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DRUG INTERACTIONS AND FACTORS CONTRIBUTING DRUG INTERACTIONS
- 1. DRUG INTERACTIONS Dr. HasanAbbas Junior resident Dept. of Pharmacology & Therapeutics King George’s Medical University, Lucknow
- 2. DRUG INTERACTIONS Definition- Druginteraction is defined as pharmacological activity of one drug being altered by the concomitant use of another drug or by the presence of some other substances
- 3. Outcomes of druginteractions Beneficial • Well recognised interaction; do not pose any undue risk to the patient • E.g. Amoxicillin+clavulinic acid, Sulfadoxime+pyrimethamine Harmful • Unintended antagonism and loss of therapeutic effect • Toxicity
- 4. Factors contributing todrug interactions • Multiple diseases or predisposing illness • Multiple drug therapy • Multiple prescribers • Poor patients compliance to instructions • Advancing age of patient • Drug related factors
- 5. Drug commonly involvedin interactions • Drugs with narrow safety margin: aminoglycosides, digoxin, lithium • Drugs affecting closely regulated body functions: antihypertensive, antidiabetics, anticoagulants • Highly plasma protein bound drugs: oral anticoagulant, NSAIDS, sulfonylureas • Drugs metabolised by saturation kinetics: theophylline, phenytoin.
- 6. Types of druginteractions 1. DRUG-DRUG INTERACTIONS 2. DRUG-FOOD INTERACTIONS 3. DRUG-DISEASE INTERACTIONS
- 7. 1. DRUG-DRUG INTERACTIONS Threemechanisms by which an interaction can occur: I. Pharmaceutical interaction II. Pharmacokinetics interaction III. Pharmacodynamic interaction
- 8. I. PHARMACEUTICAL INTERACTIONS •Certain drugs react with each other and get inactivated if their solution is mixed before administration • In practice, these in vitro interactions can occur when injectable drugs are mixed in the same syringe or infusion bottle 1. Diazepam + infusion fluid Precipitation 2. Phenytoin + infusion fluid Precipitation
- 9. 3. Heparin +Hydrocortisone Inactivation of heparin 4. Kanamycin + Hydrocortisone Inactivated of kanamycin 5. Carbenicillin + Gentamicin Inactivation by gentamicin • In general, it is advisable to avoid mixing of any two or more parenteral drugs before injecting.
- 10. II. PHARMACOKINETIC INTERACTIONS Involvethe effect of drug on another from the point of view that includes: 1.Absorption 2.Distribution 3.Metabolism 4.Excretion
- 11. 1. Absorption interactions A.Altered pH B. Formation of drug chelates and complex C. Drug induced mucosal damage D. Altered GIT motility E. Altered bacterial flora
- 12. A. Altered pH •Non ionized forms are more lipid soluble and more readily absorbed from GIT than ionized form • Example- Antacid and H2 antagonist cause decrease in pH, which causes decrease dissolution of tablet ketoconazole(acidic) • Therefore, these drugs must be separated by at least 2 hours in the time of administration of both
- 13. B. Complexation orchelation • Eg. 1. Tetracycline interacts with iron preparations OR Milk(Ca++) Unabsorbable complex • Eg. 2. Antacids(Aluminium or magnesium hydroxide) Decrease absorption of Tetracycline by 85% due to chelation.
- 14. C. Drug inducedmucosal damage Antineoplastic agents eg. Cyclophosphamide, vincristine and procarbazine Absorption of several drugs, eg. Digoxin inhibit
- 15. D. Altered motility Metoclopramide(anti-emetics)causes increase absorption of cyclosporine due to increase stomach emptying time( Increase toxicity of cyclosporine).
- 16. E. Altered intestinalbacterial flora • In 10% of patient receiving digoxin....40% or more of administered dose is metabolised by intestinal flora • Broad spectrum antibiotics kill large number of normal flora of intestine which causes increased concentration of digoxin and increased toxicity of digoxin.
- 17. 2.Distribution interactions These interactionsinvolve displacement of one drug from plasma protein binding site by another drug: • Eg. 1: Long acting sulfonamides, indomethacin, phenytoin displaces warfarin from plasma protein binding site & increase risk of hemorrhage. • Eg.2: Quinidine reduces binding of digoxin to tissue proteins, increasing digoxin blood level & toxicity.
- 18. contd… These interactions involvedisplacement of one drug from plasma protein binding site by another drug DISPLACED DRUG DISPLACER EFFECT Anticoagulants Phenylbutazone,chloral hydrate Increased clotting time. Increased risk of hemorrhage. Tolbutamide Sulphonamide Increased hypoglycemic index
- 19. 3.Metabolism Interactions • Enzymeinduction: A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself • Eg. Rifampicin decrease plasma concentration of OCPs that causes contraception failure.
- 20. Enzyme inhibition: • Decreasein rate of metabolism in drug by another • This will lead to increase concentration of target drug, leading to its increased toxicity • Eg. Erythromycin causes increased plasma concentration of Terfenadine that leads to cardiac toxicity.
- 21. 4.Excretion Interactions Seen mostlyin case of drug actively secreted by tubular transport mechanism • Eg. 1. Probenecid inhibits tubular secretion of Penicillins and Cephalosporins and prolongs their plasma half life • Eg. 2. Aspirin blocks the uricosuric action of probenecid and decreases tubular secretion of methotrexate.
- 22. III. PHARMACODYNAMIC INTERACTIONS •Modification of the action of one drug at target site by another drug, independent of a change in its concentration • May results in synergism/additive effect/antagonism Synergism- When the therapeutic or toxic effect of two drugs are greater than the sum of effects of individual drugs • Eg. Combination of Sulfamethoxazole and trimethoprim is used for antimicrobial agent.
- 23. Additive effect- Neteffect of two drugs used together is equal to the sum of individual drug effects • Eg. Excessive sedation, respiratory depression, motor incoordination due to concurrent administration of benzodiazepine(diazepam) and sedating antihistaminic(promethazine).
- 24. Antagonism- The effectof one drug can be reduced or abolished by the presence of another drug • Eg. Antagonism of bactericidal action of beta lactam antibiotic by combining it with a bacteriostatic drug like tetracycline.
- 25. 2.DRUG FOOD INTERACTIONS •Garlic when combined with diabetes medication could cause dangerous decrease in blood glucose level • Some garlic sensitive individuals may experience heart burn and flatulence • Garlic also has anti clotting properties(interactions with anticoagulant).
- 26. Contd… • Orange juicemust not consume with antacids containing aluminium • The juice increases the absorption of aluminium and leads to severe constipation • Milk contains elements like Ca++ and Mg++ which chelates antibiotics like tetracycline and hence decrease its absorption and effect.
- 27. Contd… • Grape fruitjuice inhibit CYP3A4 increasing level of antidepressants (sertraline), benzodiazepine and verapamil • Vitamin K rich food reduce the effectiveness of anticoagulants(such as Warfarin), increasing risk of clotting • Fiber in Oatmeal and other cereals when consumed in large amount, can interfere with absorption of digoxin.
- 28. Contd… • Alcohol beveragestend to increase the depressive effect of medication such as: • Benzodiazepines • Antihistamines • Antidepressants • Antipsychotics • Muscle relaxants and narcotics • Disulfiram like reaction with metronidazole • Increase metabolism of Warfarin and Phenytoin.
- 29. Contd… Smoking increases activityof drug metabolizing enzymes in the liver. Eg.Diazepam, theophylline, Olanzapine are metabolized rapidly and their effect is decreased.
- 30. 3.DRUG DISEASE INTERACTIONS •Drug- Condition interaction occurs when a drug worsens or exacerbates an existing medical condition. • Nasal decongestants + Hypertension…. Blood pressure • NSAIDS + Asthmatic patients …. Airway obstruction • Nicotine + Hypertension … Heart rate • Metformin + Heart failure … Lactate level
- 31. References: • Tripathi, K.D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical