1. Dr. Kh. Hakobyan Chair of Biomedicine of YSU PHARMACODYNAMICS

2. In Greek Pharmacon =Drug Dynamics= Action/Power It covers all the aspects relating to “Whatadrugdoestothebody”

3. Action: How and Where the effect is produced is called as Action. Effect: The type of response producing by drug.

4. Site of Drug Action Where: 1.Extra cellular 2.Cellular 3.Intracellular

5. Types of Drug Action EFFECT (Type of responses):- 1.Stimulation 2.Inhibition/Depression 3.Replacement 4.Irritation 5.Cytotoxic

6. Mechanism of Action of Drugs Drug act either by receptor or by non receptor or by targeting specific genetic changes. Majority of drugs acts by (HOW) Receptor mediatedNon receptor mediated

7. Receptor Mediated action Drug produce their effect through interacting with some chemical compartment of living organism i.e Receptor. Receptors are macromolecules Most are proteins Present either on the cell surface, cytoplasm or in the nucleus

8. Receptor Functions : Two essential functions 1. Recognization of specific ligand molecule (Ligand binding domain) 2. Transduction of signal into response (Effector domain) Ligand binding domain Transduction of signal into response

9. Drug receptor complex Biological effect Drug receptor interaction:- 1. Selectivity:- Degree of complimentary corelation between drug and receptor. Ex:- Adrenaline Selectivity for α, ß Receptor 2.Affinity:- receptor. Abilityofdrugtogetboundtothe 3. Intrinsic activity (IA) or Efficacy:- Ability of drug to produce a pharmacological response after making the drug receptor complex. Drug +Receptor

10. Drug classification (on the basis of affinity & efficacy)

11. Response No response

12. Agonist:Boththehighaffinityaswellas intrinsic activity (IA=1) These drug trigger the maximal biological responseor mimic effect of the endogenous substance.. Ex:-ethacholine M is a cholinomimetic drug which mimics the effect of Ach on сholinergic receptors

13. Types of agonism Summation:- Twodrugs eliciting same response, but with different mechanism and their combined effect is equal to their summation. (1+1=2) Aspirin Codiene PGOpiods receptor Analgesic+ ++

14. Types of agonism Additive: combined effect of two drugs acting by same mechanism Aspirin Celecoxib PG Analgesic+ + ++ +

15. Synergism (Supra additive):-(1+1=3)(1+1=3) Thecombinedeffectoftwodrugeffectis higher than either individual effect. Ex:- 1.Sulfamethaxazole + Trimethoprim 2.Levodopa + Carbidopa.

16. Types of antagonism Antagonism: Effect of two drugs is less than sum of the effects of the individual drugs. 1.Chemical antagonism Ex: -heparin(-ve) protamine +ve, Chelating agents 1.Physiological /Functional antagonism 2.Pharmacokinetic antagonism 3.Pharmacological antagonism I.Competitive ( Reversible) II.Non competitive (Irreversible )

17. Pharmacokinetic antagonism One drug affects the absorption, metabolism or excretion of other drug and reduce their effect. Ex:-Warfarin in presence of phenobarbitone, warfarin metabolism is increased, it effect is reduced.

18. Pharmacological antagonism Pharmacodynamic antagonism between two drugs acting at same receptors. Two important mechanism according to which these antagonists 1.Reversible(Competitive) 2.Irreversible(Non)

19. Reversible antagonism (Competitive antagonism) These inhibition is commonly observed with antagonists that bind reversibly to the same receptor site as that of an agonist. Thesetypeinhibitioncanbe overcome increasing the concentration of agonist Ex:- Atropine is a competitive antagonist of Ach.

20. Irreversible Antagonism It occurs when the antagonist dissociates very slow or not at all from the receptors result that no change when the agonist applied. Antagonist effect cannot be overcome even after increasing the concentration of agonist

21. Dose Itistherequired amountofdruginweight, volumes, moles or IU to provide a desired effect. In clinical it is called as Therapeutic dose Inexperimentalpurposeitis called as effective dose. Thetherapeuticdosevariesfrompersonto person

22. Single dose: 1.Piperazine (4-5g) is sufficient to eradicate round worm. 2.Single IM dose of 250mg of ceftriaxone totreat gonorrhoea. Daily dose: It is the quantity of a drug to be administered in 24hr, all at once or equally divided dose. 1.10mg of cetrizine (all at once) is sufficientto relive allergic reactions. 2.Erythromycin is 1g per dayto be given in 4 equally divided dose (i.e., 250mg every 6 hr)

23. Total dose: It is the maximum quantity of the drug that is needed the complete course of the therapy.Total dose: It is the maximum quantity of the drug that is needed the complete course of the therapy. Ex:-procainepenicillin  earlysyphilisis6millionunit  given as 0.6 million units per day for 10 days. Loading dose:- It is the large dose of drug to be given initially to provide the effective plasma concentration rapidly. The drugs having high Vd of distribution. Chloroquine in Malaria – 600 mg 300mg after 8 hours 300 mg after 2 days.

24. Maintenance dose:- Loading dose normally followed by maintenance dose. Needed to maintain the steady state plasma concentration attained after giving the loading dose.

25. Partialagonist:Thesedrughavefullaffinityto receptor but with low efficacy (0 to 1 range). These are only partly as effective as agonist ( Affinity is lesser when comparison to agonist) Ex: Pindolol, Pentazocine

26. Inverseagonist:Thesehavefullaffinity towards the receptor but intrinsic activity is zeroto-1i.e.,produces opposite to that of agonist. effectisjust Ex: -ß-Carbolineisinverseagonistforagonistfor Benzodiazepines receptors.

27. Receptor families Four types of receptors families 1. Ligand-gated ion channels (inotropic receptors) 2.G-protien coupled receptor (Metabotropic receptors) 3. Enzymatic receptors (tyrosinekinase) 4.Receptor regulating gene expression (transcription factors/ Steroid )

28. Signal transduction mechanism 1. Ion gated receptors :- Localized oncell membraneandcoupleddirectlytoanion channel Receptor Blocker Agonist Hyperpolarization or depolarization Receptor Permeation of ion is blocked No cellular effect Cellular effect Io n Na +

29. Ex: Nicotinic cholinergicreceptor

30. 2. G-protein coupled receptors Membrane bound, which are coupled to effector system through GTP binding proteins called as G-proteins Bound to inner face of plasma membrane (2 nd messenger)

31. Varieties of G-protein G-proteinReceptor for Signaling pathway/ Effector Gsß adrenegic, H,5HT,Glucagon AC—cAMP AC—cAMP, Open K + Gi 1,2,3 α 2 adrenergic, Ach, GqAchPhospholipase-C, IP 3’ cytoplasmic Ca +2 GoNeurotransmitters in brain Not yet clear

32. G-protein effector systems 1. Adenylase cyclase : cAMP system 2. Phospholipase -C: Inositol phosphate system 3. Ion channels

33. cAMP system

34. Ion channel regulation G-proteincoupledreceptors cancontrol thefunctioningofionchannel involving any second messenger Ex:- In cardiac muscle bydon't

35. These receptor are directly linked tyrosine kinase. Receptorbindingdomainpresent inextra cellular site. Produceconformationalchangesin intra cellular Ex:- Insulin receptors Enzymatic receptors

36. Extra cellular receptor bindingdomain Intra cellular changes

37. Receptor regulating gene expression(transcription factors) Unfolds the receptor and expose normally masked DNA binding site Increase RNA polymerase activity

39. Drug classification (on the basis of affinity & efficacy) Agonist:Boththehighaffinityaswellas intrinsic activity (IA=1) These drug trigger the maximal biological responseor mimic effect of the endogenous substance. Ex:-Methacholineisa cholinomimeticdrugwhich mimics the effect of Ach on cholinergic receptors.

40. pharmacological activity. Ratherthesedrugbindtothereceptor and produce receptor blockade. AtropineblockstheeffectsofAchonthe cholinergic muscarinic receptors. Antagonist:-Whichhaveonlytheaffinity nointrinsicactivity(IA=0).IA=0sono

41. cAMP system Some drugs, hormones or neurotransmitters produce their effect by increasing or decreasing the activity of adenylate cyclase and thus raising or lower cAMP with in the cell.

42. Stimulation Some of drug act by increasing the activity of specialized cells. Ex: Catecholamines stimulate the heart and Heart rate,Force of contraction

43. Inhibition Some drug act by decreasingthe activity of specialized cells. Ex:Alcohol,Barbiturates,Generalanesthetic these drug depress the CNS system. Atropine inhibits Ach action.

44. Replacement When there is a deficiency of endogenous substances, they canreplacedby drugs. Ex: Insulin in Diabetes mellitus Throxine in cretinism and myxedema

45. Irritation Certain drugs on topical application cause irritation of the skin and adjacent tissues. These drugs are using for counter irritant. Ex:Eucalyptusoil,methyl salicylates(Used in sprains, joint pain, myalgia.

46. Cytotoxic Treatment of infectious disease/cancer with drugs that are selectively toxic for infecting organism/cancer cells Ex: Anticancer drugs All Antibiotics

47. ECam E* Gq PLCPLC PIP 2 DAGDAG S Agonist Phospholipase-C system Hydrolysis Activation IP3IP3 PKC ATPATPADP Product Water soluble release Response Hydrolysis PLC= Phospholipase-CPIP2 =Phosphotiydl inositol 4,5 di phosphate IP3 =Inositol tri phosphateDAG =Diacylglycerol E= EzymePKC = Phosphokinase -C CamCam Ca +2

48. Extra cellular site of action 1.Antacids neutralizing gastric acidity. 2.Chelatingagentsforming complexes with heavy metals. 3.MgSo 4 acting as purgative by retaining the fluid inside the lumen of intestine.

49. Cellular Site of Action 1.Ach on Nicotinic receptors of motor end plate, leading to contraction of skeletal muscle. 2.Effectofsympathomimetics muscle and blood vessels. onheart

50. Intracellular site of action -Folic acid synthesis inhibitors. Folicacidwhichisintracellular component essential for synthesis ofproteins. Trimethoprimandsulfadruginterfere with synthesis.

51. + or -+ or - FC of heart muscle G protein Effector AC cAMPATPATP Protein kinase Active Ca +2 release Phosphorylation Gs/Gi LipolysisGlycogenGlycogen breakdown synthesisto glucose

52. Physical action Absorption: Kaolin absorbs bacterilal toxin and thus acts as antidiarrhoeal agent. Protectives:- Various dusting powders.

53. pharmacological activity. Ratherthesedrugbindtothereceptor and produce receptor blockade. AtropineblockstheeffectsofAchonthe cholinergic muscarinic receptors. Antagonist:-Whichhaveonlytheaffinity nointrinsicactivity(IA=0).IA=0sono

54. Physical Action Osmosis:- MgSo 4 acts as a purgative by exerting osmatic effect within lumen of the intestine. Astringents:- They precipitate the surface proteins and protect the mucosa Ex: tannic acid in gum patients Demulcent:- These drugs coat the inflamed mucus membrane and provide soothing effect. Ex: Menthol

55. False incorporation Bacteria synthesis folic acid from PABA (Para Amino Benzoic Acid), for growth sand development. SulfadrugsresemblePABA,therefore falsely enter into the synthesis process of PABA, cause nonfunctional production and no utility for bacterial growth.

56. Protoplasmic poison Germicides and antiseptics like phenol and formaldehyde act as non specifically as protoplasmic poison causing the death of bacteria

57. Through formation of antibodies Vaccines produce their effect by inducing the formation of antibodies and thus stimulate the defense mechanism of the body Ex:- Vaccines against small pox and cholera

58. Targeting specific genetic changes. Anticancerdrugsthatspecificallytarget genetic changes. kinases. Inhibitorsofspecifictyrosinekinasethat thatblocktheactivityofoncogenic

59. Physiological antagonism producingopp.effect physiological system. onsame Histamine –Vasodilatation Nor epinephrine – Vasoconstriction Twoantagonists,actingatdifferent sites,counterbalanceeachotherby

60. Chemical action 1.Ion Exchanges:-Anticoagulant effectof by heparin(-vecharge)antagonized protamine (+ve charged) protein. 2.Neutralization:-Excessivegastricacidis neutralized by antacids. 3.Chelation:-Thesearetraptheheavy metals. Ex:-EDTA, BAL.