Inter-individual Differences - Pharmacokinetics

Inter-individual Differences

·        There are large inter-individual differences in the capacity to metabolise drugs, due to:

Genetic factors

·        Characteristics can be autosomal dominant, autosomal recessive, sex-linked, etc 

·        Either polygenic or monogenic (present either as polymorphisms – more than 1% - or as rare phenotypes - <1 %) 

·        Cytochrome P450: a group of enzymes located on the endoplasmic reticulum. Divided into families and sub-families

·        3 polymorphisms have been well defined: 

o  Acetylation: enzyme: n-acetyl-transferase 2. Leads to slow and fast acetylators. 90% of Japanese are fast acetylators (autosomal dominant) compared with 55 – 60% of Europeans who are slow acetylators. Affects eg isoniazid and caffeine 

o  Oxidation: poor metabolisers are deficient in enzyme CYP2D6, affects 4 hydroxylation pathway. Covers lots of drugs – TCAs, antipsychotics (e.g. haloperidol), b blockers (e.g. metoprolol). ­Risk of accumulation. Rest of population are extensive metabolisers 

o  Oxidation (CYP2C19): affects diazepam, omeprazole, others

Disease

·        Absorption in disease:

o  Can affect gastric emptying rate: affects rate not extent

o  ¯Absorption rate in migraine, acute MI, labour, malabsorption syndromes (variable effect) 

o  Low cardiac output ® ¯IM absorption

·        Distribution: 

o  For drugs with low Vd and high binding (only), changes in protein binding: e.g. ¯albumin in hepatic disease, nephrotic syndrome, ­a1AGP in RA, Crohn‟s. Amount of free drug is the same. 

o   But normally total plasma concentration measured (and this will be reduced) ® danger of overdose 

o  Cardiac disease ® altered distribution (eg due to reduced gut flow ® poor absorption, ¯renal and hepatic perfusion ® ¯clearance) 

o  Obesity ® increased Vd for lipophilic drugs

·        Metabolism: 

o  Most biotransformation occurs in liver. For some drugs, extraction depends on blood flow (where extraction ratio tends to 1) 

o  Liver disease ® ¯capacity of metabolising enzymes (eg ­warfarin, phenytoin) and possibly shunting of blood around liver (affects drugs with high first pass metabolism) 

o  Thyroid diseases ® ­ or ¯ metabolism

o  Diabetes mellitus ® fatty liver ® change in metabolism 

o  Low clearance with high (>90%) degree of protein binding – generally ¯clearance

o  Low clearance, low binding (e.g. paracetamol) – variable but can be ¯clearance

·        Excretion: 

o  For many drugs, reduction in clearance ® ­half-life 

o  Adjust dose using creatinine clearance formula: Cockcroft Gault Formula (a prediction which saves doing a 24 hr urine):

§  Cr.Cl ml/sec = (140 – age) * wt(kg)/  50,000 * serum Cr (mmol/L)

·        Normal is 1.5 mls/sec.  For mls/min, replace 50,000 by 815

·        For females, multiply by 0.85

o   Important for eg digoxin and aminoglycosides which are excreted unchanged. If elderly ®¯excretion ® ­plasma concentration 

·        Dose rate for a drug excreted 100% by the kidney (e.g. antibiotics) is:

·        DR = (Cr.Cl / 1.5) * normal DR

·        This dose requires adjustment when not all the drug is excreted unchanged. 

DR = (1 – fu) + fu * Cr.Cl / 1.5 * DR 

        Fu = fraction excreted unchanged

·        Liver disease: arbitrary rule:

o   ¯Dose by 50% for high clearance drugs (high 1^st pass metabolism)

o   ¯Dose by 25% for low clearance drugs (enzyme capacity only)

·        Dosing in CV disease:

o   ¯Vd (vasoconstriction) 

o   ¯Renal flow ® ¯excretion

o   ¯Mesenteric blood flow ® ¯absorption of frusemide

Age

·        Epidemiology:

o   Elderly > 75 years

o   More likely to have multiple drugs (median per person over 65 is 3), 90% have one drug 

o   2 * incidence of adverse reactions (20 – 25%).  ­ in proportion to number of drugs

o   30% of elderly admissions due to drug problems 

·        Absorption: little difference compared with young, except if other drugs interfere (eg ¯ transit time)

·        Distribution: 

o   ¯Lean body weight.  ­Vd of fat soluble drugs (eg diazepam), possible problems with accumulation 

o   May be ­adipose compared with lean body tissue. Eg smaller loading dose of drugs with low Vd (eg digoxin and cimetidine) 

o   Protein binding: Albumin declines with age ® significant change only in tightly bound drugs (ie small Vd, eg phenytoin) or zero order elimination (eg warfarin) 

·        Metabolism:  Hepatic clearance: 

§  Liver has significant residual capacity so not much decline with age, especially given ¯ lean body weight 

§  But significant (50%) reduction in liver blood flow, so significant reduction in metabolism of 1^st pass metabolism (eg propranolol) or capacity limited metabolism (phenytoin or theophylline). Problem if narrow TI 

§  ¯Hepatic blood flow and hepatic mass

§  ¯First pass clearance: eg major tranquillisers, TCAs, antiarrhythmics

·        Excretion: 

o   Decline in renal function. ¯GRF by 50% (although wider spread of function ® ­inter-individual variability). Problems with digoxin, lithium and gentamycin 

o   ¯Renal clearance (see creatinine clearance above). However, ­variability in serum creatinine (eg proportional to lean body mass) ® less reliable estimate of renal function 

o   Delayed action of renal acting drugs (eg diuretics)

o   Tolerate renal side effects less well (eg NSAIDs)

o Need to adjust dose of: digoxin, cimitidine, ACE inhibitors, NSAID, Diazepam, aminoglycosides.

o Dose adjustment factor =

• F = fraction of drug normally excreted unchanged

• Kf = relative renal function of a patient = actual or derived Cr clearance [use Cockcroft & Gault formula ]  / normal Cr clearance

• Principles of geriatric prescribing: