Drug Interactions

Question 1

What is the definition of a drug-drug interaction?

Answer 1

When two or more drugs interact in such a way that the effectiveness or toxicity of one or more of the drugs is altered.

These can be:

• harmful
  - increasing drug toxicity
  - reducing drug efficacy
• beneficial
  - increasing blood levels
  - additive therapeutics

Question 2

What types of PK interactions are possible?

Answer 2

• absorption
• protein binding
• metabolism
• excretion

… of one of the drugs is changed by the presence of another drug in the body

Question 3

Which patients are most likely to be affected, and at what timing?

Answer 3

Those most likely to be affected are:

• Elderly people
• Those taking multiple drugs
• with impaired renal or hepatic function
• with certain genetic characteristics
• with concomitant disease

Timing is most likely when a:
- drug is being started
- being stopped
Factors involved:
- half life of drug
- mechanism of interaction
- ‘as required’ drugs (body is very good at adapting, but can’t in this case

Question 4

What can affect the rate of absorption?

Answer 4

Rate is affected by the time to reach site of absorption
Rarely of clinical importance as total amount absorbed is usually unchanged

Example:
- What is the effect of taking paracetamol with metoclopramide?
- Answer - Rate of absorption of paracetamol increased by
metoclopramide

Question 5

What can affect the extent of adsorption?

Answer 5

Formation of complexes
- eg tetracycline and antacids
= Absorption of tetracycline reduced by antacids

Changes in pH of stomach
- eg Ketoconazole and omeprazole
= Absoroption of ketoconazole reduced by PPIs

Question 6

What types of PD interactions are possible?

Answer 6

The effects of one drug are changed by the presence of another drug at its site of action.

These can be:
- Additive interactions
- Same pharmacological effect (eg enhanced hypotensive
effect when diuretics given with beta blockers – BLACK DOT,
increased risk of hyperkalaemia when potassium sparing
diuretics given with potassium salts – BLACK DOT, increased
sedative effects when hypnotics given with alcohol)
- Same toxicity (eg increased risk of renal impairment when
ACEi given with NSAIDs)
- Antagonistic interactions: drug activity is directly opposed (eg
effects of levodopa antagonised by antipsychotics)
- Disturbances in electrolyte balance: increases sensitivity to toxic
effects (eg Increased cardiac toxicity with cardiac gycosides if
hypokalaemia occurs with loop diuretics – BLACK DOT)

Question 7

What are displacement interactions?

Answer 7

One predominantly bound drug can displace another:
Only significant if drug >90% bound
- eg warfarin displaced by aspirin: free warfarin changed from 1% to 4%

This effect is transient as the body can adapt to metabolism the excess warfarin. The new steady state of 99:1 bound:unbound takes ~5 days. This is only the case if both are taken regularly, is aspirin is taken occasionally the body can’t adapt.

Question 8

How does induction of enzymes, such as CYPs, effect drug metabolism? Similarly, how does inhibition affect metabolism?

Answer 8

For example, increases in endoplasmic reticulum and cytochrome P450
- effects can take 2-3 weeks (similar to wear off after cessation)

Examples of inducers:

• Barbiturates, Carbamazepine,
• Phenytoin, Rifampicin,
• Tobacco

Enzymes are inhibited by other drugs:
- effects occur within 2-3 days

Examples of inhibitors:

• Allopurinol, Cimetidine
• Erythromycin, Ketoconazole
• Phenylbutazone

Question 9

How do DDIs influence urinary excretion?

Answer 9

Only non-ionised form of drug can diffuse, this depends upon drug pKa and urinary pH.

For example the interaction between aspirin and antacids
- aspirin excretion is increased by antacids as they make the urine
more alkaline, hence aspirin is more greatly ionised (not absorbed into
tissues) and excreted.

Question 10

How do DDIs influence excretion by active transport?

Answer 10

There is competition for the excretory mechanism & ‘loser’ is retained.

Examples:
- penicillin and probenecid (gout treatment)
Probenecid reduces excretion of penicillins as it is preferentially lost.
This can be useful for extending the half life of penicillin.
- methotrexate and aspirin
Excretion of methotrexate reduced by NSAIDs - BLACK DOT (bad
interaction)

Question 11

How do DDIs influence eGFR?

Answer 11

GFR partially controlled by prostaglandins

NSAIDs may block prostaglandins

Question 12

How are interactions managed?

Answer 12

Assess risk
- no black dot: Continue medication as before unless there are
other relevant factors
- black dot: If possible - avoid combination – choose alternative
drugs. If combination required - monitor patient and adjust dose

Question 13

How is the patient monitored?

Answer 13

Determine the nature of the interaction:

Pharmacokinetic interaction -
- Increased blood levels
- Look for signs of toxicity (adverse effects more likely)
- Decreased blood levels
- Look for signs of decreased effectiveness (condition not
controlled)

Pharmacodynamic interaction:
- Same pharmacological effect (monitor therapy, adverse effects)
- Same toxic effects (monitor adverse effects)
- Antagonistic effects (monitor effects of therapy)
- Disturbances in electrolytes (monitor electrolytes, monitor adverse
effects)