Barbitoin

Uses

Phenobarbital is used as-

• Sedative and hence it relieves anxiety, tension and fear
• Hypnotic and hence it is used for short term insomnia
• Pre-anaesthetics
• Anti-epileptic in epilepsy with Partial seizure or Generalized Tonic-clonic seizure, status epilepticus
• Certain acute convulsive episodes

Parenteral Phenytoin is used for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous Phenytoin can also be substituted, as short-term use, for oral phenytoin. Parenteral Phenytoin should be used only when oral Phenytoin administration is not possible

Barbitoin is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Anxiety, Febrile Convulsions, Hyperbilirubinemia, Insomnia, Menopausal Symptoms, Partial-Onset Seizures, Withdrawal Symptoms, Generalized seizure, SedationComplex Partial Seizures, Grand Mal Status Epilepticus, Grand mal Generalized tonic-clonic seizure, Jacksonian epilepsy, Partial-Onset Seizures, Petit Mal Epilepsy, Post-Traumatic Seizure Disorder, Seizures, Status; Epilepticus, Tonic-clonic, Temporal Lobe Epilepsy (TLE), Convulsive disorders

How Barbitoin works

Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.

Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels.

Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.

Dosage

Barbitoin dosage

Adults:

• Hypnosis: 100 to 320 mg
• Sedation: 30 to 120 mg/day in 2 to 3 divided doses
• Epilepsy: 60 to 250 mg/day
• Convulsion: 50 to 100 mg/day in 2 to 3 divided doses
• Status epilepticus: IV 10-20 mg/Kg, repeat if needed

Children:

• Preoperative: 1-3 mg/Kg body weight
• Convulsion: 4-6 mg/Kg/day
• Status epilepticus: IV 15-20 mg/Kg over 10-15 minutes

Oral:Epilepsy:

• Adult: Initially, 3-4 mg/kg daily as single dose or in divided doses. Alternatively, 150-300 mg daily increased gradually to 600 mg daily if necessary. Maintenance: 200-500 mg daily.
• Child: Initially, 5 mg/kg daily in 2-3 divided doses. Maintenance: 4-8 mg/kg daily in divided doses. Max dose: 300 mg daily.

Intravenous:Tonic-clonic status epilepticus:

• Adult: Adjunctive therapy with a benzodiazepine (e.g. diazepam): 10-15 mg/kg by slow inj or intermittent infusion at a max rate of 50 mg/min. Maintenance: 100 mg IV (or orally) given every 6-8 hr.
• Child: Neonates: 20 mg/kg as a loading dose, then 2.5-5 mg/kg bid; 1 mth-12 yr: 18 mg/kg as a loading dose, then 2.5-5 mg/kg bid; >12 yr: 18 mg/kg as a loading dose, then up to 100 mg 3-4 times daily.

Dilute with most IV infusion soln (e.g. NaCl 0.45% or 0.9%, lactated Ringer's, dextrose 5%, Ringer's).

Should be taken with food. When administering to patients on nasogastric or other enteral feeds, do not administer feeds 2 hr before or after a dose. Be consistent throughout therapy in relation to feed times. Do not switch dosage forms/brands w/o prior consideration.

Side Effects

Drowsiness is the most common side effect. Less common side effects are CNS depression, nervousness, agitation, psychiatric disturbance, lethargy, mental depression, ataxia, nightmares, bradycardia, apnea, nausea, vomiting, constipation, restlessness and confusion in the elderly and hyperkinesia in children.

Hypersensitivity, lack of appetite, headache, dizziness, tremor, transient nervousness, insomnia, GI disturbances (e.g. nausea, vomiting, constipation), tenderness and hyperplasia of the gums, acne, hirsutism, coarsening of the facial features, rashes, osteomalacia. Phenytoin toxicity as manifested as a syndrome of cerebellar, vestibular, ocular effects, notably nystagmus, diplopia, slurred speech, and ataxia; also with mental confusion, dyskinesias, exacerbations of seizure frequency, hyperglycaemia. Solutions for inj may cause local irritation or phlebitis. Prolonged use may produce subtle effects on mental function and cognition, especially in children.

Toxicity

CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.

The experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism. Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.

Phenytoin toxicity most often affects the cardiovascular and nervous systems. The most common presentation of toxicity depends on the route of administration. Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.

Neurotoxicity is usually dependent on serum concentrations. When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L. At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported. In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.

Phenytoin is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels. Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant. The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.

Treatment for phenytoin toxicity is non-specific and centres around supportive care. One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.

Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.

Precaution

Phenobarbital is potentially habit forming if taken over an extended period of time. When being prescribed to overcome insomnia, the drug should not be used for a period longer than two weeks. Caution should be taken in patients who are mentally depressed, have hepatic damage, suicidal tendencies or a history of drug abuse.

Cardiovascular disease, e.g. sinus bradycardia, heart blocks; DM; hepatic impairment; hypoalbuminemia; porphyria; seizures (may increase frequency of petit mal seizures); debilitated patients; elderly. Caution in IV admin in hypotension, heart failure or MI, monitor BP and ECG during therapy. IV must be given slowly (too rapid admin may cause hypotension, CNS depression, cardiac arrhythmias and impaired heart conduction). Extravasation and intra-arterial admin must be avoided. Do not discontinue abruptly (may increase seizure frequency), unless safety concerns require a more rapid withdrawal. May impair ability to drive or operate machinery.

Interaction

Phenobarbital can interact with a number of prescription and nonprescription medications including acetaminophen, anticoagulants such as warfarin, chloramphenicol, monoamine oxidase inhibitors (MAOIs), antidepressants, asthma medicine, cold medicine, anti-allergy medicine, sedatives, steroids, tranquilizers, and vitamins. Interactions with these medications can increase the drowsiness caused by phenobarbital.

Effects with other sedative drugs or ethanol may be potentiated. Enhances toxic effects of paracetamol, lithium. Increased risk of osteomalacia with acetazolamide. Decreased serum levels/effects with acyclovir, antineoplastics, benzodiazeines, ciprofloxacin, CYP2C9 inducers (e.g. carbamazepine), CYP2C19 inducers (e.g. rifampin), folic acid, vigabatrin. Increased serum concentrations with allopurinol, capecitabine, cimetidine, CYP2C9 inhibitors (e.g. fluconazole), CYP2C19 inhibitors (e.g. delavirdine), disulfiram, methylphenidate, metronidazole, omeprazole, SSRI, trazodone, trimethoprim. Increases metabolism of antiarrhythmics, anticonvulsants, antipsychotics, beta-blockers, calcium channel blockers, chloramphenicol, corticosteroids, doxycycline, oestrogens, HMG-CoA reductase inhibitors, methadone, theophylline, TCAs. Decreases levels/effects of clozapine, ciclosporin, tacrolimus, CYP2B6 substrates (e.g. bupropion, selegiline), CYP2C8 substrates (e.g. amiodarone), CYP2C9 substrates (e.g. celecoxib), CYP2C19 substrates (e.g. citalopram), CYP3A4 substrates (e.g. benzodiazepines), digoxin, itraconazole, levodopa, neuromuscular-blocking agents, thyroid hormones, topiramate. Increases levels/effect of dopamine, ticlopidine. Valproic acid may displace phenytoin from binding sites; and affect phenytoin serum concentrations. Transiently increases the hypothrombinaemia response to warfarin initially, followed by an inhibition of the response.

Volume of Distribution

The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.

Elimination Route

Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing. Phenytoin is completely absorbed. Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively. It should be noted that absorption can be markedly prolonged in situations of acute ingestion.

Half Life

53 to 118 hours (mean 79 hours)

Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average.

Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.

Clearance

The clearance of phenytoin is non-linear. At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics. As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.

Elimination Route

The majority of phenytoin is excreted as inactive metabolites in the bile. An estimated 1-5% of phenytoin is eliminated unchanged in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category D. Phenobarbital can cause potential fetal damage. Their use in pregnancy alone, or in combination with other anticonvulsants, can cause coagulation defects in the newborn infant which may be preventable by the prophylactic administration of Vitamin K to the mother prior to delivery. Phenobarbital is excreted through human milk; so caution should be taken during lactation period.

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Phenobarbital is contraindicated in patients with acute intermittent porphyria and who have a natural or idiosyncrasy to barbiturates

Phenytoin Sodium is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.
• A history of prior acute hepatotoxicity attributable to phenytoin
• Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Special Warning

Debilitated patient: Reduce dose

Renal Impairment: Reduce dose. Severe: Contraindicated

Hepatic Impairment: Reduce dose. Severe: Contraindicated

Pediatric Use: A loading dose of 15 to 20 mg/kg of Phenytoin intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower

Geriatric Use: Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required

Renal and Hepatic Impairment Or Hypoalbuminemia: The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Acute Overdose

Phenobarbital should not be used more than the dosage guide line. 1 gm Phenobarbital oral dose may cause serious poisoning and 2 gm may cause even death. Over dosage produces severe, persistent depression. Treatment includes artificial respiration, maintenance of fluid balance and antibiotics to prevent pneumonia. Alkalinisation of the urine and forced diuresis or haemodialysis have been used in cases of severe poisoning.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Storage Condition

Protect from light, store in cool and dry place. Keep out of reach of children.

Intravenous: Store at room temperature of 15-30°C.Oral:

• Tablet/capsule: Store below 30°C. Protect from light and moisture;
• Oral suspension: Store at room temperature of 20-25°C, do not freeze, protect from light.

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