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Drug Interactions 2


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PGP can be competitively inhibited by
e.g. cyclosporin A, quinidine, verapamil, itraconazole, clarithromycin), or have its levels induced (rifampin).
10% of caucasians are
CYP2D6 poor metabolizers (homozygous for mutant alleles) & have a 10-fold reduced metabolic efficiency. They can have 10-fold higher steady-state drug levels. CYP2D6 metabolizes beta blockers & antiarrhythmics.
Properties Promoting Digoxin Interaction:
* Digoxin is susceptible to inhibition of its GI absorption.
* Digoxin toxicity may be increased by drug-induced electrolyte imbalances (e.g. hypokalemia).
* Renal excretion of digoxin is susceptible to inhibition.
Drugs that may increase digitalis effect:
Amiodarone, Verapamil, Itraconazole Erythromycin & Clarithromycin: inhibit renal digoxin (excretion via p-glycoprotein. Increased plasma digoxin levels.)

Potassium-depleting drugs: (increased likelihood of digoxin toxicity)

Quinidine: (displacement from tissue binding sites & reduced renal digoxin excretion via p-glycoprotein. Plasma digoxin levels will double immediately due to acute reduction of digoxin Vd by 50% (displacement from tissue binding sites), and steady state levels will double because of reduced digoxin clearance.)
Drugs that may decrease digoxin effect:

Rifampin (# is the strongest inducer of both cyt P450 & p-glycoprotein & will reduce plasma digoxin levels primarily by inducing intestinal p-glycoprotein. P-glycoprotein acts to reduce drug absorption in the GI tract by pumping drug back into the GI lumen.)
# St. John's wort: (St. John's wort is a potent p-glycoprotein inducer that will increase digoxin's renal clearance & reduce intestinal absorption of digoxin. Induction may take 2-4 weeks to develop & may persist for 2-4 weeks after the inducer is stopped.)
Drug: Quinidine (generic)
Properties Promoting Drug Interaction:
* Metabolism is inducible
* Quinidine is a potent inhibitor of CYP2D6. It will conver a rapid metabolizer to a slow metabolizer phenotype. This is the same isozyme inhibited by fluoxetine, etc.
* Renal excretion is susceptible to changes in urine pH
* Renal excretion occurs via p-glycoprotein & can antagonize elimination of other drugs
* additive effects with other agents that prolong the QTc interval
Drug Interactions: Quinidine

* Drugs that alkalinize the urine (Acetazolamide, Na bicarbonate, Carbonic Anhydrase Inhibitors): decreases renal excretion & elevate plasma quinidine levels.
* Cimetidine: cimetidine is a potent inhibitor of all clinically relevant CYP isozymes and p-glycoprotein. Avoid use with amiodarone, digoxin & warfarin.
* Digoxin: quinidine displaces digoxin from tissue binding sites & inhibits p-glycoprotein mediated renal excretion
* Drugs that prolong the QTc interval: additive effects to prolong the QTc and cause cardiac arrhythmias (torsade de pointes)
* Rifampin: (increases hepatic metabolism of quinidine)
Properties Promoting Drug Interaction:rone (Cordarone ®)
* Metabolized by CYP2C9 isozyme
* Eliminated into urine by p-glycoprotein medicated excretion
Amiodarone (Cordarone ®) drug interactions

* Digoxin: amiodarone inhibits renal digoxin excretion via p-glycoprotein. Coadministration will increase digoxin plasma levels.
* Warfarin: amiodarone inhibits the CYP2C9 mediated metabolism of S-warfarin, resulting in increased warfarin plasma levels.
* Cimetidine: cimetidine is a potent inhibitor of all clinically relevant CYP isozymes and p-glycoprotein. Avoid use with amiodarone & warfarin.
Drug:Warfarin (Coumadin ®), Properties Promoting Drug Interaction:
* Metabolized by CYP2C9 isozyme (which can be induced or inhibited by other drugs)
* Binding to plasma proteins (can be reduced by other drugs)
* Action to inhibit synthesis of Vit K dependent clotting factors (can be antagonized or increased by other drugs & conditions)
* Vit K producing bacteria in the gut can be eliminated by antibiotics
* Anticoagulant effects can be altered with other drugs
Drugs that may increase warfarin effect:

* Phenylbutazone & Sulfinpyrazone : inhibit platelet function, inhibit warfarin metabolism of S-warfarin & displace warfarin from albumin (these drugs are not commonly used).
* Metronidazole, Fluconazole & Trimethoprim-Sulfamethoxazole : inhibit metabolism of S-warfarin
* Aspirin, hepatic disease, heparin, hyperthyroidism: increase warfarin effect pharmacodynamically
* Third generation Cephalosporins : eliminate bacteria in GI tract produce Vit K & inhibit Vit K expoxide reductase.
Drugs that may decrease warfarin effect:
* Vitamin K: increased synthesis of clotting factors
* Chlorthalidone & Spironolactone: increased synthesis of clotting factors
* Hypothyroidism: decreased turnover of clotting factors.
Drug: Grapefruit JUICE
Properties Promoting Drug Interaction:
Properties Promoting Drug Interaction:

* contains bioflavonoids that are potent inhibitors of CYP 3A4 & 1A2
* The inhibition lasts about 24 hours and occurs in all forms of the juice - fresh fruit and fresh and frozen juice.
Drug: Grapefruit JUICE
Drug Interactions:
* Astemizole: inhibited metabolism results in the potential for dangerous arrhytmias (as well as for off the market drugs - terfanadine & cisapride).
* Statins, calcium channel blockers, cyclosporine & tacrolimis: increased plasma levels due to CYP inhibition
Drug: Statins (HMG-CoA reductase inhibitors)
Properties Promoting Drug Interaction:
* most are substrates of CYP 3A4 (NOTE: pravastatin & fluvastatin are exceptions to the rule & are not CYP34A substrates).
* increased risk of additive myopathy with other drugs that can cause myopathy
Drug Interactions: Statins
* Clarithromycin, Cyclosporin, Erythromycin: decreased statin metabolism due to competitive inhibition of CYP 3A4, elevated statin levels
Drug: Cyclosporin
Properties Promoting Drug Interaction:
* Susceptible to inhibition of its metabolism by CYP3A4 inhibitors
* Metabolism is inducible
Drug Interactions:Drug: Cyclosporin
* Barbiturates: induce CYP & increase cyclosporin metabolism
* Rifampin, St. John's wort: induce CYP & increase cyclosporin metabolism
* Macrolide antibiotics: compete for CYP, decrease cyclosporin metabolism
Drug: Cimetidine (Tagamet ®)
Properties Promoting Drug Interaction:
inhibits all relevant CYP & PGP
Drug: Cimetidine (Tagamet ®)
Drug Interactions:
* Amiodarone, Quinidine, Procainamide, Benzodiazepines, Theophylline & Warfarin: cimetidine inhibits the metabolism of these drugs, elevating plasma drug levels
Drug: Rifampin
Properties Promoting Drug Interaction:
* Induction of CYP isozymes & PGP
Drug: Rifampin
Drug Interactions:
It will acclerate the metabolism of other drugs that are metabolized by CYP. The list is very long, but include oral contraceptives, anticonvulsants, theophylline, sulfonylurea hypoglycemic drugs, corticosteroids, etc.
Drug: St. John's wort
Properties Promoting Drug Interaction:
* potent PGP inducer
* CYP 3A4 inducer
* inhibition of reuptake of amines (pharmacodynamic interaction)
Drug Interactions:
Drug: St. John's wort
* HIV protease inhibitors, NNRTIs, warfarin, oral contraceptives, anticonvulsants, digoxin, theophylline, cyclosporin, etc.: accelerated metabolism and lower plasma levels
* Antidepressants, MAOIs, Stimulants: Serotonergic crisis

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