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Pharmacology of Phenytoin

Pharmacology of Phenytoin
 

Introduction

Phenytoin is a common anti-seizure (anticonvulsant) drug that aids in the management and prevention of various forms of seizures. Historically, it assisted in the treatment of dysrhythmias. Phenytoin is included in a class of drugs called hydantoins. This paper aims at describing the pharmacology of phenytoin, including its generic name and brand name, pharmacokinetics, pharmacodynamics, indications, contraindications, side effects and adverse effects. It also analyzes patient variables, including geriatrics, pediatrics, pregnancy, and lactation period, and examines the off-label uses.

Generic Name and Brand Name

The generic name is Phenytoin, while the brand name is Dilantin. Other brand names are Phenytek and Epanutin. This anticonvulsant is available in three forms in the United States of America, namely 125 mg/5ml suspension, 100 mg capsules, and 50 mg/ml of injectable solution. The capsules should neither be chewed nor smashed, but swallowed whole. The medication should be stored at a temperature of 30 degrees Celsius. Phenytoin needs protection from moisture and light; thus, in case the capsules get discolored, they must become disposed. The suspension requires room temperature for storage. It also needs protection from freezing and light. Patients can take phenytoin with or without food (EPILEPSY FOUNDATION, n.d.).

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion of phenytoin. The medication is weakly acid and insoluble in water. The rate of absorption of phenytoin and its bioavailability differ among the different formulations. The absorption occurs in the small intestines, and large doses get absorbed slowly. Due to its slow absorption rate, patients who have a rapid onset of drug action can get intravenous injections.

The drug gets widely distributed in the body tissues, including the brain, within 30 to 60 minutes after entering the systemic circulation. The apparent volume of distribution is around 0.5 to 0.8 L/kg. Moreover, it becomes highly bound to plasma proteins, particularly albumin (87%-93%). Phenytoin has a variable dose-dependent half-life after oral administration of therapeutic doses. In fact, the half-life can range from 8 to 60 hours with an average of 20-30 hours. In overdosed individuals, the half-life varies between 24 and 230 hours (Katzung & Trevor, 2014).

Phenytoin gets metabolized by the liver to an inactive metabolite, 5-(4-hydroxyphenyl)-5-phenyl-hydantoin through para-hydroxylation by the cytochrome p450 2C9 enzyme. This para-hydroxylated phenytoin then transforms into a glucuronide. The enzyme systems within the liver can become saturated; thus, phenytoin hydroxylation is capacity-limited. The metabolism of phenytoin at toxic dosages takes the zero-order kinetics (linear), while it uses first-order kinetics (non-linear) at therapeutic doses. The para-hydroxylated phenytoin can get oxidized to the catechol metabolite of phenytoin called 3, 4-dihydroxyphenyl-phenylhydantoin and again to the metabolite 3-0-methylated catechol (Katzung & Trevor, 2014).

Phenytoin clearance from the plasma is 5.9 ml/minute/kg. It is excreted as the hydroxylated metabolite in its free or conjugated state mainly via urine, whereas small quantities get excreted via milk. Furthermore, around 5 percent is excreted unchanged in feces, while urine contains 4 percent of the substance.

Pharmacodynamics

Pharmacodynamics entails the influence of the drug on the body, including binding of phenytoin to receptors, the post-receptor effects, and all chemical interactions of phenytoin. It binds on voltage-dependent neuronal sodium channels where it limits the sodium flux through these voltage-dependent channels, thereby suppressing the repetitive firing by neurons and causing anti-epileptic effects. The drug protects the sodium pumps in the heart and brain by normalizing the sodium gradient and stabilizing membranes. Moreover, it suppresses the development of maximl convulsive activity and decreases the spread of epileptic activity from the point of discharge without influencing the focus itself (Katzung & Trevor, 2014).

It also contains antiarrhythmic properties, while improving atrioventricular conduction, decreasing the force of contraction, and depressing the action of the pacemaker.

Indications

Phenytoin is used prophylactically to manage generalized tonic-clonic seizures and focal seizures. It also aids in the management of status epilepticus. Moreover, it helps control and prevent convulsions that develop during and after surgery of the nervous system and brain (Katzung & Trevor, 2014).

Contraindications

It is contraindicated in individuals who are allergic to phenytoin or other hydantoins. People with acute intermittent porphyria should not take it as well. In addition, it is prohibited for patients with Adam-Stokes syndrome, SA block, sinus bradycardia, second or third degree AV block (Ballinger, 2011). Furthermore, patients with hepatic dysfunction, alcohol use, viral hepatitis, uremia, diabetes, respiratory depression, myocardial insufficiency, and hypoalbuminemia should use it cautiously (Aschenbrenner & Venable, 2009).

Side Effects

Common side effects are dose-related and neurotoxic. They include nausea, vomiting, constipation, slurred speech, impaired memory, headaches, dizziness, sedation, confusion, reduced coordination, and nystagmus (Ballinger, 2011). They normally last a few days and reduce with a decrease in the dosage. Rashes are also a common side effect and appear within the first 5 to 17 days after the initial dosage. Replacing phenytoin with other antiepileptics helps to stop the rashes. What is more, long-term use causes side effects on the appearance. These individuals develop acne, hirsutism, coarseness of facial features, and gingival hyperplasia (commonest in children) (Ballinger, 2011). Acne can get treated with proper facial hygiene, antibiotic creams, and lotions. Hirsutism resolves with the use of hair removal creams, while good dental care, flossing, and daily brushing help to minimize gingival hyperplasia (EPILEPSY FOUNDATION, n.d.).

Adverse Effects

Osteomalacia (bone weakness) results from long-term use of phenytoin. The patients suffering from this side effect need to take vitamin D supplements, exercise and take foods rich in calcium. Some patients develop local or generalized lymphadenopathy (swollen glands), including benign lymph node hyperplasia, lymphoma, and even Hodgkin’s disease. Patients using this medication may develop fever, labored breathing, painful mouth sores, sore throat, easy bleeding and bruising, and severe muscle pain and weakness. Phenytoin can also lead to serious dermatological issues such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), lupus erythematosus, exfoliative, purpuric, or bullous dermatitis. Furthermore, about sixty percent of patients may develop hepatitis causing liver failure and death (EPILEPSY FOUNDATION, n.d.).

Patient Variables: Geriatrics, Pediatrics, Pregnancy, Lactation

Elderly patients metabolize phenytoin at a slower rate in comparison with the younger ones, and they are at more risk of developing side effects. Thus, titration of their doses requires caution and the initial dosages are low. The drug half-life becomes prolonged due to the reduced elimination; hence, they take the medication once a day as this dose is sufficient for them. Additionally, these patients have low levels of albumin in their serum; resultantly, much phenytoin remains unbound, meaning that there will be a higher concentration of unbound drug than expected in relation to the total concentration of the medication. Consequently, the clinical response does not correspond to the total drug level. Varying gastrointestinal function in the elderly patients affect absorption, and this may cause difficulties in achieving constant levels of phenytoin in blood even if the patient takes a steady dose. In faact, some of these patients take many drugs, and this may cause drug interactions because phenytoin interacts with plenty of medications e.g. aspirin. The geriatric population is at high risk of injury from accidental falls, and this may be of concern as the drug causes reduced coordination in patients (EPILEPSY FOUNDATION, n.d.).

Although phenytoin is efficient for the treatment of generalized and partial seizures in children, it causes hirsutism and gingival hyperplasia and is not frequently the first-choice drug for theses seizures. In fact, almost fifty percent of children using the medicine get gum hyperplasia, and use of braces worsens it. Infants should not use oral phenytoin due to issues with bioavailability and the narrow therapeutic index. To minimize the side effects, children often begin with a dosage of 5 mg/kg/day divided into two or three equal doses. A gradual increase in the doses also helps minimize side effects. Thus, 300 mg per day is the maximum dose that children should take. When using suspension in children, caregivers should thoroughly shake the bottle to avoid dosing errors as the drug is poorly soluble.

Phenytoin falls under pregnancy group D according to the USA FDA and is, thus, a teratogen. However, its advantages outweigh the risks for pregnant women with serious seizures. Pregnant women taking this medication to manage their epilepsy have a higher risk of delivering infants with congenital defects such as heart malformations, cleft lip, cleft palate, brachydactyly, and widely spaced eyes. The risk for congenital malformation gets higher when one has a family history of these birth defects and for women taking more than one anticonvulsant medicine. Therefore, gravid women should take folic acid daily to reduce these defects. The convulsions are frequent during pregnancy owing to hormonal changes and alterations in how the body handles phenytoin. Blood coagulation may get affected within the first twenty-four hours in infants born to mothers taking phenytoin, and these women should take 10 mg of vitamin K in their final month of pregnancy to avoid the problem.

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Although some small amounts of phenytoin are present in breast milk, lactating mothers with healthy and full-term infants should continue breastfeeding because most of the drug becomes protein bound in the mother’s serum and only ten percent gets excreted in milk (EPILEPSY FOUNDATION, n.d.).

Off-Label Uses

Sometimes, physicians prescribe phenytoin for unapproved conditions. These disorders include anxiety, depression, claustrophobia, migraines, attention deficit hyperactivity disorder, dysphoria, restless leg syndrome, obsessive-compulsive disorder, eating disorders, and temper tantrums (Whitaker, 2016). Other off-label uses include treatment of neuropathic pain, trigeminal neuralgia, and motion sickness. It also assists in treating abnormal heart rhythms e.g. ventral and atrial tachycardia and treat digoxin toxicity (Aschenbrenner & Venable, 2009).

Conclusion

In summary, phenytoin is used in the treatment of various forms of seizures. Its rate of absorption is slow, and it has a wide distribution. The drug gets metabolized in the liver and is excreted via urine and feces. It works by suppressing voltage-dependent sodium channels, thereby limiting firing of neurons. The contraindications are hypersensitivity to phenytoin and in patients with disorders such as Adam-Stoke syndrome and sinus bradycardia. The examples of side effects are dizziness, nausea, and nystagmus. Adverse effects include lymphadenopathy, SJS, and osteomalacia. Metabolism of phenytoin is slower in elderly patients, and they receive a lower dose at first. Phenytoin causes gingival hyperplasia and hirsutism in children. It also causes various birth defects in newborns e.g. cleft palate. Lactating mothers should still breastfeed because only a small amount of the drug gets excreted via breast milk. Off-label uses of phenytoin include motion sickness, trigeminal pain, arrhythmias, and depression.

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