Pharmacodynamics part 1

This presentation includes basic concepts about pharmacodynamics. It discusses about:
Definition of Pharmacodynamics
Types of drug tragets
Stay tuned for more!

1. Pharmacodynamics-I Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Lecturer, Lumbini Medical College & TH 11 December, 2018 (25 Mangsir , 2075), Tuesday

2. By the end of the class, MBBS I st year students will be able to: Explain the term pharmacodynamics and its components List the common drug targets involved in drug action with examples Appraise the different types of: Drug enzyme interaction Drug receptor interaction

3. Introduction

4. Introduction Pharmacodynamics is the study of the biochemical cellular and physiological effects of drugs and their mechanisms of action Pharmacodynamics: What drugs do? Effects How drugs do it? Mechanism

5. Components of Pharmacodynamics

6. Principles of Drug action Stimulation: Selective enhancement of the level of activity of specialized cells Acetylcholine on salivary glands Increases secretion of saliva

7. Principles of Drug action Depression: Selective diminution of the level of activity of specialized cells Salbutamol on uterine muscles Contraction of uterus decreased

8. Principles of Drug action Irritation: Non-selective, often noxious effect on less specialized cells Capsaicin in herpetic neuralgia Strong irritation  inflammation, necrosis, morphological damage Local alcohol injection in refractory neuralgia

9. Principles of Drug action Replacement: Use of natural metabolites, hormones, or their congeners in deficiency states Iron supplementation in Iron deficiency anaemia Insulin in Diabetes mellitus

10. Principles of Drug action Cytotoxic Action: Selective cytotoxic action on invading microbes Penicillin, cephalosporins Selective cytotoxic action on cancer cells Methotrexate, Cisplatin

11. Mechanism of Action of Drugs By virtue of physical property: Isaphgula Laxatives Dimethicone Ulcer dressing Para-amino benzoic acid Sunscreen Activated charcoal Drug overdose 131 I radioisotopes Hyperthyroidism

12. Mechanism of Action of Drugs By virtue of chemical property: Antacids Hyper-acidity Potassium permanganate Antibacterial Chelating agents Heavy metal poisoning Cholestyramine Hypercholesterolemia Mesna Cyclophosphamide toxicity

13. Mechanism of Action of Drugs By interacting with protein molecules: Colchicine Vinca alkaloids Taxanes By interacting with nucleic acids: Alkylating agents Sulfonamides

14. By interacting with macromolecular functional proteins: Ion channels Transporters (Carriers) Enzymes Receptors Drug targets Cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response. Mechanism of Action of Drugs RICE

15. Drug Targets- Ion channels

16. Drug Targets- Ion channels Ion channels- Modify the intracellular ionic composition of cells Drugs can be used to modify their conductance Can be: Ligand gated G-protein gated Voltage gated Receptors

17. Drug Targets- Ion channels Drug Ion channel Use Quinidine Myocardial Na + channels Arrhythmia Amiodarone Myocardial K + channels Arrhythmia Sulfonylureas Pancreatic K + channels Insulin Phenytoin Neuronal Na + channels Epilepsy Amlodipine L type Ca 2+ channels Hypertension Ethosuximide T type Ca 2+ channels Epilepsy

18. Drug Targets- Transporters (Carriers)

19. Drug Targets- Transporters Carrier Transports Blockers Norepinephrine transporters Noradrenaline (Norepinephrine) Desipramine , Cocaine Gamma butyric acid transporter (GAT1) GABA Tiagabine Na + - K + - 2Cl - co-transporter Na + , K + , Cl - Furosemide Serotonin Transporter Serotonin Fluoxetine

20. Drug Targets- Enzymes Enzymes: Optimises the rate of chemical reaction in our body Can be stimulated or inhibited using drugs Increase in activity can also occur by enzyme induction

21. Drug Targets- Enzymes Enzyme stimulation: Thiamine, Pyridoxine: increase decarboxylase activity Directly stimulated Metabolism of formaldehyde, formic acid enhanced Adrenaline: increases hepatic glycogen phosphorylase Stimulated through beta receptors Increased glycogen breakdown

22. Drug Targets- Enzymes Enzyme inhibition: Nonselective inhibition Denature proteins Heavy metal salts, strong acids and alkalis Selective inhibition Competitive (equilibrium, non-equilibrium type) Non-competitive

23. Drug Targets- Receptors Receptors: Are the macromolecule or binding site located on the surface or inside the effector cell that serves to recognise the signal molecule/drug, and initiate a response to it, but itself has no other function

24. Drug Targets- Receptors Has two sites Ligand binding domain Recognition of physiological molecules/ drugs Effector domain Undergoes functional conformational changes

25. Drug Targets- Receptors Site 1 Site 2

26. Drug Targets- Receptors Types (Based on intracellular signalling molecules) G-protein Coupled receptors Ion channel receptors Transmembrane-enzyme linked receptors Transmembrane JAK-STAT binding receptors Intracellular receptors (cytoplasmic/nuclear)

27. Drug Targets- Receptors G-protein coupled receptors (GPCRs) Examples: α , β receptors, muscarinic receptors Consists of 7 transmembrane helices Linked to various effectors Action seen in seconds Coupled to G-protein ( α , β and γ ) α subunit has enzymatic activity

28. Drug Targets- Receptors G-protein coupled receptors (GPCRs) Coupled to different transducer mechanisms G s  cAMP, G i  cAMP G q  Phospholipase C, G o  Ca 2+ channel β and γ subunits: As chaperone Receptor operated K + channels Voltage gated Ca 2+ channels GPCR desensitization

29. Drug Targets- Receptors β G α G γ cAMP Phospholipase C Ca 2+ channels K + , Ca 2+ channels

30. Drug Targets- Receptors Ion channel receptors Examples: nicotinic ACh receptors, GABA A receptors Two types: G-protein gated Ligand gated Encloses ion selective channels within their molecules Fastest response (milliseconds)

31. Drug Targets- Receptors Agonist binding Site α Na + , K + , Ca 2+ , Cl -

32. Drug Targets- Receptors Transmembrane enzyme-linked receptors Examples: insulin, epidermal growth factors, transforming growth factors Extracellular and intracellular subunits connected with single transmembrane helix Intracellular subunit has enzymatic activity Tyrosine, serine/threonine Response seen in minutes to hours

33. Drug Targets- Receptors Agonist binding site Intracellular subunit having enzymatic activity t

34. Drug Targets- Receptors Transmembrane JAK-STAT binding receptors Examples: cytokines, growth factors, prolactin Extracellular and intracellular subunits connected with single transmembrane helix Intracellular subunit has no enzymatic activity On activation, binds to cytosolic protein Janus Kinase (has enzymatic activity) Takes longer to generate response

35. Drug Targets- Receptors Agonist binding site Intracellular subunit with NO enzymatic activity t

36. Drug Targets- Receptors Intracellular receptors Examples: glucocorticoids, androgens, thyroxine, vitamin D Can be present in cytoplasm or within nucleus Ligand binding domain- carboxy terminus Effector domain – N-terminus Response generated by modification of gene transcription (very slow)

37. Drug Targets- Receptors Ligand binding domain Effector domain

38. Conclusion Pharmacodynamics: What drug does, How it does and modification of drug action by another drug Five principles of drug action Drug Targets: mainly proteins (RICE) Other drug targets do exists

39. Next class… Tomorrow (10-11 am) Topics: Intracellular signaling mechanism, Dose Response Curve, Therapeutic index, Therapeutic Window Any queries? Thank you!