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Pharmacodynamics

Pharmacodynamics. What is Pharmacodynamics. Pharmacodynamics is the study of action of drugs on the body i.e. what effect a drug has on the patient, including mechanism of action, beneficial and adverse effects of the drug, and the drug’s clinical applications

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Pharmacodynamics

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  1. Pharmacodynamics

  2. What is Pharmacodynamics • Pharmacodynamics is the study of action of drugs on the body i.e. what effect a drug has on the patient, including mechanism of action, beneficial and adverse effects of the drug, and the drug’s clinical applications • In other words pharmacodynamics is what does the drug do to the body. • Modification of the effects of one drug by another drug and by other factors is also part of pharmacodynamics Ligand + Receptor = Ligand-Receptor complex

  3. Why do we use drugs? • Drugs do not start new functions in the body or any system • The only change the speed of the ongoing activity e.g. by • Stimulation • Depression • Irritation • Replacement • Cytotoxic action

  4. Why do we use drugs? • Stimulation • It is selective enhancement of the level of activity of specialized cell e.g. epinephrine stimulates heart e.g. Pilocarpine stimulates salivary glands • Excessive stimulation is followed by depression of that function

  5. Principles of drug action……….. • Depression It is selective diminution of activity of specialized cells e.g. barbiturates depress CNS, quinidine depresses heart • Irritation Often noxious effect applied to less specialized cells e.g. bitter increase salivary and gastric secretion Counter irritant increase blood flow to the site

  6. Principles of drug action……….. • Replacement This refers to the use of natural metabolites, hormones in deficiency states. e.g. levodopa in parkinsonism e.g. insulin in diabetes mellitus • Cytotoxic Selective cytotoxic action for invading parasites or cancer cells. e.g. penicillin, chloroquine, mebendazole

  7. Mechanism of action of drugs

  8. Mechanism of drug action…. • Physical • Chemical • Through enzymes e.g specific inhibition, non-specific inhibition • Through receptors

  9. Physical action • A physical property of drug is responsible for its drug action

  10. Chemical Action • Drug reacts extracellularly and without binding to receptors. There is a simple chemical reaction e.g. antacids (NaHCO3) reacts with HCl in the stomach to form NaCl and H2CO3 Oxidizing agent (KMnO4) are germicidal Chelating agents e.g. EDTA

  11. What do the drugs act on? • Enzymes • Ion channels • Receptors e.g. G protein coupled receptors • Transporters • May act chemically

  12. Through enzymes • Almost all biological reactions are carried out under catalytic influence of enzyme so enzymes are very important target of drug action

  13. Inhibition Non specific: Drugs alter the tertiary structure of enzyme when they come in contact thus inhibit it. Not desirable. Specific Inhibition: Many drugs inhibit a particular enzyme without effecting others e.g. Statins HMG-CoA Reductase inhibitors

  14. Competitive Inhibition e.g. Physostigmine and neostigmine compete with acetylcholine for cholinesterase e.g. Sulphonomides compete with PABA for bacterial folate synthase

  15. Non competitive • e.g. Acetazolamide – carbonic anhydrase Aspirin – cyclooxygenase Digoxin – Na+ K+ ATPase Theophylline - Phosphodiesterase

  16. Through receptor

  17. Neuromuscular Blocking Drugs Cholinergic nerve terminal Action Potential Arrives Competitive Tubocurarine Gallamine Pancuronium Vecuronium Atracurium Rocuronium Depolarizing Suxamethonium Agents that reduce ACh release Acetyl CoA + Choline Cholineacetyl Transferase Hemicholinium Botulinum toxin Aminoglycosides Mg2+, Ca2+ ions Ca++ Influx Ca++ ACh Vesamicol Choline Uptake ACh ACh Potentiate Transmission ACh Synaptic Cleft ANTICHOLINESTERASES Pyridostigmine Neostigmine Distigmine edrophonium Closed Channels Triggers exocytosis Na+ Na+ ACh ACh ACh Na+ ACh ACh Binds to alpha subunit of receptor ACh ACh ACh ACh Choline + Acetic Acid ACh ACh ACh ACh ACh ACh ACh Post-Synaptic membrane Intracellular Na+ increases … depolarization (end plate potential

  18. Receptor Specificity • There are a number of specific ligands and and a number of associate receptors

  19. The receptor affinity • Affinity The extent to which the ligand is capable of binding and remains bound to a receptor High affinity: The ligand bind well and remains bound for long enough to activate the receptor Low Affinity: The ligand binds less well and may not remain bound long enough to activate the receptor

  20. The receptor intrinsic activity • The extent to which the ligand activates the receptor • High intrinsic activity: the ligand produces a large effect on the post synaptic cell • Low intrinsic activity: the ligand produces a small or inconsistent effect on the post synaptic cell

  21. Classes of Ligands • Agonists • High affinity • High intrinsic activity • Antagonist • High affinity • Low intrinsic activity

  22. Antagonist • Reversible: • Can be unbound from the receptor • Irreversible: • Cannot be unbound from the receptor • Competitive: • Competes with other ligands for binding to the receptor • Non competitive: • Exerts its antagonist effects without competition for occupancy of the receptor

  23. Presynaptic Adrenergic Neurons (Blue balls = NE) Yellow Balls = Beta Blocker

  24. Types of receptors • Ion gated channels • G-protein coupled receptors • Cellular receptors • Nuclear receptors

  25. Ion Channel

  26. Na+ ACh Neuromuscular Junction Na+ Neuromuscular Blocking Drugs ACh Competitive Tubocurarine Gallamine Pancuronium Vecuronium Atracurium Rocuronium Depolarizing Suxamethonium δ α γ α β

  27. G-protein coupled receptors • Membrane bound receptors which are bound to effector system through G-proteins • These are hetero trimeric molecules having 3 subunits alpha, beta, and gamma • Based on alpha subunits they are further classified into 3 main subtypes Gs, Gi, and Gq

  28. GPCR GPCR GPCR Neuromuscular Blocking Drugs Cholinergic nerve terminal Action Potential Arrives • Synthesis • Storage • Release • Termination of • action • Receptor Competitive Tubocurarine Gallamine Pancuronium Vecuronium Atracurium Rocuronium Depolarizing Suxamethonium Acetyl CoA + Choline CholineacetylTransferase ACh Ca++ ACh ACh ACh ACh ACh ACh ACh ACh ACh ACh ACh ACh Vesamicol ACh ACh ACh ACh ACh ACh Potentiate Transmission Agents that reduce ACh release Hemicholinium Botulinum toxin Aminoglycosides Mg2+, Ca2+ ions Synaptic Cleft Pyridostigmine Neostigmine Distigmine edrophonium + Na+ Acetate ion Choline Acetylcholinesterase inhhbitors Post-Synaptic membrane

  29. Cyclic AMP is the second messenger that leads to cell response

  30. Enzyme linked receptors • Intrinsic enzyme receptors • Intracellular domain is either • Protein kinase or guanylcyclase linked • E.g. insulin, epidermal growth factor, nerve growth factor • JAK-STAT kinase binding receptor • No intrinsic catalytic domain but agonist induces dimerization e.g. cytokines, growth hormones etc.

  31. Transcription receptors • Receptors regulating gene expression • Intracellular- cytoplasmic or nuclear • All steroid hormones, thyroxine, vit A

  32. Functions of receptors • To propagate signals from outside to inside • To amplify signals • To integrate various extracellular and intracellular regulatory signals • To adapt to long term changes in maintaining homeostasis

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