Drug Interactions Flashcards
4 characteristics of drugs that are most likely to pose interaction problems
- Narrow therapeutic index
- Steep dose-response curve
- High first-pass metabolism
- Single, inhibitable route of elimination
2 mechanisms of drug interactions
- Pharmacodynamic
- Pharmacokinetic
Explain pharmacodynamic drug interactions
The intended or expected effect produced by a given plasma level of a drug in the presence of a second drug is altered:
- Change in drug action w/o altering plasma concentration
- Concurrent administration of 2 drugs that have a similar/opposite effect
- Synergistic or antagonistic
Explain pharmacokinetic drug interactions
The duration and intensity of a drug’s action is a function of the plasma level of the drug, which is directly related to the drug’s rate of:
- Absorption
- Distribution
- Metabolism
- Excretion
Measured by a change in one or mre kinetic parameters (i.e. max serm conc and half-life amount of drug excreted)
Explain how PPI’s may affect drug absorption
Increase in gastric pH –> may reduce the absorption of drugs (i.e. ketoconazole & itraconazole) which are best absorbed in an acidic environment
3 factors affecting rate of drug metabolism
- Largely the result of oxidation reactions catalyzed by CYP450 enzyme system
- CYP3A4 alone is involved in the metabolism of about half of all drugs currently prescribed
- May be increased or decreased based on enzyme induction or inhibition
Consequence of induction
Increased rate of metabolism, enhanced oral first pass metabolism, reduced bioavailability –> decreased drug plasma concentration
Substrate for induction and its inducer
Substrate: Ibuprofen
Inducer: Phenytoin
Consequene of inhibition
Increase in plasma concentration of parent drug –> exaggerated prolonged pharmacologic effect & reduction in metabolite –> possible toxicity
Substrate for inhibition and its inhibitor
Substrate: rosiglitazone
Inhibitor: metronidazole
Interaction of NSAID’s with lithium
- Increase plasma lithium concentration
- Lithium toxicity –> nausea & vomiting, tremors –> slurred speech, confusion –> seizures, coma, CV collapse
- Mechanism unknown, possibly decreased renal clearance of lithium
Interaction of NSAID’s with ACE inhibitors
- Diminished antihypertensive effect of ACE inhibitors
- Most concern w/ long term use
- Mechanism possibly related to ability of prostaglandins to reduce synthesis of vasodilating renal prostaglandins
Interaction of NSAID’s with methotrexate
Has been shown to decrease the clearance of methotrexate, probably by reduction on vasodilating renal prostaglandins
Interaction of NSAID’s with warfarin (4)
- Increased risk of warfarin-related bleeding by inhibition of platelet function
- ASA most significant risk
- Possible mechanism = displacement of warfarin from plasma protein-binding sites
- ASA & NSAIDs also produce gastric erosion
Interaction of acetaminophen with warfarin (3)
- Acetaminophen appears to increase anticoagulant effect of warfarin in dose-dependent manner
- More likely w/ continued daily doses of approx 2g/day acetaminophen
- Mechanism unknown (inhibition of CYP450 suggested)
Primary interaction of macrolides with other drugs
Inhibtion of hepatic microsomal metabolism (inhibit CYP3A-mediated metabolism of many drugs)
Exception to general interaction of macrolide with other drugs
Increase in digoxin bioavailability caused by erythromycin’s suppression of gut bacteria that normally degrades some digoxin prior to absorption
Interaction of metronidazole with other drugs
- Imidazole ring found in many other drugs known to inhibit hepatic drug metabolism (similar shape –> similar effect)
- Important interaction with warfarin: inhibit metabolism of warfarin –> enhanced anticoagulation effect
Interaction of antibiotics with oral contraceptives
- First report of interaction with rifampin (antituberculosis drug and potent inducer of CYP-450 enzyme system) –> increased metabolism of oral contraceptives
- Failure with other antibiotics less clear –> possible lack of induction of P-450 –> reduced plasma level of steroids
