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

  • 1. PHARMACOLOGY- PART II DEEPTHI P.R. 1st 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. CONTENTS  Fate of a drug  Reactions: synthetic non- synthetic
  • 4. 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:
  • 5. FATE OF A DRUG I. Metabolic transformation by enzymes  Microsomal/ cytosolic/ mitochondrial  Inactivate an active drug  Activate a prodrug  Generate active metabolites of an active drug
  • 6. FATE OF A DRUG II. Spontaneous change into other substances  No enzymes III. Excretion unchanged
  • 7. 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:
  • 8. REACTIONS Non synthetic/ Phase I/ Synthetic/ Phase II/ Conjugation Functionalization  Glucuronide conjugation  Oxidation  Acetylation  Reduction  Hydrolysis  Cyclization  Decyclization  Methylation  Sulfate conjugation  Glutathione conjugation  Ribonucleoside/ nucleotide synthesis
  • 9. REACTIONS  Phase I reactions: OH-, NH2, SH-, COO- into drugs: water soluble & less active  Initial stages: active & more toxic products also formed
  • 10. REACTIONS  Tissues metabolising drugs: liver  Enzymes : drug metabolism- liver microsomes- sER  Esterases, amidases, glucuronyl transferases: catalyse oxidative & reductive reactions  Variety of enzymes- CYP450 system : absorbs light maximally at 450nm
  • 11. 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
  • 12. FACTORS AFFECTING DRUG METABOLISM  Animal species & strain  Route & duration of admn  Age & sex  Environmental determinants:  Genetic determinants  Nutritional status  Altitude & temperature pollutants  Drug interactions (inducers & inhibitors)  Disease- hepatic/ renal damage
  • 13. PHASE I REACTIONS OXIDATION  Hydroxylation: salicylic acid to gentisic acid  Dealkylation: phenacetin to p-acetaminophenol  Deamination: amphetamine to benzyl-methyl-ketone REDUCTION  Microsomal enzymes- halothane & chloramphenicol  Non microsomal enzymes: chloral hydrate, disulfiram, nitrites
  • 14. 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
  • 15. SYNTHETIC REACTION  Conjugation/ transfer reactions  Drug/ Phase I metabolite + endogenous substance conjugates large molecules: bile  Inactivation small molecules: urine
  • 16. SYNTHETIC REACTION GLUCURONIDE CONJUGATION  Chloramphenicol, aspirin, paracetamol  Bilirubin, steroidal hormones, thyroxine hydrolysis  MW: excretion in bile Gut bacteria  Enterohepatic cycling: duration of action- OCPs reabsorbed
  • 17. SYNTHETIC REACTION ACETYLATION  Sulfonamides, isoniazid, PAS, h ydralazine,  Genetic polymorphism: slow & GLYCINE CONJUGATION  Minor pathway- Salicylates GLUTATHIONE fast acetylators CONJUGATION METHYLATION  Highly reactive intermediates:  Adrenaline, histamine, nicotinic inactivated- paracetamol acid, methyldopa, captopril
  • 18. SYNTHETIC REACTION RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:  Activation of purine & pyrimidine antimetabolites in cancer chemotherapy SULFATE CONJUGATION  Chloramphenicol, methyldopa, adrenal & sex steroids
  • 19. E N Z Y M E S O F I N T E R M E D I A RY M E TA B O L I S M  Alcohol: alcohol dehydrogenase  Allopurinol: xanthine oxidase  SCh & procaine: plasma cholinesterase  Adrenaline: mono amino oxidase Majority: microsomal & non microsomal drug metabolising enzymes
  • 20. 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
  • 21. 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
  • 22. 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
  • 23. 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
  • 24. CROSS TOLERANCE  Tolerance to pharmacologically related drugs  Alcoholics: barbiturates & general anesthetics  Partial: morphine & barbiturates  Complete: morphine & pethidine
  • 25. A P PA R E N T / P S E U D O 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
  • 26. MECHANSIM OF DEVELOPMENT OF TOLERANCE 1. Pharmacokinetic/ Drug 2.Pharmacodynamic/ disposition tolerance: Functional/Cellular tolerance:  Changes in absorption,  Target tissue changes- distribution, metabolism & Decrease in drug receptors/ down excretion: effective concentration regulation or weakening of at the site of action reduced response effectuation  Barbiturates, carbamazepine,  Alcohol, barbiturates, nitrates, amphetamine morphine
  • 27. TACHYPHYLAXIS  Acute tolerance  Slow dissociation of drug  Doses of a drug are repeated from receptor: reduced intrinsic in quick succession: marked activity; continued blockade reduction in response  Unidentified ‘adaptive  Ephedrine, nicotine response’ of tissue/ compensatory homeostatic adaptation
  • 28. TACHYPHYLA X IS VS  Rare in clinical practice: TOLERANCE  More common repeated admn in quick succession not customary  Faster  Drug effect cant be obtained  Slower development with increased dose  Original effect obtained with increasing dose
  • 29. 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
  • 30. 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
  • 31. DRUG INTOLERANCE Also used: any Adverse Drug Reaction (ADR) DRUG INTOLERANCE QUANTITATIVE AUGMENTED PREDICTABLE TYPE A IDIOSYNCRASY ALLERGY QUANLITATIVE BIZZARE UNPREDICTABLE TYPE B
  • 32. TYPE A ADR TYPE B ADR  Dose related & predictable :  Less common, not dose- pharmacological actions related, more serious, require  Preventable & reversible drug withdrawal  Hyper response to the main  Idiosyncrasy: genetic/ action: insulin hypoglycemia unknown mechanism  Allergy: Immunological- type I, II, III, IV
  • 33. IDIOSYNCRASY  Genetically determined abnormal reactivity: uncharacteristic reaction with drug  Due to individual peculiarities  Chloramphenicol: non- dose related serious aplastic anemia
  • 34. 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
  • 35. TREATMENT OF ALLERGY Anaphylactic shock/ laryngeal angioedema:  Immediate stoppage of  Patient in reclining position, O2 admn offending drug at high flow rate, CPR  Mild rxns: self subsiding  Inj. Adrenaline 0.5mg (0.5 ml of 1 in  Antihistamines: type I rxns & 100 solution) im skin rashes  chlorpheniramine 10-20 mg i.m/ slow i.v  i.v. hydrocortisone sodium succinate 100-200 mg- severe/ recurrent cases
  • 36. DRUGS CAUSING ALLERGY FREQUENTLY  Penicillins  Salicylates  Cephalosporins  Carbamazepine  Sulfonamides  Allopurinol  Tetracyclines  ACE inhibitors  Quinolones  Methyldopa  AntiTB drugs  Hydralazine  Phenothiazines  Local anesthetics
  • 37. CUMULATIVE ACTION  Repeated admn. Of slow excreted drug: high concentrationtoxicity  Digoxin, emetine, heavy metals  Cumulative effect desired: phenytoin in epilepsy  Passive cumulation: remain deposited in bones without toxic effectsLEAD;Toxic: once in blood  Liver & kidney impairment : non- cumulative drugs also cumulate
  • 38. 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
  • 39. SYNERGISM Additive: Supraadditive  Effect of 2 drugs: same  The effect of the combination > direction- adds up  1+1=2 individual effects  2+2=5  Combination- better tolerated  prolongation of duration of than higher dose of individual action of one – time synergism drug  Levodopa + Carbidopa/  Aspirin + Paracetamol- benserazide- inhibition of peripheral analgesic/ antipyretic metabolism
  • 40. 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
  • 41. ANTAGONISM Physical:  Physical property  Charcoal adsorbs alkaloids: poisoning Chemical:  Chemical reaction of 2 drugs: inactive product  KMnO4 + alkaloids- gastric lavage in poisoning  Chelating agents + toxic heavy metals
  • 42. ANTAGONISM Physiological/ functional Receptor:  Different receptors/  Antagonist drug blocks the mechanisms- opposite effects on same function  Opposing pharmacological receptor action of agonist  Specific & profound actions pharmacological effect  Glucagon & insulin on blood  Antagonists: selective sugar level  Competitive/ non competitive
  • 43. 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
  • 44. COMPETITIVE ANTAGONISM  Partial agonist: competes with full agonist- submaximal response
  • 45. 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
  • 46. NONCOMPETITIVE ANTAGONISM  ACh & papaverine: smooth muscle  Ach & decamethonium : NMJ  Reversible/ irreversible effect
  • 47. 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
  • 48. CONTENTS  Dose  Fixed dose ratio combinations  Factors necessitating dose modification - body size - age - sex - race &genetics - pathological states - other drugs
  • 49. 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
  • 50. DRUG DOSAGE  Prophylactic/ Therapeutic/ Toxic dose  Inherent potency & pharmacokinetic properties : dose  Recommended doses: ‘average’ patient  Individual patients: differ from this
  • 51. DRUG DOSAGE Standard dose: Regulated dose:  Same dose appropriate for  Finely regulated & easily most: minor variations & wide measured body function – safety margin modified  OCPs, Penicillin, chloroquine, mebendazole  Dosage adjusted : measurement of parameter  Antihypertensives
  • 52. DRUG DOSAGE Target level dose: Titrated dose:  Response: not measurable  Dose: maximal therapeutic effect  Certain plasma levels of drug : cant be given: adverse effects achieved  Compromise between submaximal  Facilities unavailable: crude therapeutic effect & tolerable side adjustments – observing patient at effects long intervals  Antidepressants, antiepileptics, digoxin, lithium  Anticancer drugs, levodopa, steroids
  • 53. FIXED DOSE RATIO COMBINATIONS: A D VA N T A G E S & D I S A D VA N T A G E S  Convenience & better patient compliance  All components may not be needed  Dose needs adjustment &  Synergistic combinations individualising  Elimination & counteraction  Time course of action of of side effects components: different  Ensures single drug is not  Cause of adverse effect: doubtful administered: AIDS, TB  Contraindication to one component: whole preparation
  • 54. FAC T O R S M O D I F Y I N G D RU G AC T I O N  Different pharmacokinetic handling of drugs  Variations in number/ state of receptors  Variations in neurogenic/ hormonal tone  Genetic/ non genetic factors modify drug action: quantitatively Most factors cause such change: dealt by adjustment of drug dosage qualitatively Less common: precludes the use of the drug in the patient
  • 55. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N Body size:  Average adult dose: medium built Individual dose= BW (kg) x avg adult dose 70 2 Individual dose = BSA(m ) x avg adult dose 1.7
  • 56. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N Age: Age Child dose= Age +12 x adult dose-----------(Young’s formula) Child dose = Age x adult dose-----------(Dilling’s 20 formula)
  • 57. PHYSIOLOGICAL DIFFERENCES FROM A D U LT S R E Q U I R I N G C A U T I O N :  Low GFR, immature tubular Growth transport: gentamicin, penicillin  Suppression – corticosteroids  Inadequate hepatic drug  Stunting of stature: metabolizing system: androgens chloramphenicol- gray baby syndrome  Discoloration of teeth:  Permeable blood brain barrier tetracycline  Faster drug metabolism than in  Dystonic reactions: adults after 1st year phenothiazines
  • 58. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N 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
  • 59. 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  RBF: faster elimination of polar drugs  Induction of hepatic enzymes: faster metabolism and basic drugs
  • 60. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N Race: Genetics:  Blacks require higher &  Dose of a drug- same effect: 4-6 mongols lower concentrations fold variation of atropine & ephedrine to dilate  Pharmacogenetics: the study of genetic their pupil basis for variability in drug response  Pharmacogenomics: the use of genetic information to guide the choice of drug & dose on an individual basis
  • 61. PATHOLOGICAL STATES I. GI diseases: II. Liver diseases:  serum albumin: more free form of  Coeliac disease- Absorption of amoxicillin cephalexin & cotrimoxazole  achlorhydria aspirin absorption diclofenac, warfarin  Dose reduction needed: lidocaine, morphine, propanolol  Normal doses of CNS depressants: toxic in cirrhotics  Oral anticoagulants: marked PT
  • 62. 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
  • 63. 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
  • 64. PATHOLOGICAL STATES IV. Congestive heart failure V. Thyroid disease:  Decreased absorption from  Clearance of digoxin- roughly GIT: procainamide, hydrochlorothiazide  Loading doses and dosing rates of lidocaine reduced parallels thyroid function  Hypothyroid: more sensitive to digoxin, morphine, CNS depressants  Compensated heart; more  Hyperthyroid: prone to arrhythmic sensitive to digitalis action of digoxin
  • 65. 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
  • 66. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N 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
  • 67. FAC T O R S N E C E S S I TAT I N G D O S E M O D I F I C AT I O N 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
  • 68. CLASSIFICATION OF DRUGS  Single, rational classification system: not possible  Requirements of chemists, pharmacologists, doctors differ  Categorised according to the convenience of the discussing group
  • 69. CLASSIFICATION OF DRUGS I. BODY SYSTEM: II. THERAPEUTIC USE:  Alimentary  Receptor blockers  Cardiovascular  Enzyme inhibitors  ANS, PNS, CNS  Carrier molecules  Respiratory system  Renal system  Blood & blood formation  Ion channels
  • 70. 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  Steroid
  • 71. ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM  Controlled by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC)  First published in 1976  Drugs 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- A01AD05 - local oral treatment, B01AC06 - antiplatelet, N02BA01 – analgesic, antipyretic en. wikipedia.org
  • 72. 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
  • 73. 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 immunomodulating agents M Musculo-skeletal system N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various
  • 74. 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: G03C High-ceiling diuretics en. wikipedia.org
  • 75. ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM Fourth level  the chemical/therapeutic/pharmacological subgroup and consists of one letter. Eg: G03CA Sulfonamides Fifth level  the chemical substance and consists of two digits. Eg: G03CA01 Furosemide en. wikipedia.org
  • 76. BIBLIOGRAPHY  Pharmacology & Pharmacotherapeutics- Satoskar, Bhandarkar, Rege: 9th edition  Essentials of Medical Pharmacology- Tripathi, 6th edition  Clinical Pharmacology- Bennett, Brown- 9th edition  Textbook of Dental Pharmacology- Sharma, Sharma, Gupta  en. Wikipedia.com
  • 77. THANK YOU!!!!