PHARMACODYNAMICS- BPHARM SYLLABUS- UNIT II.pptx

This presentation explains the principle of pharmacodynamics including drug-receptor interactions, dose-response relationships and the mechanism of drug actions.
IT aligns with the BPharm syllabus for pharmacy students.

1. PHARMACODYNAMICS Ms. FATHIMATH RAIHANA ASSISTANT PROFESSOR P A COLLEGE OF PHARMACY

2. Pharmacodynamics is the study of action of drugs on the body and their mechanism of action. ‘What the drug does to the body’ PRINCIPLE OF DRUG ACTION : Drugs produce the effects by interacting with physiological systems of the organism. Drug cannot change the basic functions of the body. They modify the rate of functions.

3. Drugs act by : Stimulation Depression Irritation Replacement Anti-infective or cytotoxic action Modification of immune status

4. Stimulation : It is the increase in activity of the specialised cells. Eg : A drenaline stimulates heart. ii. Depression : It is the decrease in activity of specialised cells. Eg : Quinidine - heart Barbiturates - CNS Some drugs stimulate one system and depress another. Morphine depress the CNS ; stimulates the vagus .

5. iii. Irritation : It can occur on all type of tissues in the body. It may result in inflammation, corrosion and necrosis of cells. iv. Replacement : It may be given when there is deficiency of natural substances like hormones, metabolites or nutrients. Eg : Insulin in diabetes mellitus Iron in anaemia Vitamin C in scurvy.

6. v. Anti-infective and cytotoxic action: Drugs act by specifically destroying infective organisms. Eg : Antibiotic – penicillin, ciprofloxacin , etc.. Anti-cancer drugs – cyclophosphamide vi. Modification of immune status : Vaccines and sera boost immunity Immunosuppressants – depress immunity Eg : Glucocorticoids

7. MECHANISM OF DRUG ACTION : Drugs produce their effect by binding to specific target proteins like : Receptors Enzymes Ion channels They may produce action on cell membrane, inside or outside the cell membrane.

8. Mechanism of action R eceptor mediated Non-receptor mediated Non-receptor mediated : Enzymes and pumps Ion channels Transporters and symporters Physical action Chemical interaction Altering metabolic process

9. Non – receptor mediated : i . By physical action : The action of drug is due to its physical properties. Eg : Adsorption – activated charcoal Mass of drug – bulk laxatives Osmosis – Osmotic diuretics : mannitol Demulcent – cough syrup – soothing effect in pharyngitis – coating to mucosa Radioactivity – emit rays and destroy the tissues Eg : I 131 – Hyperthyroidism.

10. ii . Through ion channels : Drugs may interfere with the movement of ions by opening or closing the channel. For Eg : Calcium channel - Verapamil – blocks L-type calcium channel Potassium channel - Nicorandil opens the potassium channel in the heart Sodium channel - Lignocaine blocks the sodium channel and depress CNS GABA gated chloride channel - Diazepam acts through GABA receptor to increase the frequency of chloride channel opening .

11. iii . Through enzymes and pumps : Most of the drugs act by inhibition of various enzymes thereby altering the enzyme mediated reactions. Eg : Allopurinol inhibits enzyme xanthine oxidase (gout) Acetazolamide inhibits carbonic anhydrase (diuretic) iv. Through transporters and symporters : Transported across the biological membrane with the help of carriers. Drugs act by blocking or inhibiting the movement of transporters, symporters or antiporters. Eg : Imipramine acts by binding to transporters SERT and NET to inhibit the reuptake of serotonin and norepinephrine.

12. 6. By chemical interaction : Drugs may act by chemical reaction. Antacids – neutralise gastric acids 7. By altering metabolic processes : Drugs like antimicrobials - alter the metabolic pathway of microbes, thus killing the microbes. Eg : Sulfonamides – interfere with folic acid synthesis .

13. 8. RECEPTOR : It is a macromolecular site on the cell to which a drug binds to produce a change .

14. Receptor theory : Occupation theory Rate theory Induced fit theory Macromolecular perturbation theory Activation aggregation theory Two state model receptor activation

15. Occupational theory : Drug act on binding site and activate – resulting in biological response that is equal to the amount of drug receptor complex. The response stops when the complex dissociates. Intensity of pharmacological response is directly proportional to the number of receptors occupied. Response is proportional to the fraction of occupied receptors. Maximal response occurs when all the receptors are occupied. DR complex Response D + R

16. ii. Rate theory : Response is proportional to the rate of drug-receptor complex formation. Activation of receptor is proportional to the total number of drugs binding to that receptor. The duration of receptor occupation determines whether the molecule is agonist , partial agonist.

17. iii. Induced fit theory : According to this theory, binding produces a mutual plastic molding of both the ligand and receptor as a dynamic process. The conformational change produced by the mutually induced fit in the receptor is then translated into biological effect . As per this theory, the response will progressively increase till a steady state is reached . Interaction of the agonist with the receptor, brings about changes in the receptor which in turn conveys the signal to the effector. The final response is brought by effector system through secondary messengers. The entire process involves a chain of events triggered by drug-receptor interaction. The transduction process which links the binding of the receptor and actual response is called coupling.

18. iii. Macromolecular perturbation theory : It suggest that drug-receptor interaction occur, two types of macromolecular perturbation is possible. A specific conformational pertubation /changes leads to biological response. ( Agonist ) Non-specific conformational perturbation leads to no response. ( Antagonist )

19. iv. Activation aggregation theory : Receptor is always in a state of dynamic equilibrium between activate form (R ) and inactive form ( T ). R T Agonist shift equilibrium to R 0. Antagonist shift equilibrium to T

20. v. Two state receptor model : I. The receptor is believed to exist in 2 interchangeable states : Ra –active Ri – inactive II. The agonist binds to the Ra shifts the equilibrium and Ra predominates thus produces a response. III. The antagonist binds to the Ra and Ri with equal affinity and equilibrium is not altered, hence no response. w hich are in equilibrium

21. IV. When the agonist is applied, only fewer Ra are available to bind it, response is decreased. If an agonist is having only slightly greater affinity towards Ra than Ri , a submaximal response is produced - Partial agonist . V. The inverse agonist have high affinity for the Ri state, therefore produce opposite response. The resting equilibrium is in favour of Ra state.

22. TYPES OF RECEPTORS : G protein coupled receptors Ligand gated ion channels Enzymatic receptors Nuclear receptor

23. G-Protein coupled receptors : (Metabotropic receptors) Guanine nucleotide binding receptors. Also known as cell surface receptors, h eptahelical receptors, 7- trans membrane transporter. The extracellular domain of this receptor contains the ligand binding area and the intracellular domain interacts with G-protein receptor. They are called G-protein because of their interaction with guanine nucleotides GTP and GDP. The G-protein consist of three subunits: α , β and ϒ . When the receptor is inactive form, these 3 subunits are held together and bound with GDP.

24. Drug binds to the G-protein receptor Signal flows through the helix and G-Protein gets activated. GDP bound to α subunit is converted to GTP Dissociation of G-protein α subunit and βϒ subunits. α -GTP and βϒ subunits are released. This activates adenylyl cyclase or phospholipase C to generate secondary messengers. The secondary messengers include cAMP , IP 3 , DAG, Ca 2+ and cGMP.

25. Effect is produced depends on the type of G-Protein ( Gs , Gi , Gq and Go ). Types of G-protein receptors : Gs - Activates adenylyl cyclase – I ncreasescAMP – activate protein kinase Gi – Inhibits adenylyl cyclase – Inhibit cAMP . Gq – Activates phospholipase C and produce IP3 and Diacylglycerol (DAG) DAG – Activates protein kinase C. IP3 – Regulates intracellular free Ca 2 + concentration and some protein kinases. Gs activation opens Ca 2 + channels in myocardium and skeletal muscles. Gi activation opens K + channels in heart and smooth muscles . Eg : Adrenergic receptors, muscarinic receptors of cholinergic receptor.

26. ii. Ligand gated ion channels : Also known as ion channel receptors or ionotropic receptors. The drug binds directly to the receptor present on the cell membrane. These are the fastest acting receptors. Eg : Nicotinic receptors GABA receptors NMDA receptors.

27. The extracellular portion of ligand-gated ion channels usually contain the ligand binding site. When the ligand binds to the receptor, it opens the ion channels and ions can flow across the cell membrane. The channel is usually closed until the receptor is activated by an agonist. Depending on the ions conducted through these channels, receptors mediate diverse function including neurotransmission and cardiac or muscle contraction. Eg : Stimulation of nicotinic receptors by acetyl choline results in Na + influx and K + efflux resulting in contraction of muscles.

28. iii. Enzymatic receptors or protein kinase linked receptors : They are transmembrane proteins with the extracellular domain for ligand binding and intracellular domain to carry out the catalytic activity. They are kinase linked receptors. They has two sites : Extracellular domain – drug binds. Intracellular site – has enzymatic activity. The agonist binds to the extracellular domain. Activate the intracellular domain and form dimers. Then they activate the protein kinase and phosphorylation takes place. Eg : I nsulin receptors, cytokine receptors

29. OR

30. iv. JAK-STAT binding receptor / Non-enzymatic receptor: When an agonist binds to the receptor, it activates the intracellular domain. They attaches together and form dimers. These dimers then activate the enzyme JAK (Janus kinase). These molecules then activate the signal transducers and activate the transcription protein – STAT molecules. Then they move to the nucleus and regulate transcription. Eg : Growth hormones, cytokines

31. v. Nuclear receptors / Receptors that regulate gene transcription : They are intracellular proteins which are in inactive state. Binding of the agonist activates the receptor. The agonist-receptor complex moves to the nucleus where it interacts with DNA. This regulates gene transcription and directs the synthesis of specific protein to regulate the activity of target cells. Eg : Steroidal hormones, Vitamin D.

32. Receptor regulation : It is the homeostatic increase or decrease in receptor activity or number in response to activation or blockade. Upregulation Down regulation

33. Upregulation Downregulation Prolonged deprivation of agonist Or Constant use of antagonist Increase in the number and sensitivity of the receptors On sudden stoppage of the antagonist Increased response/drug effect Prolonged use of agonist Or Continuous stimulation of receptors Decrease in number of receptors and decrease sensitivity. Decreased response /effect

34. Clinical significance : Upregulation : After prolonged administration, a receptor antagonist should always be tapered. For eg : Propranolol, β adrenoreceptor blocker is suddenly withdrawn after long term use, it may cause angina. This is due to upregulation of β receptors. Normal amount of noradrenaline released during stress stimulate heart and cause angina. Downregulation : Constant use of β adrenergic agonist ( Eg : Salbutamol) in bronchial asthma results in reduced response. This is due to down regulation of β -receptors.

35. Drug-receptor interactions : Drug + Receptor Drug-receptor complex Response

36. Full action Agonist No action Antagonist Less action Partial agonist Reverse action Inverse agonist Drug + Receptor

37. Partial agonist : A drug that binds to the receptor and produces effect less than that of an agonist. It inhibits the effect of agonist. Partial agonist has affinity + less intrinsic activity . Eg : Pindolol and buprenorphine

38. Inverse agonist : It has full affinity but produces opposite effect to that of an agonist. Eg : Benzodiazepines – antianxiety and anticonvulsant β - carbolines - anxiety and convulsant . Benzodiazepine receptor

39. Signal Transduction Mechanisms : Signal transduction is a series of steps by which external stimuli are converted into chemical signals and then into cellular responses. Ligand / Drug Binds to receptor Transduce signals to the target cell Triggers the cell or nucleus Cellular response Drug Receptor Response

40. Basic elements of signal transduction : Ligand, receptor, secondary messengers. Secondary messengers : A molecule inside the cells that acts to transmit signals from a receptor to a target.

41. Dose-response relationship : The pharmacological effect of a drug depends on its concentration at the site of action , which is determined by dose of drug administered. Such relationship is called Dose-response relationship. The clinical response to the increasing dose of a drug is plotted in a graph, is called Dose response curve. ( DRC) Dose response curve is a graph between the dose of drug administered on X-axis and the effect produced by the drug on Y-axis.

42. Two types of DRC : 1. Graded DRC : The response can be graded. ( Eg : Reduction in BP) Dose-response curve gives hyperbola. After the maximum effect, increase in dose doesnot increase the response. Log dose response curve gives Sigmoid curve.

43. 2. Quantal DRC : Certain pharmacological effects cannot be quantified but can only be said present or absent ( all or none phenomena). Eg : Anti-emetic drug – Stops vomiting or not. Drugs causing ovulation. It is used to calculate ED 50 and LD 50 . The graph is plotted between the number of responders and plasma drug concentration. Bell-shaped plot.

44. Dose No. of responders

45. ED 50 : ( Median Effective Dose ) It is the dose of a drug which produces the desired effect in half of the population. LD 50 : ( Median Lethal Dose ) It is the dose of a drug which is lethal for 50% of test population. (50% death) More the LD 50 safer the drug.

46. Therapeutic I ndex : It is an index of drug safety. It is the ratio of the dose that produces toxicity in half of the population to the dose that produces effective response in half of the population. TI = LD 50 ED 50 Higher TI – safer. Eg : Penicillin Lower TI – likely to be toxic. Eg : Digitalis, lithium

47. Therapeutic window : It is the range of plasma concentration below which the drug is ineffective and above which toxicity appears. It is desirable to have plasma concentration of drugs within this optimal therapeutic range in order to get optimal therapeutic effect without toxic effects. Drugs with low therapeutic index have narrow therapeutic window. Eg : Imipramine produces optimal effect when plasma levels are maintained between 50-200ng/ml.

48. Log dose % Response A B Therapeutic effect Unwanted effect Therapeutic Index Therapeutic range Therapeutic window

49. Potency : The amount of drug required to produce a desired response is called potency. Lower the dose given for a response, more potent the drug is. Eg : Bumatenide - 1mg Furosemide – 40mg Morphine – 10mg Pethidine – 100mg Diuretic Analgesic

50. Efficacy : It is the maximum effect produced by the drug. It is clinically important than potency.

51. A B C D Log dose Response

52. Combined effects of drugs : A combination of 2 or more drugs can either increase or decrease the response of a drug. I. Additive effect : The combination of 2 or more drugs is equal to the sum of their individual effect. Effect of drugs A + B = Effect of drug A + Effect of drug B Eg : Combination of paracetamol and aceclofenac – analgesic effect

53. ii. Potentiation or Supra-additive : The enhancement of action of one drug by another drug which is inactive is called potentiation. Effect of drugs A + B > Effect of Drug A + Effect of Drug B Eg : Levodopa + carbidopa Carbidopa inhibit breakdown of levodopa iii. Synergism : When 2 or more drugs are administered simultaneously, their combined effect is greater than elicited by drug alone. Eg : Trimethoprim + sulphamethoxazole ( cotrimoxazole )

54. II. Decreased response : ( Antagonism ) T he effect of one drug is decreased or inhibited by the other drug. i . Physical antagonism : The opposing action of 2 drugs is due to their physical property. Eg : Adsorption of alkaloids by activated charcoal. ii. Chemical antagonism : Due to chemical property. Eg : Antacids neutralize gastric acid

55. iii. Physiological or functional antagonism : Two drugs acts at different receptors or by different mechanisms on the same physiological system and produce opposite effects. Eg : Adrenaline + histamine Adrenaline – bronchodilation Histamine - bronchoconstriction iv. Receptor antagonism : Competitive antagonism Non-competitive antagonism

56. Factors modifying drug action : Body size Age Sex Species and race Genetics Route and Time of administration 7. Psychological status 8 . Other drugs 9. Diet and Environment 10. Pathological status 11. Cumulation 12. Tolerance

57. 1. Body size : It influences the concentration of drug attained on site of action. Dose = Body weight * average adult dose Dose = Body surface area (m 2 )* average adult dose 2. Age : Infants and children are not small adults . They have major physiological difference from adults The dose of a drug for children is often calculated from the adult dose. 70 1.7

58. Young’ s Formula : Age (years) Age + 12 * Adult dose Dilling’s Formula : Age * Adult dose 20 3. Sex : Females have smaller body size and require lesser doses. Maintenance treatment of heart failure with digoxin is reported to be associated with higher mortality among women than men. A number of antihypertensives interfere with renal function in males but not in females. Eg : Clonidine, methyl dopa Drugs given during pregnancy may affect foetus .

59. 4. Species and race : There are many differences in response to drug among different species. Eg : Rabbits are resistant to atropine Rat and mice – digitalis Among human, some renal differences are observed. Eg : Black require higher dose and Mangols require lower doses of atropine. 5. Genetics : The dose of drug to produce same effect may vary by 4-6 folds among different individuals. All key determinants of drug responses through transporter, metabolizing enzymes, ion channels, receptors are controlled genetically.

60. 6. Route and Time of administration : It governs the speed and intensity of drug response . Parenteral administration are more rapid and have more predictable drug action. The effect of drug correlate with time based on circadian rhythm. Eg : Secretion of glucocorticoids is highest in the morning. 7. Psychological status : Efficacy of drug can be affected by patient’s belief, attitude and consumption. 8. Diet and Environment : Food interferes with the absorption of many drugs. For eg : Tetracycline may form complex with calcium present in the food and are poorly absorbed. Absorption increases by food – Spironolactone, lithium Absorption reduced by food – Ampicillin, rifampicin

61. 9. Other drugs : Drugs can modify the response of each other by pharmacokinetic or pharmacodynamic interaction between them . 10. Pathological status : Not only drugs modify disease process, several disease can influence drug disposition and drug action. GI disease : Certain GI disease can alter absorption of orally administered drugs. Liver disease : can influence drug disposition in several ways. Kidney disease : it affects pharmacokinetic property of many drugs as well as alters the effect of some drug.

62. 11.Cumulation : Any drug will accumulate in the body, if rate of administration is more than the rate of elimination. 12. Tolerance : It refers to the requirement of higher dose of a drug to produce a given response. Eg : Loss of therapeutic efficacy : Sulphonyl ureas – Type II Diabetes mellitus.