Simple Pharmacokinetics

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Simple Pharmacokinetics


 

The relationship between the administration of a drug, the time-course of its distribution and the magnitude of the concentration, attained in different regions of the body, is termed pharmacokinetics. Knowing the effects of absorption, distribution, metabolism and excretion can enable us to synthesise a model of drug concentration which will enable us to predict the time-course of drug action, which is extremely important from a clinical viewpoint.

 

This graph represents an i.v. infusion of a drug into the body.  At time zero, as the infusion is started, the drug concentration in the body is also zero. The concentration rises rapidly at first and then more slowly until a plateau is reached that represents a steady state. At steady state the rate of input of drug to the body (as determined by the concentration of drug in the syringe and the setting of the infusion pump) is equal to the rate of elimination of drug from the body. The plasma drug concentration at plateau is called the steady state concentration (Css). The steady-state concentration depends on the rate of drug infusion and on the clearance of the drug from the body, such that the greater the infusion rate of the lower the clearance, the greater is the Css. The clearance is the volume of plasma from which the drug is totally eliminated (i.e. cleared) per unit time. At steady state:

 

Administration rate = elimination rate

Elimination rate = Css x clearance

 

So: Clearance = administration rate/Css

 

After the infusion is stopped, in a 1st order curve such as this, the rate of removal of the drug is proportional to concentration of drug in the plasma.

 

Creatinine Clearance

The most common clinical measurement of renal function is creatinine clearance. Creatinine is a waste product of normal muscle metabolism. It is eliminated primarily by filtration with only minimal secretion, therefore the rate of clearance of creatinine can be used as an indicator of the glomerular filtration rate (GFR).

 

Clearance  =   _[Urine creatinine] x Volume_ 

                          [Plasma creatinine] x Time

 

This measurement is of importance therapeutically as if the clearance decreases either we must decrease the rate at which the drug is delivered or the average total plasma concentration of the drug will increase.

GFR and renal clearances decrease with age and in renal failure when drug doses must be carefully monitored.

 

Half life

When the drug infusion is stopped the plasma concentration declines again towards zero. The time taken for plasma concentration to halve is the half-life (t1/2) . The length of the half-life has an important practical implication namely that the half-life of a drug no only determines the time course of its disappearance when administration is stopped but also determines the time course of its accumulation when administration is started. The half life is a very useful concept for the clinician helping to determine a sensible dose interval, indicating the time over which drug accumulation occurs after starting a patient on a regular dose regimen, and helping to determine the advisability or otherwise of a loading dose.

It takes about 4 or 5 half lives to reach steady state. Knowing the t1/2 alerts the prescriber to the likely time course of accumulation.

 

A short half-life means that the steady state is reached quickly whereas a long half-life means it will take longer to get to therapeutic levels.

 

Volume of distribution

The apparent volume of distribution Vd is defined as the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma Cp.

 

Vd   = _Q_

           Cp

 

Zero order kinetics

In a few cases such as ethanol, phenytoin and salicylate, the time course of disappearance of the drug from the plasma does not follow the exponential pattern, but is initially linear i.e. the drug is removed at a constant rate that is independent of plasma concentration.

 

 

Drugs for which therapeutic drug monitoring is used

 

The pharmacokinetics of certain drugs have to be examined carefully as their toxic doses are close to their useful therapeutic doses. The levels of these drugs are monitored carefully when prescribed to the patient.

 

Digoxin – Therapeutic range 0.8 – 2.0mg/l

Measuring the plasma concentration can help as a guide to individualising therapy and may also be a useful adjunct in cases of suspected toxicity or poor compliance.

 

Lithium - Therapeutic range 0.4-1.0 mmol/l

Plasma concentrations in samples obtained 12 hours after dosing of 0.4-1.0 mmol/l are usually regarded as therapeutic.

 

Aminoglycosides - Therapeutic range – various

 

Phenytoin - Therapeutic range 10-20 mg/l

When using the steady state plasma concentration of phenytoin as a guide to dose adjustment, it is important to be aware of the non-linear nature of its pharmacokinetics and of the possible effects of concurrent renal or hepatic disease or of pregnancy on its distribution.

 

Cyclosporin - Therapeutic range 50-200 mg/l

Careful pharmacokinetic monitoring of this uniquely valuable but toxic immunosuppressant is essential. Compliance is a particular problem in children and deterioration in renal function can reflect either graft rejection due to inadequate cyclosporin concentrations or toxicity from excessive concentrations.

 

Theophylline - Therapeutic range 5-20mg/l

This is an effective drug with a narrow therapeutic index and many factors influence its clearance. Measurement of plasma theophylline concentration can help to minimise toxicity, which can be severe. The therapeutic range given is rather an oversimplification and may be associated with severe toxicity in neonates due to decreased protein binding and accumulation of caffeine, to which theophylline is methylated in neonates but not in older children.

 


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