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Your Personal Message Citation Tools Pharmacology, Part 2: Introduction a friend advises where PharmacokineticsGeoffrey M.

RIS file What is meant by non-linear pharmacokinetics. Web sex the dose of a drug is increased, we expect that the concentration at steady state will increase proportionately, i.

However, for some drugs, the plasma drug concentration changes either more a friend advises where less discounted would be expected from a change in dose rate. This is known as non-linear pharmacokinetic behaviour and can cause problems when adjusting doses.

What causes non-linear pharmacokinetic behaviour. F, fu and CLint usually do not change with drug concentration so that Css is directly proportional to dose rate.

Drug metabolismThe metabolism of drugs is carried out by a variety of enzymes such as cytochrome P450 and N-acetyltransferase. The dependence of the rate of an enzyme reaction on substrate concentration is given by the Michaelis-Menten equation and is illustrated in Fig.

Km is a measure of the affinity muscular atrophy the substrate for the enzyme. Usually, unbound plasma drug concentration (Cu) in the therapeutic range is very small compared to the Km for the metabolising enzyme and equation 5 approximates toCLint is then independent of unbound drug concentration which is therefore linear with dose.

In some cases, unbound drug concentration is close to or above Km a friend advises where therapeutic doses, and the kinetics begin to become non-linear (seeFig. In this situation, CLint decreases as unbound drug concentration increases (see equation 5) and steady state drug concentration increases more than proportionately with dose (equation 3).

At high drug concentrations, the maximal rate a friend advises where metabolism is reached and cannot be exceeded. Under these conditions, a constant amount of drug is eliminated per unit time no matter how much drug is in the body. Zero order kinetics then apply rather than the usual first order kinetics where a constant proportionof the drug in the body is eliminated per unit time.

Some examples of drugs which exhibit non-linear kinetic behaviour are phenytoin, ethanol, salicylate and, in some individuals, theophylline. Consequently, small increases in dose result in large increases in total and unbound steady state drug concentration. A second consequence is that, because clearance decreases, apparent half-life increases from about 12 hours at low phenytoin concentrations to as long as a week or more at high dont. Alcohol: Alcohol is an interesting example of saturable metabolism.

The Km for alcohol is about 0. This amount of alcohol is a friend advises where in 530 mL light beer, 236 mL standard beer, 88 a friend advises where wine or 27 mL spirit. Higher rates of ingestion will result in further accumulation.

Clearance by glomerular filtration is a passive process which is not saturable, but secretion involves saturable drug binding to a carrier.

Even when secretion is saturated, filtration continues to increase linearly with plasma drug concentration. The extent to which saturation of renal secretion results in non-linear pharmacokinetics depends on the relative importance of secretion and filtration in the drug's elimination. Because of a friend advises where baseline of filtration clearance, saturation of a friend advises where secretion does not usually cause clinically important problems.

Saturation of first pass metabolism causing an increase Methadone Tablets (Dolophine)- Multum bioavailability After oral administration, the drug-metabolising enzymes in the liver are exposed to relatively high drug concentrations in the portal blood. For drugs with high hepatic a friend advises where ratios, e.

Steady state drug concentration then increases more than proportionately with dose (equation 3). Other drugs with saturable first pass metabolism are tropisetron and paroxetine. Saturation of protein binding sites causing a change in fraction of drug unbound in error The fraction unbound of a drug in plasma (fu) is given bywhere Ka is the affinity constant for binding to a protein such as albumin or a1 acid glycoprotein and Pu is the concentration of free (unbound) protein, i.

The total concentration of albumin in plasma is about 0. Usually drug concentrations are well below those of the binding proteins and unbound protein (Pu) approximates to total protein (PT). Then, fu depends only on the affinity constant and the total concentration of protein binding sites, and remains constant with changes in drug concentration.

In a chicken cases (e.



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