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Clinical Pharmacokinetics of PHENYTOIN & OTHER ANTIEPILEPTICS

Oct 22, 2014

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Clinical Pharmacokinetics of PHENYTOIN & OTHER ANTIEPILEPTICS. Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Faculty of Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur. PHENYTOIN. Primarily used as an anticonvulsant.

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Clinical Pharmacokinetics ofPHENYTOIN & OTHER ANTIEPILEPTICS Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Faculty of Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur

PHENYTOIN • Primarily used as an anticonvulsant. • Occasionally used in the treatment of certain types of cardiac arrhythmias. • Two major problems: • Binding of PHT to plasma protein is decreased in patients with renal failure or hypoalbuminemia. • The metabolic capacity for PHT is limited

ADVERSE DRUG REACTION • Gingival hyperplasia • Folate deficiency • Peripheral neuropathy • Far-lateral nystagmus (>20mg/L) • Ataxia (>30mg/L) • Diminished mental capacity (>40mg/L) • Encephalopathy

PHARMACOKINETIC CHARACTERISTICS • Bioavailability • Completely absorbed F = 1.0. • Injectable/Capsule consist of the sodium salt (S = 0.92). • Chewable tablet and suspension contain the acid form (S = 1.0). • PO: Peak concentration time at 3 to 12 hours. • Insoluble in water, slow absorption. • Bioavailability reduced: • Rapid gastrointestinal transit times. • Receiving liquid dietary supplement (NG feeding)

PHARMACOKINETIC CHARACTERISTICS (CONT’) • Distribution • Approximately 90% of PHT bound to serum albumin • 10% is unbound and free to equilibrate with the tissues • Metabolism • Rate of metabolism (and/or excretion) is proportional to the plasma concentration. Concentration t½ (hours) 1 12.8 10 25.8 20 40.2 40 69.0

PHARMACOKINETIC CHARACTERISTICS (CONT’) • Drug interactions • Interaction with valproic acid (displacement and inhibition of CYP450) • Phenytoin displaced from binding sites. • Reduced (~50%) total concentration. • Increased (9.6 – 15.5%) of the unbound PHT.

KEY PARAMETERS • Target concentration 10 – 20 mg/L • F 1.0 • S 0.92 • Vd 0.65 L/kg of body wt • CL - Vmax 7.2 mg/kg/day - Km 4.4 mg/L

HYPOALBUMINEMIA CORRECTION • Hypoalbumin only: Cpnormal = Cppatient . 0.9 (Albpatient/4.4) + 0.1 • Hypoalbumin with renal failure: Cpnormal = Cppatient . 0.48(0.9)(Albpatient/4.4) + 0.1 *Albpatient in g/dL

INITIATING/ADJUSTINGPHENYTOIN DOSAGE REGIMEN • Michaelis-Menten Kinetics Dose = VmaxCave . (Km + Cave) SF (mg/kg QH) Ro = VmaxCp . Km + Cp(mg/kg/day) where: Vmax = maximum rate of metabolism (mg/kg/day) Km = constant (mg/L)

Orbit Graph Ro, Vm 14 12 10 8 6 4 2 Cp Km 24 20 16 12 8 4 0 4 8 12 16

Phenytoin Nomogram

INITIATING PHT REGIMEN(USING EQUATION) Ro = VmaxCp . Km + Cp (mg/kg/day) Ro = 7.2 x 15 . 4.4 + 15 = 5.57 mg/kg/day

INITIATING PHT REGIMEN(USING ORBIT GRAPH) Ro, Vm 14 12 10 8 x 6 Ro 4 2 Cptarget Cp x Km 24 20 16 12 8 4 0 4 8 12 16

ADJUSTING PHT DOSAGE REGIMEN(WITH ONE SERUM DRUG LEVEL – EQUATION) Ro = VmaxCp . Km + Cp Vmax* = Rogiven (Kmpop + Cpachieved) Cpachieved Ronew = Vmax*Cptarget . Kmpop + Cptarget (mg/kg/day)

ADJUSTING PHT DOSAGE REGIMEN(WITH ONE SERUM DRUG LEVEL – ORBIT GRAPH) Ro, Vm Example: Ro1 = 5.5, Cp1 = 22 mg/L 14 12 10 8 6 x 4 2 x Cp Km 24 20 16 12 8 4 0 4 8 12 16

ADJUSTING PHT DOSAGE REGIMEN(WITH ONE SERUM DRUG LEVEL – ORBIT GRAPH) Ro, Vm Example: Ro1 = 5.5, Cp1 = 22 mg/L 14 12 10 8 x 6 x 4 Ronew 2 x x Cp Km 24 20 16 12 8 4 0 4 8 12 16

ADJUSTING PHT DOSAGE REGIMEN(WITH ONE SERUM DRUG LEVEL – NOMOGRAM) Example: Wt = 70 kg Ro1 = 5.5 Dgiven = 390 mg/D Cp1 = 28 mg/L x x x x Dnew

ADJUSTING PHT DOSAGE REGIMEN(WITH TWO SERUM DRUG LEVELS – EQUATION) Ro1 = VmaxCp1 . Km + Cp1 Ro2 = VmaxCp2 . Km + Cp2 Ronew = Vmax* x Cptarget . Km* + Cptarget

ADJUSTING PHT DOSAGE REGIMEN(WITH TWO SERUM DRUG LEVELS – ORBIT GRAPH) Ro, Vm Example: Ro1 = 5.5 C1 = 8 mg/L Ro2 = 6.4 C2 = 24 mg/L 14 12 10 Ronew 8 x x 6 x 4 2 x x x Cp Km 24 20 16 12 8 4 0 4 8 12 16

OTHER ANTIEPILEPTICSVALPROIC ACID • Pharmacokinetic Characteristics • Many formulation • Diurnal variation in absorption: night times AUC for enteric coated tablet was 32% lower than day times AUC. • CLVPA increase by CBZ, PHB, PHT and PRI. • Metabolized to active metabolite: 4-ene VPA • Protein binding 90 – 95%

VALPROIC ACID (CONT’) • Key Parameters • Target concentration 50 – 100 mg/L • F 1.0 • S 1.0 • Vd~0.2 L/kg • CL - Children 13 ml/kg/H - Adults 8 ml/kg/H • t½ - Children 6 – 8 H - Adults 10 – 12 H

VALPROIC ACID (CONT’) • Dose Requirement: • Maintenance Dose Adults 10 – 45 mg/kg/day PO Children 10 – 60 mg/kg/day PO • Toxic Effects • Gastric irritation, nausea, vomiting • Weight gain • Sedation, stupor, tremor • Thrombocytopenia • Hepatotoxicity, pancreatitis • Hyperammonemia

OTHER ANTIEPILEPTICSCARBAMAZEPINE • Insoluble in water. • Humidity will reduced dissolution. • Autoinduction is concentration dependent: increase DM and CL of unbound drug. Time t½ (H) After initial dose ~35 After 3 – 4 weeks ~12

CARBAMAZEPINE (CONT’) • Pharmacokinetic Characteristics • Metabolized to active metabolite: CBZ epoxide • Drug interaction: CYP450 inhibitors eg. Erythromycin, Fluoxetine, Propoxyphene, VPA and Verapamil. • Bound to -acid glycoprotein. • 1% excreted unchanged in the urine.

CARBAMAZEPINE (CONT’) • Key Parameters • Target concentration 4 – 12 mg/L • F 0.8 • S 1.0 • Vd 1.4 L/kg • CL - Monotherapy 0.064 L/kg/H - Polytherapy 0.1 L/kg/H • t½ - Monotherapy 15 H - Polytherapy 10 H

CARBAMAZEPINE (CONT’) • Dose Requirement: • Anticonvulsant Adults 5 – 25 mg/kg/day PO Children 5 – 30 mg/kg/day PO • Trigeminal neuralgia Adults 3 – 20 mg/kg/day PO • Toxic Effects • Diplopia • Hyponatremia, water intoxication • Seizures • Arrhythmias

DOSE ADJUSTMENT FOR VAPROIC ACID AND CARBAMAZEPINE Cave = D . Ke Vd  = D . CL 

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Continuing Education Activity

Phenytoin is a medication used in the management and treatment of epilepsy, generalized tonic-clonic seizures, complex partial seizures, and status epilepticus. It is in the anticonvulsants class of drugs. This activity describes the indications, action, and contraindications for phenytoin as a valuable agent in the treatment of epilepsy.

Outline the mechanism of action of phenytoin for the proper treatment of seizure disorders.
Explain the adverse effects and outline the contraindications of phenytoin therapy.
Identify the appropriate methods for therapeutic drug monitoring and select the course of action for phenytoin toxicity.
Describe some inter-professional team strategies for improving care coordination and communication to advance phenytoin therapy and improve outcomes.
Indications

The FDA approved phenytoin in 1939 for the treatment of epilepsy. Despite its narrow therapeutic index, the drug has seen robust use in the treatment of generalized tonic-clonic seizures, complex partial seizures, status epilepticus, trigeminal neuralgia, and behavior disorders.

The drug had previously been used as an anti-arrhythmic and treatment of digoxin toxicity and tricyclic antidepressant toxicity but is now obsolete in these settings. [1]

Mechanism of Action

Phenytoin is a hydantoin derivative, a first-generation anti-convulsant drug that is effective in the treatment of generalized tonic-clonic seizures, complex partial seizures, and status epilepticus without significantly impairing neurological function.

Phenytoin works by blockade of voltage-dependent membrane sodium channels responsible for increasing the action potential. This action obstructs the positive feedback that sustains high-frequency repetitive firing, thus preventing the spread of the seizure focal point. [2] [3] [4]

Administration

Phenytoin is available in oral and parenteral formulations. Intramuscular administration is not recommended due to its erratic absorption and local reaction. The drug is slowly administered intravenously directly into a large central or peripheral vein through an IV catheter less than 20 gauge, not exceeding a rate of 50 mg/minute. It requires dilution with sodium chloride. Crystals will form when diluted with a dextrose solution.

Due to its poor solubility, parenteral phenytoin is available in a solution of propylene glycol and alcohol, which are responsible for some of the adverse effects of its intravenous administration. Fosphenytoin underwent development as a water-soluble prodrug of phenytoin, devoid of these compounds, which is only available in an injection formulation and may be administered intravenously or intramuscularly. [1] [5]

Adverse Effects

Adverse effects potentially include the following:

Sedation
Peripheral neuropathy [6]
Phenytoin encephalopathy [7]
Locomotor dysfunction
Hyperkinesia
Megaloblastic anemia
Decreased bone mineral content
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Immunoglobulin A deficiency
Gingival hyperplasia
Dress syndrome (drug reaction accompanied by eosinophilia and systemic symptoms)
Cardiovascular collapse
Hypotension
Arrhythmias
Hydantoin syndrome in newborns
Purple glove syndrome [8]
Hypertrichosis [9]
Contraindications

Hypersensitivity to phenytoin or other hydantoins is a contraindication for using phenytoin. Pregnancy is another absolute contraindication for phenytoin use.

Hanson et al. reported a prevalence of fetal hydantoin syndrome (FHS) of 11% in pregnant women receiving treatment for epilepsy with phenytoin, with an additional 30% of the in utero -exposed children expressing some of the syndrome’s features such as epicanthic folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips and, also, distal digital hypoplasia, intrauterine growth retardation, and diminished mental capacity. [10]

Pharmacokinetics

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 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.

The hepatic P450 enzyme system metabolizes phenytoin (predominantly CYP2C9 and CYP 2C19) to inactive metabolites and is an inducer of CYP3A4, which accounts 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. [1]

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. [1]

Therapeutic drug monitoring of phenytoin is necessary to ensure dosage delivery is at therapeutic levels. The therapeutic range for phenytoin is 10 to 20 mcg/mL.

Knowledge of its pharmacokinetic properties is crucial for the 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 the dosage of phenytoin. However, they have not seen broad implementation in clinical practice due to poor patient outcomes.

A closer investigation of total serum phenytoin and serum albumin ratio by healthcare providers is critical for proper monitoring of phenytoin therapy. [11] [12] [13]

Phenytoin displays its primary signs of toxicity on the nervous and cardiovascular systems. Overdose of 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):

Below 10 mg/L: Rare side effects
10 to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze
20 to 30 mg/L: Nystagmus
30 to 40 mg/L: Ataxia, slurred speech, tremors, nausea, and vomiting
40 to 50 mg/L: Lethargy, confusion, hyperactivity
Over 50 mg/L: Coma and seizures

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. [4]

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. [4]

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 is extensive skin necrosis and limb ischemia, this can lead to amputations. [8]

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. [4]

There is no specific antidote for phenytoin toxicity; supportive care is the hallmark of treatment.

Enhancing Healthcare Team Outcomes

Managing phenytoin overdose requires an interprofessional team of healthcare professionals, including a nurse, laboratory technologists, pharmacists, and 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:

Ordering drug levels in the blood and or urine
Monitor the patient for signs and symptoms of neurological or cardiac toxicity.
Performing various tasks to help limit the absorption of the drug in the body
Consult with the pharmacist about the use of activated charcoal and perform a medication record check [Level 1]
Consult with a toxicologist and nephrologist on further management, which may include dialysis, to assist in the removal of the drug from the system, as well as a board-certified applied toxicology pharmacist as part of the toxicology consult.
Check of ingestion of other substances that the patient could have consumed with the drug
Consult with the intensivist regarding possible placement into the intensive care unit for care and monitoring in the hospital.

The management of phenytoin overdose does not stop in the emergency department. Nurses will continue to provide follow-up 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.

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. [4] [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]

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Disclosure: Mohit Gupta declares no relevant financial relationships with ineligible companies.

Disclosure: Jayson Tripp declares no relevant financial relationships with ineligible companies.

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