Pharmacodynamics

Site of action of drugs Type of action of drugs Mechanism of action of drugs

Cell wall Cell membrane Ribosomes DNA Intracellular proteins Like tubulin Site of action of drugs Ribosomes Cell wall Cell membrane DNA (Chromosomes)‏ Bacterial cell

The drug may act by: 1. Stimulation: of various functions. Eg. Adrenaline -  Heart rate,  BP etc. Acetylcholine –  the smooth muscle tone – bronchospasm 2. Depression: of various functions. Eg. Acetylcholine -  in heart rate Opioids - respiratory depression

The drug may act by : (contd.) 3. Irritation: Irritation is generally localized. Alcohol acts as an appetiser by gastric irritation. 4. Replacement: Hormones, Vitamins Hypothyroidism – Thyroxine Rickets – Vit. D & Calcium 5. Cytotoxic action: selective toxicity on parasite or bacteria or cancer cells. Eg.Penicillin(lysis of cell wall), Anticancer drugs

Mechanism of action of drugs Physical action Chemical action Action on Target proteins - Molecular mechanism of action Carrier proteins (Transporters) Ion channels Enzymes Receptors

Mechanism of Action of Drugs Physical action: physical property is responsible for the action of the drug: –Adsorption - Charcoal –Osmotic activity - Mannitol, Mag. sulphate –Bulk action - Bulk purgatives (methylcellulose) Chemical action: chemical property is responsible for the action of the drug: –Antacids - neutralise acid in the stomach –Chelating agents - form complexes with heavy metals. –Oxidising agents – potassium permanganate oxidises snake venom Action on Target proteins (Molecular mechanism of action)‏

Mechanism of action of drugs Action on Target proteins - Molecular mechanism of action Carrier proteins (Transporters) Ion channels Enzymes Receptors

Action on Target proteins Carrier proteins (Transporters) – Facilitate the transport of less lipid soluble molecules. Drugs acting on these are – Diuretics, Digoxin

Ion channels (voltage gated ion channels) – are pores that span across the membranes & can switch between open & closed states. Activated by membrane voltage alterations. Na + channels open when membrane is depolarized to a threshold potential & contribute to further depolarization by allowing Na + influx into cell. Cation channels: Na +, K +, Ca ++ channels – Eg. Na + channels are blocked by Local anaesthetics Anion channels: Cl - channels activated by GABA & Diazepam

Action on enzymes: 1. Stimulation: stimulation of microsomal enzyme activity in liver. Eg. Alcohol - enhanced metabolism of drugs 2. Inhibition: is a common mode of action Lisinopril - Angiotensin converting enzyme inhibitor - used in treatment of Hypertension Physostigmine – Cholinesterase inhibitor – used in treatment of Glaucoma (increased intraocular tension)

3. Substrate competition: when 2 substrates compete for the same enzyme. Sulphonamides compete with PABA for enzyme Folate synthetase & inhibit synthesis of folic acid in bacteria. 4. False substrate act as false substrate for the enzymes to form an abnormal product toxic to the cell. Fluorouracil – anticancer drug 5. Enzymes activate Prodrugs Enalapril, Aciclovir

Action on Receptors : Receptors (R) are macromolecular components present on the surface or inside a cell with which the drug interacts to produce its action. Confirmational changes in the R lead to a cascade of events mediating the pharmacological action of the drug. Drug + Receptor --> Drug-Receptor complex -> Effect

Receptors Usually they are proteins. Receptor specificity - interact with only a limited number of structurally related compounds known as ligands. Selectivity of drug action – is due to combination with specific receptors to produce effect e.g. Propanolol Vs Atenolol

Ligand: is a molecule that attaches selectively to a receptor. Eg. Agonists – ACh, Adrenaline Antagonists - Atropine, Propranolol

Affinity: ability of the drug to combine with R Efficacy (Intrinsic activity): ability of the drug to activate the R consequent on occupation to produce response.

Partial agonist: produces lower response at full R occupancy & has low efficacy. Affinity + partial intrinsic activity Also act as weak antagonists & competitively inhibit the binding of full agonists to the R. Eg: Nalorphine is a partial agonist at morphine receptors. Agonist: is a ligand that can bind to a receptor & elicit a pharmacological response. Affinity + Intrinsic activity Adrenaline, Acetylcholine

Antagonist: binds to a receptor without producing a pharmacological response Affinity + No intrinsic activity Prevents agonist from occupying a receptor. Agonists – ACh, Adrenaline Antagonists - Atropine, Propranolol

Receptor functions: Receptors are present in various tissues & distribution determines the actions of drugs. Receptors function as regulatory proteins & are the key determinants of therapeutic & toxic effects of drugs. The response to a drug is proportional to the number of drug - receptor complexes formed. Receptors are the sensing elements of chemical signaling mechanisms that coordinate the function of all the cells in the body. Binding of drugs to receptors initiates a chain of events involving `Second Messengers'. 11

Action on Receptors : Confirmational changes in the Receptor lead to a cascade of events mediating the pharmacological action of the drug. Drug + Receptor  Drug-Receptor complex  Cascade of events  Effect or response to drug

Receptor super families (Types)‏ Classification is based on receptor structure & transduction (sequence of events between R occupancy & response to drug) mechanisms: 1. Ligand gated ion channels (Inotropic R): Eg. Nicotinic ACh R 2. G-protein coupled receptors – GPCR - Metabotropic R – Serpentine R Eg. Receptors to many hormones, muscarinic R Drug + Receptor --> Drug-Receptor complex -> Effect

Receptor super families 3. Enzyme or Kinase linked receptors: Eg. Insulin Receptors 4. DNA linked Receptors (Nuclear receptors)‏ Eg.: Steroid, Thyroid, Vit. D Receptors

Eg. Acetylcholine (Nicotinic R)‏

Ligand gated ion channels (Inotropic R)‏ Ion channels are transmembrane spanning proteins for the passage of specific ions altering the electrical potential across the membrane. Ion passage may depend on concentration gradient or voltage gradient. When drug binds to a receptor, the channel either opens or closes. The lag period between the binding of the agonist & the cellular response is in milliseconds. This allows rapid moment to moment transfer of information across synapses. In most cases an agonist opens the channel while antagonist prevents this opening

Inotropic Rceptor

G-protein coupled receptors Comprise a large class of membrane-bound Receptor. Structure: 7- transmembrane domain where a single polypeptide chain snakes across the plasma membrane 7 times (Serpentine R). G protein activation, in turn activates ion channels or other enzymes (eg. adenylate cyclase), leading to stimulation of many other enzymes (eg. protein kinase A) resulting in amplification of the signal. The duration of activation of G protein may be longer relative to the binding of drug to R leading to maximal effects even when only a small proportion of receptors are activated.

G-protein coupled receptors

Tyrosine-kinase receptors Eg. Insulin, Atrial natriuretic peptide (ANP)‏ Receptors exist as individual polypeptides Each has an extracellular ligand binding site and cytoplasmic enzyme domain, which may be a protein tyrosine kinase or other enzymes. Spanning the membrane the two domains are connected by a polypeptide chain that crosses the lipid bilayer of the plasma membrane. Enzyme or Kinase linked receptors

DNA linked receptors Receptors are intracellular. E.g. Corticosteroids, Thyroid hormone, Vit. D Drug first binds to a cytoplasmic receptor & the drug- receptor complex enters the nucleus & binds to genes to produce mRNA mRNA expresses proteins which regulate / alter cell function. Lag period for onset of action (required for synthesis of new proteins) is lengthy. Hence, the agonists are ineffective in emergency due to delay in onset of action & duration of action may extend beyond the presence of the drug in the body.

DNA linked receptors

Different mechanisms by which drugs act through receptors

Objectives for Self study Receptors – various terminology related to receptors. Receptor Ligand Agonist Antagonist Partial agonist Receptor functions Receptor superfamilies Structure, function & examples for Ligand regulated ion channels GPCR Tyrosinekinase linked receptors DNA linked receptors