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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
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