either mimicking the body’s own (endogenous) substances binding to receptors or preventing their binding or actions II. Non-receptor mechanisms: These include: 1. Changing Cell Membrane Permeability (Ion Channels) 2. Actions on enzymes 3. Carrier Molecules, e.g. uptake proteins 4. Changing Physical Properties 5. Combining with Other Chemicals 6. Anti-metabolites Drug Mechanisms (How Drugs Act?)

Drugs typically exert their effects by interacting with a receptor Chemical bonds  Electrostatic  Hydrogen bond  Van der Waals Binding  Receptor selective  Requires exact fit  Usually reversible + I. Receptor Mechanisms

Types of receptor-effector linkage: E, enzyme; G, G-protein; R, receptor.

Major Receptor Families 1. Ligand-Gated Ion Channels  Regulation of flow of ions across cell membranes  Depolarization/Hyperpolarization of membrane  Associated with receptors for fast neurotransmitters  Nicotic receptor - Na +

Major Receptor Families 2. G-Protein coupled receptors – Largest family  3 components  7 membrane-spanning α helices  G protein – α subunit - GTPase & βγ  cAMP / IP3/ Phospholipase A2/ ion Ch  Four Steps  Ligand binding  G protein activation (cytoplasmic side)  Activity of effector (ion channel or enzyme) changed  Intracellular second messenger concentration changes cAMP: effector enzyme -- adenylyl cyclase, converting ATP to cAMP – phosphorylates proteins

G-Protein Coupled Receptor

Major Receptor Families 3. Kinase-linked receptors  Cytosolic enzyme activity as integral structure or function  Most common tyrosine kinase activity (Kinase = Phosphate)  Addition of phosphate changes 3D structure of protein  Insulin

Major Receptor Families 4. Nuclear receptors  TWO main categories  Those present in cytoplasm form complex with ligand – migrate to the nucleus eg. Steroid hormones  Present in nucleus – ligands usually lipids  Binds to specific DNA sequences resulting in regulating gene sequences – protein synthesis  Longer time course of action  Responsible for 10% of pharmacology and the pharmacokinetics of 60% of all prescription drugs

DRUG RECEPTOR INTERACTION DRUG DOSE-RESPONSE RELATIONSHIP THERAPEUTIC INDEX Topics of Discussion

Drug Dose-Response Relationship Graded dose-response relations  Drug-Receptor binding  Relationship of binding to effect  Potency  Efficacy Nature of interactions  Agonists  Antagonists  Functional antagonism  Partial agonists

Drug-receptor Binding Effect of dose on the magnitude of drug binding Relationship of binding to effect assumes  Magnitude proportional to receptors bound  Maximum efficacy when all receptors bound  Binding does not show cooperation Interactive Pharmacology

II. Non-receptor Mechanisms 1. Actions on Enzymes  Enzymes = Biological catalysts  Speed chemical reactions  Are not changed themselves  Some drugs alter enzyme activity & alter processes catalyzed by the enzymes  Examples  Cholinesterase inhibitors  Monoamine oxidase inhibitors  Example: Maprotiline inhibits NE carrier  blocks re-uptake of NE and increase its concentrations at the synapse 2. Interacting With Carrier/Transporter Proteins 3. Changing Physical Properties  Example: Mannitol  Changes osmotic balance across membranes  Causes urine production (osmotic diuresis)

Non-receptor Mechanisms, contd. 4. Changing Cell Membrane Permeability (Ion Channels)  Lidocaine (a local anesthetic)  decreases permeability of the nerve cell membrane to NA +  the rate of depolarization of the nerve membrane, threshold for electrical excitability, & propagation of the action potential  Verapamil & nefedipine (calcium channel blockers)  Block calcium channels  Ca influx into smooth and cardiac muscle  vasodialate vascular smooth muscle & myocardial contractility, slow AV nodal conduction  Adenosine (an inhibitory neurotransmitter)  Opens potassium channels 5. Combining with Other Chemicals  Examples  Antacids  Chelating agents (e.g., dimercaprol) that bind heavy metals, and thus reduce their toxicity

6. Anti-metabolites  An anti-metabolite is a chemical with a similar structure to a substance (a metabolite) required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division  Examples:  Anti-neoplastics e.g., 5-FU (5-fluorouracil)  inhibits RNA synthesis  Antimicrobials such as sulfonamide drugs, which inhibit dihydrofolate synthesis in bacteria by competing with para-aminobenzoic acid Non-receptor Mechanisms, contd.

Potency Graded dose-response curve shows potency  Determine Effective Concentration 50% EC50 ED50: The dose or concentration required to produce 50% of the maximal effect 50%

Efficacy Efficiency is dependent on number of drug-receptor complexes formed and corresponding cellular response A drug with more efficacy is better than drug with more potency

Nature of Interactions Agonist  If a drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand Partial agonist  Has intrinsic activity less than that of a full agonist

Theoretical occupancy and response curves for full vs partial agonists The occupancy curve is for both drugs, the response curves a and b are for full and partial agonist, respectively. The relationship between response and occupancy for full and partial agonist, corresponding to the response curves in A. Note that curve a produces maximal response at about 20% occupancy, while curve b produces only a submaximal response even at 100% occupancy.

Nature of Interactions Antagonist  Drugs that decrease the actions of the endogenous ligand.  Reversible vs Irreversible Functional antagonism (physiologic antagonism)  Antagonist binds completely separate receptor initiating effects functionally opposite of the agonist  Epinephine binding to ( β 2 adrenergic receptor ) reversing Histamine-induced bronchoconstriction (H 1 receptor)

Reversible vs irreversible competitive antagonists A.Reversible competitive antagonism – log concentration-effect curve shifts to right without change in slope maximum B.Irreversible competitive antagonism – Covalent bond formed with receptor eg. Aspirin & Omeprazole 1 = 50% occupancy

Body adapts to drugs Change in receptors  Refractory period after effect of first dose - Desensitisation Loss or addition of receptors  Internalization of receptors due to prolonged exposure to agonist – and converse. Exhaustion of mediators  Amphetamine release cathecholamine – stores depleted Increased metabolic degradation of drug  Tolerance Physiological adaptation

DRUG RECEPTOR INTERACTION DRUG DOSE-RESPONSE RELATIONSHIP THERAPEUTIC INDEX Topics of Discussion

Therapeutic Index Therapeutic index is the ratio of the dose that produces toxicity : dose for clinically desired effective response (50% o f population) Therapeutic Index = TD50/ ED50

High therapeutic index  NSAIDs  Aspirin  Tylenol  Ibuprofen  Most antibiotics  Beta-blockers Low therapeutic index  Lithium  Neuroleptics  Phenytoin  Phenobarbital  Digoxin  Immunosuppressives Therapeutic Index (T.I.), contd.

Summary Drugs only modify underlying biochemical and physiological processes, they do not create effects de novo (anew) 4 ways drugs and receptors interact Dose-Response Curve  Potency vs Efficacy  4 Nature of Interactions  Body adapts to drug Therapeutic Index

References Howland et al (2006) Lippincott’s Pharmacology 3 rd Ed. Rang et al (2007) Rang & Dale’s Pharmacology 6 th Ed.