Drug Interactions Flashcards
What are phase I trials?
Healthy human subjects (approx 100)
First use in man
Evaluation of safety and toxicity
Pharmacokinetic (and sometimes pharmacodynamic) assessment
What are phase II trials?
First assessment in patients (approx 500)
Safety and toxicity evaluated
Dose range identified
Pharmacokinetic and pharmacodynamic monitoring
What are phase III trials?
Use in wider patient population (approx 2000), usually multi-centre
Efficacy main objective
Safety and toxicity also carefully monitored
What are phase IV trials?
Post-marketing surveillance
All patients prescribed drug monitored
Efficacy, safety and toxicity measured
Quantification of unusual adverse drug events
Name some drugs that have potentially serious drug interactions.
Warfarin, digoxin, beta blockers…
What is a drug interaction?
a predisposing factor to adverse drug reactions
What is a medication error?
Any unintentional error in the prescribing, dispensing, or administration [including preparation for administration] of a medicinal product while in control of the healthcare professional, patient or consumer
What is an adverse drug reaction?
A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function
What are adverse drug events?
Harm caused by the drug (adverse drug reactions and overdoses) and harm from the use of the drug (including dose reductions and discontinuations of drug therapy)
What makes a drug ‘high risk’ in terms of interactions?
– Narrow therapeutic index drugs
– Recognised enzyme inhibitors or inducers
What is meant by a narrow/low therapeutic index?
Small range between drug’s risks and benefits
Give some examples of drugs with low therapeutic indices.
Lithium Digoxin Carbamazepine Cyclosporin Phenytoin Phenobarbitone Theophylline Warfarin
Types of drug interactions (3)
Pharmaceutical interactions
Pharmacodynamic interaction
Pharmacokinetic interaction
What is a pharmaceutical interaction?
An interaction between drugs (outside the body) leading to inactivation of one or both drugs
What is a pharmacodynamic interaction?
The pharmacological effect of drug (B) is modified by another drug (A) There is no change in tissue concentration of drug B
What is a pharmacokinetic interaction?
Delivery of drug to its site of action is altered by another drug
Tissue concentration of drug B increased/decreased
The pharmacokinetic behaviour of drugs is determined by what 4 major processes?
Absorption
Distribution
Metabolism
Excretion
How might absorption be affected by drugs?
Drugs may slow gastric emptying e.g. opiates, accelerate gastric emptying e.g. anti-emetic metoclopramide, or bind other drugs which prevents their absorption
How might distribution be affected by drugs?
A drug (A) may be displaced from binding sites on plasma proteins or tissue by another drug (B). Rarely clinically significant due to establishment of new steady state with unaltered concentrations of free (unbound) drug A. May be important if the displacing drug B concomitantly inhibits metabolism or excretion of drug A leading to increased free (unbound) drug A.
How are hydrophilic drugs excreted?
Hydrophilic drugs are excreted unchanged in urine
How are lipophilic drugs excreted?
Lipophilic drugs require prior metabolism and conversion to polar metabolites in the liver and thereafter are excreted in the urine
The main mechanisms by which one drug can affect the rate of renal excretion of another are…?
- by altering protein binding and hence filtration
- by inhibiting tubular secretion
- by altering urine flow / pH
