Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)
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Toxicity
The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the initial dose is too large; gradual increments are indicated when starting the drug in either children or adults.
VIgabatrin
Current investigations that seek drugs to enhance the effects of GABA include efforts to find GABA agonists and prodrugs, GABA transaminase inhibitors, and GABA uptake inhibitors. Vigabatrin (
-vinyl-GABA) is one of these new drugs and has been registered in Europe and South America.
Mechanism of Action
Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for the degradation of GABA. It apparently acts by increasing the amount of GABA released at synaptic sites, thereby enhancing inhibitory effects. Vigabatrin may also potentiate GABA by inhibiting the GABA transporter. It is effective in a wide range of seizure models. Vigabatrin is marketed as a racemate; the S(+) enantiomer is active and the R(–) enantiomer appears to be inactive.
Clinical Use
Vigabatrin is useful in the treatment of partial seizures and West's syndrome. The half-life is approximately 6–8 hours, but considerable evidence suggests that the pharmacodynamic activity of the drug is more prolonged and not well correlated with the plasma half-life. In adults, vigabatrin should be started at an oral dosage of 500 mg twice daily; a total of 2–3 g (rarely more) daily may be required for full effectiveness. Typical toxicities include drowsiness, dizziness, and weight gain. Less common but more troublesome adverse reactions are agitation, confusion, and psychosis; preexisting mental illness is a relative contraindication. The drug was delayed in its worldwide introduction by the appearance in rats and dogs of a reversible intramyelinic edema; this phenomenon has not been observed in any patient to date. More recently, unfortunately, long-term therapy with vigabatrin has been associated with development of visual field defects in up to one third of patients. This adverse effect may not be reversible, and vigabatrin may therefore be relegated to use in patients—such as those with infantile spasms—who are refractory to other treatments.
Lamotrigine
Lamotrigine was developed when some investigators thought that the antifolate effects of certain antiseizure drugs (eg, phenytoin) may contribute to their effectiveness. Several phenyltriazines were developed, and although their antifolate properties were weak, some were active in seizure screening tests.
Mechanism of Action
Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltageand use-dependent inactivation of sodium channels. This action probably explains lamotrigine's efficacy in focal epilepsy. It appears likely that lamotrigine has another mechanism of action to account for its efficacy in primary generalized seizures in childhood, including absence attacks; this mechanism may involve actions on voltage-activated Ca2+ channels.
Clinical Use
Although most controlled studies have evaluated lamotrigine as add-on therapy, some also suggest that the drug is effective as monotherapy for partial seizures. Some authorities feel that the drug is also active against absence and myoclonic seizures in children. Adverse effects include dizziness, headache, diplopia, nausea, somnolence, and skin rash. The rash is considered a typical hypersensitivity reaction. Although the risk of rash may be diminished by introducing the drug slowly, pediatric patients are at high risk; some studies suggest that a potentially life-threatening dermatitis will develop in 1–2% of pediatric patients.
Pharmacokinetics & Dosage
Lamotrigine is almost completely absorbed and has a volume of distribution in the range of 1–1.4 L/kg. Protein binding is only about 55%. The drug has linear kinetics and is metabolized primarily by glucuronidation to the 2-N-glucuronide, which is excreted in the urine. Lamotrigine has a halflife of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients taking enzyme-inducing drugs. Lamotrigine is effective against partial seizures in adults, with dosages typically between 100 mg/d and 300 mg/d and with a therapeutic blood level near 3 
g/mL. Valproate causes a twofold increase in the drug's half-life; in patients receiving valproate, the initial dosage of lamotrigine must be reduced to 25 mg every other day.
Felbamate
Felbamate has been approved and marketed in the USA and in some European countries. Although it is effective in some patients with partial seizures, the drug causes aplastic anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases.
The mechanism of action of felbamate is not established. The strongest evidence suggests NMDA receptor blockade via the glycine binding site. Felbamate has a half-life of 20 hours (somewhat shorter when administered with either phenytoin or carbamazepine) and is metabolized by hydroxylation and conjugation; a significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine.
In spite of the seriousness of the adverse effects, more than 10,000 patients worldwide remain on the medication. Usual dosages are 2000–4000 mg/d in adults, and effective plasma levels range from 30 
g/mL to 100 g/mL. In addition to its usefulness in partial seizures, felbamate has proved effective against the seizures that occur in Lennox-Gastaut syndrome.
Gabapentin
Gabapentin is an amino acid, an analog of GABA, that is effective against partial seizures. Originally planned as a spasmolytic, it was found to be more effective as an antiseizure drug.
Mechanism of Action
In spite of its close structural relationship to GABA, gabapentin appears not to act on GABA receptors. It may, however, alter GABA metabolism, its nonsynaptic release, or its reuptake by GABA transporters. An increase in brain GABA concentration is observed in man. Gabapentin is transported into the brain by the L-amino acid transporter. Its anticonvulsant effect in the electroshock model is delayed relative to its peak plasma concentration. The drug also binds to the 
2
subunit of voltage-sensitive Ca2+ channels.
Clinical Use & Dosage
Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures at dosages that range up to 2400 mg/d in controlled clinical trials. Open follow-on studies permitted
dosages up to 4800 mg/d, but data are inconclusive on the effectiveness or tolerability of such doses. Monotherapy studies also document some efficacy. Very high dosages have been needed by some clinicians to achieve improvement in seizure control. Effectiveness in other seizure types has not been well demonstrated. Gabapentin has also been found effective in the treatment of neuropathic pain and is now indicated for postherpetic neuralgia in adults at doses of 1800 mg and above. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor.
Pharmacokinetics
Gabapentin is not metabolized and does not induce hepatic enzymes. Absorption is nonlinear and dose-dependent at very high doses, but otherwise the elimination kinetics are linear. The drug is not bound to plasma proteins. Drug-drug interactions are negligible. Elimination is via renal mechanisms; the drug is excreted unchanged. The half-life is short, ranging from 5 hours to 8 hours; the drug is typically administered two or three times per day.
Topiramate
Topiramate is a substituted monosaccharide that is structurally different from all other antiseizure drugs.
Mechanism of Action
Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltagedependent sodium channels. Topiramate also appears to potentiate the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on AMPA receptors. It is possible that all three of these actions contribute to topiramate's anticonvulsant effect.
Clinical Use
Clinical trials of topiramate demonstrated a dose-response relationship, and monotherapy trials (using a pseudoplacebo) showed the drug to be effective against partial and generalized tonic-clonic seizures. Some evidence suggests that the drug has a broader spectrum, with effectiveness against Lennox-Gestaut syndrome, West's syndrome, and even absence seizures. Dosages typically ranged from 200 mg/d to 600 mg/d, with a few patients tolerating dosages greater than 1000 mg/d. Most clinicians begin slowly (50 mg/d) and increase slowly to avoid adverse effects. Although no idiosyncratic reactions have been noted, dose-related side effects occur most frequently in the first 4 weeks and include somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion. Acute myopia and glaucoma may require prompt drug withdrawal. Urolithiasis has also been reported. However, the discontinuation rate is apparently only about 15%. The drug is teratogenic in animal models, but no human fetal deformities have been noted in the very few
pregnancies that have occurred during the course of topiramate administration.
Pharmacokinetics
Topiramate is rapidly absorbed (about 2 hours) and is 80% bioavailable. There is no food effect on absorption, minimal (15%) plasma protein binding, and only moderate (20–50%) metabolism; no active metabolites are formed. The drug is primarily excreted unchanged in the urine. The half-life is about 20–30 hours. Although increased levels are seen with renal failure and hepatic impairment, there is no age or gender effect, no autoinduction, no inhibition of metabolism, and kinetics are linear. Drug interactions do occur and can be complex, but the major effect is on topiramate levels rather than on the levels of other antiseizure drugs. Birth control pills may be less effective in the presence of topiramate, and higher estrogen doses may be required.
Tiagabine
Tiagabine is a derivative of nipecotic acid and was "rationally designed" as an inhibitor of GABA uptake (as opposed to discovery through random screening).
Mechanism of Action
Tiagabine is an inhibitor of GABA uptake in both neurons and glia. It preferentially inhibits the transporter isoform 1 (GAT-1) rather than GAT-2 or GAT-3 and increases extracellular GABA levels in the forebrain and hippocampus. It prolongs the inhibitory action of synaptically released GABA. In rodents it is potent against kindled seizures but weak against the maximum electroshock model.
Clinical Use
Tiagabine is indicated for the adjunctive treatment of partial seizures and is effective in doses ranging from 16 mg/d to 56 mg/d. Divided doses as often as four times per day are sometimes required. Some patients appear to do well with tiagabine monotherapy, which is generally well tolerated. Minor adverse events are dose-related and include nervousness, dizziness, tremor, difficulty in concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discontinuation. Psychosis occurs rarely. Rash is an uncommon idiosyncratic adverse effect. Laboratory studies are usually normal.
Pharmacokinetics
Ethosuximide
Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures and was introduced as a "pure petit mal" drug. Its continued popularity is based on its safety and efficacy, and its role as the first choice anti-absence drug remains undiminished—in part because of the idiosyncratic hepatotoxicity of the alternative drug, valproic acid.
Chemistry
Ethosuximide is the last antiseizure drug to be marketed whose origin is in the cyclic ureide structure. The three antiseizure succinimides marketed in the USA are ethosuximide, phensuximide, and methsuximide. All three are substituted at the 2 position. (See structure below, and note the difference in numbering relative to Figure 24–1.) Methsuximide and phensuximide have phenyl substituents, while ethosuximide is 2-ethyl-2-methylsuccinimide.
Mechanism of Action
Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type calcium currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack. Inhibition of this current could therefore account for the specific therapeutic action of ethosuximide. Ethosuximide also inhibits Na+/K+ ATPase, depresses the cerebral metabolic rate, and inhibits GABA aminotransferase. However, none of these actions are seen at therapeutic concentrations.
Clinical Use
As predicted from its activity in laboratory models, ethosuximide is particularly effective against absence seizures. Documentation of its effectiveness required specific advances in quantitation of absence seizures; this was accomplished in the 1970s, when the characteristic generalized 3/s spikewave electroencephalographic abnormality was correlated with a decrement in consciousness even when the abnormality occurs for only a few seconds. Long-term electroencephalographic recordings, therefore, provided the necessary quantitative method for determining the frequency of absence attacks and allowed rapid and effective evaluation of the efficacy of anti-absence drugs. Although ethosuximide was marketed in advance of the federal requirements for efficacy, these techniques were applied to later drugs such as clonazepam and valproic acid in documentation of their efficacy. This was accomplished by comparison with ethosuximide.
Pharmacokinetics
Absorption is complete following administration of the oral dosage forms. Peak levels are observed 3–7 hours after oral administration of the capsules. Animal studies indicate that chronic administration of the solution may prove irritating to the gastric mucosa. Ethosuximide is uniformly distributed in total body water, ie, 0.7 L/kg and does not penetrate fat. Ethosuximide is not proteinbound, and spinal fluid concentrations are therefore equal to plasma concentrations.
Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metabolites. The drug has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.
Therapeutic Levels & Dosage
Therapeutic levels of 60–100 
g/mL can be achieved in adults with dosages of 750–1500 mg/d, although lower or higher dosages and blood levels may be necessary and tolerated (up to 125 g/mL) in some patients. Ethosuximide has a linear relationship between dose and steady-state plasma levels. The drug might be administered as a single daily dose were it not for its adverse gastrointestinal effects; twice-a-day dosage is common.
Drug Interactions
Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism. No other important drug interactions have been reported for the succinimides.
Toxicity
The most common dose-related adverse effect of ethosuximide is gastric distress, including pain, nausea, and vomiting. This can often be avoided by starting therapy at a low dose, with gradual increases into the therapeutic range. When the adverse effect does occur, temporary dosage reductions may allow adaptation. Ethosuximide is a highly efficacious and safe drug for absence seizures; the appearance of relatively mild, dose-related adverse effects should not immediately call for its abandonment. Other dose-related adverse effects include transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction of improvement.
Non-dose-related or idiosyncratic adverse effects of ethosuximide are extremely uncommon. Skin rashes have been reported, including at least one case of Stevens-Johnson syndrome. A few patients have had eosinophilia, thrombocytopenia, leukopenia, or pancytopenia; it is not entirely certain that ethosuximide was the causal agent. The development of systemic lupus erythematosus has also been reported, but other drugs may have been involved.
Phensuximide & Methsuximide
Phensuximide and methsuximide are phenylsuccinimides that were developed and marketed before ethosuximide. They are used primarily as anti-absence drugs. Methsuximide is generally considered more toxic, and phensuximide less effective, than ethosuximide. Unlike ethosuximide, these two compounds have some activity against maximal electroshock seizures, and methsuximide has been used for partial seizures by some investigators. The desmethyl metabolite of methsuximide has a half-life of 25 hours or more and exerts the major antiseizure effect. The toxicity and reduced effectiveness of phensuximide when compared with methsuximide has been investigated, and the failure of the desmethyl metabolite to accumulate in the former probably explains its relatively
weak effect.
Valproic Acid & Sodium Valproate
Sodium valproate, also used as the free acid, valproic acid, was found to have antiseizure properties when it was used as a solvent in the search for other drugs effective against seizures. It was marketed in France in 1969 but was not licensed in the USA until 1978. Valproic acid is fully ionized at body pH, and for that reason the active form of the drug may be assumed to be the valproate ion regardless of whether valproic acid or a salt of the acid is administered.
Chemistry
Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity; this activity appears to be greatest for carbon chain lengths of five to eight atoms. Branching and unsaturation do not significantly alter the drug's activity but may increase its lipophilicity, thereby increasing its duration of action. The amides and esters of valproic acid are also active antiseizure agents.
Mechanism of Action
The time course of valproate's anticonvulsant activity appears to be poorly correlated with blood or tissue levels of the parent drug, an observation giving rise to considerable speculation regarding both the active species and the mechanism of action of valproic acid. Valproate is active against both pentylenetetrazol and maximal electroshock seizures. Like phenytoin and carbamazepine, valproate blocks sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on Na+ currents. Blockade of NMDA receptor-mediated excitation may also be important. Much attention has been paid to the effects of valproate on GABA. Several studies have shown increased levels of GABA in the brain after administration of valproate, although the mechanism for this increase remains unclear. An effect of valproate to facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, has been described. An inhibitory effect on the GABA transporter GAT-1 may contribute. At very high concentrations, valproate inhibits GABA-T in the brain, thus blocking degradation of GABA. However, at the relatively low doses of valproate needed to abolish pentylenetetrazol seizures, brain GABA levels may remain unchanged. Valproate produces a reduction in the aspartate content of rodent brain, but the relevance of this effect to its anticonvulsant action is not known.
At high concentrations, valproate has been shown to increase membrane potassium conductance. Furthermore, low concentrations of valproate tend to hyperpolarize membrane potentials. These findings have led to speculation that valproate may exert an action through a direct effect on the potassium channels of the membrane.
Valproate probably owes its broad spectrum of action to more than one molecular mechanism. Its action against absence attacks remains to be explained.
Clinical Use
Valproate is very effective against absence seizures. Although ethosuximide is the drug of choice when absence seizures occur alone, valproate is preferred if the patient has concomitant generalized tonic-clonic attacks. The reason for preferring ethosuximide for uncomplicated absence seizures is valproate's idiosyncratic hepatotoxicity, described below. Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drug is effective in generalized tonic-clonic seizures, especially those which are primarily generalized. A few patients with atonic attacks may also respond, and some evidence suggests that the drug is effective in partial seizures.
Other uses of valproate include management of bipolar disorder and migraine prophylaxis.
Pharmacokinetics
Valproate is well absorbed following an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and decreased toxicity may result if the drug is given after meals.
Valproic acid is 90% bound to plasma proteins, although the fraction bound is somewhat reduced at blood levels greater than 150 g/mL. Since valproate is both highly ionized and highly proteinbound, its distribution is essentially confined to extracellular water, with a volume of distribution of approximately 0.15 L/kg.
Clearance for valproate is low; its half-life varies from 9 hours to 18 hours. At very high blood levels, the clearance of valproate is dose-dependent. There appear to be offsetting changes in the intrinsic clearance and protein binding at higher doses. Approximately 20% of the drug is excreted as a direct conjugate of valproate.
The sodium salt of valproate is marketed in Europe as a tablet protected by aluminum foil, as it is quite hygroscopic. In Central and South America, the magnesium salt is available, which is considerably less hygroscopic. The free acid of valproate was first marketed in the USA in a capsule containing corn oil; the sodium salt is also available in syrup, primarily for pediatric use. An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1:1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by most patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3–4 hours.
Therapeutic Levels & Dosage
Dosages of 25–30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg/d or even more. Therapeutic levels of valproate range from 50 g/mL to 100 
g/mL. In testing efficacy, this drug should not be abandoned until morning trough levels of at least 80 g/mL have been attained; some patients may require and tolerate trough levels in excess of 100 g/mL.
Drug Interactions
As noted above, the clearance of valproate is dose-dependent, caused by changes in both the intrinsic clearance and protein binding. Valproate inhibits its own metabolism at low doses, thus decreasing intrinsic clearance. At higher doses, there is an increased free fraction of valproate, resulting in lower total drug levels than expected. It may be clinically useful, therefore, to measure both total and free drug levels. Valproate also displaces phenytoin from plasma proteins. In addition to binding interactions, valproate inhibits the metabolism of several drugs, including phenobarbital,