Anticonvulsant drugs phenytoin

Phenytoin Synthesis of this anticonvulsant drug phenytoin (9.1.1) is described in Chapter 9. 

Figure 1.14 Ab initio quantum mechanics calculations can be employed to rigorously provide geometries (bond lengths, bond angles, torsional angles) for a drug molecule. This figure shows such values for the anticonvulsant drug phenytoin.

Oxidation Aromatic Hydroxylation. Since many drugs contain aromatic rings, this is a very common metabolic transformation. The process tends to be species specific, with human showing a strong tendency to hydroxylation in the para position. This reaction proceeds via an arene epoxide intermediate. The anticonvulsant drug phenytoin is metabolized by being para-hydroxylated in its aromatic rings. 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

The anticonvulsant drug phenytoin (5,5-diphenylhy-dantoin) is sparingly soluble in water (0.02mg/mL) and is therefore formulated as sodium enolate for intravenous or intramuscular injections. The solvent is a mixture of 40% propylene glycol, 10% ethanol and 50% water and the pH of the solution is alkaline (pH 12), due to the weak acidity... 

Here B is the product of a Phase I reaction and Y is the product of a Phase II reaction, and Y is less active than A. This occurs, for example, in the metabolism of the anticonvulsant drug, phenytoin. Phenytoin (A) is hydroxylated to an inactive metabolite, 5-(4 -hydro-xyphenyl)-5-phenylhydantoin (4 -HPPH) (B), which is subsequently glucuronidated to 5-(4 -hydroxyphenyl)-5-phenylhydantoin (4 -HPPH) O-glucuronide (Y), an inactive metabolite and the most abundant form of phenytoin found in human urine of patients taking phenytoin. 

The mechanisms of action, metabolism, and the adverse effect of the primary anticonvulsant drugs (phenytoin, carbamazepine, ethosuximide, valproic acid, and the barbiturates and benzodiazepines) are discussed. 

I with seizures and require anticonvulsant therapy. Phenytoin is the most frequently used agent, with a loading dose of 15 mg/kg followed by 300 mg by mouth daily (titrated to therapeutic levels between 10 and 20 mcg/mL). Diazepam 5 mg intravenously may be used for rapid control of persistent seizures. Prophylactic anticonvulsants have been used frequently, but a recent meta-analysis did not support their use.23 Thus, because adverse effects and drug interactions are common, the routine use of prophylactic anticonvulsants is not recommended. 

Ibeanu GC, Blaisdell ], Ferguson R], Ghanayem Bl, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-me-phenytoin. J Pharmacol Exp Ther 1999 290[2] 635—640. 

Phenytoin, introduced as an anticonvulsant drug in 1938, remains one of the drugs most frequently prescribed for convulsive disorders. The precise mode of action is unknown, but it appears to inhibit the accumulation of sodium in nerve cells, thus stabilizing hyperexcitable cell membranes (A13)—a property also utilized in the treatment of cardiac arrhythmias. 

While regular monitoring of plasma phenytoin levels can result in improved seizure control, the benefit derived from measuring other commonly prescribed anticonvulsant drugs is difficult to assess. Phenobarbitone, primidone, and carbamazepine will be discussed briefly. 

Regular monitoring of blood phenytoin levels provides a valuable contribution to the management of patients with epilepsy. The value of determining the blood level of other anticonvulsant drugs is unconfirmed. At present such work should be undertaken only as prospective research procedures combining clinical and biochemical methods of assessment and patient-management. 

Drugs that may affect methylphenidate include MAOIs. Drugs that may be affected by methylphenidate hydrochloride include guanethidine, anticonvulsants (eg, phenytoin, phenobarbital, primidone), selective serotonin reuptake inhibitors, coumarin anticoagulants, and tricyclic antidepressants. 

If we apply this concept of samration to drug elimination we get a similar picture. The anticonvulsant phenytoin depends critically for its elimination on one enzyme reaction (to produce the p-hydroxy-phenyl metabolite) and this, like the turnstile, can exceed its capacity to metabolize the drug. Phenytoin is then eliminated at a constant amount (not a constant proportion) per unit time. If input then exceeds this elimination capacity (and volume of distribution does not change), plasma concentration will rise rapidly into the toxic range. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

---