Drug-drug interactions

What is a drug interaction?

Occurs when the effect of 1 drug is altered by taking another drug, chemical or food

Implications of drug interactions

BNF focuses on interactions and classifies them as:

Examples of drug interactions

1. Drug-food interactions: grapefruit and pills mix warning

2. Drug-herbal medicine interaction: St John’s wort blights contraceptive

Risk factors for experiencing drug interactions

• Age

• Sex

• Genetics

• Co-morbidities

• Number of medicines taken

• Lifestyle factors e.g. diet, smoking, illicit drugs

Risk factors - preterm neonates

Risk factors - older age

Risk factors - sex

Women are more prone to drug interactions than men

Possible reasons are:

• Reduced body weight

• Reduced organ size

• Greater proportion of body fat

• Gastric pH is lower

• Gastric emptying time is slower

• Hormonal changes during the menstrual cycle

Risk factors - genetics

Risk factors - co-morbidities

Co-morbidity:

• The simultaneous presence of 2 or more disease or medical conditions in patient

Why does this cause more drug interactions:

• Physiological changes due to the diagnosed conditions

• Polypharmacy due to drugs prescribed for multiple conditions

Risk factors - number of medicines taken (diagram)

Risk factors - diet (examples)

Risk factors - smoking

• Smoke from tobacco can induce cytochrome P450 enzymes

• This results in medicines being metabolised more quickly

• If a person stops smoking this can affect their response to a particular dose

Risk factors - illicit drugs

• Most information about opioid and benzodiazepine interactions due to their therapeutic use

• For other illicit drugs interaction data mainly from case reports or small studies

• Some illicit drugs are ‘cut’ with other substances that could also interact

• Illicit drugs may be fake and not contain what the person thinks they do

What is pharmacogenomics?

The study of how a patient’s genome can influence how they respond to medicines. Variants in an inidividual’s genome can increase the functioning of medicines or make them effective

Mechanisms - classification

Mechanisms - pharmacodynamic interactions

• Direct effect at receptor

• Interference in biological or physiological process

• Additive or opposite pharmacological effect

• Usually predictable as they occur between drugs that have the same or opposite mechanisms of action

Mechanisms - pharmacokinetic interactions

An alteration in the absorption, distribution, metabolism or excretion of a drug due to another drug/chemical/food

Mechanism - absorption

Drugs that alter gastric pH (e.g. PPIs or H2-antagonists) can affect the absorption of other drugs

Mechanism - absorption

Mechanism - active transport pumps

• Drug interactions occur when these pumps are inhibited or induced

• Affects absorption, distribution and excretion of drugs

P-glycoprotein - efflux pump

• Present throughout the body

• In the gastrointestinal system, has major role in absorption of drugs

• Transmembrane efflux transporter which pumps drugs back into the gut lumen decreasing absorption

• Transports drugs of many classes e.g. digoxin, calcium channel blockers, macrolide antibiotics

Organic anion transporting polypeptides (OATPs)

• Membrane-influx transporters

• 11 subtypes - OATP1B1, 1A2, 1B3 and 2B1 are most studies

• Can be genetic variation in activity of OATPs

• These subtypes are primarily involved in drug uptake in the GI system and liver

Mechanisms - distribution

• Many drugs are transported by protein-binding

• Albumin is most important in this process

• Drugs bind competitively to albumin and can displace drugs with lower affinity to the binding sites

Mechanisms - first pass metabolism

Mechanisms - cytochrome P450 system

Major role in biotransformation of drugs

• Usually occurs in the liver

• Catalyse oxidation

• Chemical/physical alteration of drug

• Creates metabolites or converts prodrug to active drug

• Produces more water-soluble compounds for renal excretion

• Common pathways mean potential drug interactions

Mechanisms - cytochrome P450 examples

Mechanisms - cytochrome P450 inhibitors

• Occurs within hours to days

• Duration of inhibition related to half-life of drug

• Ability of drug to bind to CYP enzyme that affects metabolism

• Can be dose dependent:

  • Sertraline 50 mg = mild inhibitor of CYP2D6

  • Sertraline 200 mg = potent inhibitor of CYP2D6

• Inhibition of CYP → co-administered drugs can accumulate → toxicity?

Mechanisms - cytochrome P450 inducers

• Time lag for inducer to occur - days to weeks

• Can be dependent of half-life of drug:

  • Rifampicin = inductions can occur within 24 hours of adminitration

  • Phenobarbital = induction can take up to a week after administration

• If inducer stopped, inductive effect lost in days

• May need higher doses of other drugs (when co-administered)

• Caution when stopping enzyme inducers as plasma concentrations of other drugs could increase - toxicity possible

Cytochrome P450 Interaction - Voriconazole

• Voriconazole inhibits CYP3A4, CYP2C9 and CYP2C19

• Contraindicated with certain other CYP3A4 substrates (e.g. terfenadine, ivabradine,etc) → voriconazole increases concentrations of other drugs → prolonged QTc interval/risk of torsades de pointes

• Contraindicated with drugs that induce CYP3A4 (e.g. rifampicin, carbamazepine, etc) as these drugs reduce voriconazole concentrations

Specific dosing in SmPC:

• Phenytoin and rifabutin - higher dose of voriconazole required

• Efavirenz – higher dose of voriconazole required and reduced dose of efarirenz required

• Tacrolimus – tacrolimus dose reduced to one third of normal when taken with voriconazole

Mechanisms - excretion

Excretion mainly through:

• Kidneys - renal tubular excretion

• Liver - biliary excretion

Interactions can occur if both drugs competing for the same excretion pathway