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Drug Interactions

Drug Interactions. modification of action of one drug by another eg.neostigmine to reverse non-depolarizing neuromuscular block atropine to block muscarinic effects. Summation additive effect of similarly acting drugs 1+1=2 nitrous oxide and inhalational agents.

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Drug Interactions

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  1. Drug Interactions modification of action of one drug by another eg.neostigmine to reverse non-depolarizing neuromuscular block atropine to block muscarinic effects

  2. Summation additive effect of similarly acting drugs 1+1=2 nitrous oxide and inhalational agents

  3. Synergism Drugs with similarpharmacological properties related sites of action producing an effect greater than summation of effect of individual drugs 1+1=>2 Benzodiazepines-induction agents

  4. Potentiation enhancement of effect of one drug by another with dissimilar pharmacological activity midazolam-erythromycin digoxin-thiazide diuretics

  5. Antagonism inhibition or prevention of effects of a drug pharmacokinetic reduced drug absorption enzyme induction chemical heparin-protamine iron-desferroxime Receptor antagonism morphine-naloxone phenoxybenzamine-noradrenaline

  6. Isoboles graphic illustration of relationship between drugs for a specific pharmacologic effect

  7. ED 50 of drug A&B plotted on X-Y axis and joined by a straight line equi-effective combinations of A&B are plotted points falling below the ED 50 line-synergism points close to line –summation points above line -antagonism

  8. Phamaceutical interactions chemical physical Pharmacokinetic dissolution distribution metabolism elimination pharmacodynamic

  9. chemical interactions decomposition of barbiturate solutions decomposition by light halothane catecholamines,SNP decomposition by heat suxamethonium precipitation mixing solutions of different pH LA-sodium bicarbonate loss of action alkaline hydrolysis of scholine by thiopentone

  10. trichlorethylene+soda lime – dichloracetylene enflurane/isoflurane+sodalime – CO Penicillin drugs+ amino acid soln drug protien complex-IgE antibodies epimerisation- pH dependent change in steric configuration adrenaline

  11. physical osmolarity – RBCs damaged by 5DW/mannitol adminisration set - nitroglycerine salting out

  12. Dissolution/absorption oral tetracyclin – antacids,H2 antagonist levadopa - antimuscarinic drugs cholestyramine – digoxin,warfarine parenteral drugs prepared in organic solvents phenytoin,diazepam drugs affecting tissue blood flow

  13. Distribution inhalational agents – minute ventilation (narcotics) cardiac output (beta blockers)

  14. Protein binding acidic drugs - albumin basic drugs - lipoproteins lipoproteins globulin Drugs compete for protein binding Usually insignificant modification of action Low volume distribution drugs-significant phenylbutazone displacing warfarin sulphonamides enhancing STP

  15. Hepatic metabolism first pass effect – diminished response(opioid) depend on liver blood flow decreased liver perfusion – incrased oral bio-availability propranolol inhalational agents cimmetidine

  16. Enzyme induction oxidative enzymes,glucuronyl transferase phenobarbitone phenytoin carbamazepine oral anticoagulants refampicin anticonvulsants corticosteroids tobacco chronic alcoholism

  17. Enzyme inhibition isoforms of P-450 competitive inhibition -same metabolic pathway :tolbutamide/sulphonamide diltiazem,verapamil/midazolam CYP3A4 cimmetidine/diazepam -different metabolic :quinidine on CYP 2D6 non-competitive -reversible :ketaconazole forms a complex and inhibit CYP 3A4 -irreversible :carbamates /P450 isoforms plasma choline esterase trimetaphan,neostigmine cyclophosphamide

  18. Elimination kidney urine pH : alkaline urine-weak acids ionised cannot diffuse back across renal tubules neutral/acid urine- nonionised diffuse back into plasma elimination reduced acidic urine-weak bases ionised enhanced elimination forced alkaline diuresis for salicylate,phenobarbital acid diuresis for amfetamine,quinine,phencyclidine

  19. kidney-- Competitive inhibition of proximal renal tubular secretion probencid,NSAIDs,diuretics / benzyl penicillin thiazide duretic/uric acid – acute gout

  20. liver morphine,oestrogens – excreted in bile as water soluble conjugates metabolised to parent compound gut flora reabsorbed (entero-hepatic shunt) antibiotics inhibit the gut flora oral contraceptive failure /penicillins

  21. Pharmacodynamic interactions at site of action of drugs anticholinesterase drugs-non-depolarising MR protamine-heparin chlorpromazine enhancing hypotensive effects interference with drug transport to site of action pottentiation of noradrenaline by TCADs disturbance of fluid,electrolyte balance digoxin/furosemide lithium/ thiazide diuretics

  22. Interaction with general anaesthetics requirement reduced – opioid analgesics,hypnotics,antidepressants clonidine increased – amphetamine,theophylline concentration/second gas effect by nitrous oxide antihypertensive,antianginal drugs- hypotension betablokers-inhalation agent - bradycardia calcium channel blockers-inhalation agent – reduce MAC heart block myocardial depression-decreased COP fast inhalational induction amiadarone-inhalational - bradyarrhythmias,complete heart block sympathomimetic drugs - tachyarrhythmias (halogenated agents) phenylephrine eye drops/halothane

  23. ketamine/theophylline – tachyarrhythmias,convulsion induction agents/ACE inhibitors – hypotension hypokalemic drugs ( diuretics,insulin,corticosteroids) /inhalational agents – supraventicular,ventricular ectopics hyperkalemic drugs(suxamethonium,spironolactone) SA block NDMR,DMR - potentiated by inhalation agents Aminoglycosides/isoflurane,enflurane - nephrotoxicity

  24. Interactions with LA vasoconstrictors increase duration hyaluronidase decreases duration TCADs –potentiate action of NA/Adrenaline used with LA (felypressin may be used) ester group LA compete for Che- prolong scholine block Che inhibited by neostigmine,suxamethonium,acetazolamide LA reduce Ach release – prolong ND block Ca channel blockers increase CVS toxicity of LA

  25. Muscle relaxants & antagonists inhalational agents –enhance and prolong (iso/sevoflurane) central action,presynaptic effect altered sensitivity of post synaptic receptor propanidid/suxamethonium – prolonged block isoflurane/suxamethonium - phase II block antiarrhythmic drugs,antihistiminics – increase blockade Mg salts - augments ND block antagonises depolarising block Ca salts -opposite effects hyperkalemic drugs - augments DMR hypokalemic drugs - augments NDMR resp acidosis,metabolic alkalosis – prolong ND block

  26. Opioid analgesics pethidine/monoamine oxidase inhibitors (MAOI) excitatory-agitation,confusion,headache,rigidity, hyperpyrexia,convulsions increased 5HT levels in CNS inhibitory- resp depression,circulatory collapse ,coma hepatic microsomal enzyme inhibition accumulation of pethidine& its metabolites methadone and fentanyl are safe tramadol not safe

  27. naloxone,naltrexone – pure antagonists nalbuphine,pentazocine – antagonist with some agonist activity cimmetidine,erythromycin – inhibits cytochrome P450 prolonged effects rifampicin,carbamazepine - induces enzymes increased metabolism shortens action precipitates withdrawl symptoms with methadone

  28. Non-opioid analgesics aspirin - high affinity for plasma proteins displaces warfarin,oral hypoglycemic agents - inhibits renal tubular secretion indomethacin - inhibits renal excretion of Na opposes effects of diuretics,ACE inhibitors

  29. prevention of adverse drug reactions detailed drug history use minimum drugs cautious use of drugs in renal,hepatic impaired use drugs with good margin of safety

  30. VARIABILITY IN DRUG RESPONSE

  31. Descriptive statistics in study of drug response measurement of central tendency mode ,median, mean measurement of dispersion frequency interquartile range standard deviation

  32. Levels of measurement – parameters used nominal measurement data classified by names or chracterestics male/female obese/non obese ordinal measurement data ranked according to their relative magnitude body wt above 80kg/ body wt below 80kg visual analogue pain scale apgar score continuous measurements each data with definite magnitude body wt 50kg/60kg/70kg drug dose-response

  33. Descriptive statistics level of measurement central tendency variability Nominal mode frequency Ordinal median interquartile range Continous mean standard deviation

  34. standard deviation root mean square deviate eg: 24,27,28,31,34 mean = 144/5 = 28.8 deviation of each from mean : -4.8,-18,-0.8,2.2,5.2 variance = sum of squares of deviation no:of observations = 58.8/5 = 11.6 square root of variance = SD = 3.43 as no: observation is small,<30 true SD = 58.5/ 5-1 = 3.83 = 3.8 means 95% observations are expected with in 2 SD from mean coefficient of variance = ( SD/mean)X 100

  35. standard error of mean SEM predicts the accuracy of sample mean in predicting population mean SEM = SD/square root n larger the value of n, smaller the SEM if n > 30, 95% chance that true population mean lies within 2 SE from sample mean 2SEM +/_ sample mean = 95% confidence limit for population mean

  36. Normal distribution cuve graphical representation of scatter of individual observations in population sample

  37. causes of variability in drug response physiological&social : age,pregnancy tobacco,alcohol pharmacological : idiosyncracy,supersensitivity tachyphylaxis,tolerance hypersensitivity pathological : liver,renal,cardiac,neurological endocrine disease

  38. pediatric absorption of oral drugs slower-slow gastric emptying more intestine transit time oral ampicillin better absorbed –gastric content less acidic lower body fat,higher total body water %, higher permeability of BBB decreased plasma proteins metabolism-immature/decreased enzyme activity relatively larger size of liver-enhanced metabolism GFR decreased in neonates(digoxin,gentamicin slow elimination

  39. non-depolarising MR – similar initial dose/wt frequency of increments decreased depolarising MR - relatively resistant drug dosage better assessed in terms of body surface area relatively more body water

  40. geriatric reduced proportion of total body water low albumin levels decreased hepatic enzyme activity decreased liver blood flow decreased GFR decreased receptor population decreased receptor sensitivity enhanced action of anaesthetic drugs

  41. Pregnancy slow gastric emptying increased gastric acidity activity of placental enzymes increased glucuronidase activity increased plasma volume,COP decreased binding of drugs with proteins Smoking ,alcoholism induction of hepatic microsomal enzymes

  42. Pharmacologicalvariability genetically determined,abnormal reaction to a drug prolongation of suxamethonium variants of plasma Che normal,atypical,fluoride resistant & silent described by resistance to inhibition by dibuciane % of enzyme inhibition by dibucaine-dibucaine number normal homozygotes - 80 atypical - 20

  43. A/c hepatic porphyria inducers of ALA synthetase increased hepatic production & renal excretion of porphyrins demyelination of peripheral& central pathways barbiturate phenytoin alcohol benzodiazepines sulphonamides

  44. Malignant hyperthermia hypermetabolic reaction sudden increase in myoplasmic Ca genetic disorder of Ca rekeasing ryanodine receptor suxamethonium inhalational agents Hereditory resistance to oral anticoagulants altered reactivity with vit k,antagonists/both G6PD defficiency hemolysis after exposure to antimalarials,sulphonamides, NSAIDs

  45. Supersesitivity due to up-regulation of receptor density c/c drug therapy,sympathetic denervation exaggerated response to normal drug doses hyperkalemic response to suxamethonium in burns/spinal cord injuries Desensitisation decrease in cellular sensitivity/responsiveness due to continous or repeated exposure to agonists a/c desensitisation is called tachyphylaxis readily reversible repeated doses of suxamethonium c/c desensitisation – tolerance receptor degradation,receptor down regulation auto enzyme induction -barbiturates sympathomimetics in Bro: asthma vasodialatory effects of NTG

  46. hypersensitivity abnormal reaction to drugs,involving immunological mechanisms and formation of antibodies type1:immediate type,IgE mediated type2:cytolytic reactions,IgG&IgM agranulocytosis – indomethacin thrombocytopenia – thiazide diuretics halothane hepatitis type3:immune complex mediated compliment fixation by IgG a/c glomerulonephritis,rh.arthritis type4:delayed cell mediated mantoux reaction

  47. Pathological variability liver disease: altered hepatic blood flow altered ptn binding,intrinsic clearance obstructive disease:reduced clearance of MR c/c hepatic dysfunction-decreased STP requirements decreased synthesis of plasma Che renal disease: increased toxicity from accumulation of active metabolites enhanced,prolonged response alteration in protein binding respiratory : COAD resp centre insensitive to CO2 resp depressant effects of opioid,iv induction agents exaggerated bronchospasm with STP,morphine,neostigmine

  48. Cardiac disease : most anaesthetics myocardial depressants exaggerated depression in constrictive pericarditis suxamethonium/halothane – arrhythmias myasthenia gravis extremely sensitive to NDMR resistant to DMR myasthenic syndrome sensitive to both NDMR/DMR dystrophia myotonica suxamethonium- hyperkalemia,prolonged muscle contraction

  49. Endocrine disease increased sensitivity to CNS depressant drugs myxoedematuos pts enhanced microsomal oxidation in thyrotoxicosis decreased ptn binding Pheochromocytoma-arrhytmias Carcinoid tumours-tachyarrhythmias,hypertension

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