Drug detoxication, Tolerance, Intolerance, Combined effects, Dosage, Classification

1. PHARMACOLOGY- PART II DEEPTHI P.R. 1 st YEAR MDS DEPT.OF CONSERVATIVE DENTISTRY & ENDODONTICS

2. CONTENTS Mechanism of drug Detoxication in the Body. Intolerance, Tolerance, Cumulative action, Synergism, Antagonism. Dosage, Classification of Drugs

3. MECHANISM OF DRUG DETOXICATION IN THE BODY

4. CONTENTS Fate of a drug Reactions: synthetic non- synthetic

5. FATE OF A DRUG Changes that drug undergoes & its ultimate elimination Alteration of a drug within a living organism: biotransformation Metabolism: detoxication process 3 possible fates after absorption:

6. FATE OF A DRUG Metabolic transformation by enzymes Microsomal/ cytosolic/ mitochondrial Inactivate an active drug Activate a prodrug Generate active metabolites of an active drug

7. FATE OF A DRUG II. Spontaneous change into other substances No enzymes III. Excretion unchanged

8. FATE OF A DRUG Less polar, lipid soluble  more polar, water soluble: excretion by kidneys Already polar & soluble: excreted as such- aminoglycosides Activation/ inactivation/ modification Reactions:

9. Non synthetic/ Phase I/ Functionalization Oxidation Reduction Hydrolysis Cyclization Decyclization REACTIONS Synthetic/ Phase II/ Conjugation Glucuronide conjugation Acetylation Methylation Sulfate conjugation Glutathione conjugation Ribonucleoside / nucleotide synthesis

10. REACTIONS Phase I reactions: OH-, NH 2 , SH-, COO- into drugs: water soluble & less active Initial stages: active & more toxic products also formed

11. REACTIONS Tissues metabolising drugs: liver Enzymes : drug metabolism- liver microsomes - sER Esterases , amidases , glucuronyl transferases : catalyse oxidative & reductive reactions Variety of enzymes- CYP 450 system : absorbs light maximally at 450nm

12. REACTIONS Drugs – barbiturates: enzyme induction- rapid metabolism of substrate drugs Enzyme induction: kidney, gut, plasma, skin, lung Non microsomal enzymes & intestinal microfloral enzymes : MAO, alcohol dehydrogenase, xanthine oxidase

13. Animal species & strain Age & sex Genetic determinants Nutritional status Altitude & temperature FACTORS AFFECTING DRUG METABOLISM Route & duration of admn Environmental determinants: pollutants Drug interactions (inducers & inhibitors) Disease- hepatic/ renal damage

14. PHASE I REACTIONS OXIDATION Hydroxylation: salicylic acid to gentisic acid Dealkylation : phenacetin to p- acetaminophenol Deamination: amphetamine to benzyl-methyl-ketone REDUCTION M icrosomal enzymes- halothane & chloramphenicol Non microsomal enzymes: chloral hydrate, disulfiram , nitrites

15. PHASE I REACTIONS HYDROLYSIS Esterases : microsomal/ non microsomal/ microfloral Pethidine , procaine, acetyl choline CYCLIZATION Ring structure from a straight chain compound: proguanil DECYCLIZATION Opening up of ring structure – cyclic drug molecule: barbiturates, phenytoin

16. SYNTHETIC REACTION Conjugation/ transfer reactions Drug/ Phase I metabolite + endogenous substance  conjugates Inactivation large molecules: bile small molecules: urine

17. SYNTHETIC REACTION GLUCURONIDE CONJUGATION Chloramphenicol, aspirin, paracetamol Bilirubin, steroidal hormones, thyroxine MW: excretion in bile reabsorbed Enterohepatic cycling: duration of action- OCPs hydrolysis Gut bacteria

18. ACETYLATION Sulfonamides, isoniazid, PAS, hydralazine, Genetic polymorphism: slow & fast acetylators METHYLATION Adrenaline , histamine, nicotinic acid, methyldopa, captopril SYNTHETIC REACTION GLYCINE CONJUGATION Minor pathway- Salicylates GLUTATHIONE CONJUGATION Highly reactive intermediates: inactivated- paracetamol

19. SYNTHETIC REACTION RIBONUCLEOSIDE / NUCLEOTIDE SYNTHESIS: Activation of purine & pyrimidine antimetabolites in cancer chemotherapy SULFATE CONJUGATION Chloramphenicol , methyldopa, adrenal & sex steroids

20. ENZYMES OF INTERMEDIARY METABOLISM Alcohol: alcohol dehydrogenase Allopurinol: xanthine oxidase SCh & procaine: plasma cholinesterase Adrenaline: mono amino oxidase Majority: microsomal & non microsomal drug metabolising enzymes

21. tolerance Intolerance Cumulative action Synergism Antagonism

22. TOLERANCE Requirement of higher dose of a drug to produce a given response Refractoriness: loss of therapeutic efficiency – a form of tolerance Types: Natural Acquired

23. NATURAL TOLERANCE Innate/ congenital tolerance Species/Racial/ individual: inherently less sensitive to the drug Rabbits: atropine Black races : mydriatics Some individuals: hyporesponders – alcohol, β -blockers

24. ACQUIRED TOLERANCE Repeated administration: in initially responsive Seen with most drugs: significant in CNS depressants Opiates, barbiturates, nitrites, xanthines Not with: atropine, sodium nitroprusside , digitalis, cocaine

25. TISSUE TOLERANCE Develops unequally: different effects of same drug Sedative action of chlorpromazine: not to antipsychotic Analgesic & euphoric action of morphine & not constipating & miotic actions

26. CROSS TOLERANCE Tolerance to pharmacologically related drugs Alcoholics: barbiturates & general anesthetics Partial: morphine & barbiturates Complete: morphine & pethidine

27. APPARENT/ PSEUDO TOLERANCE Confined to oral administration of drug Taking small amounts of poisons orally: render immunity to oral poisons Mucosal changes in GIT: prevents systemic absorption of poison Can occur through other routes

28. 1. Pharmacokinetic/ Drug disposition tolerance: Changes in absorption, distribution, metabolism & excretion: effective concentration at the site of action reduced Barbiturates, carbamazepine, amphetamine MECHANSIM OF DEVELOPMENT OF TOLERANCE 2. Pharmacodynamic/ Functional/Cellular tolerance: Target tissue changes- Decrease in drug receptors/ down regulation or weakening of response effectuation Alcohol, barbiturates, nitrates, morphine

29. Acute tolerance Doses of a drug are repeated in quick succession: marked reduction in response Ephedrine, nicotine TACHYPHYLAXIS Slow dissociation of drug from receptor: reduced intrinsic activity; continued blockade Unidentified ‘adaptive response’ of tissue/ compensatory homeostatic adaptation

30. Rare in clinical practice: repeated admn in quick succession not customary Faster Drug effect cant be obtained with increased dose Tachyphylaxis vs Tolerance More common Slower development Original effect obtained with increasing dose

31. REVERSE TOLERANCE Sensitisation Intermittent dosing schedule Greater response seen for a given dose than after an initial dose Repeated daily administration of cocaine/ amphetamine: gradual increase in motor activity with constant dose

32. DRUG INTOLERANCE ‘ Failure to tolerate’ : Appearance of toxic effects of a drug in an individual at therapeutic doses Low threshold to the action of a drug Single tablet of chloroquine : vomiting & abdominal pain

33. DRUG INTOLERANCE Also used: any Adverse D rug Reaction (ADR) DRUG INTOLERANCE QUANTITATIVE AUGMENTED PREDICTABLE TYPE A QUANLITATIVE BIZZARE UNPREDICTABLE TYPE B IDIOSYNCRASY ALLERGY

34. Dose related & predictable : pharmacological actions Preventable & reversible Hyper response to the main action: insulin hypoglycemia TYPE A ADR Less common, not dose-related, more serious, require drug withdrawal Idiosyncrasy: genetic/ unknown mechanism Allergy: Immunological- type I, II, III, IV TYPE B ADR

35. Idiosyncrasy Genetically determined abnormal reactivity: uncharacteristic reaction with drug Due to individual peculiarities Chloramphenicol: non- dose related serious aplastic anemia

36. Allergy Type I/ Anaphylactic reactions : Urticaria angioedema bronchospasm anaphylactic shock Type II/ Cytolytic reactions : Thrombocytopenia agranulocytosis aplastic anemia hemolysis SLE Type III/ retarded, Arthus reaction : Rashes , serum sickness, polyateritis nodosa , SJS Type IV/ Delayed hypersensitivity reactions : Contact dermatitis, rashes, fever, photosensitisation

37. Immediate stoppage of offending drug Mild rxns : self subsiding Antihistamines: type I rxns & skin rashes Treatment of Allergy Anaphylactic shock/ laryngeal angioedema: Patient in reclining position, O 2 admn at high flow rate, CPR Inj. Adrenaline 0.5mg (0.5 ml of 1 in 100 solution) im chlorpheniramine 10-20 mg i.m / slow i.v i.v. hydrocortisone sodium succinate 100-200 mg- severe/ recurrent cases

38. Penicillins Cephalosporins Sulfonamides Tetracyclines Quinolones AntiTB drugs Phenothiazines Drugs causing allergy frequently Salicylates Carbamazepine Allopurinol ACE inhibitors Methyldopa Hydralazine Local anesthetics

39. CUMULATIVE ACTION Repeated admn . Of slow excreted drug: high concentration- toxicity Digoxin, emetine, heavy metals Cumulative effect desired: phenytoin in epilepsy Passive cumulation : remain deposited in bones without toxic effects- LEAD;Toxic : once in blood Liver & kidney impairment : non- cumulative drugs also cumulate

40. SYNERGISM Greek: syn - together; ergon - work Action of one drug facilitated by the other Both may have action in same direction Given alone: one inactive, still enhance the other when together 2 types : additive & supraadditive

41. Additive: Effect of 2 drugs: same direction- adds up  1+1=2 Combination- better tolerated than higher dose of individual drug Aspirin + Paracetamol - analgesic/ antipyretic SYNERGISM Supraadditive The effect of the combination > individual effects  2+2=5 prolongation of duration of action of one – time synergism Levodopa + Carbidopa / benserazide - inhibition of peripheral metabolism

42. ANTAGONISM Phenomenon of opposing actions of two drugs on the same physiological system Effect of drugs A+B< effect of drug A + effect of drug B One is inactive & decreases the effect of the other Physical Chemical Physiological/ Functional Receptor

43. ANTAGONISM Physical: Physical property Charcoal adsorbs alkaloids: poisoning Chemical: Chemical reaction of 2 drugs: inactive product KMnO 4 + alkaloids- gastric lavage in poisoning Chelating agents + toxic heavy metals

44. Physiological/ functional Different receptors/ mechanisms- opposite effects on same function Opposing pharmacological actions Glucagon & insulin on blood sugar level ANTAGONISM Receptor: Antagonist drug blocks the receptor action of agonist Specific & profound pharmacological effect Antagonists: selective Competitive/ non competitive

45. COMPETITIVE ANTAGONISM Equilibrium type/ Reversible Antagonist chemically similar to agonist: competes for same binding site No response Reversible: concentration of both ACh & atropine: muscarinic Adrenaline & prazosin : α

46. COMPETITIVE ANTAGONISM Partial agonist: competes with full agonist- submaximal response

47. NONCOMPETITIVE ANTAGONISM Antagonist inactivates the receptor : effective complex with the agonist not formed 3 ways: Combination with same binding site: firm, not displaced by higher agonist concentration Combination at a different site/ allosteric site: prevent characteristic change by agonist Change induced in agonist binding site: reactivity abolished

48. NONCOMPETITIVE ANTAGONISM ACh & papaverine : smooth muscle Ach & decamethonium : NMJ Reversible/ irreversible effect

49. SIGNIFICANCE OF ANTAGONISM Correcting adverse effects: chlorpromazine & benzhexol Treating drug poisoning: morphine with naloxone Predicting drug combinations which would reduce drug efficacy: penicillin & tetracycline inferior to penicillin alone in pneumococcal meningitis

50. DOSAGE CLASSIFICATION OF DRUGS

51. CONTENTS Dose Fixed dose ratio combinations Factors necessitating dose modification - body size - age - sex - race &genetics - pathological states - other drugs

52. DRUG DOSAGE ‘DOSE’ The appropriate amount of a drug needed to produce a certain degree of response in a patient Qualified in terms of the chosen response: Aspirin: 0.3- 0.6g - headache 60-150mg - antiplatelet action 3-5g – rheumatoid arthritis

53. DRUG DOSAGE Prophylactic/ Therapeutic/ Toxic dose Inherent potency & pharmacokinetic properties : dose Recommended doses: ‘average’ patient Individual patients: differ from this

54. Standard dose: Same dose appropriate for most: minor variations & wide safety margin OCPs, Penicillin, chloroquine , mebendazole DRUG DOSAGE Regulated dose: Finely regulated & easily measured body function – modified Dosage adjusted : measurement of parameter Antihypertensives

55. Target level dose: Response: not measurable Certain plasma levels of drug : achieved Facilities unavailable: crude adjustments – observing patient at long intervals Antidepressants, antiepileptics , digoxin, lithium DRUG DOSAGE Titrated dose: Dose: maximal therapeutic effect cant be given: adverse effects Compromise between submaximal therapeutic effect & tolerable side effects Anticancer drugs, levodopa, steroids

56. Convenience & better patient compliance Synergistic combinations Elimination & counteraction of side effects Ensures single drug is not administered: AIDS, TB FIXED DOSE RATIO COMBINATIONS: ADVANTAGES & DISADVANTAGES All components may not be needed Dose needs adjustment & individualising Time course of action of components: different Cause of adverse effect: doubtful Contraindication to one component: whole preparation

57. FACTORS MODIFYING DRUG ACTION Different pharmacokinetic handling of drugs Variations in number/ state of receptors Variations in neurogenic/ hormonal tone Genetic/ non genetic factors modify drug action: quantitatively qualitatively Most factors cause such change: dealt by adjustment of drug dosage Less common: precludes the use of the drug in the patient

58. FACTORS NECESSITATING DOSE MODIFICATION Body size: Average adult dose: medium built Individual dose= x avg adult dose Individual dose = x avg adult dose BW (kg) 70 BSA(m 2 ) 1.7

59. FACTORS NECESSITATING DOSE MODIFICATION Age: Child dose= x adult dose-----------(Young’s formula) Child dose = x adult dose-----------( Dilling’s formula) Age Age +12 Age 20

60. Low GFR, immature tubular transport: gentamicin, penicillin Inadequate hepatic drug metabolizing system: chloramphenicol- gray baby syndrome Permeable blood brain barrier Faster drug metabolism than in adults after 1 st year Physiological differences from adults requiring caution: Growth S uppression – corticosteroids Stunting of stature: androgens Discoloration of teeth: tetracycline Dystonic reactions: phenothiazines

61. FACTORS NECESSITATING DOSE MODIFICATION Elderly: Drug doses reduced: GFR~ 75% -50 years & ~50%- 75 years Reduction in hepatic drug metabolism: oral bioavailability Intolerant to digitalis Reduced responsiveness of β receptors

62. FACTORS NECESSITATING DOSE MODIFICATION Sex: Females: doses on lower side of the range Changes altering drug disposition in pregnancy: GI motility: delayed absorption of oral drugs plasma albumin levels: fraction of acidic drugs and basic drugs RBF: faster elimination of polar drugs Induction of hepatic enzymes: faster metabolism

63. Race: Blacks require higher & mongols lower concentrations of atropine & ephedrine to dilate their pupil FACTORS NECESSITATING DOSE MODIFICATION Genetics: Dose of a drug- same effect: 4-6 fold variation Pharmacogenetics : the study of genetic basis for variability in drug response Pharmacogenomics: the use of genetic information to guide the choice of drug & dose on an individual basis

64. GI diseases: Coeliac disease- Absorption of amoxicillin cephalexin & cotrimoxazole achlorhydria aspirin absorption Pathological states II. Liver diseases: serum albumin : more free form of diclofenac , warfarin Dose reduction needed: lidocaine , morphine, propanolol Normal doses of CNS depressants: toxic in cirrhotics Oral anticoagulants: marked PT

65. Pathological states III. Renal diseases Maintenance dose of drugs excreted unchanged & partly unchanged: reduced or dose interval prolonged Free form of acidic drugs : reduction in albumin level CNS depressants : more due to permeability of BBB Pethidine : seizures Urinary antiseptics: systemic toxicity

66. Pathological states Antimicrobials needing dose reduction Even in mild failure Only in severe failure Aminoglycosides Cotrimoxazole Cephalexin Carbenicillin Ethambutol Cefotaxime Vancomycin Norfloxacin Amphotericin B Ciprofloxacin Acyclovir Metronidazole

67. IV. Congestive heart failure Decreased absorption from GIT: procainamide, hydrochlorothiazide Loading doses and dosing rates of lidocaine reduced Compensated heart; more sensitive to digitalis Pathological states V. Thyroid disease: Clearance of digoxin- roughly parallels thyroid function Hypothyroid : more sensitive to digoxin, morphine, CNS depressants Hyperthyroid: prone to arrhythmic action of digoxin

68. Pathological states VI. Others: Schizophrenics tolerate large doses of phenothiazines Head injury patients: respiratory failure- normal doses of morphine MI patients: prone to digitalis & adrenaline induced arrhythmias

69. FACTORS NECESSITATING DOSE MODIFICATION Other drugs: Concurrent administration of inhibitors of hepatic microsomal enzymes: (macrolides, chloramphenicol, cimetidine, metronidazole)- dose reduction of drugs metabolised : (azathioprine, warfarin, theophylline) Propanolol : lidocaine , morphine, verapamil, imipramine & self metabolism- reduction in hepatic blood flow

70. FACTORS NECESSITATING DOSE MODIFICATION Enzyme inducers: barbiturates, phenytoin, carbamzepine - failure of antimicrobial therapy with metronidazole, doxycycline, chloramphenicol contraceptive failure Paracetamol toxicity at lower doses: toxic metabolite Oral anticoagulants, hypoglycemics , antiepileptics , antihypertensives : dose adjustment

71. CLASSIFICATION OF DRUGS Single, rational classification system: not possible Requirements of chemists, pharmacologists, doctors differ Categorised according to the convenience of the discussing group

72. I. BODY SYSTEM : Alimentary Cardiovascular ANS, PNS, CNS Respiratory system Renal system Blood & blood formation CLASSIFICATION OF DRUGS II. THERAPEUTIC USE : Receptor blockers Enzyme inhibitors Carrier molecules Ion channels

73. CLASSIFICATION OF DRUGS III. MODE/ SITE OF ACTION : Molecular interaction: glucoside , alkaloid, steroid Cellular site: loop diuretic, catecholamine uptake inhibitor IV. MOLECULAR STRUCTURE : Glycoside Alkaloid S teroid

74. Anatomical Therapeutic Chemical (ATC) Classification System Controlled by the WHO Collaborating Centre for Drug Statistics Methodology ( WHOCC) First published in 1976 D rugs into different groups: the organ or system on which they act and/or their therapeutic and chemical characteristics Same drug: more than one code Eg : Aspirin- A01 AD05 - local oral treatment , B01 AC06 - antiplatelet, N02 BA01 – analgesic, antipyretic en. wikipedia.org

75. Anatomical Therapeutic Chemical (ATC) Classification System drugs are classified into groups at 5 different levels First level the anatomical main group and consists of one letter. 14 main groups en. wikipedia.org

76. Code Contents A Alimentary tract and metabolism B Blood and blood forming organs C Cardiovascular system D Dermatologicals G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins J Antiinfectives for systemic use L Antineoplastic and i mmunomodulating agents M Musculo -skeletal system N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various

77. Anatomical Therapeutic Chemical (ATC) Classification System Second level the therapeutic main group and consists of two digits. Eg : G03 Diuretics Third level the therapeutic/pharmacological subgroup and consists of one letter. Example : G03 C High-ceiling diuretics en. wikipedia.org

78. Anatomical Therapeutic Chemical (ATC) Classification System Fourth level the chemical/therapeutic/pharmacological subgroup and consists of one letter. Eg : G03C A Sulfonamides Fifth level the chemical substance and consists of two digits. Eg : G03CA 01 Furosemide en. wikipedia.org

79. BIBLIOGRAPHY Pharmacology & Pharmacotherapeutics - Satoskar , Bhandarkar , Rege : 9 th edition Essentials of Medical Pharmacology- Tripathi , 6 th edition Clinical Pharmacology- Bennett, Brown- 9 th edition Textbook of Dental Pharmacology- Sharma, Sharma, Gupta en. Wikipedia.com

80. Thank you!!!!