Drug interactions

Anticoagulants Antimicrobial agents Pharmacology and Toxicology Department Interactions of Anticoagulant/Anti-thrombotic Drugs • ►AnticoaguIants + Aspirin & other salicylate: • - Aspirin in doses of 500 mg daily increase the likelihood of bleeding in patient already taken anticoagulants. • - Aspirin decreases platelet aggregation and so, prolong bleeding time. • - Larger doses of Aspirin alone have direct hypoprothrombinemic effect like the anticoagulants which is reversible by vit.k. • - Aspirin has direct irritant effect on stomach lining, can cause GIT bleedingand prolong bleeding time. • - This interaction is documented & clinically important. • • Avoid concurrent use of Aspirin in normal analgesic and inflammatory doses with anticoagulants • Low-dose Aspirin. (75 mg) does not matter. • Patient on anticoagulants should avoid many OTC analgesic & antipyretic preparations contains substantial amount of Aspirin. • - Paracetamol is safer analgesic substitute • ►Anticoagulant + H2 blockers (Cimetidine, Rantidine & Nizatidine) • - Potential effects: • The anticoagulant effect of warfarin can be increased if Cimetidine is given concurrently and can lead to bleeding. • Rantidine or Nizatidine appear to be non reacting H2 blockers. • Cimetidne inhibit liver microsomal enzyme and increase the effect of warfarin. • It is of a clinical importance. • Monitor concurrent use closely & observe for need to reduce warfarin dosage. • Use of non reacting alternative to Cimetidine like Rantidine & Nizatidine ► Anticoagulant + antiacids • Potential effects: AL(OH)3 and Mg(OH)2 do not interact with warfarin. • Dicoumarol serum level increased by Mg(OH)2 but no interaction with AL(OH)2. • It is suggested that dicoumarol forms more rapidly absorbed chelate with Mg2+ so that its effect is increased. • - Management: Monitor prothrombine time if Mg(OH)2 is given to patient on anticoagulants.

►Anticoagulants + cholestyramine • Warfarin effect can be decreased by cholestyramine • Cholestyramine binds to bile acids & anticoagulants within the gut ---> preventing their absorption. • Cholestyramine reduces the absorption of fat soluble vitamin, so cholastyramine can have some direct hypoprothrombinemic effect of its own. • Separating the dosages as much as possible may help to minimize the Interaction. • Chlolestyramine should be given 3-6 h after warfarin • If concurrent use is necessary prothrombine time should be monitored & the dose of anticoagulants should be increased appropriately ►Anticoagulants + Hypoglycemics • dicumarol (anticoagulant) has higher affinity to PP than tolbutamide & chlorpropamide (hypoglycemics) ---- > displacement of tolbutamide and chlorpropamide from PP and increase its toxicity --- > hypoglycemic coma • Management : avoid combination

• ►Anticoagulants + Vitamin K (Phytonadione)

• Potential effects: Decreased or reversed effects of warfarin • Management: Avoid or minimize intake of foods with high vitamin K. • Monitor prothrombine time . Adjust warfarin dose as needed ►Anticoagulants + Phenytoin

• anticoagulant effect may increase transiently at start of phenytoin therapy due to PP-binding displacement ------> bleeding. • Management: Avoid combination.

►Anticoagulants + chloral hydrate • patients take warfarin and chloral hydrate may suffer from bleeding. • Chloral hydrate metabolite is trichloroacetic acid, which is a highly bound compound that successfully displaces warfarin from PP, thereby increasing its anticoagulant effects (bleeding). • Anticoagulants + Enzyme inducers (e.g. Barbiturates)

• Potential effects: Decreased effects of warfarin • Management: Adjust warfarin dose as needed when starting or stopping. Use benzodiazepine instead

►Anticoagulant + allopurinol • -Potential effects: most patients on oral anticoagulants given oral allopurinol do not develop an adverse interactions • But since excessive hypoprothrombinemia and bleeding occur unpredictably , it is important to monitor the initial response of the anticoagulant. • -Allopurinol inhibit metabolism of anticoagulants by the liver leading to prolong their effects & half life. • Management: This interaction is of clinical importance. Its incidence is impossible to predict. prothrombin time should be monitored. Interactions of Antimicrobial Drugs I- ANTIBIOTICS • Aminoglycosides [Gentamicin, Kanamycin, Neomycin, Streptomycin] 1. Aminoglycosides with Cyclosporine • - Increased risk of nephrotoxicity. • kidney function. - Monitor aminoglycoside concentrations 2. Aminoglycosides with Loop Diuretics [bumetanide, ethacrynic acid, furosemide] • Increased risk of Ototoxicity. • Avoid excessive doses of either drug. Monitor Aminoglycoside concentrations. Use alternative antibiotic if possible. 3. Aminoglycosides with NSAIDs [diclofenac, ibuprofen, piroxicam, indomethacin] • - Increased concentrations of aminoglycoside in premature infants. • - Avoid combination if possible. Otherwise, decrease aminoglycoside dose • before starting NSAID. Monitor aminoglycoside concentrations and renal function. 4. Aminoglycosides with Penicillin [ampicillin, methicillin, nafcillin, oxacillin, penicillin G] • - Inactivation of aminoglycoside when combined in the same infusion fluid. • - Do not mix drugs in same solution. Penicillins [Amoxicillin, Ampicillin, Cloxacillin, Dicloxacillin, Methicillin, Penicillin G, Penicillin V, Piperacillin]. • 1. Penicillins with Food • - Decreased or delayed GIT absorption of oral penicillins. • - Administer penicillin at least 2 hours before or after a meal. • 2. Penicillins with Tetracyclines • - Decreased effects of penicillins. Avoid combination 3. Penicillins with Probenecid • - Probencid interferences with renal excretion of drugs that undergo active tubular secretion, especially weak acids. Decreased renal penicillin excretion.

4. Ampicillin with Allopurinol • - Increased rate of ampicillin-associated skin rash. • - Decrease allopurinol dose or use alternative drug if rash develops.

5. Ampicillin with Estrogens • Enterohepatic circulation of estrogen may be interrupted by alteration in • bowel flora; possible reduction in oral contraceptive efficacy. Tetracyclines [Tetracycline, Doxycycline, Minocycline, Oxytetracycline]

1. Tetracyclines with Bismuth Salts [bismuth subsalicylate] - Decreased GIT absorption of tetracycline. - Separate administration times by at least 2 hours. 2. Tetracyclines with Iron Salts [ferrous gluconate, ferrous sulfate] - Decreased absorption of tetracycline and decreased efficacy of iron. - Separate administration times by at least 3-4 hours. Use enteric-coated or sustained-release formulation of iron salt. 3. Tetracyclines with Antacids :aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbona ] -Decreased GI absorption of tetracycline . - Separate administration times by at least 4-3hours .

4.Tetracyclines with Urinary Alkalinizers [potassium citrate, sodium bicarbonate]

Decreased concentrations of tetracycline. Separate administration times by at least 4-3hours. Increase tetracycline dose if necessary .

5 .Doxycycline with Barbiturates:

Decreased concentrations of doxycycline . Increase doxycycline dose if necessary. Use alternative tetracycline Macrolides 1. .Macrolide with Food : Decreased GIT absorption of erythromycin . Administer erythromycin stearate and non-enteric tablets at least 2 hours before or after a meal .

2. Macrolide with Grapefruit Juice : Increased concentrations of erythromycin .

3.Macrolide with Digoxin and Bromocriptine Reduced renal excretion of digoxin. Increased concentrations of digoxin and bromocriptine toxicity. Monitor for signs/symptoms of digoxin and bromocriptine toxicity. Decrease digoxin and bromocriptine dose if necessary . 4.Macrolide with Statins (Lovastatin, simvastatin, atorvastatin): Decreased statins metabolism. Increased risk of severe myopathy and rhabdomyolysis , Exceptions: fluvastatin, pravastatin Avoid combination. or use alternative antibiotic or non-interacting statin (eg, fluvastatin, pravastatin)

5.Macrolide and Colchicine

Colchicine is metabolized by CYP3A4 and is transported by P-glycoprotein. Macrolide increases the risk of fatal colchicine toxicity, especially for patients with renal insufficiency Quinolones (Ciprofloxacin, Nalidixic Acid, Norfloxacin) .1.Quinolones with Food [milk]

Decreased GI absorption of ciprofloxacin . Separate administration times by at least 4-3h.

.2.Quinolones with Iron Salts (Oral)

Decreased GI absorption of quinolone . Avoid combination; Separate administration times by at least 4-3hours ..

.3. Quinolones with Sucralfate

Decreased GI absorption of quinolone . Administer sucralfate at least 6 hours after quinolone . .4. Ciprofloxacin with Theophylline :

• Concurrent administration may lead to toxic increases in theophylline plasma level . (Signs of theophylline toxicity include headache, dizziness, hypotension, hallucinations, tachycardia, and seizures)

• Hepatic metabolism of theophylline is inhibited by Ciprofloxacin via the cytochrome P- 450 enzyme system

• levofloxacin or ofloxacin should be considered as an alternative to ciprofloxacin because they have little effect on CYP1A 2 Chloramphenicol 1. Chloramphenicol with Iron Products

Increased concentrations of iron . Use alternative antibiotic if possible. Monitor iron and adjust iron as needed .

.2.Chloramphenicol with Phenytoin:

Increased concentrations of phenytoin Monitor phenytoin concentrations. Adjust dose of one or both drugs as needed.

3. Chloramphenicol with Sulfonylureas:

Increased hypoglycemic effects of sulfonylurea Monitor blood glucose concentration. Decrease sulfonylurea dose if necessary.

4. Chloramphenicol with Warfarin

Increased effects of warfarin. Monitor PT. Decrease warfarin dose if necessary Metronidazole + Barbiturates Therapeutic failure of metronidazole . Monitor for metronidazole treatment failure. Increase metronidazole dose if necessary

Metronidazole + ethanol Disulfiram-like reaction. Avoid combination

Sulfonamides (Sulfamethoxazole, sulfamethizole, sulfadiazine) + warfarin Increased effects of warfarin. Monitor PT. Decrease warfarin dose if necessary

Sulfonamides + Phenytoin Increased concentrations of phenytoin Monitor phenytoin concentrations. Decrease phenytoin dose if necessary .

Sulfonamides + Methotrexate

Increased risk of bone marrow suppression and megaloblastic anemia . Avoid combination. Otherwise, monitor for signs/symptoms of hematologic toxicity . Sulfonamides + sulfonylurea drugs (Chlorpropamide, Tolbutamide, Glimepride, Glipizide, Glyburide,Tolazamide)

Increased concentrations of sulfonylurea [Exception: Glyburide] leading to hypoglycemic coma. Monitor blood glucose level, Decrease sulfonylurea dose, Use noninteracting sulfonylurea (eg, glyburide).

Azole Antifungals [ketoconazole, miconazole, itraconazole] + Statins

Increased risk of rhabdomyolysis. Avoid combination if possible. Otherwise, monitor for signs/symptoms of statin toxicity. Decrease statin dose if necessary. Pravastatin is least affected by the interaction.

Azole Antifungals + corticosteroid (Prednisolone, Dexamethasone)

Increased plasma level and effects Prednisone Decrease corticosteroid dose if necessary

Ketoconazole + Histamine H ,enidtiomaf ,enidtiemic( stsinogatnA-2 ranitidine) or proton pump inhibitors (omeprazole, esomeprazole, lansoprazole)

Decreased GIT absorption of ketoconazol Avoid combination if possible End of the lecture