Mechanism of drug action


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MECHANISM OF DRUG ACTION By Dr.K.Chandrakala Assistant professor

What is Pharmacodynamics? : 

9/26/2010 2 What is Pharmacodynamics? What the drug does to the body when it enters? Defn: It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level as well as cellular level.


PRINCIPLES OF DRUG ACTION Do NOT impart new functions on any system, organ or cell Only alter the PACE of ongoing activity STIMULATION DEPRESSION IRRITATION REPLACEMENT CYTOTOXIC ACTION 9/26/2010 3

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Enhancement of level of activity of specialised cells –Pilocarpine stimulates salivary glands, Picrotoxin – CNS stimulant Depression - Barbiturates depress CNS, Quinidine depresses Heart Certain drugs – stimulate one cell type and depress others Ex: Ach – stimulates smooth muscle but depresses SA node 9/26/2010 4

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Excessive stimulation is often followed by depression of that function Certain drug –depression coma Irritation-- Non-selective often noxious effect – applied to less specialised cells (epithelium, connective tissue) Replacement-- Use of natural metabolites, hormones or their congeners in deficiency states Levodopa in parkinsonism, Iron in anaemia 9/26/2010 5 convulsions death

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Cytotoxic action--Selective cytotoxic action for invading parasites or cancer cells – for attenuating them without affecting the host cells Penicillin, chloroquine Counterirritants-- increase blood flow to a site 9/26/2010 6

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1. Enzymes – drug targets All Biological reactions are carried out under catalytic influence of enzymes – major drug target Drugs – increases/decreases enzyme mediated reactions In physiological system enzyme activities are optimally set Enzyme stimulation is less common by drugs – common by endogenous substrates Pyridoxine (cofactor in decarboxylase activity) Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia) Enzyme inhibition – common mode of drug action

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Enzyme Inhibition - Examples Equilibrium: Physostigmine Vs Acetylcholine (cholinesterase) Sulfonamides Vs PABA (folate synthetase) Moclobemide Vs Catecholamines (MAO-A) Captopril Vs Angiotensin 1 (ACE) Nonequilibrium: Orgnophosphorous compounds/Nerve gases (cholinesterase) Non-competitive: Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) , Aspirin (cyclooxygenase)

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Ion Channnels Proteins take part in transmembrane signaling and regulates ionic composition Drugs also target these channels: Ligand gated channels G-protein operated channels Direct action on channels Examples: Local anaethetics and Class I anti arrythmics act/depress Na+ channels

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Transporters Substrates are translocated across membrane by binding to specific transporters (carriers) – Solute Carrier Proteins (SLC),ATP binding cassettes(ABC). Pump the metabolites/ions In the direction of concentration gradient or against it Drugs interact with these transport system Examples: Probenecid (penicillin and uric acid), Furosmide (Na+K+2Cl- cotransport), Hemicholinium (choline uptake) and Vesamicol (active transport of Ach to vesicles 9/26/2010 11

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Receptors Drugs usually do not bind directly with enzymes, channels, transporters or structural proteins, but act through specific macromolecules – RECEPTORS Definition: It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. G-protein coupled receptor 9/26/2010 12

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Some Definitions Agonist: An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine) response Ra Ri RaA Ri

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Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine no response 9/26/2010 14 Ra Ri RaB RiB

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Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. pentazocine Partial response 9/26/2010 15 RaC+Ra Ri+RiC

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Inverse agonist: an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM on bzp receptors opposite response 9/26/2010 16 Ra Ri+RiD

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Ligand: any molecule which attaches selectively to particular receptors or sites (only binding or affinity) Affinity: Ability of a substrate to bind with receptor Intrinsic activity (IA): Capacity to induce functional change in the receptor If explained Agonist: Affinity+ IA Antagonist: Affinity+ IA (0) Partial agonist: Affinity + IA (0-1) Inverse agonist: Affinity + IA (0 to -1)

Drug Mechanisms : 

Drug Mechanisms Receptor interactions Non-receptor mechanisms

Receptor Interactions : 

Receptor Interactions Agonist Receptor Agonist-Receptor Interaction Lock and key mechanism

Receptor Interactions : 

Receptor Interactions Receptor Perfect Fit! Induced Fit

Receptor Interactions : 

Receptor Interactions Antagonist Receptor Antagonist-Receptor Complex DENIED! Competitive Inhibition

Receptor Interactions : 

Agonist Receptor Antagonist ‘Inhibited’-Receptor DENIED! Receptor Interactions Non-competitive Inhibition


TYPES OF RECEPTORS 1.Ion gated channels 2.G- protein coupled receptors 3.Cellular receptors 4.Nuclear receptors 9/26/2010 23

Ion channels : 

Ion channels

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Ligand gated ion chanels Fastest intracellular responce, ms Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce Ligands Fast neurotransmittors ex. Acetylcholine (nicotinic reseptors) Nobel prize chemistry 2003, Roderick MacKinnon “for structural and mechanistic studies of ion channels”.

G-Protein coupled receptor : 

G-Protein coupled receptor Membrane bound receptors which are bound to effector system through G-proteins. These are hetero trimeric molecules having 3 subunits α,β and ϒ. Based on α-sub unit they are further classified into 3 main varieties Gs, Gi and Gq 9/26/2010 26

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G-Protein coupled receptors G-protein: Guanine nucleotide binding protein

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Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C One ligand can bind to more than one type of G-prot. coupled receptors second messenger pathways

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Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C second messenger pathways


ENZYME LINKED RECEPTORS a. Intrinsic enzyme receptors intracellular domain is either protein kinase or guanyl cyclase Ex:Insulin,EGF,NGF b.JAK-STAT-Kinase binding receptors no intrinsic catalytic domain but agonist induced dimerization affinity for cytosolic tyrosine kinase protein Ex:cytokines,growth hormone,IF 9/26/2010 30

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Enzyme coupled receptors - Catalytic receptors STAT: Signal transducers and activators of transcription Ligands: Peptide hormones


TRANSCRIPTION RECEPTORS Receptors regulating gene expression Intracellular- cytoplasmic or nuclear Ex:All steroid hormones,thyroxine, Vit A 9/26/2010 32

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Cytoplasmic receptors (not bound to cell membranes) (HSP-90: Heat shock protein)

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Receptor subtypes Most receptor classes - several sub-types Each subtypes - differend A(nta)gonists Sub types cholinerge reseptors Nicotinerge receptors Muscarinerge receptors Acetylcholine M1: G-Protein coupled receptors Stimulate phopholipase A M2: G-Protein coupled receptors Inhib. adenylyl cyclase Nmuscle: Ligand gated ion chanels Incr. Na+/Ca2+ Nneuro: Ligand gated ion chanels Incr. Na+/Ca2+

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Spare receptors - Partial agonist

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Desensitizing Sensitizing


FUNCTIONS OF RECEPTORS To propogate signals from outside to inside To amplify the signal To integrate various extracellular and intracellular regulatory signals To adapt to long term changes in maintaining homeostasis 9/26/2010 37

Non-receptor Mechanisms : 

Non-receptor Mechanisms Actions on Enzymes Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves Drugs altering enzyme activity alter processes catalyzed by the enzymes Examples Cholinesterase inhibitors Monoamine oxidase inhibitors

Non-receptor Mechanisms : 

Non-receptor Mechanisms Changing Physical Properties Mannitol Changes osmotic balance across membranes Causes urine production (osmotic diuresis)

Non-receptor Mechanisms : 

Non-receptor Mechanisms Changing Cell Membrane Permeability Lidocaine Blocks sodium channels Verapamil, nefedipine Block calcium channels Bretylium Blocks potassium channels Adenosine Opens potassium channels

Non-receptor Mechanisms : 

Non-receptor Mechanisms Combining With Other Chemicals Antacids Antiseptic effects of alcohol, phenol Chelation of heavy metals

Non-receptor Mechanisms : 

Non-receptor Mechanisms Anti-metabolites Enter biochemical reactions in place of normal substrate “competitors” Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives


THANKYOU 9/26/2010 43

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