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DRUGS THAT INTERACT WITH WARFARIN Abciximab Acetaminophen Alcohol (acute and chronic) Allopurinol Aminodarone Aminoglutethimide Amobarbital Anabolic steroids Aspirin Azathioprine Butabarbital Butalbital Carbamazepine Cefoperazone Cefotetan Cefoxitin Ceftriaxone Chenodiol Chloral hydrate Chloramphenicol Chlorpropamide Chlorthalidone Cholestyramine Cimetidine Ciprofloxacin Clarithromycin Clofibrate Corticotropin Cortisone Coumadin Cyclophosphamide Danazol Dextran Dextrothyroxine Diazoxide Diclofenac Dicloxaxillin Diflunsial Disulfram Doxycycline Erythromycin Ethacrynic acid Ethchlorvynol Fenoprofen Fluconazole Fluorouracil Gemfibrozil Glucagon Glutethimide Griseofulvin Haloperidol Halothane Heparin Ofloxacin Olsalazine Omeprazole Oxaprozin Oxymetholone Paraldehyde Paroxetine Penicillin G Pentobarbital Pentoxifylline Phenobarbital Phenylbutazone Phenytoin Piperacillin Piroxicam Prednisone Primidone Propafenone Propoxyphene Propranolol Propylthiouracil Phytonadione Quinidine Quinine Ranitidine Rifampin Ibuprofen Ifosamide Indomethacin Influenza virus vaccine Itraconazole Ketoprofen Ketorolac Levamisol Levothyroxine Liothyronine Lovastatin Mefenamic Meprobamate Methimazole Methyldopa Methylphenidate Methylsalicylate Miconzale Metronidazole Miconazole Moricizine HCl Nafcillin Nalidixic acid Naproxen Neomycin Norfloxacin Secobarbital Sertaline Simvastatin Spironolactone Stanozolol Streptokinase Sucralfate Sulfamethizole Sulfamethoxazole Sulfinpyrazone Sulfinpyrazone Sulfisoxazole Sulindac Tamoxifen Tetracycline Thyroid hormone Ticacillin Ticlopidine t-PA Tolbutamide Trazodone Trimethoprim-sulfamethoxazole Urokinase Valproate Vitamin C Vitamin E



Drug interactions:

Drug interactions Definition:- An alteration in the effectiveness or toxicity of one drug due to another simultaneously administered drug is known as Drug-Drug- Interaction. Antagonistic or synergistic. Additive or supra-additive.

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Accordingly the interactions are classified into : Drug - drug interactions Drug - herb interactions Drug - food interactions Drug - lab test interactions Drug - disease interactions .

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Harmful Drug Interactions can: E.g. Failure of oral contraceptive with Rifampicin(enzyme inducer). Beneficial drug interactions : E.g. Probenecid + Penicillin – prolongs duration of action of Penicillin. Naloxone(antidote) for Morphine overdose.

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Factors predisposing to drug interactions:- Insufficient knowledge . Diet ary factors (milk/vegetables). Presence of disease states(liver/kidney). Patient behavior(self medication/OTC). Physiology of individual(age/genetic factor) Environmental factors. Dosage form factors

Outcomes of drug interactions:

Outcomes of drug interactions Loss of therapeutic effect Toxicity( narrow therapeutic index or zero order kinetics) Increase in pharmacological activity (FDC) Additive & potentiation (intended) or antagonism (unintended).


MECHANISM OF DRUG INTERACTIONS Interactions outside the body (IN VITRO) Interactions inside the body (IN VIVO)


IN VITRO INTERACTIONS E.g. Penicillin & Aminoglycosides mixed in same syringes may get precipitated & the efficacy of the individual drugs is reduced. Diazepam will get precipitated in distilled water .


IN VIVO INTERACTIONS These are of two types: Pharmacokinetic interactions Pharmacodynamic interactions .

Pharmacokinetic Interactions:

Pharmacokinetic Interactions

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Ex1., antiacids Decrease the pH Decrease the tablet dissolution of Ketoconazole (acidic) Ex2., H2 antagonists pH Therefore , these drugs must be separated by at least 2h in the time of administration of both . Absorption

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EX1., Tetracycline interacts with iron preparations or Milk (Ca 2+ ) Unabsorpable complex Ex2., Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

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Drug-induced mucosal damage. Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine Inhibit absorption of several drugs eg., digoxin Altered motility Metoclopramide (antiemitic) Increase absorption of cyclosporine due to the increase of stomach empting time Increase the toxicity of cyclosporine

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Distribution: Displaced protein binding The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity. Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%) Drugs that displace these agents are Aspirin Sulfonamides

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EX1., Microsomal Enzyme induction A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g., Carbamazepine (antiepileptic drug ) increases its own Metabolism and OCP Phenytoin increases hepatic metabolism of theophylline Leading to decrease its level Reduces its action and Vice versa Metabolism

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Ex., Erythromycin inhibit metabolism of astemazole and terfenadine Increase the serum conc. of the antihistaminic leading to increasing the life threatening cardiotoxicity EX2., Enzyme inhibition; It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity .

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First-pass metabolism: Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action . EX., Rifampin lowers serum con. of verapamil level by increase its first pass . Also, Rifampin induces the hepatic metabolism of verapamil

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Renal excretion Active tubular secretion : When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug .This will reduce such a drug excretion increasing its con. and hence its toxicity. EX., Probenecid Decreases tubular secretion of Penicillin or methotrexate.

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Passive tubular reabsorption ; Excretion and reabsorption of drugs occur in the tubules By passive which is regulated by concentration and lipid solubility . N.B., Ionized drugs are reabsorbed lower than non-ionized ones Ex1., Sod.bicarb. Increases lithium(acidic) clearance and decreases its action Ex2., Antacids Increases salicylates clearance and decreases its action

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Pharmacodynamic interactions; It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors. EX., Propranolol + verapamil Synergistic or additive effect Cotrimoxazole Naloxone + morphine overdose Desferioxamine for iron poisoing Amoxicillin + clavulanic acid Severe hyperkalemia by concurrent use of ACE inhibitors & K+ sparing diuretics Additive ototoxicity with aminoglycoside & frusemide

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Prevention of drug interaction

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Avoid polypharmacy (>3 drugs) to the maximum extend. Monitor the therapy given including Therapeutic Drug Monitoring . Be particularly vigilant when patient is taking narrow therapeutics index drugs. Educate the patient about the prescribed drugs. .

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