Phil Rowe Reader in pharmaceutical computing School of Pharmacy

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Phil RoweReader in pharmaceutical
computingSchool of Pharmacy Chemistry
All these presentations can be downloaded
fromhttp//www.staff.livjm.ac.uk/phaprowe/then
follow 'Nurse prescribing'
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Lecture 3 Factors affecting ADME

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Spotting the cases that really matter

• Three questions to consider ...
• Does it affect drug elimination?
• Has the drug got a narrow therapeutic window?
• Is the drug primarily metabolised or excreted?

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Does it affect drug elimination?

Generally, it is changes in drug elimination that
produce increases/decreases in blood levels big
enough to do real clinical harm. Text books
rabbit on about changes in volume of distribution
etc, but these rarely do any real harm. A few
exceptions do exist (e.g. massive increase in
volume of distribution for gentamicin in burns
victims.)
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Has the drug got a narrow therapeutic window?
Drug likely to produce adverse side effects
A narrow window will mean that small increases
can easily lead to toxicity and decreases to
ineffectiveness. These are the drugs we need to
worry about!
Therapeutic window
Drug likely to fail to produce therapeutic effect
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Has the drug got a narrow therapeutic window?
Narrow window

• Examples
• Digoxin
• Lignocaine
• Theophylline
• Aminoglycosides
• Lithium
• Most anti-epileptics (Valproate less problem.)

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Is the drug primarily metabolised or excreted?

Mainly excreted AminoglycosidesDigoxin
LithiumMethotrexatePenicillins/cephalosporins C
ondition that affects renal function could be a
real problem. Changes in liver function not
likely to matter.
Mainly metabolised PhenytoinPropranololTheophyl
lineValproateWarfarin Condition that affects
hepatic function could be a real problem.
Changes in kidney function not likely to matter.
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Factors affecting ADME
Age (Young and old) Liver disease Renal
disease Thyroid disease Congestive heart
failure Pregnancy Lactation Smoking

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Age (Young and old)Liver metabolism in the
young

• Most of the drug metabolising systems in the
  liver are functional in the very young. But, the
  ability to metabolise by the addition of
  glucuronic acid is very underdeveloped in
  neonates.
• Difficulty in metabolising bilirubin (From
  breakdown of haemoglobin) - neonatal jaundice
• Very slow metabolism of chloramphenicol - grey
  baby syndrome.

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Age (Young and old)Renal excretion in the
young
Renal excretion is very under-developed in the
neo-nate, and takes several months to
mature. e.g. Gentamicin has a long t-half
especially in the first week of life.
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Age (Young and old)Liver metabolism in the
elderly
A general tendency for liver metabolism to be
less effective in the elderly, but it is not a
major reduction and it is very variable between
individuals. Of little value in practical dosage
decisions. Just be aware of a general danger
that a dose might be excessive in an elderly
person.
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Age (Young and old)Renal excretion in the
elderly
Renal excretion becomes significantly less
efficient in almost all elderly people. Most
elderly patients will require dosage reductions
for drugs that are primarily excreted through the
kidneys. e.g. Aminoglycosides e.g.
Gentamicin Lithium Chlorpropamide Digoxin
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Liver disease

• Reductions in rates of elimination - doses need
  to be reduced.
• Only relevant to drugs primarily metabolised (not
  excreted).
• Cirrhosis - major reductions in clearance
• Theophylline 50
• Lignocaine 40
• Viral hepatitis - lesser reductions

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Renal disease
Reductions in rates of elimination - doses need
to be reduced. Only relevant to drugs primarily
excreted (not metabolised). e.g. gentamicin or
digoxin
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Renal disease - creatinine clearance
Creatinine is a chemical produced by muscles and
excreted via the kidneys. If renal function is
normal, creatinine is cleared quickly and blood
levels remain low - in renal disease creatinine
levels increase. 'Creatinine clearance'
therefore used as a marker of renal function. If
creatinine clearance is (say) 50 of normal, then
renally cleared drugs (such as gentamicin) will
also be cleared at 50 of the normal rate. Need
to reduce rate of administration by 50 - in the
case of gentamicin, probably by doubling the
dosage interval.
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Thyroid disease
Thyroid hormones speed up most processes within
the body. Hyperthyroidism - faster
Hypothyroidism - slower Some evidence that drug
elimination is affected. e.g. normal clearance of
propranolol 725 ml/min, but increases to 1193
ml/min in hyperthyroidism. Thyroid dysfunction no
way near as significant as liver or kidney
disease.
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Congestive heart failure
and liver metabolism of drugs
In CHF, cardiac output is reduced. But, vital
organs (e.g. brain and myocardium) are protected
- no reduction in blood flow. This means that
other organs have to suffer a disproportionately
large reduction in blood flow. Liver is one of
the organs that suffers - function markedly
reduced. e.g. In CHF, clearance of theophylline
reduced by 60
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Congestive heart failure
and renal excretion of drugs
Kidneys are also significantly affected by CHF.
The flow of blood to the kidneys is reduced, but
not as dramatically as that to the
liver. Evidence is not as clear cut as with the
liver, but there is evidence that digoxin
excretion is reduced. (Complication is that
digoxin is also partially eliminated by liver
metabolism and clearance by metabolism is
definitely reduced.)
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Pregnancy

• The most important pharmacokinetic change in
  pregnancy is an increase in renal clearance. The
  mother has to dispose not only of her own waste
  material, but also the baby's.
• Only affects clearance of renally excreted drugs.
  (Some of these shouldn't be given in pregnancy
  anyway!)
• As examples, BNF advises
• Aminoglycosides "Monitor plasma concentration."
• Digoxin "May need dosage adjustment."
• Lithium "Dose requirements increased." (Should
  be avoided if possible in 1st trimester)

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Lactation

• Transfer of drug from the mother to the baby is
  irrelevant to the mother (No significant
  excretion), but may be relevant to the baby.
• Chloramphenicol Possible bone marrow
  suppression
• Cyclophosphamide Do not breast feed during
  treatment or for next 36 hours
• Doxepin Antidepressant - Accumulation of
  sedative metabolite
• Heroin Possible withdrawal syndrome in infant
  of dependent mother
• Lithium Risk of toxicity best avoided

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Smoking

• Cigarette smoke contains chemicals referred to as
  liver enzyme inducers. These increase
• Size of the liver
• Blood flow to the liver
• Amount of enzymes in the liver that metabolise
  drugs (inc Cytochrome P450)
• Drugs eliminated more rapidly
• Blood levels are lower
• Higher doses are needed.

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Smoking
Example Theophylline doses need to be increased
60 above what would be appropriate in a
non-smoker. (Seems extraordinary that anybody who
needs theophylline treatment would continue to
smoke!)
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Other inducers
A number of other things can act as inducers.
Brussel sprouts and barbecued steak increase the
elimination of model drugs just as much as many
of the "Significant drug interactions" that the
text books rabbit on about. (This slide only for
amusement.)
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Clinically important effects
Liver metabolism Renal excretion
Young Elderly Cirrhosis C.H.F. Pregnancy Smoking