mechanism of drug action department of pharmacology

mechanism of drug action department of pharmacology

1. MECHANISM OF DRUG ACTION

2. PHARMACODYNAMICS It is the study of biochemical and physiological effects of drug and their mode of action.

3. PRINCIPLES OF DRUG ACTION

4. Drug targets Primary drug targets are:- Receptors Ion channels Enzymes Carrier molecules (transporters )

5. Mechanism of drug action SITE OF DRUG ACTION: -INTRACELLULAR -CELLULAR -EXTRACELLULAR Receptor mediated Non receptor mediated

6. RECEPTORS 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.

7. 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) 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 Inverse agonist : an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM Partial agonist : An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. pentazocine

8. 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 in terms of affinity and IA: Agonist: Affinity + IA (1) Antagonist: Affinity + IA (0) Partial agonist: Affinity + IA (0-1) Inverse agonist: Affinity + IA (0 to -1)

9. The two-state Receptor model

10. D + R DR Complex Affinity – ability of the drug to bind with the receptor Covalent bonds are stable and essentially irreversible Electrostatic bonds may be strong or weak, but are usually reversible Drug - Receptor Binding Affinity

11. Drug Receptor Interaction Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy DR Complex Effect (E)

12. Two essential functions: Recognition of specific ligand molecule Transduction of signal into response Two Domains: Ligand binding domain Effectors Domain – undergoes functional conformational change

13. Receptor superfamilies Ligand gated ion channels (ionotrophic receptors) G Protein coupled receptors (metabotropic receptors) Kinase linked receptors Nuclear receptors

14. C alled ionotropic receptors. Responsible for regulation of the flow of ions across cell membranes Involved mainly in fast synaptic transmission. Several structural families, the commonest being heteromeric assemblies of 4 - 5 subunits, with transmembrane helices arranged around a central aqueous channel. Ligand binding and channel opening occur on a milliseconds. Response to these receptors is very rapid. Examples : nicotinic acetylcholine, gamma- aminobutyric acid type A (GABA A ) and 5-hydroxytryptamine type 3 (5-HT 3) receptors. Ligand -gated ion channels

15. Ligand gated ion channel

16. Ligand gated ion channel

17. GPCR

18. GPCR families Family Receptors Rhodopsin family Largest group. Neurotransmittter,neuropeptides,cannabinoid Secretin family Receptors for peptide hormones secretin, glucagon and calcitonin Metabotropic glutamate receptor/calcium channel family GABA B , calcium sensing receptors, Glutamate

19. Function of G Protein

20. G-proteins and Effectors Large number can be distinguished by their α -subunits G protein Effector pathway Substrates Gs Adenylyl cyclase Beta-receptors, H2, D1 Gi Adenylyl cyclase Muscarinic M2 D2, alpha-2 Gq Phospholipase C Alph-1, H1, M1, M3 Go Ca++ channel K+ channel in heart, SM

21. Adenylyl cyclase and cAMP pathway Increased lipolysis Reduced glycogen synthesis Increased glycogen breakdown

22. Main effector pathways of GPCR

23. Ion channels Activated G protein can open or close ion channels. G α s open ca 2+ in myocardium and skeletal muscle G i open K + channel in heart, smooth muscles and close neuronal ca channel opiate analgesics open K + channels through β ϒ

24. Kinase linked receptor Main types Receptor tyrosine kinases Serine/ threonine kinases Cytokine receptors

25. Two important pathways are : ― the Ras / Raf /MAP kinase pathway, which is important in cell division, growth and differentiation ― the Jak /Stat pathway - is activated by many cytokines ; it controls the synthesis and release of many inflammatory mediators .

26. Nuclear receptor

27. Receptors regulating gene expression – Clinical implication Hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins – gene active hormonal drugs take time to be active Beneficial or toxic effects persists even after withdrawal

28. Types of nuclear receptor Class I Hybrid class Class II Cytoplasm Homodimers Ex:- GR,MR,ER,PR,AR Heterodimers with RXR TR,VDR Nucleus Heterodimers Except RXR PPAR,LXR, induce drug metabolising enzymes CYP3A.

29. Repeated or continuous administration of agonist or antagonist may lead to changes in the responsiveness of the receptor. The onset and recovery varies from seconds to minutes ( called DESENSITISATION - TACHYPHYLAXIS) to days or weeks (called TOLERANCE) TWO MAIN PROCESSESS ARE INVOLVED: Receptor phosphorylation Receptor internalisation Desensitisation ( tachyphylaxis ) and tolerance

30. Receptor regulation D Down regulation u UP regulation

31. Spare Receptor Only a fraction of the total population of receptors in a cell, are needed to produce maximal effect, then the cell is said to have spare receptors Example - Beta-adrenergic blocking

32. Non receptor mediated Ion channels Enzymes Transporters

33. Voltage gated sodium channel

34. Voltage gated sodium channel These ion channels are operated by voltage gradient across plasma membrane Ion channel is controlled by changes in membrane potential Types 1.voltage gated K + channel :- aminopyridine 2. voltage gatedCa + channels :- L type : nifedipine,diltiazam T type: ethosuximide , flunarazine N type: ω conotoxin 3. voltage gated Na-channels: eg .,local anaesthetics These channels undergo three states Open ,closed and refractory states

35. THROUGH ENZYMES Almost all biological reactions are carried out under catalytic influence of enzymes. Drug can increase or decrease the rate of enzymatically mediated reactions. -STIMULATION : Eg ., Adrenaline stimulates hepatic glycogen phosphorylase –beta adreno receptora and cAMP -INHIBITION : 1.NON SPECIFIC INHIBITION: eg :acids and alkalies 2.SPECIFIC INHIBITION a) competitive eg:neostimine for cholinesterases . b ) non –competitive eg:acetozolamide for carbonic anhydrase

36. Transporters Substrates are translocated across membrane by binding to specific transporters (carriers) – ATP binding cassette or Solute Carrier Proteins (SLC) Examples : Probenecid (penicillin and uric acid ) Hemicholinium ( choline uptake) and Vesamicol (active transport of Ach to vesicles)

37. BY PHYSICAL ACTION : Physical property of drug is responsible for its action. eg : Mass of the drug-bulk luxatives Radioactivity- iodine-131 and other radio isotopes

38. BY CHEMICAL ACTION : T he drug reacts extracellulary according to their chemical property. Eg : antaacids neutralize gastric acid Acidifying and alkalinizing agents react with buffers in plasma and alter PH of urine Chelating agents trap heavy metals in their ring structure, and form water soluble complexes that are excreted.

39. Receptor and diseases The principle mechanism involved are: - autoantibodies directed against receptor proteins -mutations in genes encoding receptor and proteins involved in signal transduction. Eg : Myasthenia gravis Mutation in GPCR(G α ) and G βϒ :- hypoparathyroidism and hypertension respectively

40. Recent advances GPCR oligomerization:- new targets for drug development. Signaling by internalized GPCR.

41. THANK YOU