Pharmacodynamics.pptx

Pharmacodynamics-General Pharmacology

1. Pharmacodynamics

2. Pharmacodynamics means →what the drug does to the body It is the study of drugs —their mechanism of action, pharmacological actions and adverse effects Types of Drug Action :- 1. Stimulation : Some drugs act by increasing the activity of specialized cells, E.g. adrenaline stimulates the heart resulting in ↑HR & FOC. 2. Depression : Some drugs act by decreasing the activity of specialized cells E.g. alcohol, barbiturates, general anaesthetics, etc. depress the CNS. 3. Irritation : Certain agents on topical application can cause irritation of the skin and adjacent tissues. E.g. Counterirritant :- an agent upon topical application to the skin relieves deep-seated pain e.g. eucalyptus oil, methyl salicylate, etc. useful in sprains, joint pain, myalgia, etc.

3. 4. Replacement : When there is a deficiency of endogenous substances, they can be replaced by drugs E.g. Insulin →in diabetes mellitus, Thyroxine → in cretinism and myxoedema, etc. 5. Cytotoxic : Drugs are selectively toxic for the infecting organism/cancer cells, e.g. antibiotics/anticancer drugs. Mechanism of Drug Action :- Mechanism of action of drugs -: Non-receptor mediated :- 1. By physical Action :- (A.) Osmosis : Some drugs act by exerting an osmotic effect, e.g. 20% mannitol in cerebral oedema and acute congestive glaucoma. Receptor Mediated Nonreceptor mediated

4. (B.) Adsorption : Activated charcoal adsorbs toxins→ used in the treatment of drug poisoning. (C.) Demulcent :- Cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa. (D.) Radioactivity : Radioactive isotopes emit rays and destroy the tissues, e.g. 131I in hyperthyroidism. 2. By chemical action :- A. Antacids →neutralize acid in the stomach in peptic ulcer. B. Chelation :-Metals like iron, copper, mercury, etc. are eliminated from the body with the help of chelating agents. They trap the metals in their ring structure and form water-soluble complexes, which are rapidly excreted from the body. E.g.- Dimercaprol (BAL)→ Arsenic poisoning, Desferrioxamine→ Iron poisoning, D-penicillamine→ Copper poisoning.

5. 3. Through enzymes :-Enzymes are Biocatalysts present in the cell. Some drugs act either by activating or inhibiting the enzyme activity. a. Drug action via enzyme inhibition :- Competitive inhibition :-drug is structural analogue of enzyme which prevent the formation of enzyme-substrate complex. Non-Competitive inhibition :- drug binds to allosteric site which prevent the formation of ES-complex Enzyme Competitive inhibitors Therapeutic use Acetyle cholinesterase Physostigmine, Neostigmine Galucoma, Myasthenia gravis Angiotensin converting enzyme Captopril, Lisinopril Hypertension Dopa decarboxylase Carbidopa Parkinson disease Xanthine oxidase Allopurinol Acute Gout Folate synthetase Sulfonamides conjunctivitis

6. Enzyme Competitive inhibitors Therapeutic use Aldehyde dehydrogenase Disulfiram Alcohol Aversion therapy HMG-CoA reductase Atorvastatin Dyslipidaemia H+ K+ ATPase Lansoprazole Peptic ulcer Carbonic Anhydrase Acetazolamide Glaucoma 4. Through ion channels :- minute pores present in the cell membrane. common ion channels are of Na+, K+, Ca +2 and Cl – Some drugs directly bind to ion channels and alter the flow of ions, Ion channel →have gating properties Ligand – gated channels – activated by binding of a chemical ligand. Voltage – gated channels – open when the cell membrane is depolarized. E .g. LA block sodium channels in neuronal membrane to produce local anaesthesia, CCB-D iltiazem

7. 5. Through antibody production :- Vaccines produce their effect by stimulating the formation of antibodies, E.g.- vaccines against tuberculosis (BCG), oral polio vaccine, etc. 6. Carrier molecules (transporters) :- The transport of ions and small organic polar molecules across cell membranes generally requires a carrier protein. E.g.-Selective serotonin reuptake inhibitors (SSRIs)→ bind to 5-HT transporter→ block 5-HT reuptake into neurons→ A ntidepressant effect Others :- Anticancer drugs like cyclophosphamide produce their effect by binding to nucleic acids

8. Receptor-mediated Mechanisms :- Receptor :- “ Receptors are macromolecules present either on the cell surface, cytoplasm or in the nucleus with which the drug binds and interacts to produce cellular changes” E.g.-adrenergic receptors ( α and β ), cholinergic receptors (muscarinic and nicotinic),opioid receptors( μ , κ ), etc. Drug (D) + Receptor (R) = Drug – receptor complex → Response Terminologies :- Affinity :- The ability of the drug to get bound to the receptor Intrinsic activity :- The ability of the drug to produce pharmacological action after combining with the receptor is known as intrinsic activity of the drug. Agonist : A drug that is capable of producing pharmacological action after binding to the receptor is called an agonist. Agonist has high affinity + high intrinsic activity (e.g. morphine and adrenaline)

9. Antagonist :- A drug that binds to receptors but is not capable of producing pharmacological action is called an antagonist. Antagonist has high affinity without intrinsic activity e.g. naloxone and atropine E.g.- It produces receptor blockade If binding is reversible - Competitive antagonists If binding is irreversible - Noncompetitive antagonists Acetylcholine Muscarinic receptor Atropine Agonist Antagonist

10. Partial agonist:- A drug that binds to the receptor but produces an effect less than that of an agonist is called partial agonist. Partial agonist has affinity + less intrinsic activity E.g. -Pindolol and buprenorphine Inverse agonist : It has full affinity towards the receptor but produces effect opposite to that of an agonist. E.g.- β -carbolines act as inverse agonist at benzodiazepine receptor, and produce anxiety and convulsions where B ZD’s produce antianxiety and anticonvulsant effects.

11. HOW DO DRUGS WORK BY interacting with CELL SURFACE RECEPTORS? Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment

12. Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Cellular Response HOW DO DRUGS WORK BY interacting with CELL SURFACE RECEPTORS?

13. Receptor Families:- Based on molecular structure & signal transduction- 4 type Ligand-gated ion channels (inotropic receptors). G-protein-coupled receptors (metabotropic receptors). Enzymatic receptors. Receptor regulating gene expression (transcription factors) or the nuclear receptor

14. Ligand-gated ion Channels G-protein- coupled Receptors Enzymatic Receptors Nuclear Receptors Location Membrane Membrane Membrane Intracellular(cytoplasm on nuclear membrane) Effector Ion channel Channel or enzyme Enzyme Gene transcription Coupling Direct G-proteins (Gs, Gi, Gq , etc.) Direct Via DNA Examples Nicotinic, GABA A –receptors Muscarinic, adrenergic receptors Insulin, growth factor, cytokine receptors Steroid, thyroid hormone receptors Time required For Response Milliseconds Seconds Hours Hours Characteristics of Various Receptor Families :-

15. Ligand-gated Ion Channels (Inotropic Receptors) :- These are cell surface receptor linked to ion channels E.g.- nicotinic (N M ) acetylcholine receptors of neuromuscular junction, GABA and glutamate receptors in the central nervous system (CNS),5-HT 3 Agonist binding to the receptor opens the channel & cause hyperpolarization, depolarization depending on the ion that flows through Binding of agonist to ionotropic receptors Opens the ion channels (Na + , K + , Ca 2+ , Cl – ) Flow of ions through channels Hyperpolarization/ Depolarization Tissue response Extracellular Intracellular Glutamate

16. G-Protein couple receptors(GPCR)/7-pass receptor/Serpentine receptor:- They are coupled to intracellular effectors through G-proteins G-proteins :- They are membrane proteins They are called “G” protein because of their interaction with guanine nucleotides, GTP & GDP have three subunits ( α , β , ϒ ) α-subunit has GTPase activity that hydrolyzes GTP to GDP Types of G-protein :- Gs & Gq -(Stimulatory types) Gi-(Inhibitory types) second messengers :- cAMP (generated by adenylyl cyclase), cGMP (generated by guanylyl cyclase), Ca2+, inositol triphosphate–diacylglycerol (IP3–DAG) (generated by phospholipase C), nitric oxide, etc.

17. Effector pathways :- G-protein-coupled receptors control cell function via 1. Adenylyl cyclase(AC) ↑ Adenylyl cyclase(by Gs)→↑cAMP ↓Adenyl cyclase(by Gi) → ↓cAMP 2. Phospholipase C :- 3. Ion channels :- activated G-protein can open or close ion channels-Ca++, K+,Na +

18. Gq Phospholipase-C ↑ IP3 & DAG ↑ Cytosolic Ca +2 & Protein kinase-C Gs E.g.-M1,M3,H1, α 1 M2,M4 receptor

19. Enzyme-linked Receptors :- For example, receptors for insulin (receptor tyrosine kinase) and growth factors (epidermal growth factor, platelet derived growth factor, etc.) Mechanism :- Binding of agonist to extracellular domain of enzyme linked receptors ↓ Dimerization of the receptor ↓ Stimulates intrinsic/cytosolic kinase activity ↓ Activates intracellular signaling pathways ↓ Gene transcription→ Tissue response

20. Nuclear Receptors They are distributed in cytoplasm & regulate gene transcription This is slowest acting transduction mechanism E.g.-receptors for sex steroids and glucocorticoids, thyroid hormones, Vit-D receptor Mechanism :- If a drug acts on cytoplasmic receptor then after combining with receptor the drug-receptor complex goes to nucleus leading to gene transcription & subsequent protein synthesis

21. Dose–Response Relationship :- Pharmacological effect of a drug depends on→ its concentration at the site of action Which, in turn, is determined by the dose of the drug administered. Such a relationship is called “ Dose–response relationship” Quantitative measurement of drug effect is very important & helpful to make a decision on its mode of use. DRC :- Plots of dose versus response for drugs(agonist) gives rise to DRC Types of drug response :- 1.Graded response 2.Quantal response

22. Graded response :- Degree of response changes as per the concentration ↑Concentration →↑Response Response increases with increase in concentration of agonist till it reaches the maximum response This curve, when plotted on a graph, takes the form of a rectangular hyperbola Disadvantage :- Difficult to derive statistical Relationship b/w two Variable Thus log-dose(concentration Response curve) is plotted Which is sigmoidal.

23. X-axis Y-axis A-DRUG B-DRUG Log dose response Curve C-DRUG A drug having more affinity & potency than B & C C -drug having less efficacy & potency

24. Drug Potency :- The amount of a drug required to produce a desired response is called the potency of the drug. The lower the dose required for a given response →the drug is more potent. E.g.-analgesic dose of morphine is 10 mg and that of pethidine is 100 mg. Therefore, morphine is ten times more potent than pethidine as an analgesic. Drug Efficacy :- It is the maximum effect of a drug. E.g.-morphine is more efficacious than aspirin as an analgesic Therapeutic Window :- It is the range of plasma concentration of the drug that produces desired response with minimal toxicity

25. Since middle portion is linear so it can be considered that the response is directly proportional to log concentration within a wide range of dose The effective dose(ED) & effective concentration(EC) can be calculated such as ED 50 & ED max (maximum effective dose) Therapeutic Index :- Therapeutic index (TI) is an index of drug safety It is the ratio of median lethal dose to the median effective dose TI= LD 50 → dose that will result in death of 50% of population receiving the drug Median Lethal dose(LD50) of the drug Median effective dose(ED50) of the drug

26. More is LD50→safer is the drug ED50 →It is the dose of the drug that produces desired effect in 50% of the population More is ED50 → lower is potency Wider the value of therapeutic index → safer is the drug E.g.- Penicillin has a high TI , digitalis, lithium and phenytoin have narrow TI Limitation of TI :- effect of drug In pregnancy cant be predicted on t he basis of T.I. safety margin

27. Combined Effects of Drugs :- A combination of two or more drugs can result in an increase or a decrease in response Increased response :- 1. Additive effect : The combined effect of two 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 E.g. Ibuprofen and paracetamol as analgesic Potentiation (supra-additive):- The enhancement of action of one drug by another drug that is inactive is called potentiation. Effect of drugs A + B > Effect of drug A + Effect of drug B E.g.-levodopa + carbidopa; acetylcholine + physostigmine

28. Carbidopa and physostigmine inhibit the breakdown of levodopa and acetylcholine, respectively thus enhancing their effects Synergism :- When two or more drugs are administered simultaneously, their combined effect is greater than that elicited by either drug alone . E.g.-sulphamethoxazole + trimethoprim Decreased response (drug antagonism) :- In antagonism, the effect of one drug is decreased or abolished in the presence of another drug 1. Physical antagonism :- The opposing action of the two drugs is due to their physical property, e.g. activated charcoal adsorbs toxic substances in poisoning. 2. Chemical antagonism :- The opposing action of two drugs is due to their chemical property, e.g. antacids are weak bases that neutralize gastric acid; chelating agents complex metals and are useful in heavy metal poisoning

29. 3. Physiological (functional) antagonism :- two drugs act at different receptors or by different mechanisms on the same physiological system and produce opposite effects. E.g.- insulin and glucagon on blood sugar, In Anaphylactic shock- adrenaline helps to reverse bronchospasm in anaphylactic shock Histamine produces→ Bronchoconstriction (via histamine receptors) Adrenaline produces → Bronchodilatation (via ( β 2) receptors) 4. Receptor antagonism : The antagonist binds to the same receptor as the agonist and inhibits its effects. Types :- competitive or noncompetitive Competitive antagonism (equilibrium type) :- both agonist and the antagonist bind reversibly to the same site on the receptor

30. Antagonism can be overcome (reversible) by increasing the concentration of agonist. The log DRC of the agonist shows a rightward parallel shift in the presence of competitive antagonist For example :- Acetylcholine→ Muscarinic receptors ← Atropine Morphine→ Opioid receptors← Naloxone

31. Non-competitive antagonism:- The antagonist binds to a different site on the receptor and prevents the agonist from interacting with the receptor. the antagonistic effect cannot be overcome by ↑↑concentration of the agonist There is a flattening of DRC in noncompetitive antagonism E.g. Diazepam and Bicuculline

32. FACTORS MODIFYING DRUG ACTION

33. Drug Factors:- 1. Route of administration :- Quantitative variations common than Qualitative variations Quantitative variations :- Oral dose of the drugs are usually larger than intravenous dose (since i.v. route produces 100% bioavailability) E .g. intravenous dose of morphine is 5–10 mg, whereas oral dose is 30–60 mg for analgesic effect. Qualitative variation :- The drug response differ with different routes. E.g.-MgSo4 :- Orally → Produces purgative effect Parenterally → it causes CNS depression Locally →↓oedema in the inflamed area

34. 2. Presence of other drugs:- Additive effect:- Potentiation (supra-additive):- Synergism:- 3. Cumulation: When the elimination of a drug is slower than the rate of administration, the drug may accumulate in the body causing cumulative toxicity E .g.- digoxin, emetine, chloroquine, etc. Patient Factors:- 1. Age:- In neonates, the metabolizing function of the liver and excretory function of the kidney is not fully developed, E.g.- Chloramphenicol → Cause grey baby syndrome in neonates (metabolizing enzymes are not fully developed) Penicillin G → in infant administered less frequently than adult as the excretory function is not completely developed

35. Dose of Aminoglycosides → in elderly is less than normal adult dose due to the renal and hepatic functions progressively decline with age. The dose of a drug for a child can be calculated as follows:- Young’s formula :- Child dose= × Adult dose 2. Body weight and body surface:- An average dose of a drug is calculated in terms of body weight(mg/kg). Dose for an individual = × Average adult dose Since it is inconvenient to calculate BSA, routinely dose is calculated on body weight basis. Exception :-Dose of anticancer drugs and a few other drugs are calculated on the basis of BSA Age Age + 12 Body weight (kg) 70

36. 3. Sex :- Drugs like β - blockers, diuretics and clonidine can cause↓ libido in males not in women Alcohol dehydrogenase→ In stomach is less in women than men so effect of the same amount of alcohol is more as compare to men 4. Diet and environmental factors :- Milk ↓ absorption of tetracyclines Fatty meal ↑absorption of griseofulvin ( Antifungal agent ). Certain environmental pollutants such as DDT, cigarette smoke, insecticides, etc. induce hepatic microsomal enzymes and ↑ metabolism of drugs such as oral contraceptives, theophylline, etc. So the dose of these drugs administered may be inadequate in smokers. 5. Genetic factor :- Isoniazid Peripheral neuritis in slow acetylators, Hepatotoxicity in fast acetylators

37. 6.Psychological factor :- Personality of the doctor as well as the patient can affect response to a drug. Some patients even respond to inert dosage forms (placebo) in conditions like pain, bronchial asthma, anxiety, etc. 7 . Pathological states :- GI disorders :- Achlorhydria→ ↓absorption of acidic drugs in the stomach by causing its ionization. In malabsorption syndrome , ↓absorption of some drugs B. Liver disease:- In chronic liver diseases- ↓metabolism of drugs resulted ↑BA of drugs having high first-pass metabolism, e.g. propranolol. C. Renal failure :- ↓ Clearance of drugs by kidney E.g.-incidence of nephrotoxicity and ototoxicity is more with aminoglycosides in the presence of renal failure.

38. 8. Tolerance/Receptor desensitization/Adaptation :- Repeated administration of drugs can result in ↓ pharmacological effect . ↑ doses of such drugs are needed to achieve same response e.g. Ephedrine, organic nitrates, opioids, etc. Tolerance develops to nasal decongestant effect of ephedrine on repeated use. Patients on organic nitrates for angina develop tolerance on long-term therapy. Tolerance is commonly seen with drugs like morphine, alcohol, amphetamine, etc. Types :- (1)Natural (2)Acquired Natural tolerance :- Genetically determined reduced/lack of response to a drug Species tolerance:- Some species are tolerant to certain drugs, e.g. rabbits can tolerate large doses of atropine Racial tolerance:- Some races show tolerance to certain drugs, e.g. blacks are tolerant to mydriatics

39. Acquired tolerance:- It develops on repeated exposure to a drug. Sometimes, tolerance develops only to certain effects, E.g. on repeated use of morphine, tolerance develops to its euphoriant and analgesic effects but not to its miotic and constipating effects Mechanism of development of tolerance: It could be pharmacokinetic or pharmacodynamic tolerance. (I.) Pharmacokinetic tolerance (Dispositional tolerance): Reduced concentration of the drug at the site of action may be due to decreased absorption, increased metabolism and excretion, e.g. development of tolerance to phenobarbitone on repeated use is due to enhancement of Metabolism as a result of enzyme induction (II.) Pharmacodynamic tolerance (Functional tolerance) :- The drug effect is reduced, which may be due to a decrease in the number of receptors, decrease in the activity of receptors and decreased neurotransmitter. E.g.- Repeated use of opioids, barbiturates, etc. results in the development of tolerance due to a decrease in the number of receptors (downregulation).

40. (III.) Cross-tolerance : it is the development of tolerance to drugs having similar action that may be from same chemical group or different chemical group. E.g.- if a person is tolerated to 1 opioid (morphine) shows tolerance to other opioids(heroin) as well. Others- nitrates, opioids, and between ether and alcohol. (IV.) Tachyphylaxis (tachy = rapid; phylaxis = protection; acute tolerance): When a drug is administered repeatedly at short intervals , the response diminishes rapidly and original effect cant be achieved even after increasing the dose. This is commonly seen with noncatecholamines e.g. Tyramine, ephedrine, amphetamine. These drugs act by releasing noradrenaline from the adrenergic nerve endings. Repeated administration of the drug causes gradual depletion of the neurotransmitter and hence reduction in the response (V.) Drug dependance :-a state—psychic and sometimes also physical—resulting from the interaction between a living organism and a drug, characterized by behavioral and other response that always includes a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects and sometimes to avoid the discomfort of its absence.

41. DRUG INTERACTIONS :- When two or more drugs are administered simultaneously, the effects of one drug may be altered by the other drug. Drug interactions can occur either in vitro (outside the body) or in vivo (inside the body). Resulted- either beneficial or harmful effects

42. Pharmaceutical Interactions:- These can occur as a result of incompatibility (physical or chemical) of a drug with an intravenous solution or when two or more drugs are mixed in the same syringe/i.v. infusion. This may result in precipitation or inactivation of one or more drugs. E.g.-Phenytoin should not be administered in dextrose solution as it gets precipitated. Dextrose solution is not suitable for i.v. infusion of ampicillin, as it is unstable at acidic pH of dextrose. Gentamicin and carbenicillin should not be given in the same infusion as it may result in loss of their potency. Pharmacokinetic Interactions :- These occur when one drug alters the absorption, distribution, metabolism or excretion of another drug

43. Absorption :- Antacids (containing aluminium, magnesium, calcium, iron, etc.)× tetracyclines (Antacids interfere absorption of tetracyclines by forming unabsorbable complexes with it) Metoclopramide × Aspirin(Metoclopramide increases the rate of gastric emptying and promotes absorption of aspirin) Distribution :- Salicylates× warfarin (Salicylates displace warfarin from binding sites resulting in increased free warfarin levels and an enhanced anticoagulant effect (bleeding). Metabolism :- enzyme induction & enzyme inhibition e.g. Carbamazepine× warfarin (↑Metabolism)→↓ anticoagulant effect Erythromycin× carbamazepine (inhibit metabolizing enzyme) →↑Toxicity Excretion:- Salicylates× methotrexate (↓excretion →↑toxicity)

44. Probenecid decreases the renal tubular secretion of penicillins and prolongs the duration of action of penicillins (beneficial interaction) Pharmacodynamic Interactions :- The interaction is due to the action of drugs on receptors or physiological system. This may result in either additive, synergistic or antagonistic effects Harmful effects due to interaction :- e.g. enhanced nephrotoxicity seen with the concurrent use of aminoglycosides and amphotericin-B; Beneficial effect due to interaction :- e.g. levodopa and carbidopa in parkinsonism.

45. ADVERSE DRUG REACTION (ADR)

46. ADR is defined as “any response to a drug that is noxious, unintended & that occurs at doses used in man for prophylaxis, diagnosis or therapy’’ Types of ADR :- 1. Predictable reactions (Type A or Augmented reactions):- These are predictable dose related reactions to a drug related to its pharmacological actions. They include→ side effects, secondary effects and toxic effects. The undesirable effects of the drug are called Adverse Drug Reactions Drug Actions Desirable Undesirable

47. Side Effects:- Undesired effects in the therapeutic doses are called side effect E.g. Atropine used in the treatment of heart block also produces dryness of mouth, blurring of vision, urinary retention, etc., which are the side effects. Secondary Effects :- The primary action of a drug may result in other effects These effects are not the direct effect of drugs but secondary to pharmacodynamic effect of a drug. E.g. immunosuppression by corticosteroids can lead to development of opportunistic infections like oral candidiasis. Toxic Effects :- These are the effects of a drug that are either due to overdosage or chronic use e.g. Bleeding due to chronic use/overdosage of anticoagulants and nephrotoxicity with aminoglycosides, especially in patients with renal failure

48. Unpredictable reactions (Type B or Bizarre reactions): These are non-dose-related unpredictable reactions to a drug. They are not related to the pharmacological actions of the drug. They includes- Idiosyncrasy :- It is usually a genetically determined abnormal reaction to drugs E.g.- succinylcholine apnoea, aplastic anaemia caused by chloramphenicol, haemolytic anaemia seen with primaquine and sulphonamides Drug Allergy :- It is an abnormal response (local or systemic) to a drug/foreign antigen mediated by the immune system. It is also known as “ drug hypersensitivity ”. Different types of hypersensitivity reactions are discussed below Those associated with humoral antibodies: Types I, II and III.

49. Those associated with cell-mediated immunity: Type IV (delayed hypersensitivity). Type I hypersensitivity (immediate type, anaphylactic shock):- It is a rapidly occurring reaction; hence they are called immediate hypersensitivity reaction. The manifestations are itching, urticaria, hay fever, asthma or even anaphylactic shock. Ig-E mediated reactions takes place on the surface of mast cells Release of mediators like Histamine, Serotonin, Leukotrienes, Prostaglandins, Platelet activating factor etc occurs. It results in Urticaria, Itching, Angioedema, Asthma, Rhinitis or Anaphylactic Shock. Also known as Immediate hypersensitivity.

50. It is a medical emergency and should be treated promptly with: 1. Inj. adrenaline (1:1000) 0.3–0.5 mL I.M. 2. Inj. hydrocortisone 100–200 mg I.V. 3. Inj. pheniramine 45 mg intramuscularly / intravenously. 4. Intravenous fluids

51. Type II hypersensitivity (cytotoxic reaction):- The antibodies (IgG and IgM) react with cell-bound antigen and cause activation of complement, which destroys the cells E.g.- blood transfusion reactions, haemolytic anemias produced by quinine, quinidine, cephalosporins, etc.

52. 3. Type-III reactions (Retarded, Arthus)IgG mediated:- In this type of reaction antibodies involved are mainly IgG AG:AB complexes are formed ↓↓ Fix complement ↓↓ Deposition of complexes on vascular endothelium ↓↓ Destructive inflammatory response. E.g.- Serum sickness (fever, urticaria, joint pain, lymphadenopathy)→ with penicillins and sulphonamides Acute interstitial nephritis → with NSAIDs Stevens–Johnson syndrome → with sulphonamides.

53. Type IV hypersensitivity (cell-mediated or delayed hypersensitivity): It is mediated by sensitized T-lymphocytes. Re-exposure to the antigen leads to a local inflammatory response. The manifestations usually occur 1–2 days after exposure to the sensitizing antigen, e.g. contact dermatitis due to local anaesthetic creams, topical antibiotics and antifungal agents. Type II, type III and type IV reactions are treated with glucocorticoids. Drug Dependence :- 1. Psychological dependence :- There is an intense desire to continue taking the drug as the patients feel that their well-being depends upon the drug. 2. Physical dependence : Repeated drug use produces physiological changes in the body that makes continuous presence of the drug in the body necessary to maintain normal function. Abrupt stoppage of the drug results in an imbalance wherein the body has to readjust to the

54. Absence of the drug resulting in the development of signs and symptoms known as withdrawal syndrome. The withdrawal signs and symptoms are generally opposite to the effects produced by the drug Principles of treatment of drug dependence are:- 1. Hospitalization. 2. Substitution therapy: e.g. Methadone/buprenorphine substitution for morphine addiction. 3. Aversion therapy: Disulfiram for alcohol addiction. 4. Psychotherapy. 5. General measures: Maintain nutrition, family support and rehabilitation. Iatrogenic Diseases:- It is physician-induced disease (‘Iatros’ is a Greek word, means ‘physician’) due to drug therapy e.g. parkinsonism due to metoclopramide; acute gastritis and peptic ulcer due to nonsteroidal anti-inflammatory drugs

55. Teratogenicity :- Certain drugs when given during pregnancy may cross the placenta and cause various dangerous effects in the foetus. Or “ It refers to the capacity of a drug to cause foetal abnormalities when administered to a pregnant woman ” Administration of drugs during early pregnancy (from conception to 16 days) could result in abortion; during 2–8 weeks( 18-55 days) of gestation, it can affect organogenesis and produce structural abnormalities; During second and third trimester ( 56 days onward) , drugs can affect growth and development of the foetus. Hence, drug administration during pregnancy should be restricted. E.g.-

56. Carcinogenicity and Mutagenicity:- The ability of a drug to cause cancer is carcinogenicity and the agent is known as carcinogen. The abnormalities of genetic material in a cell produced by a drug are known as mutagenicity, e.g. anticancer drugs and oestrogens. Photosensitivity Reactions It is a drug-induced cutaneous reaction following exposure to ultraviolet radiation, e.g. demeclocycline, doxycycline, etc. Hepatotoxicity:- Some of the hepatotoxic drugs are isoniazid, rifampicin, pyrazinamide, halothane, paracetamol, etc. Nephrotoxicity:- Aminoglycosides, amphotericin B, cisplatin, cyclosporine, heavy metals, etc. are nephrotoxic drugs. Ototoxicity:- It can occur with aminoglycosides, loop diuretics, cisplatin, etc.

57. Ocular Toxicity:- Ethambutol, chloroquine, glucocorticoids, etc. can cause ocular toxicity Pharmacovigilance :- (WHO) define “It is the science and activities relating to D etection, A ssessment, U nderstanding and P revention of adverse effects or any other possible drug-related problems” Uppsala monitoring centre (sweden)- international Collaborating centre Central Drugs standard control Organization(CDSCO)- The National Pharmacovigilance Centre is located at Ghaziabad Aim :- To improve patient care and safety related to use of drugs, Promote rational use of medicines, Develop regulations for use of drugs Educate healthcare professionals about adverse drug reactions.

58. Indian Pharmacopoeia Commission (IPC) Ghaziabad, Government of India, is functioning as NCC for PvPI since 15 th April 2011

59. How to decrease the incidence of ADR Take detail drug history of patient. In case of prescribing more than one drug, rule out the drug interaction between two drugs. Use accurate drug administration technique . For drugs with narrow safety margin go for TDM .

60. Question paper 1.Giving suitable examples discuss factors modifying Drug responses.(8M/4M) 2.Discuss the following :- Mechanisms of action of drugs Drug-drug interaction with suitable example(4M) 3.Write a short note on :- Adverse drug reactions (3M) Tolerance (3M/5M/4M) Signal transduction mechanism (5M) Partial agonist (3M) Drug receptor Antagonism(5M) Therapeutic index(2.5M) G protein couple receptors (5M) 4.Write the difference between:-(3M) Physical dependance & psychological dependance Competitive & Non-competitive antagonists