Pharmacokinetic drug interactions

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Pharmacokinetic drug interactions
Phil Rowe Reader in Pharmaceutical
Computing Liverpool School of Pharmacy
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Drug interactions Lecture 3

• Interactions based upon
• Excretion
• Entero-hepatic circulation
• Identifying significant interactions

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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.
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Excretion Interactions
Mechanisms of urinary excretion - Simple
filtration - Active secretion Mechanisms for
active secretion - Acids - Bases
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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
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Example 1Methotrexate Probenecid
Probenecid saturates the renal acid drug
secreting mechanism. Methotrexate normally
excreted by this mechanism. Methotrexate
accumulates to toxic levels. Dangerous!
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Example 2Penicillin Probenecid
Exactly as previous example. But, prolonged
higher levels of penicillin are beneficial. Not
an adverse interaction. Used deliberately.
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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)
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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.

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Interactions via Enterohepatic Circulation (EHC)
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EHC and Oral Contraceptives
Oestrogen (Ethinyoestradiol) A proportion
undergoes phase II metabolism (conjugation) witho
ut 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.
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Antibiotics and Oral Contraceptives ... the theory
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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???
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Antibiotics and the pill.The evidence (2)
Nobody has ever measured levels of
ethinyl- oestradiol (EE) in pill-users taking
antibiotics and demonstrated a reduction in EE
levels.
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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???
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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?
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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.
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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.
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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
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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)
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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
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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.
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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.
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Examples of drugs eliminated by hepatic metabolism

• Carbamazepine
• Corticosteroids
• Cyclosporin
• Oral contraceptives
• Phenytoin
• Sulphonylureas
• Theophylline
• Warfarin

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Examples of drugs eliminated by renal excretion

• Digoxin
• Lithium
• Methotrexate

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Terms with which you should be familiar

• Entero-hepatic circulation
• Therapeutic index

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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.