Antiepileptic Medications(1) PDF

ANTIEPILEPTIC DRUGS Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Objectives Review the pharmacology of the anti-epileptic medications Review the anesthetic considerations for patients receiving anti-epileptic medications Review the anesthetic implicatio...

ANTIEPILEPTIC DRUGS Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Objectives Review the pharmacology of the anti-epileptic medications Review the anesthetic considerations for patients receiving anti-epileptic medications Review the anesthetic implications for the administration of certain anti-epileptic medications in the operative setting 2 Status Epilepticus Is any seizure that lasts more than 30 minutes of either continuous seizure activity OR two or more sequential seizures without full recovery of consciousness between seizures Can effect ventilation When seizures lasts more than 30 to 60 minutes, CNS damage may result Status epilepticus is considered a neurologic emergency that requires prompt treatment to prevent permanent neurologic damage. As in stroke, the saying “time is brain” is true in status epilepticus Give a fast-acting medication to stop the seizure immediately and then follow with a longer acting agent to prevent recurrence 3 Status Epilepticus (cont.) Status epilepticus INITIAL therapy of choice Lorazepam IV – Drug of choice Diazepam IV Midazolam IM Status epilepticus SECOND therapy of choice Fosphenytoin or Phenytoin IV Valproic Acid IV Levetiracetam IV NOTE: Neuromuscular Blocking agents DO NOT stop seizures - they only stop the muscular response to the brain’s electrical activity 4 AEDs & Drug Interactions Chronic anticonvulsant therapy Patients taking chronic anticonvulsant therapy are resistant to nondepolarizing neuromuscular blockers such as rocuronium (Infusion rate of rocuronium may have to be increased) No effect on atracurium, mivacurium, and cisatracurium Patients being treated with AEDs have increased dose requirements for thiopental, propofol, midazolam, and opioids AEDs have numerous drug-drug interactions since most AEDs are highly metabolized in the liver and interactions occur with other drugs that are liver enzyme inhibitors and inducers AEDs can either increase or decrease the serum concentrations of other AEDs or non-AED medications ie: Phenytoin decreases serum carbamazepine, lamotrigine, oxcarbazepine but increases phenobarbital serum concentrations 5 AEDs & Drug Interactions (cont.) Chronic anticonvulsant therapy (cont.) For those AED agents that are highly protein bound (primarily to albumin), displacement from binding sites by other highly protein bound drugs can occur and lead to increased plasma concentrations of the AED medication Hypoalbuminemia as may accompany renal or hepatic disease, malnutrition, or pregnancy can result in increased plasma concentrations of unbound AEDs, resulting in toxicity Most older/traditional anticonvulsant medications enhance the metabolism of oral contraceptives (increase the risk of unexpected pregnancy), where as newer agents have less of a risk with this interaction Acute administration of phenytoin Prolongs non-depolarizing neuromuscular blockers 6 AEDs: Class Side Effects Adverse effects from AEDs can be either dose-related or non- dose related Dose-related Sedation/somnolence, fatigue, nausea, lethargy, dizziness, ataxia, gait disturbances Non-dose related Leukopenia, hepatitis, pancreatitis, hepatic failure, aplastic anemia, coagulopathy, cardiotoxicity, hypothyroidism Dermatologic Rash that can progress to stevens-johnson syndrome (SJS), toxic epidermal necrolysis (TEN) Multiorgan hypersensitivity reactions (also called Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) 7 AEDs: Mechanism of Action Antiepileptic drugs (AEDs) exert their anticonvulsant activity by the following proposed general mechanisms: 1. Inactivate either voltage-gated Na+ or voltage-gated Ca++ currents via blockade. Some AEDs can inactive both currents 2. Enhance GABA-mediated neuronal inhibition synaptic activity GABA (g-aminobutyric acid) modulators/enhancers GABA (g-aminobutyric acid) re-uptake inhibitors GABA (g-aminobutyric acid) transaminase inhibitors 3. Decrease glutamate (excitatory neurotransmitter) synaptic activity NMDA (N-methyl-D-aspartate) receptor antagonists AMPA/kainate receptor antagonist 4. Inhibition of brain carbonic anhydrase enzyme Some agents act through a combination of these mechanisms 8 AEDs: Mechanism of Action (cont.) Anti-seizure drug-enhanced Na+ channel inactivation: Some anti-seizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate (1). A, activation gate 9 AEDs: Mechanism of Action (cont.) Enhanced GABA synaptic transmission In the presence of GABA, the GABA-A receptor is opened, allowing an influx of chloride, which in turn increases membrane polarization Some anti-seizure drugs act by reducing the metabolism of GABA while others act at the GABA-A receptor enhancing chloride influx in response to GABA 10 AEDs & Pregnancy AEDs can cause teratogenic effects Neural tube defects such as spina bifida can occur, cleft lip & palate Phenobarbital, phenytoin, carbamazepine, valproic acid increase the incidence of congenital malformations Valproic acid (VPA) is generally considered to have the highest incidence of teratogenic malformations of all AEDs. VPA is the agent to always avoid in pregnancy during the first trimester Most newer agents are pregnancy category C since there have been insufficient data on their teratogenic effects 11 Antiepileptic Agents (AED’s) 12 AED Classification AED medications are categorized as either traditional first generation agents or the newer second generation agents First generation agents (Traditional AEDs) Phenobarbital, primidone, phenytoin, valproate, carbamazepine and ethosuximide Second generation agents (Newer agents) Felbamate, gabapentin, lamotrigine, topiramate, tiagabine, zonisamide, levetiracetam, oxcarbazepine, pregabalin, lacosamide, rufinamide, vigabatrin, ezogabine, perampanel, eslicarbazepine, and brivaracetam 13 Benzodiazepines Benzodiazepines display anxiolytic, sedative, muscle-relaxant, and anticonvulsant effects Mechanism of action Potentiate GABA-mediated neuronal inhibition by binding to the benzodiazepine receptor site on GABAA receptors, which increases the frequency of GABA-mediated ion channel opening and increases chloride permeability and thereby leads to cellular hyperpolarization and inhibition of neuronal firing 14 Benzodiazepines (cont.) Diazepam Useful for treatment of status epilepticus Has a rapid onset and short duration of action Has a faster onset but has a shorter duration of action than lorazepam since diazepam is more lipophilic (gets in and out of the CNS faster than lorazepam) Metabolized in the liver to several active metabolites 15 Benzodiazepines (cont.) Lorazepam Drug of choice for treatment of status epilepticus Has a rapid onset but has a longer duration of action than diazepam (is less lipophilic than diazepam, therefore, it does not redistribute from the CNS as quickly as diazepam) Has a shorter elimination half-life but a longer duration of antiepileptic action than diazepam Metabolized in the liver but does not have active metabolites 16 Phenytoin (Dilantin®) Hydantoin class anti-epileptic agent Available in both ORAL and IV formulations Mechanism of action Fast Na+ Channel Blocker Regulates neuronal excitability and prevents the spread of seizure activity from a seizure focus by regulating Na+ across neuronal membranes. The effect is mediated by a slowing of the rate of recovery of the Na+ channel Associated with use-dependent blockade of Na+ channels Pharmacological effects Exerts anti-seizure activity without causing general depression of the CNS (usually not associated with excessive sedation) In toxic cases, it may produce excitatory CNS signs & symptoms 17 Phenytoin (Dilantin®) Clinical uses Effective against all types of partial & generalized tonic-clonic seizures Prevention and treatment of seizures occurring during neurosurgery or following head trauma Also can be used for ventricular fibrillation or treatment of cardiac arrhythmia from digoxin toxicity Remember, phenytoin is a class Ib anti-arrhythmic agent 18 Phenytoin (Dilantin®): Pharmacokinetics Displays variable oral absorption from the GI system based on the type of oral dosage form being used Is a weak acid drug (pKa 8.3) & maintained in an aqueous solution as a Na+ salt Protein Binding: >90% protein bound Primarily bound to albumin A greater fraction remains unbound (free concentration) in neonates, uremic patients and patients with hypoalbuminemia Plasma t1/2: 6-24 hours but the t1/2 increases when phenytoin’s plasma concentration becomes > 10 mcg/mL 19 Phenytoin (Dilantin®): Pharmacokinetics (cont.) Metabolism: Liver via several CYP 450 enzyme systems to inactive metabolites with plasma concentrations < 10 mcg/mL, phenytoin follows linear pharmacokinetics with plasma concentrations > 10 mcg/mL, the enzymes necessary for metabolism of phenytoin become saturated and the half-life becomes dose-dependent and elimination follows non-linear pharmacokinetics (zero-order kinetics) Exhibits saturable metabolism OR Michaelis-Menten pharmacokinetics (a type of non-linear pharmacokinetics) Excretion Only ~2% of unchanged phenytoin appears in the urine 20 Phenytoin (Dilantin®): Plasma Concentrations Control of seizures is usually obtained with total plasma concentrations of 10-20 mcg/mL (Free concentration: 1-2 mcg/mL) Several adverse effects of phenytoin correlate with phenytoin’s plasma concentrations, meaning the higher the plasma concentration the greater the risk of certain dose-related adverse effects 21 Phenytoin (Dilantin®): Drug Interactions Phenytoin is an potent enzyme inducer!!!!!!!!!!!!! Has multiple drug-drug interactions where by phenytoin can alter the plasma concentrations of many other drugs via enzyme induction Since phenytoin is metabolized by CYP 450 enzymes, administering phenytoin with CYP 450 inducers or inhibitors will alter phenytoin’s plasma CYP 450 inducers will decrease phenytoin’s plasma concentrations CYP 450 inhibitors will increase phenytoin’s plasma concentrations Phenytoin is a highly protein bound drug to albumin. Administering other drugs that are bound to albumin will increase phenytoin’s free, unbound concentration and potentially increase the risk of toxicity 22 Phenytoin (Dilantin®): Dosing & Administration Loading dose Status epilepticus: 16-20 mg/kg IV total body weight Administration recommendations Avoid IM injections – painful, precipitates at injection site & erratic absorption IV infusion rate should NEVER exceed 50 mg/min Why? The propylene glycol diluent in the phenytoin injection dosage formulation is a known cardiac depressant and can cause severe hypotension, bradycardia and other cardiac arrhythmias if infused too fast! Watch drug-drug compatibility interaction so precipitation does not occur AVOID dextrose solutions Phenytoin precipitates in solutions with pH < 7.8 23 Phenytoin (Dilantin®): Adverse Effects Dose-related Nystagmus, diplopia (>20 mcg/mL) Vertigo (>20 mcg/mL) Ataxia (>20 mcg/mL) Drowsiness Cognitive impairment/mental changes Infusion related Hypotension Bradycardia Cardiac arrhythmias 24 Phenytoin (Dilantin®): Adverse Effects (cont.) Non-dose related GI disturbances such as nausea and vomiting Peripheral neuropathy, gingival hyperplasia Hypertrichosis Hirsutism Acne Rash – that can progress to toxic epidermal necrolysis (TEN), stevens-johnson syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Increase in serum glucose Hepatotoxicity (rare) Fetal-abnormalities – wide-set eyes, broad mandible, finger abnormalities (Fetal Hydantoin Syndrome) 25 Fosphenytoin (Cerebyx®) Fosphenytoin is a water-soluble prodrug of phenytoin Only available via injectable formulation 26 Fosphenytoin (Cerebyx®) Absorption Maximum concentrations achieved after/at the end of IV infusion IM administration – peak concentrations ~30 min post dose Protein binding >90%, primarily bound to albumin Metabolism/Elimination Phenytoin is cleaved from fosphenytoin by phosphatase enzymes in the liver and red blood cells Complete conversion occurs in ~2 hours after IV administration No drugs are known to interfere with the metabolic conversion of fosphenytoin into phenytoin 27 Fosphenytoin (Cerebyx®): Advantages over Phenytoin The ability to administer the fosphenytoin intramuscularly and in either NS or D5W The ability to administer intravenously more rapidly Less risk of hypotension and cardiac arrhythmias with rapid IV loading Less phlebitis & local tissue damage at injection site Less frequent need to re-start IV lines due to local irritation Elimination of the need to administer with an IV filter 28 Fosphenytoin (Cerebyx®): Dosing/Monitoring Loading Dose 15-20 mg phenytoin equivalents (PE)/kg: Treatment of status epilepticus Parenteral substitution of fosphenytoin for oral phenytoin is administered as the same total daily dose Because of the risk of hypotension, administer fosphenytoin NO FASTER THAN 150 mg PE/min 29 Carbamazepine (Tegretol®) Is structurally related chemically to the tricyclic antidepressants Only available as an ORAL agent Pharmacologic effects Similar to those of phenytoin but the 2 drugs have very important differences Produces therapeutic response in manic-depressive patients Has an anti-diuretic effect that is sometimes associated with increased concentrations of ADH in the plasma 30 Carbamazepine (Tegretol®) Mechanism of action Fast Na+ Channel Blocker Regulates neuronal excitability and prevents the spread of seizure activity from a seizure focus by regulating Na+ across neuronal membranes (membrane-stabilizing effect similar to phenytoin) Has an active metabolite (10,11-epoxycarbamzepine) which has similar anti-seizure effects Clinical uses Useful in general tonic-clonic and both simple and complex partial seizures (similar to phenytoin) Trigeminal neuralgia and other neuralgias Manic-Depressive disorder 31 Carbamazepine (Tegretol®): Pharmacokinetics Protein Binding: 80% Metabolism: Liver via multiple CYP 450 enzyme systems Auto-Inducer: Carbamazepine induces it’s own metabolism May result in dose increases weeks after starting carbamazepine Metabolized by the liver to an active metabolite (10,11epoxycarbamzepine), which is then further metabolized into inactive metabolites & excreted via the urine Plasma t1/2 : 12-17 hours Excretion: Active metabolite in the urine Drug-Drug interactions Carbamazepine is a strong enzyme inducer of CYP 450 and non CYP 450 liver enzymes Increases metabolism of oral contraceptives, phenytoin and many other drugs that require those enzymes for metabolism 32 Carbamazepine (Tegretol®): Adverse Effects Most common Drowsiness/sedation, vertigo, diplopia, nausea/vomiting Others Blurred vision Ataxia Congenital malformations such as neural tube defects Syndrome of inappropriate anti-diuretic hormone causes water retention and hyponatremia Rash – can progress to Steven’s Johnson Syndrome Hematologic Aplastic anemia, agranulocytosis, thrombocytopenia, leukopenia 33 Phenytoin and Carbamazepine: Nondepolarizing Neuromuscular Blocker Drug Interaction Nondepolarizing neuromuscular-blocking agents such as vecuronium and rocuronium may have resistance occur in patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin When vecuronium or rocuronium are administered to patients who are receiving either phenytoin or carbamazepine, shorter durations of neuromuscular blockade may occur, and infusion rates may be higher due to the development of resistance to the nondepolarizing neuromuscular blocking agent Higher dosage requirements for vecuronium and rocuronium are required Potential resistance mechanism: receptor up-regulation of skeletal muscle acetylcholine receptors or hepatic enzymes are induced & it is likely that metabolism & elimination of the nondepolarizing neuromuscular-blocking agents are increased 34 Phenobarbital Is a long-acting barbiturate that is effective against all seizure types except nonconvulsive primary generalized seizures The first effective organic anti-seizure medication Relatively low toxicity, low cost and is a very effective and widely used agent Exerts maximal anti-seizure action at doses BELOW those required for hypnosis Has a slow onset and very long duration (long-acting agent) Mechanism of action Binds to GABAA receptors via the barbiturate binding site and increases GABA (g-aminobutyric acid)-mediated chloride influx Prolongs the opening of chloride channels, which increases chloride influx, which in turn increases membrane polarization (causes hyperpolarization) 35 Phenobarbital: Pharmacokinetics Oral absorption is slow and complete Protein binding: 40-60% Metabolism: Liver via multiple CYP 450 enzyme systems No active metabolites t1/2 = 80-100 hours (LONG!) Elimination: 25% excreted unchanged via kidneys, with the remainder inactivated by hepatic microsomal enzymes Phenobarbital is also an enzyme inducer of several CYP 450 enzymes and UGT enzyme system Increases metabolism of oral contraceptives and many other drugs that require these enzymes for metabolism Phenobarbital can either increase or decrease phenytoin serum concentrations Numerous drug-drug interactions 36 Phenobarbital: Adverse Effects Dose-related Sedation – the most frequent undesired side effect of phenobarbital. Tolerance can develop with chronic administration Nystagmus, ataxia, cognitive impairment such as slowed mentation, respiratory depression Non-dose related Rash Irritability and hyperactivity Phenobarbital may cause major fetal malformations 37 Primidone (Mysoline®) Primidone is an oral only anti-epileptic drug Primidone is metabolized into 2 active metabolites, phenobarbital and phenylethylmalonamide (PEMA) Primidone acts similar to phenobarbital The most frequently occurring early side effects are vertigo, ataxia and sedation 38 Ethosuximide (Zarontin®) Succinimide class anti-epileptic drug only available in oral dosage form Pharmacokinetics: Bioavailability: 100% Protein binding: 0% Metabolism: Liver via hepatic microsomal enzymes t1/2 = 52-60 hours Excretion: 25% unchanged in urine Mechanism of action T-type Ca2+ channel blocker in thalamic neurons 39 Ethosuximide & T-type Ca2+ Channel Reducing the flow of Ca2+ through T-type Ca2+ channels reduces the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures 40 Ethosuximide (Zarontin®) Adverse effects Most common dose-related: GI – nausea, vomiting, anorexia CNS – drowsiness, lethargy, euphoria, dizziness, headache, hiccups, photophobia Bone marrow suppression is serious but extremely rare side effect Clinical use: Absence Seizures ONLY – is the drug of choice 41 Valproate Sodium or Valproic Acid A non-selective anti-seizure medication used for various types of seizures Is very different compared with other types of anti-epileptic agents such as phenytoin, ethosuximide, carbamazepine in that it is effective in inhibiting a wide variety of seizures (broadspectrum agent) Available as capsules, enteric-coated tablets, syrup, IV formulations Valproic Acid – Oral agent Divalproex Sodium – Oral agent Valproate Sodium – IV agent 42 Valproate Sodium or Valproic Acid Mechanism of action Fast Na+ Channel Blocker T-type Ca2+ channel blocker Increases the amount of GABA production by stimulating GABA synthesis and also inhibiting GABA metabolism 43 Valproate Sodium or Valproic Acid: Clinical Uses Very effective against absence, myoclonic, atonic, infantile spasms seizures, generalized tonic-clonic seizures Is a first-line agent in all these types of seizures Second-line for status epilepticus and focal seizures Less effective as compared to carbamazepine for partial seizures Treatment of mania associated with bipolar disorder Prophylaxis of migraine headaches 44 Valproate Sodium or Valproic Acid: Pharmacokinetics Absorption is rapid and complete VPA is a GI irritant (enteric coated dosage forms helps decrease GI side effects) Protein binding: ~95% (High) t1/2 = 8-17 hours Metabolism Undergoes extensive hepatic metabolism mainly by hepatic UGT enzymes but also undergoes minor CYP 450 metabolism Several active metabolites exist Excretion: < 5% as unchanged drug in urine 45 Valproate Sodium or Valproic Acid Valproic acid has numerous drug-drug interactions VPA is highly protein bound so it interacts with other highly protein bound drugs VPA can displace phenytoin and diazepam from protein-binding sites and increase these drugs free, unbound concentrations VPA is a strong enzyme inhibitor of both UGT and several CYP 450 enzyme systems and will inhibit the metabolism of other antiepileptic drugs such as carbamazepine, phenytoin, phenobarbital and topiramate Question: What will happen to the plasma concentrations of these medications OR any other medication metabolized by these enzymes? VPA is extensively metabolized in the liver and numerous drugs can either inhibit and induce VPA’s metabolism 46 Valproate Sodium or Valproic Acid: Adverse Effects Dose-related GI – Nausea, vomiting, abdominal pain Weight gain (chronic therapy), alopecia CNS – Sedation/drowsiness, fine distal tremor, ataxia Neural tube defects such as spina bifida VPA is contraindicated in pregnancy Non-dose related Rash, thrombocytopenia, aplastic anemia Hepatotoxicity – has been fatal Increased hepatic transaminases Requires liver function test monitoring Pancreatitis – has been fatal 47 Oxcarbazepine (Trileptal®) Is a keto analog of carbamazepine Is a prodrug agent (It is NOT a prodrug of carbamazepine) that is primarily converted to its pharmacologically active 10monohydroxy metabolite (MHD). MHD is then further metabolized and inactivated by glucuronide conjugation and renally eliminated Oxcarbazepine has no anti-seizure activity itself Only available as an ORAL agent Mechanism of action Fast Na+ Channel blocker Useful in the management of partial and generalized tonic- clonic seizures 48 Oxcarbazepine (Trileptal®): Pharmacokinetics Protein binding: ~40% Metabolism Occurs in the liver via UGT (uridine diphosphateglucuronosyltransferase) enzyme, which is a non-CYP 450 enzyme DOES NOT undergo auto-induction like carbamazepine Excretion Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys Oxcarbazepine is an enzyme inducer of CYP 3A4/5 and UGT enzyme systems Oxcarbazepine is also an enzyme inhibitor of some CYP 450 enzymes 49 Oxcarbazepine (Trileptal®): Adverse Effects Most common Sedation/somnolence, dizziness, headache, nausea, vertigo Others Hyponatremia (SIADH) can occur and is MORE COMMON compared with carbamazepine Blood dyscrasias less common than with carbamazepine Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) can occur Cross-reactivity: 25-30% of patient’s with hypersensitivity to carbamazepine will have hypersensitivity to oxcarbazepine 50 Lamotrigine (Lamictal®) Is effective against a broader spectrum of seizures compared with phenytoin and carbamazepine Mechanism of action Exact mechanism is not yet well understood Decreases presynaptic release of excitatory amino acids (i.e.: glutamate and aspartate) via inhibiting voltage-sensitive Na+ channels Oral only agent Clinical uses Monotherapy in partial seizures or add-on in partial or primarily generalized seizures and used in Lennox-Gastaut seizures Bipolar I Disorder 51 Lamotrigine (Lamictal®) Pharmacokinetics Protein binding: 55% Plasma t1/2 = 25.4 hours Metabolism: Liver but via UGT enzyme No active metabolite Excreted: 10% unchanged in urine Drug-Drug Interactions Lamotrigine is not an inhibitor or inducer of CYP 450 – advantage to this drug Valproic acid decreases lamotrigine’s metabolism and increases its serum concentration and half-life Carbamazepine, phenytoin, primidone, phenobarbital all induce lamotrigine’s metabolism and decrease its serum concentrations (as much as 40%) 52 Lamotrigine (Lamictal®): Rash Adverse Reaction Rash is the most serious potential adverse effect from lamotrigine Can be severe and life-threatening Rashes include Stevens-Johnson Syndrome Toxic Epidermal Necrolysis (TEN) 53 Lamotrigine (Lamictal®) Other Adverse Effects Most common: Headaches, dizziness, nausea, vomiting, diplopia, ataxia, and somnolence Tremor at high doses Fatal or life-threatening hypersensitivity reactions can occur Multiorgan hypersensitivity reactions, aka: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) can occur Blood dyscrasias: neutropenia, thrombocytopenia, pancytopenia can occur but are rare 54 Levetiracetam (Keppra®) A racemically pure S-isomer compound that belongs to the “racetam” drug class Available as both IV and oral dosage forms Mechanism of action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. It is suggested that levetiracetam binds to the synaptic vesicle protein SV2A and this may mediate the anticonvulsant activity of levetiracetam Clinical uses Adjunctive therapy in the treatment of partial onset seizures, myoclonic seizures, primary generalized seizures Can be used for status epilepticus but is NEVER the drug of choice 55 Levetiracetam (Keppra®) Pharmacokinetics Has a very favorable pharmacokinetic profile Completely absorbed and is 100% bioavailable Protein Binding: