Pharmacodynamics - I Dr. Jyoti M. Benni Dept. of Pharmacology USM-KLE, IMP Belgaum Learning outcomes • Describe the principles of pharmacodynamics with regard to the potential targets of -drug action -receptor types -dose-response relationship (curve) -therapeutic index 2 Introduction: PK & PD 3 Pharmacodynamics Pharmacodynamics is the study of actions of the drug on the body and their mechanism of action. Stimulation Depression Irritation Replacement Modify immune status Anti-infective / Cytotoxic action 4 Mechanisms of Drug Action Non-receptor mediated Receptor mediated • Physical • Receptors on the cell • Chemical membrane • Enzymes • Ion channels • Transporters • Receptors inside the cell • Antibody • Placebo 5 Non – receptor mediated mechanisms… Physical property . Physical property of the drug is responsible E.g. Adsorption: activated charcoal in treatment of poisoning Osmotic activity: magnesium sulfate for constipation Radioactivity: radioactive iodine (I131 ) for hyperthyroidism Radioopacity: barium sulfate as contrast media 6 Non – receptor mediated mechanisms… Chemical action Antacids - neutralize gastric acid Chelating agents (EDTA) Used in heavy metal (LEAD)poisoning treatment Oxidizing agents potassium permanganate as germicidal agent 7 Non – receptor mediated mechanisms… Enzymes as targets of drug action Enzymes Inhibition Stimulation Enzyme Nonspecific Specific induction Competitive Noncompetitive 8 Non – receptor mediated mechanisms… Enzyme stimulation: • Reactivation e.g. Injection pralidoxime → for treatment of Organophosphorus (insecticide) poisoning • Induction e.g. barbiturates → treatment of neonatal jaundice Enzyme inhibition: Non specific inhibition: Heavy metal salts, strong acids and alkalis. These alter all the enzyme activity with which they come in contact 9 Specific Enzyme inhibition by drugs • A substance that decreases the velocity of an enzyme-catalyzed reaction is called an inhibitor. 10 Drug by Competitive inhibition Drug by Noncompetitive inhibition drug drug • Binds to the same site as • Binds to the site other than active substrate site • Only binds to free enzyme • Binds to either free enzyme or • Effect is reversed with ↑ in enzyme substrate complex. substrate concentration • Effect cannot be overcome by ↑ in • Vmax – same substrate concentration Km – increases • Vmax – decreases Km – same • Ex: Dopa decarboxylase – • Ex- Aspirin- cyclooxygenase carbidopa (Parkinson’s disease) (inflammation) cholinesterase – neostigmine • Omeprazole – H+K+ ATPase (myasthenia gravis) ( peptic ulcer) 11 The Michaelis - Menten constant (Km) – the substrate concentration at which the rate of a reaction is half of Vmax Vmax = 3.4 ½ V max= 1.7 Km = 0.4 Vmax – same Km – increases Vmax – decreases Km – same 12 Non – receptor mediated mechanisms… Ion channels • Ex: + local anesthetics – block Na channels ++ Nifedipine blocks L-type of voltage sensitive Ca channels (antihypertensive) 13 Non – receptor mediated mechanisms… Transporters • Drugs produce their action by directly interacting with the transporter proteins to inhibit the ongoing physiological transport of the metabolite/ion • Ex: – Fluoxetine blocks SERT (Depression) – Tiagabine blocks GAT1 (convulsions) 14 Non – receptor mediated mechanisms… Antibody production Examples • Stimulation of Antibody • BCG against Tuberculosis production in body • Polio vaccine against Polio 15 Non – receptor mediated mechanisms… Placebo (Latin term – I shall please) . Dummy medicine without Pharmacological activity Uses – Relief of subjective symptoms eg. Anxiety, headache, insomnia – In Clinical trials to reduce bias Influencing Factors Patient personality Drug -Injection, Capsule Doctor patient relationship 16 Receptor mediated drug action The concept of drugs acting on receptors generally is credited to John Langley (1878). Drug[D] + Receptor[R] DR-Complex Action 17 Drug-receptor interaction: Terms AGONIST ANTAGONIST (BLOCKERS) • Is a drug that • Is a drug that combines with the combines with the receptor but does not initiate any receptor and initiates a sequence of cellular response. biochemical or • It prevents the binding of an agonist to physiological changes. the receptor. Eg. Propranolol, atropine • Eg. Adrenaline, • Types: Acetylcholine • Competitive antagonist • Types: • noncompetitive antagonist – Partial agonist – Full agonist 18 Drug-receptor interaction: Terms Affinity: Ability of the drug to bind to the receptor Intrinsic activity or efficacy: Ability of a drug to produce pharmacological activity after binding 1. Agonists possess both affinity and intrinsic activity (IA=1) 2. Antagonists possess affinity but lack intrinsic activity (IA=0) 19 Receptor: Types (GPCRs) / nuclear receptors 20 Drugs acting through receptors : Transmembrane receptor signaling mechanisms 21 Transmembrane receptor signaling mechanisms 22 Intracellular receptors ex: steroid hormones exert their action on target cells via this receptor mechanism 24 Receptor regulation 25 Receptor Regulation Down regulation Up regulation • Prolonged use of agonists • Prolonged use of antagonists ↓ [Propranolol] ↓ Receptor [β2] no. and sensitivity decreases Receptor no. and sensitivity ↓ increases ↓ Drug effect ↓ [Sudden withdrawal → ↑ Ex: Salbutamol in trt. of sensitivity of bronchial asthma adrenoreceptors → Angina Decreased effect on chronic precipitates use 26 Receptor Regulation Target cells 27 Sites of action of agonists and antagonists 28 Receptor Antagonism Competitive Noncompetitive (Surmountable) (Unsurmountable) . Binds with the same site on the . Binds to another site receptor . Antagonist resembles agonist No resemblance with agonist . Surmountable by increasing . Not surmountable conc. of agonist . Flattening of DRC . Rightward shift of DRC Eg. Eg. Diazepam –Bicuculline Acetylcholine – Atropine Phenoxybenzamine- Morphine - Naloxone Noradrenaline 29 Receptor antagonism 30 Dose Response Relationship DRC: has 2 components Dose- Plasma conc. relationship Plasma conc. – Response relationship 31 Dose response relationship Potency of drug (X-axis) • Amount of the drug required to produce a certain response. – Ex: 1 mg of bumetanide produces same diuresis as 50mg of frusemide Efficacy (Y-axis) • Indicates maximum response that can be produced by a drug – Ex: morphine produces a degree of analgesia not obtainable with any dose of aspirin 32 Potency & Efficacy of a drug Typical dose-response curve for drugs showing differences in potency and efficacy. (EC50 = drug dose that shows fifty percent of maximal response.) 33 Therapeutic index (TI) Definition: is the ratio of the dose that produces toxicity to the dose that produces desired clinical response. TI = median toxic dose (TD50) median effective dose (ED50) Implications: • Indicates safety margin of a drug • Higher the TI, safer drug – More than 1 34 TI- calculation • TI= 400/100 = 4 35 • Drugs with low TI have low safety margin E.g. digoxin, lithium, cyclosporine, warfarin • Drugs with large TI: have high safety margin ex- paracetamol, penicillin 36 Lecture Summary • Describe the principles of pharmacodynamics with regard to the potential targets of -Mechanisms of drug action -receptor : types, transducer mechanisms agonist / antagonist , affinity / Intrinsic activity - dose-response relationship (curve) potency / efficacy -therapeutic index 45 MTF •Regarding drugs acting through receptors T A Agonists have affinity for the receptors F B Antagonists have intrinsic activity F C Antagonists down regulate the receptors F D Partial agonists are devoid of pharmacological actions T E Antagonists competitively block the actions of agonist 47 • Drugs can act through T A ion channels T B transporters T C receptors T D antibody production T E placebo effect 48 SEQ • Enumerate differences between competitive and noncompetitive drug receptor antagonism. • Define / Describe an agonist and antagonist. • Define TI of a drug. State the formula to calculate TI. 49 OSPE 50 OSPE Graph depicting dose response of a drug ‘X’ in the individuals OSPE Graph depicting the potency and efficacy of drugs .