DRUG INTERACTION AND EFFECT OF DRUGS ON VARIOUS SYSTEMS.pptx

DRUG INTEARCTIONS

1. DRUG INTERACTIONS

2. DRUG INTERACTIONS Drug interaction, The effects of one drug are altered by prior or concurrent administration of another drug, A drug interaction may result into adverse effects.  the effectiveness.  the toxicity.  in the effectiveness.  in the toxicity

3. CAUSES Self- medication, Semiqualified paramedical staff. Undue prescribing of several drugs. Drugs with low margin of safety e.g. lithium and digoxin . Enzyme induction effects. Zero-order elimination kinetics, e.g., phenytoin , warfarin , theophylline . Drugs used for prolonged period e.g., antiepileptic drugs.

4. INVITRO DRUG- DRUG INTERACTIONS DRUGS MIXED INTO RESULT Thiopental + Succinyl choline In the same syringe Precipitation Hydrocortisone + Heparin -do - Inactivation of heparin Hydrocortisone + Penicillin - do - Inactivation of Penicillin Penicillin + Gentamicin - do - Mutual inactivation Sodium salt of phenytoin , babiturates,sulfonamides , Heparin and Penicillin In I. V. infusion fluid such as 5% dextrose Drugs are precipitated in the acidic PH of dextrose solution Noradrenaline In I. V. infusion fluid such as normal saline Oxidised Aminophylline I. V. solution With I. V. epinephrine, erythromycin These drugs get decomposed at alkaline PH of aminophylline Almost all drugs (as a rule) Into blood/plasma, amino acid, mannitol I. V. transfusion Get inactivated

5. Pharmacokinetic Interactions Absorption, distribution, metabolism Absorption Atropine and atropine substitutes delay gastric emptying Gastrointestinal absorption is accelerated by e.g., metoclopramide , cisapride , domperidone . Milk, antacids containing Ca2+ Mg2+ and Al3+ iron preparations chelates /complexes with tetracylines .

6. Fluoroquinolones divalent cations - antacids Liquid paraffin emulsifies fat soluble vitamins, Cholestyramine , binds to acidic drugs like digoxin , warfarin . Erythromycin inhibit intestinal bacterial flora inactivation of digoxin to  its bioavailability. Epinephrine to local anaesthetic injection slow down the systemic absorption of local anaesthetic - vasoconstriction.

7. Distribution Sulfonamides displace bilirubin in neonates, causing kernicterus , Salicylates and sulfonamides displace tolbutamide and warfarin also methotrexate Digoxin toxicity enchanced byquinidine , verapamil and amiodarone , displace digoxin from tissue binding site  its renal clearance. Protamine sulfate combines strongly acidic heparin to limit its distribution; Desferrioxamine complexes with iron, limits its distribution,

8. Metabolism Certain drugs induce others metabolism thus decreasing the therapeutic efficacy.Hence they are called as enzyme inducers Similarly some drugs are inhibiting the metabolism of other drugs. Thus precipitating toxicity of the affected drugs.

9. Primary drug Inducing drug Effects Oral anticoagulants Phenobarbital Decreased anticoagulant effect Oral contraceptives Rifampicin unwanted pregnancy levodopa Pyridoxine Decreaesd levodopa effect in Parkinsonism Corticosteroids Rifampicin Risk of graft rejection Quinidine Phenytoin  quinidine effect Barbiturates Barbiturates  Effect due to development of pharmacokinetic tolerance Carbamazepine Carbamazepine - do -

10. Primary drug Inhibiting Drug Effects Theophylline , warfarin and carbamazepine Erythromycin ( inhibits cytochrome p-450 ) Impairs their metabolism and potentiates their effects Theophylline Fluoroquinolones Impair metabolism, potentiate toxicity Opioid analgesic Monoamine oxidase inhibitors Impair metabolism, pronounced respiratory depression Ethyl alcohol Dissulfiram , Metronidazole Inhibi t alcohol metabolism; Antabuse type reaction Tolbutamide Chlorpamide Chloramphenicol Hypoglycaemia Azathioprine Allopurinol Potentiates toxicity

11. Excretion Methylxanthines  renal blood flow & GFR, Rapid drug excretion Probenecid blocks the active tubular secretion of penicilline,cephalosporins & zidovudine Prolongs their acrion Quinidine  tubular secretion of digoxin Alkalinisation of sodium bicarbonate excretion of acidic drugs ( Asprin & barbiturates) Acidification of urine by ammonium chloride Ascorbic acid  excretion of basic drugs amphetamine , morphine

12. Loop and thiazide diuretics, indirectly the proximal tubular reabsorption of lithium in Li+ toxicity Pharmacodynamic Interaction Synergism ( leading to supra – additive toxicity ) Antagonism ( leading to  effect)

13. Thiazide diuretics elevate blood glucose levels counteract blood lowering effect All anti-platelet aggregation drugs ( aspirin ) potentiate anticoagulant effect of heparin. NSAIDs,  the antihypertensive effects of -blockers and of diuretics. Benzodiazepines + antihistamines excessive sedation falls and hip fracture, Consumption of alcohol along with prescribed CNS depressant drugs can end up in serious consequences. Aminoglycosides group of antibiotics potentiate the neuromuscular blocking effect of d- tubocurarine .

14. Loop diuretics  the ototoxicity of aminoglycosides . Tricyclic antidepressants, if given along with atropine substitutes, potentiate anticholinergic side effects. Metoclopramide aggravates extrapyramidal side effects of phenothiazines . Propranolol , with insulin agents, masks the symptoms of hypoglycaemia and hypoglycaemic coma. Unwanted loss of antihyperten sive effects of -blockers due to phenylephrine and phenylpropanolamine Propranolol digoxin leads bradycardia Halothane risk for cardiac arrhythmias.

15. Bactericidal drug penicillin, less effective with bacteriostatic drug tetracycline which arrests cell division. Sildenafil  cGMP levels by inhibiting its breakdown by phosphodiesterase isoform-5. severehypotension . Neurotransmitter Release Tricyclic antidepressants (TCAs) block the neuronal uptake of norepinephrine . TCAs reverse the antihypertensive actions of clonidine

16. Selective Serotonin-Reuptake Inhibitors (SSRIs) with MAOIs result in elevated levels of 5-HT in the synaptic cleft leading to “Serotonin Syndrome  Its reduced metabolism due to MAO inhibition and more availability for release . Its uptake is inhibited by the neuron.

17. Interactions Due to Changes in Fluid and Electrolyte Balance Thiazide /Loop diuretics cause hypokalaemia digoxin and arrhythmias may ensue. Hypokalaemia can reduce the antiarrhythmic effects of lignocaine , quinidine and procainamide . Angiotensin converting enzyme inhibitor precipitating severe hyperkalaemia . Sodium depletion is known to  lithium toxicity.

18. Interactions Leading to  ed Therapeutic Effects Cotrimoxazole , a combination of sulfamethoxazole and trimethoprim . Levodopa with carbidopa Additive effcacy of nitrates and -blockers Additive efficacy of nitrates and Ca2+ channel blockers. Thiazide diuretics + Potassium Supplements + -blockers. Thiazide diuretics + Potassium Supplements + -methyldopa. Use of probenecid to  the serum concentrations and prolong the activity of penicillins and some cephalosporins .

19. Amoxicillin with a - lactamase inhibitor  the bio availability of amoxycillin . Hydrochlorthiazide+triamterene – a combination diuretic used to treat hypertension, minimising the K+ loss. DRUG-LABORATORY TEST INTERACTIONS Occurrence of a false positive urinary glucose after cephalosporin administration. Cephalosporins - serum creatinine levels. Diuretics - electrolyte (Na+, K+ ). Alcohol  - glutamyl transpeptidase .

20. Iodohydroxy quinoline radiocontrast media,  I 131 protein bound iodine. Salicylates , nalidixic acid and vitamin-c false positive test of urine sugar. Spironolactone causes  digoxin plasma levels. Use of estrogens  in serum thyroxine values in hyperproteinaemia . Use of MAOIs  urinary VMA .

21. DRUG – FOOD INTERACTIONS Several tyramine containing foods. ( e.g., matured cheese, red wines, riped bananas, yoghurt, shrimp paste, salami) hypertensive crisis in patients taking MAOIs. Spinach and broccoli dietary source of vitamin K antagonises the effect of warfarin . Tetracyclines with calcium. Food  the bioavailability of NSAIDs, tetracycline, ethanol and didanosine .

22. Grape fruit oranges inhibit CYP3A4 isoenzyme system,  the bioavailability of indinavir , Saquinavir , midazolam , nimodipine , nifedipine , lovastain , carbamazepine and verapamil . Rich protein diet results in acidic urine excretion of basic drugs low protein diet provides an alkaline urine excretion of acidic drugs. Metabolism of theophylline is  charcoal broiled beef enzyme inducing effects. Food, orange juice and coffee/tea, reduce the bioavailability of alendronate . Acarbose immediately at the start of each meal delays the carbohydrate absorption inhibiting the enzyme alpha- glucosidase .

23. PHARMACOGENETICS The study of genetic basis for variability in drug response. Genetic influences on drug action as well as on drug handling by the body. Uses Genetic information to guide the choice of drug and dose on an individual basis.

24. Atypical pseudocholinesterase G-6-PD deficiency haemolysis - primaquine sulfonamides, dapsone , quinine, nalidixic acid, nitrofurantoin , & menadione . The low activity CYP2C9 metabolize warfarin slow action  bleeding. Thiopurine methyl transferase (TPMT) deficiency  risk of severe bone marrow toxicity of 6-mercaptopurine azathioprine . Irinotecan neutropenia - diarrhoea with UGT1A128 glucuronyl transferase .

25. 5-fluorouracil toxicity dihydropyrimidine dehydrogenase deficiency. Over expression of P- gp results in tumour resistance - pumps out the drug from the tumour cells. Polymorphism of N-acetyl transferase 2 gene rapid and slow acetylator status. Isoniazid neuropathy,Procainamide hydralazine induced Iupus mainly in slow acetylators . Acute intermittent porphyria —precipitated by barbiturates repression of porphyrin synthesis. CYP2D6 poor metoprolol / debrisoquin metabolizer status.

26. Malignant hyper thermia - Ca 2 + release channel. Inability to hydroxylate phenytoin . Coumarin anticoagulants which has low affinity for the coumarins . Attack of angle closure glaucoma mydriatics individuals with narrow iridocorneal angle. Genotype to phenotype is much better in monogenic phenotypic traits such as G-6-PD, CYP2D6, TPMT.

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