Download Phil Rowe Reader in pharmaceutical computing School of

Phil Rowe
Reader in pharmaceutical computing
School of Pharmacy & Chemistry
All these presentations can be downloaded from:
http://www.staff.livjm.ac.uk/phaprowe/
then follow 'Nurse prescribing'
Lecture 3
Factors affecting ADME
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?
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.)
Has the drug got a narrow
therapeutic window?
Drug likely to produce
adverse side effects
Therapeutic
window
Drug likely to fail to
produce therapeutic effect
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!
Has the drug got a narrow
therapeutic window?
Narrow window
Examples:
• Digoxin
• Lignocaine
• Theophylline
• Aminoglycosides
• Lithium
• Most anti-epileptics
(Valproate less problem.)
Is the drug primarily
metabolised or excreted?
Mainly excreted:
Mainly metabolised:
Aminoglycosides
Digoxin
Lithium
Methotrexate
Penicillins/cephalosporins
Phenytoin
Propranolol
Theophylline
Valproate
Warfarin
Condition that affects renal
function could be a real
problem. Changes in liver
function not likely to matter.
Condition that affects hepatic
function could be a real
problem. Changes in kidney
function not likely to matter.
Factors affecting ADME
Age (Young and old)
Liver disease
Renal disease
Thyroid disease
Congestive heart failure
Pregnancy
Lactation
Smoking
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.
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.
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.
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
Lithium
Chlorpropamide
Digoxin
e.g. Gentamicin
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
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
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.
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.
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%
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.)
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)
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
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.
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!)
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.)
Clinically important
effects:
Liver metabolism
Young
Elderly
Cirrhosis
C.H.F.
Pregnancy
Smoking
Renal excretion