What is the mechanism of action of phenytoin and what are its clinical uses?
MonitoringPharmacokinetics Show In therapeutic doses, phenytoin is absorbed entirely and reaches peak plasma concertation at 1.5 to 3 hours. However, in settings of acute ingestions, absorption tends to last longer than two weeks; this is potentially attributable to its effects on reducing the gastrointestinal motility and poor water solubility. Fosphenytoin can be administered intramuscularly (IM) or intravenously (IV) but requires enzymatic conversion by phosphatase in the body to the active phenytoin compound. Distribution Phenytoin is usually 90% bound to plasma proteins (mostly albumin), and only its unbound form is pharmacologically active. The fraction of protein binding may be lower in neonates, pregnant patients, hypoalbuminemia, and uremia. It is distributed in all tissues and becomes firmly tissue-bound with a large volume of distribution. Its levels are higher in the central nervous system as compared to the serum. Metabolism The hepatic P450 enzyme system metabolizes phenytoin, (predominantly CYP2C9 and CYP 2C19) to inactive metabolites, and is an inducer of CYP3A4, which account for many of its drug-drug interactions. Because the metabolism of phenytoin is predominantly by the cytochrome P450 enzyme system, drugs that alter the function of these enzymes either by inducing or inhibiting phenytoin would require monitoring and possible medication adjustments to phenytoin based on resulting follow up phenytoin levels. Medications that inhibit these enzymes increase the phenytoin plasma concentrations. Some of These drugs include amiodarone, cimetidine, cotrimoxazole, disulfiram, fluconazole, metronidazole, chloramphenicol, sodium valproate, 5-fluorouracil, and sulphonamides. Medications that induce the enzyme system to decrease plasma phenytoin concentrations include alcohol, barbiturates, carbamazepine, theophylline, rifampin, and other medications. Excretion 1% to 5% of the drug is excreted in the urine unchanged. At plasma concentrations below 10 mg/L, elimination will follow first-order kinetics; following saturation of the system due to increased drug concentrations, elimination changes to zero-order kinetics. Subsequently, the usual average half-life of 22 hours can become significantly prolonged with marked overdose. Monitoring Therapeutic drug monitoring of phenytoin is necessary to ensure dosage delivery is at therapeutic levels. Knowledge of its pharmacokinetic properties is crucial for correct interpretation of total serum concentrations when protein binding becomes altered due to hypoalbuminemia, renal failure, or interaction with other protein-bound drugs such as valproate. Theoretical equations such as the Sheiner-Tozer equation have been introduced to calculate adjusted serum concentration levels and avoid inappropriate adjustment of dosage of phenytoin. However, they have not seen broad implementation in clinical practice due to poor patient outcomes. Closer investigation of total serum phenytoin and serum albumin ratio by healthcare providers is critical for proper monitoring of phenytoin therapy. ToxicityPhenytoin displays its primary signs of toxicity on the nervous and cardiovascular systems. Overdose on oral phenytoin mainly causes neurotoxicity, whereas cardiovascular toxicity is the main side effect of parenteral administration. Neurotoxicity The neurotoxic effects are concentration-dependent and can range from mild nystagmus to ataxia, slurred speech, vomiting, lethargy, and eventually coma and death. The following is a generalized correlation of side effects with total plasma phenytoin concentrations (the value obtained via most laboratories):
Seizures are infrequent and usually occur at very high serum concentrations. The presence of seizures with phenytoin overdose should prompt the search for other causes. Cardiac Toxicity Phenytoin is a Class IB antiarrhythmic; its suppressant effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias as well as sinoatrial and atrioventricular blocks. These effects rarely occur with oral administration. However, in the intravenous form, the primary toxicity is believed to be from propylene glycol, which is a cardiac depressant; rapid infusions of phenytoin can lead to bradycardia, hypotension, and asystole. Care must be taken not to administer intravenous phenytoin at a rate faster than 50 mg per minute. Other Toxicities “Purple glove syndrome” is a rare side effect that can accompany the intravenous administration of phenytoin. The worsening limb edema and discoloration appear to result from the crystallization of phenytoin within the blood. When there are extensive skin necrosis and limb ischemia, this can lead to amputations. Chronic Toxicity Chronic intake of phenytoin can lead to megaloblastic anemia due to folate deficiency, peripheral neuropathy, or lupus-like syndrome. These are not commonly reported in acute overdoses. Toxicokinetics Due to its metabolism by the CP450 microsomal enzyme system, drugs that alter their function can place the patient at risk for toxicity by increasing the plasma phenytoin concentrations. These include amiodarone, cimetidine, cotrimoxazole, disulfiram, fluconazole, metronidazole, chloramphenicol, sodium valproate, 5-fluorouracil, and sulphonamides. Management There is no specific antidote for phenytoin toxicity; supportive care is the hallmark of treatment. Enhancing Healthcare Team OutcomesManaging phenytoin overdose requires an interprofessional team of healthcare professionals that includes a nurse, laboratory technologists, pharmacists, and several physicians in different specialties. Without proper management, the morbidity and mortality from phenytoin overdose are high. The moment the triage nurse has admitted a phenytoin overdose, the emergency department clinician is responsible for coordinating the care which includes the following:
The management of phenytoin overdose does not stop in the emergency department. Nursing will continue to provide followup care until the patient is stabilized and ready to move on to the next step, reporting any concerns to the treating clinicians. They will also monitor all relevant signs and symptoms of subsequent visits, informing the clinician of any concerns that arise. Following the stabilization of the patient, one has to determine how and why the patient overdosed. A consult with a mental health professional to evaluate the patient to determine if this was an intentional act and if the patient may be at continued risk for self-harm may be appropriate. The pharmacist should ensure that there is minimal drug interaction, and the risk of possible drug overdose requires monitoring and coordination with the clinical team. [Level 5] These examples and activities of an interprofessional healthcare team demonstrate that this approach is necessary for the safe and effective administration of phenytoin, as well as to provide care in cases of toxicity. [Level 5] What is the mechanism of action of phenytoin?Mechanism of Action
Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited.
What are the clinical applications of phenytoin?Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
What is phenytoin used for besides seizures?Its major uses are for the prevention of seizures, particularly tonic-clonic seizures (that affect the entire brain) or partial seizures (seizures that affect only half of the brain or one area). Phenytoin can also be used in the treatment of arrhythmia (irregular heartbeat) and neuropathic pain.
What is the most probable mechanism of anticonvulsant action of phenytoin?The molecular mechanism for this is a voltage-dependent blockade of membrane sodium channels responsible for the action potential.
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