Pharmacological Principles

Pharmacokinetics refers to drug concentrations and their variability over time based on absorption, distribution, and elimination ( .Table52-5 ). Absorption is defined as the passage of a drug from the site of administration to the vascular space. Absorption is measured in terms of rate and bioavailability, which is the amount of drug that reaches the systemic circulation. Both vary with route of administration and drug formulation. Bioavailability is 100 percent following intravenous administration, the route against which

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TABLE 52-5 -- PHARMACOKINETIC PARAMETERS OF ANTIEPI

LEPTIC DRUGS

TABLE 52-5 -- PHARMACOKINETIC PARAMETERS OF ANTIEPI

Elimination Route 1%1

Drug

Vd IL/kg)

Protein Binding(%)

T|/2 Hr

Renal

Liver

Maintenance Dose (mg/kg/d)

Dosing Interval

Loading Dose (mg/kg)

Range (,ug/ml)

Carbamazepine

0.8

75

9-15

<5

>90

10-25

BID-TID

4-12

Clonazepam

3.0

85

20-60

<5

>90

0.03-0.3

BID

5-70t

Clorazepate

1.2

97

50-100

<5

>90

0.5-1.0

BID

0.5-1.9 t

Ethosuximide

0.7

0

30-60

<20

>80

15-40

q D

40-100

Felbamate

0.8

25

13-22

50

50

15-60

BID-TID

30-100

Gabapentin

0.7

0

5-7

100

0

1800-3600 mg/d

TID

4-8

Lamotrigine

1.0

55

12-62

<5

>90

300-500 mg/d

BID

2-4

Phenobarbital

0.6

45

75-110

25

75

1-4

q D

18-20

10-40

Phenytoin

0.8

90

9-36

<5

>90

4-7

q D, BID

15-20

10-20

Pnmidone

0.7

0-20

10-15

40

60

10-20

TID

5-15

Topiramate

0.7

15

12-24

100

0

200-800 mg/d

BID

Valproate

0.2

90

6-18

<5

>90

10-60

BID-TID

*Normal values for adults on monotherapy; pediatric dosages may vary Range, therapeutic range of serum concentration; qD, once daily, BID, twice daily, TID, three times daily; Vd, volume of distribution; T12 , elimination half-life mg/ml others are measured. With oral administration, absorption is influenced by gastric pH, bowel motility, splanchnic blood flow, and concomitant medications and food intake. Large variations in absorption occur with intramuscular administration, making this an undesirable route if high drug concentrations are required rapidly.

Following absorption, drugs are distributed into other compartments. The extent of distribution is expressed as the volume of distribution (Vd), a hypothetical volume of total body fluid within which a drug is evenly distributed. Distribution depends on extent of protein binding, solubility, and blood flow. Most AEDs are partially protein bound, and only the free, or unbound, fraction penetrates the blood-brain barrier to produce an effect. The Vd required to dissolve an amount of drug (D) to achieve a given concentration (deltaC=desired minus actual concentration) can be calculated by using the equation

the dose of drug required to achieve a particular serum concentration can be determined.

Elimination of anticonvulsant medications occurs through hepatic metabolism and renal excretion. The major metabolic pathway in humans is the hepatocyte endoplasmic reticulum P-450 mixed oxidase system. Phenobarbital, primidone, phenytoin, and carbamazepine induce this enzyme system, thereby facilitating metabolism of other hepatically metabolized drugs including oral contraceptives, folic acid, warfarin, quinidine, and steroids. Conversely, valproic acid is an enzyme inhibitor which, when combined with other hepatically metabolized agents, impairs their metabolism, potentially leading to toxicity. Analgesics, cardiac drugs, antimicrobials, antiulcer agents, and psychotropics may also interfere with the metabolism of AEDs and produce toxic reactions. Carbamazepine, valproic acid, primidone, and diazepam are converted to active metabolites having additional anticonvulsant properties.

Half-life (T% ) is the time required for the serum concentration of a drug to decrease by 50 percent following complete absorption and distribution of a single dose. A drug's half-life determines the dosing frequency and, as a rule, the dosing interval should not exceed one half-life. Drugs with short half-lives should be administered multiple times per day to prevent large fluctuations in serum concentration that may produce adverse effects or breakthrough seizures. Those with longer half-lives may be administered once daily, which generally improves compliance.

A drug's half-life may be altered by hepatic enzyme induction or inhibition and impaired renal function. With the exception of phenytoin, metabolism of anticonvulsant medications follows linear, or first-order kinetics, in which the rate of metabolism is directly proportional to serum concentration. Phenytoin is metabolized through nonlinear, or zero-order kinetics. The enzymes responsible for the elimination of phenytoin become saturated at levels within the therapeutic range. Once enzyme systems are saturated, the rate of metabolism fails to increase proportionately with further dosage increments, and modest increases in dosage result in marked increases in serum concentration. To avoid toxicity, the daily dosage of phenytoin should be increased by no more than 50 mg when serum concentration exceeds 10 to 12 pg/ml.

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