Drug Interactions

Question 1

What is an object drug?

Answer 1

Drug whose effect or action is altered by introduction of another agent

Question 2

What is a precipitant drug?

Answer 2

Drug which alters or precipitates a change in the effect of the other drug

Question 3

What common drugs have DDIs?

Answer 3

Concentration-dependent toxicity e.g digoxin
Steep dose-response curve e.g. Levodopa
Patient dependent on therapeutic effect: oral contraceptives
Saturable hepatic metabolism e.g. phenytoin

Question 4

What are some patient factors for DDIs:

Answer 4

Polypharmacy
Elderly - pharmacokinetic changes e.g. renal function, Vd, muscle mass
Critically ill/multiple comorbidities - physiological changes may affect drug handling
Chronic illness - diabetes, COPD, asthma

Question 5

What are mechanisms of DDIs?

Answer 5

Pharmaceutical incompatibilities
Pharmacodynamic interactions
Pharmacokinetic interactions (ADME)

Question 6

What are pharmaceutical incompatibilities?

Answer 6

Occurs before drug introduced to the body e.g. benzodiazepines absorbed onto rubber.
Often involves precipitation of additives to intravenous fluids & other formulation.
Exposure time and number of drugs mixed important
Usually picked up at time of reconstitution or checking with pharmacist

Question 7

What are pharmacodynamic interactions?

Answer 7

Interactions related to the drug’s mechanism or site of action. This means that they great majority of such interactions are predictable.
Interactions can be classified as either competitive or additive at the same drug target. or arising from the same effect at different drug targets

Question 8

How can pharmacodynamic interactions be avoided?

Answer 8

With careful prescribing.

Question 9

What are examples of direct competitive pharmacodynamic interactions?

Answer 9

salbutamol & metoprolol

Morphine & naloxone

Question 10

What are examples of additive effects at same receptor site?

Answer 10

Two NSAIDs or two beta-blockers

Question 11

What are examples of indirect additive effects via different sites of action?

Answer 11

SSRIs & MAOIs (serotonin syndrome)

NSAIDs & Warfarin (increased risk of bleeding)

Question 12

What are some pharmacokinetic interactions during absorption?

Answer 12

Changes in pH: omeprazole decrease bioavailability of ketoconazole by altering degree of ionization
Binding and chelation: antacids and iron chelate (physically bind)
Gastrointestinal motility: drugs with anticholinergic effects (tricyclic antidepressants) reduce GI motility & increase bioavailability of levodopa

Question 13

What are some pharmacokinetic interactions during distribution?

Answer 13

Many drugs bind to plasma albumin e.g. warfarin, phenytoin, thyroxin, tricyclics.

Question 14

What are some pharmacokinetic interactions in metabolism?

Answer 14

A large number of drug interactions of clinical significance involve the effect of one drug on the metabolism of another. e.g. CYP450 enzymes

Question 15

How many subgroups of CYP450 enzymes?

Answer 15

Four main subgroups, 60 isoenzymes

Question 16

What CYP enzymes are mostly involved?

Answer 16

CYP1A2, CYP2D6, CYP2C19, CYP3A4

Question 17

How can genes and ethnic groups affect drugs?

Answer 17

Genes that encode specific isoenzymes can vary between individuals and ethnic groups
6-10% of Caucasians lack CYP2D6 (codeine)

Question 18

What are enzyme inducers?

Answer 18

Enzyme induction means that the actual amount of the enzyme is increased. Involves production of addition enzymes so takes place gradually over several days or weeks

Question 19

What are enzyme inhibitors?

Answer 19

Enzyme inhibition means that the amount of the enzyme is reduced or its effect is blocked

Question 20

What occurs is enzymes are blocked?

Answer 20

They will reduce the metabolism of the object drug using the same metabolic pathway. The object drug will accumulate and if it has a low therapeutic window then adverse effects may occur

Question 21

What are some examples of enzyme inhibitors?

Answer 21

Cimetidine, omeprazole, erythromycin, clarithromycin, allopurinol, verapamil

Question 22

What are some examples of enzyme inducers?

Answer 22

St John’s Wort, alcohol, cigarette smoke, rifampicin, phenytoin, carbamazepine

Question 23

How do enzyme inducers work?

Answer 23

Enzyme induction increases metabolism of the object drug and decreases its pharmacological effect.
For therapeutically important object drugs which rely on stable plasma concentration there is a risk of therapeutic failure

Question 24

What are pharmacokinetic interactions in excretion?

Answer 24

Changes in urinary pH - at alkaline pH weak acids are not reabsorbed and excreted, at acidic pH weak bases are not reabsorbed and excreted

Urine acidification (e.g. citric acid) or alkalisation (e.g. sodium bicarbonate) will change degree of ionisation & lipid solubility of filtered drugs

Question 25

What is an example of drug-food interaction?

Answer 25

Grapefruit juice contains flavonoids which inhibit CYP3A4 in intestinal wall - increases bioavailability of statins/felodipine

Question 26

What is an example of drug-alcohol interaction?

Answer 26

Additive or synergistic effects with most CNS active drugs: antidepressants, opioids