Drugs phenytoin

The antiepileptic drug phenytoin, an orally available class DB antiarrhythmic, is mainly effective in digitalis-induced arrhythmias. This diug exhibits nonlinear pharmacokinetics and a number of side effects including neuropathy, gingival hypetplasia, hepatitis, immunological disorders and suppression of white blood cells. 

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

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

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. 

One of the authors recently encountered a 21-year-old male presenting to the emergency room in status epilepticus (prolonged, uncontrolled seizures). This patient had a seven-year history of epilepsy, well controlled with the drug phenytoin at a dose of 300 mg/day. Indeed, he had not experienced a seizure in more than a year. In the emergency... 

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. 

Substance which remain in the stomach for a long time Barbital, aspirin, iron, alcohol, cholinergic blockers, narcotic drugs, phenytoin, antidepressants. 

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. 

Carbamazepine is a hepatic microsomal enzyme inducer and therefore will lower the serum concentration of a wide variety of drugs given concurrently. These include the antiepileptic drugs phenytoin, primidone, valproate, ethosuximide and clonazepam. In addition, carbamazepine can compromise the therapeutic effects of oral contraceptives, oral anticoagulants, beta-blockers, haloperidol and theophylline. 

Spherisorb ODS-1 (3 pm) Spherisorb ODS-1 (3 pm) Spherisorb ODS-1 (3 pm) Tricyclic antidepressants Prostaglandins Anti-epileptic drugs (phenytoin, primidon, ethosuccinimide,...)... 

Uses. Carbamazepine is used for secondary generalised and partial seizures, and primary generalised seizures. Because another antiepilepsy drug (phenytoin) was sometimes beneficial in trigeminal neuralgia, carbamazepine was tried in this condition, for which it is now the drug of choice... 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

Tegafur uracil Antimicrobiai drugs Phenytoin Risk of phenytoin toxicity Unknown... 

Drug Phenytoin (DPH) diibamazepine (CBZ) Valproic acid (VPA) and divalproex sodium Phenobarbital (PB)... 

MRP2 Similar to MRPl and MDR drugs. Phenytoin plus probenecid resulted... 

Bakes, S. et al. (2007) Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse... 

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. 

In addition to chlorpromazine, phenylbutazone (an analgesic and antiinflammatory agent), sulfonamides (chemotherapeutic agents), chlorothiazide (a diuretic), thiouracil and methima-zole (antithyroid drugs), phenytoin (an anticonvulsant), pyribenzamine (an antihistaminic), and chloramphenicol... 

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. 

There have been a number studies of the growth kinetics of biochemicals in suspension crystallization. Rodriguez-Homeda et al. (1986) used an MSMPR crystallizer to obtain the growth rate kinetics for the drug, phenytoin, as a function of pH. They found the kinetics to be size-independent and to increase at lower pH. An MSMPR crystallizer study by Harano and Yamamato (1982) determined the growth rate of glutamic acid from the measured size distribution. 

Another long-term study was conducted in 26 patients with folic acid deficiency (serum folate less than 5 nanograms/mL), and treated with two or more drugs (phenytoin, phenobarbital, primidone). The mental state of 22 of them (as shown by increased alertness, concentration, sociability etc.) improved to a variable degree when they were given folic acid 5 mg three times daily. However, the frequency and severity of seizures in 13 patients (50%) increased to such an extent that the vitamin had to be withdrawn from 9 of them. ... 

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