Introduction to Drug Interactions

Drug Drug Interaction

phenomena that occurs when the effects (pharmacodynamics) or pharmacokinetics of a drug are altered by prior administration or co-administration of a second drug
Hartshorn, EA, Tatro, DS: Drug Interactions, 2003, Facts and Comparisons, St. Louis, MO

Increasing risk of death

1 in 10
7 1 in 10 6 5 1 in 10 4 1 in 10 1 in 103 2 1 in 10

Lightning Plane crash

Murder
Auto-cash Fatal, unexpected drug reaction

Drug-Drug interaction may alter drug effect by

Additive effect : 1 + 1 =2 Synergistic effect : 1 +1 > 2 Potentiation effect : 1 + 0 =2 Antagonism : 1-1 = 0

Outcomes of drug interactions

Loss of therapeutic effect Toxicity Unexpected increase in pharmacological activity Beneficial effects e.g. additive & potentiation (intended) or antagonism (unintended). Chemical or physical interaction e.g. I.V incompatibility in fluid or syringes mixture

Risk Factors for Drug Interactions

High Risk Patients
Elderly, young, very sick, multiple disease Multiple drug therapy Renal, liver impairment

High Risk Drugs

Narrow therapeutic index drugs Recognised enzyme inhibitors or inducers

Some drugs with a low therapeutic index

Lithium Carbamazepine Phenytoin

Digoxin Cyclosporin Phenobarbitone

Theophylline (Aminophylline)

Warfarin

Sources of drug variability

Drug tablet
Release

Pharmacokinetics

Drug in gut
Absorption

Drug in blood
Distribution

Drug metabolites

Drug in tissues

Drug in urine/bile

Pharmacodynamics
Desired response

Drug at receptor

No response

Unwanted response

Mechanism of drug interaction

Pharmacokinetic interactions

Absorption Distribution Biotransformation*** Excretion

Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance

Pharmacodynamic interactions

Physiological interactions Pharmaceutical interactions

Unknown Mechanisms
Not all interactions can be predicted based upon readily recognizable mechanism Be wary of new combinations where literature is sparse or non-existent
Meropenem and Valproic Acid
VPA concentration can drop 3 to 5 fold in 24 hrs after adding Meropenem Mechanism ?

Use all available resources

Pharmacodynamic interactions
Receptor interaction Competitive Non-competitive Sensitivity of receptor Number of receptor Affinity of receptor Alter neurotransmitter release /drug transportation Alter water/electrolyte balance

Digoxin (0.25 mg) tab od pc

Furosemide (20 mg) 1 tab po od pc

Answer Increase digitalis effect due to diuretic induce hypokalemia therefor increase sensitivity of myocardium to digitalis

Physiological interactions
Drug A and Drug B bind to different receptors on the same tissue but give opposite or similar effect Aspirin (anti-platelet) +Warfarin/Coumarin (anticoagulant)

Increase bleeding

Pharmaceutical interactions
Interactions that occur prior to systemic administration. For example incompatibility between two drugs mixed in an IV fluid. These interactions can be physical (e.g. with a visible precipitate) or chemical with no visible sign of a problem

Pharmacodynamic Drug Interaction

Extension of underlying pharmacology / toxicology
Potentiation
CNS sedation antihistamines / EtOH MAOIs and SSRIs, Phenylephrine, etc Digoxin toxicity with diuretic induced potassium wasting QTc prolongation w/ Amiodarone and clarithromycin

Antagonism
Beta blockers used with terbutaline

Drug Interaction Resources

CPOE system alerts Drug Interaction Facts Facts and Comparisons quickly outdated Online Multum Database updated daily
http://www.drugs.com/drug_interactions.html

Drugs effecting QTc

University of Arizona Health Sciences http://www.arizonacert.org

Updated P450 data

http://medicine.iupui.edu/flockhart/table.htm