Most psychotropic drugs are rapidly and well absorbed after oral administration. However, it is important to distinguish between absorption (how much gets across the gut wall) and systemic availability (how much gets into the systemic circulation, commonly called bioavailability).
After oral administration drugs go via the portal circulation to the liver. If hepatic metabolism is extensive, a large amount of drug will be removed during this first passage through the liver. Thus, even if a drug is extensively absorbed, first-pass removal will reduce its systemic availability. For example, clomethiazole has extensive first-pass metabolism in the liver, and its systemic availability is low (about 40 per cent); thus, intravenous doses are considerably lower than oral doses. In severe liver disease, such as cirrhosis, or when there is arteriovenous shunting, this presystemic metabolism is reduced and the systemic availability increases up to 90 per cent; oral doses of clomethiazole should be reduced in liver disease. (6)
In the systemic circulation drugs are bound to plasma proteins and distributed to the tissues. Protein binding is important for drugs that are highly bound (over 90 per cent) and not widely distributed to the body tissues; in those cases protein-binding displacement can result in a large rise in the amount of unbound drug available to the target tissue. This is important for phenytoin, which is 90 per cent bound to plasma albumin and has a low volume of distribution. The binding of phenytoin is reduced when the serum albumin concentration falls (in chronic liver disease, the nephrotic syndrome, or the third trimester of pregnancy), when binding to the protein is abnormal (in chronic renal insufficiency), or when another drug (e.g. sodium valproate) causes displacement. Acute displacement causes phenytoin toxicity, but only transiently, because the increased unbound concentration is more rapidly eliminated. When measuring plasma phenytoin concentrations in patients in whom protein binding is reduced, the target concentration (and the laboratory will measure total drug, i.e. bound plus unbound) is reduced (see Fig, ?.) (I. Odar-Cederlof, unpublished data).
Fig. 2 In chronic renal insufficiency the protein binding of phenytoin is reduced. This leads to an increase in the unbound plasma (or serum) concentration relative to the total concentration; the target total concentration therefore falls. The shaded area shows the range of plasma phenytoin concentrations that one would generally aim to achieve (the target concentration range) in treating a patient with epilepsy. As renal function deteriorates (indicated here by an increase in serum creatinine concentration), the target range for plasma phenytoin concentration falls from 40-80 pmol/l when renal function is normal to 10-30 pmol/l in severe renal insufficiency.
After absorption and distribution most psychoactive drugs are cleared from the body by hepatic metabolism; (7) impaired liver function, if severe (for the liver has a large capacity), reduces their elimination, and dosages should be reduced.
Lithium is cleared solely by renal elimination and therefore the dosage should be reduced in proportion to the creatinine clearance value. Since renal function falls with age, lithium dosages should be lower in older people.(8)
The half-life of a drug is a function of its clearance and its distribution volume: the slower the rate of clearance or the more extensive the distribution the longer the half-life. If a drug is given in a regular maintenance dose, the amount of drug in the body will gradually accumulate; however, as the amount in the body increases, the rate at which it is eliminated also rises, and eventually a plateau (or steady state) is reached when the amount eliminated during a dosage interval equals the dose. The time it takes to reach this steady state depends on the half-life of the drug; about 94 per cent of the steady state value will be reached after four half-lives ( Fig 3, curve A). For example, lithium has a half-life of about 24 h; after 4 days of maintenance therapy with the same regular dose a steady state will be reached; this does not depend on the dose or frequency of administration ( Fig, 3, curves B and C). If a modified-release formulation is used and the half-life of absorption of the drug from the formulation is longer than the drug's own half-life, the longer (apparent) half-life will determine the time to steady state; for example, the apparent half-life of flupenthixol after the administration of flupenthixol decanoate is 17 days, compared with 36 h for flupenthixol after oral administration. When using depot antipsychotic drugs, which have long half-lives of absorption, steady state therapy must first be established with an ordinary formulation.
Fig. 3 Curve A shows that during the regular administration of a maintenance dose of a drug the amount of drug in the body rises after a dose, reaches a peak, and then falls as the drug is distributed to the tissues and eliminated. If another dose is given soon after the first, the plasma concentration will rise by the same amount as before but will fall faster after peaking, since most drugs obey first-order kinetics and the plasma concentration falls exponentially. Thus, when a drug is given repeatedly the mean plasma concentration rises more slowly with each successive dose, until eventually a steady state is reached, when the amount eliminated in a dosage interval is equal to the dose itself. This takes about four half-lives of the drug. Curve B represents the concentrations during administration of half the dose given at the same frequency. The time taken to reach steady state is the same in both cases, but the eventual steady state concentration in case B is half that in case A, being proportional to the dose. Curve C represents the concentrations during administration of half the dose given twice as often (i.e. the total dose is unchanged). Neither the time taken to reach steady state nor the eventual mean steady state concentration is affected. However, the fluctuations in plasma concentration during a dosage interval are reduced (Fig 1).
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