Lecture 24 Flashcards
Drug Interactions
PK
ADME, alters drug concentrations in the blood
PD
Toxicity and effectiveness, alters drug effect at a given drug concentration
Drug interaction
- When the administration of a drug alters the pharmacological activity of 1+ other drugs
- Can increase or decrease activity or toxicity
Multiple Drugs
- Necessary for many or concurrent disease states
- Multifocal disease states like cardiac failure (vasodilation, diuretic, cardiac glycosides)
- Combo therapy for additive or synergistic effects (Chemotherapy for complex infections or cancer)
Types of Drug Interactions (4)
- Additive
- Synergistic
- Indifferent
- Antagonistic
PD Mechanisms
- Can be based in receptors of physiology
- Two drugs acting on different sites on a receptor OR two drugs targeting linked targets within a single pathway may be synergistic (EX: Bactrim)
- One drug can cause desensitization and decrease the action of the second drug
Combined Toxicity
-Organ based - concurrent administration of two nephotoxic drugs can cause kidney damage, even though the dose of either alone may have been insufficient to produce toxicity
Different Mechanisms Colliding
- Warfarin has decreased TI with potential for bleeding complications
- NSAIDs can cause GI ulcers and co-administration with Warfarin increases the risk of GI bleeding 4x than Warfarin alone
- Antibiotics alter intestinal flora and decrease the bacterial synthesis of vitamin K and therefore increase the effect of warfarin
Low TI
- Increased risk of drug interaction
- For Low TI drugs, small variations in clinical plasma concentrations of a drug (or its metabolites) may result in serious clinical manifestations of adverse effects
- Other risks: Age, renal/hepatic disease, chronic drug therapy, polypharmacy
What is layered in with drug interactions?
Factors of individual variation
Are most drug interactions PK or PD based?
PK
Absoprtion + Drug Interactions
- Binding or chelate
- Altering gastric pH
- Altering GI motility
- Affect transport proteins such as P-glycoprotein and organic anion transporters
- Effects on extent of absorption are more clinically relevant than the rate of absorption itself (greater impact on serum drug levels)
Examples of Altered Absorption (3)
- Iron and calcium - bind to drugs and decrease absorption (like tetracycline)
- Antacids - bind drugs and/or increase gastric emptying
- PPIs and H2RAs - increase gastric pH (may alter distribution and absorption of drugs)
Transporters
-Saturated or inhibited
-Include uptake and efflux transporters
EX: Probenecid (gout) - inhibits organic acid transport proteins (OATP), prevents excretion of penicillin and other drugs using transporters, increase AUC
Distribution/Transport
- Mechanism that alters drug distribution from drug interactions
- Saturated or inhibited
- Competition for plasma protein binding
- Displacement from tissue binding sites
- Alterations in local tissue barriers (ex: P-glycoprotein inhibition in BBB)
