Pharmacokinetics lecture 12 Contents ... Non-linear kinetics Pathological and physiological influences

Non-linear kinetics

General relationship between reaction rate and substrate concentration for any enzyme catalysed reaction Graph becomes flatter as the enzyme becomes saturated with substrate. Rate Substrate concentration

Specific case of ... Drug elimination rate Drug concentration

For most drugs Elination rate Highest concentrations actually seen in real therapeutic use. Too little to saturate the enzyme. Almost no curvature. Drug concentration

For most drugs [Expansion of the relevant part of the graph] Graph would start to curve if we went to much higher concentrations and began to saturate the enzyme. Elination rate Drug concentration

Exceptions ... There are a small number of drugs where concentrations seen in real life use are high enough to saturate the eliminating enzymes. The best known are: Phenytoin - The only case of real clinical significance Salicylates Ethanol There is also some evidence that Theophylline may approach saturation but, in practice, it can be treated as following linear kinetics.

Non-linear kinetics (e.g. phenytoin) Linear kinetics (most drugs) Rate of eliminat’n Rate of eliminat’n Blood drug conc Blood drug conc

At steady state ... Linear Non-linear Blood drug conc Rate of elim = admin Rate of elim = Rate of admin Blood drug conc Blood drug conc Blood drug conc Blood drug conc Rate of admin Rate of admin

Dosage adjustment For most drugs, changes in dosage produce proportionate changes in blood concentrations. e.g. if you increase dose size by 25%, blood levels will also increase by 25%. For non-linear drugs (primarily phenytoin), an increase in dose size will cause a disproportionate increase in blood levels. A 25% increase in dose size might lead to a doubling in blood levels. So beware !!!!

Pathological and physiological influences upon pharmacokinetics

General approach Two questions to ask: Question 1 Does the drug have a low therapeutic index? Therapeutic index is the ratio between the highest tolerated blood concentrations and the lowest concentration that will be therapeutically effective.

High or low therapeutic index Drugs with a high index are safe and effective over a wide range of concentrations. No change in the body is likely to increase or decrease such a drug’s concentrations to a point where it either fails to work or becomes toxic. With a low index, even modest changes in drug handling can take concentrations out of the narrow acceptable range.

High T.I. Low T.I. Toxic Changes in this range cause serious problems Changes in this range cause no problems Safe and effective range Safe and effective range Ineffective Ineffective

Examples of low therapeutic index drugs Aminoglycosides (e.g. gentamicin) Digoxin Lidocaine Lithium Methotrexate Procainamide Quinidine Phenobarbital Phenytoin Theopylline

General approach Two questions to ask: Question 2 How is this drug eliminated? If drug is renally excreted and kidneys are under-performing, then expect clearance to be significantly reduced. But, if drug is hepatically metabolised and the kidneys are affected …so what?

Elimination of drugs with a low therapeutic index Renal Aminoglycosides Lithium Methotrexate Digoxin Procainamide Lidocaine Phenobarbital Phenytoin Quinidine Theophylline Almost exclusively renal Mainly renal (Some hepatic) Approx equal renal/hepatic Mainly hepatic Hepatic

Conditions and diseases I Renal failure Depends upon severity of the condition. Expect reduced clearance of aminoglycosides, lithium, methotrexate and digoxin. Without dosage adjustment, blood levels would rise to toxic levels. Dosage reduction needed.

Conditions and diseases II Cirrhosis of the liver Severe reduction in all drugs primarily hepatically metabolised. Dosage reductions needed.

Conditions and diseases III Old age Renal function declines quite predictably (Approx 1% per annum from age of 30). Hepatic function also declines but very variable between individuals. Old age generally suggests need to reduce doses of drugs that are renally excreted. Provides no really useful guidance in case of metabolised drugs.

Conditions and diseases IV Congestive heart failure Total cardiac output is reduced and also re-directed to crucial organs (e.g. brain). G.I.T. (and therefore liver) suffer disproportionate reduction in blood flow. Metabolised drugs show reduced clearance (e.g. theophylline clearance typically reduced by 60%). Dosage reduction required.

Conditions and diseases V Pregnancy Many minor changes. Most important is an increase in renal clearance. Need to monitor drugs that are renally excreted. (Note: Many drugs contraindicated especially in early pregnancy.)

Conditions and diseases VI Smoking Chemicals in smoke induce hepatic enzymes such as cytochrome P450. Significantly increased clearance of hepatically metabolised drugs. Dosage increases required.

Conditions and diseases VII Thyroid disease Metabolism accelerated in hyperthyroidism and slowed in hypothyroidism. On the margins of clinical significance. Dosage adjustments occasionally needed.

Terms with which you should be familiar ... Linear kinetics Non-linear kinetics Therapeutic index

What you should be able to do Explain why a small minority of drugs follow non-linear kinetics. Cite phenytoin as clinically the most significant example of a drug with non-linear kinetics. Describe the impact of non-linear kinetics upon dosage adjustment. Recognise drugs that have a low therapeutic index. Identify the mode of elimination of key drugs with low T.I.s Logically use the two pieces of information above to predict whether dosage adjustment will be necessary for a particular drug in a range of conditions.