Phil RoweReader in pharmaceutical computingSchool of Pharmacy & Chemistry All these presentations can be downloaded from:http://www.staff.livjm.ac.uk/phaprowe/then follow 'Nurse prescribing'
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 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
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: AminoglycosidesDigoxin LithiumMethotrexatePenicillins/cephalosporins Condition that affects renal function could be a real problem. Changes in liver function not likely to matter. Mainly metabolised: PhenytoinPropranololTheophyllineValproateWarfarin 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 e.g. Gentamicin· Lithium· Chlorpropamide· Digoxin
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 Renal excretion Young Elderly Cirrhosis C.H.F. Pregnancy Smoking