Download drug interactions - Liverpool John Moores University

Pharmacokinetic drug
interactions
Phil Rowe
Reader in Pharmaceutical Computing
Liverpool School of Pharmacy
Pharmacokinetic Drug Interactions
Drug interactions
Lecture 3
Interactions based upon:
• Excretion
• Entero-hepatic circulation
Identifying significant interactions
Pharmacokinetic Drug Interactions
EXCRETION
Drug A increases or reduces the excretion
(usually renal) of Drug B.
Blood levels of B fall below or rise above
normal therapeutic range.
Becomes either ineffective or toxic.
Pharmacokinetic Drug Interactions
Excretion Interactions
Mechanisms of urinary excretion:
- Simple filtration
- Active secretion
Mechanisms for active secretion
- Acids
- Bases
Pharmacokinetic Drug Interactions
Excretion interactions
Active secretion mechanisms have limited capacity.
e.g. One acid drug may saturate the acid drug
active secretion mechanism. Another acid drug
will then be secreted less efficiently
Pharmacokinetic Drug Interactions
Example 1:
Methotrexate + Probenecid
Probenecid saturates the renal acid drug secreting
mechanism. Methotrexate normally excreted by
this mechanism. Methotrexate accumulates to
toxic levels. Dangerous!
Pharmacokinetic Drug Interactions
Example 2:
Penicillin + Probenecid
Exactly as previous example.
But, prolonged higher levels of penicillin are
beneficial. Not an adverse interaction.
Used deliberately.
Pharmacokinetic Drug Interactions
Other excretion
interactions
Most other examples do not form a pattern.
Just ‘One off’ cases.
e.g.
Digoxin + quinine
Lithium + thiazides
(Reduced excretion and increased levels of
digoxin and lithium respectively)
Pharmacokinetic Drug Interactions
Lithium + Thiazide interaction
Probable mechanism:
• Thiazides cause diuresis and initial sodium loss.
• Compensatory sodium retention in proximal
tubules.
• Proximal tubules do not distinguish sodium
from lithium.
• Lithium also retained and accumulates.
Pharmacokinetic Drug Interactions
Interactions via Enterohepatic
Circulation (EHC)
Free drug
Liver
Conjugate
Bile
Free drug
Pharmacokinetic Drug Interactions
Bacteria
Conjugate
Gut
EHC and Oral Contraceptives
Oestrogen (Ethinyoestradiol): A proportion
undergoes phase II metabolism (conjugation)
without phase I metabolism. EHC re-generates
active oestrogen. Increases the effectiveness of
the oestrogen.
Progestogens: Totally inactivated by phase I
metabolism prior to conjugation. EHC only
re-generates inactive metabolites.
Pharmacokinetic Drug Interactions
Antibiotics and Oral
Contraceptives ... the theory
Antibiotics kill bacteria in gut
Oestrogen conjugates not hydrolysed
Conjugates not re-absorbed
Less oestrogen - loss of contraceptive effect
(No effect on progestogen component.)
Pharmacokinetic Drug Interactions
Antibiotics and the pill.
The evidence (1)
Millions of women must have combined these
two drugs. Number of alleged cases of contraceptive
failure very small.
How many were real interactions?
- Non-compliance???
- Would have failed anyway???
Pharmacokinetic Drug Interactions
Antibiotics and the pill.
The evidence (2)
Nobody has ever measured levels of ethinyloestradiol (EE) in pill-users taking antibiotics
and demonstrated a reduction in EE levels.
Pharmacokinetic Drug Interactions
Antibiotics and the pill.
The evidence (3)
Compare a woman taking a combined pill plus antibiotics
with one taking a Progestogen Only Pill (POP).
- Combined pill provides a high dose of progestogen
plus a significant dose of oestrogen.
- POP provides lower dose of progestogen, no
oestrogen and still gives good contraceptive cover.
Will the pill + antibiotics really fail???
Pharmacokinetic Drug Interactions
What to do???
Scientific evidence - (at worst) extremely small
proportion of women suffer a real interaction.
But, a woman is dispensed pills and antibiotics,
gets pregnant, holds the pharmacist negligent for
not warning her of the danger ... How do you
defend yourself?
Pharmacokinetic Drug Interactions
What to do???
The alleged interaction is in the literature.
Probably just non-compliance, but can you prove it!
Practical solution:
Advise use of alternative contraceptive methods
during the month in which the antibiotics were
used. You are covered. No great inconvenience
to the customer.
Pharmacokinetic Drug Interactions
Recommend Additional
Precautions?
Combined pill with short course of antibiotics
Yes, as explained before.
Combined pill with long course of antibiotics
(e.g. tetraclines for acne)
No. Gut is re-colonised by resistant bacteria.
POP with antibiotics
No. Progestogen is not affected.
Pharmacokinetic Drug Interactions
Identifying clinically significant
cases - some questions to ask
If the drug causing the interaction is a liver inducer
or inhibitor, is the target drug eliminated by the
liver?
Barbiturates + Cyclosporin - Real problem.
Cimetidine + Aminoglycoside - No problem
Pharmacokinetic Drug Interactions
Identifying clinically significant
cases - some questions to ask
If one of the drugs interferes with a renal excretion
mechanism, is the other drug handled by the same
mechanism?
Probenecid + methotrexate - real problem
Probenecid + theophylline - no problem (non-renal)
Probenecid + lithium
- no problem (renal, but
not via acidic substance secreting mechanism)
Pharmacokinetic Drug Interactions
Identifying clinically significant
cases - some questions to ask
Does the target drug have a narrow therapeutic
index? i.e. Will a modest increase or decrease
in plasma concentrations cause toxicity or
therapeutic failure?
Cimetidine + Paracetamol - no great problem
Rifampicin + Warfarin - real problem
Pharmacokinetic Drug Interactions
Identifying clinically significant
cases - some questions to ask
Oral contraceptives are a slightly unusual case.
(To avoid side effects, dose is set to be just high
enough to be effective.)
Reductions in levels - serious - loss of effect
Increases in levels - less serious - not likely to
suddenly start producing side effects.
Pharmacokinetic Drug Interactions
Examples of
narrow
therapeutic
index drugs
*
•Carbamazepine
•Corticosteroids*
•Cyclosporin
•Digoxin
•Lithium
•Methotrexate
•Oral contraceptives*
•Phenytoin
•Sulphonylureas
•Theophylline
•Warfarin
Marginal cases. Reduced blood levels could easily cause clinical
problems, but increased levels probably less of a problem.
Pharmacokinetic Drug Interactions
Examples of
drugs
eliminated by
hepatic
metabolism
Pharmacokinetic Drug Interactions
•Carbamazepine
•Corticosteroids
•Cyclosporin
•Oral contraceptives
•Phenytoin
•Sulphonylureas
•Theophylline
•Warfarin
Examples of
drugs
eliminated by
renal excretion
Pharmacokinetic Drug Interactions
•Digoxin
•Lithium
•Methotrexate
Terms with which you should
be familiar
• Entero-hepatic circulation
• Therapeutic index
Pharmacokinetic Drug Interactions
What you should be able to do
• Describe mechanisms by which one drug may alter the
excretion of another drug.
• Describe how antibiotics could theoretically reduce the
entero-hepatic circulation of another drug
• Give appropriate advice to a patient taking both an oral
contraceptive and antibiotics.
• Rationally determine the likely clinical significance of
any drug interaction
• Recognise drugs with narrow therapeutic indices and state
whether they are mainly metabolised or excreted.
Pharmacokinetic Drug Interactions