Stoletin 13 - Exam 3

Antiepileptic Drugs

• Epilepsy is a common neurologic condition.
• 10% of people will report a seizure in their lifetime.
• 1-2% of the population worldwide meets the criteria for epilepsy.
• Epilepsy is a collective term for chronic CNS disorders.
• Epilepsy is characterized by sudden sensory, motor, autonomic, or psychic disturbances.
• Disturbances are generally transient, except in status epilepticus.
• Disturbances are associated with abnormal electroencephalogram discharges.
• Only 30% of seizure patients have identifiable neurologic or systemic disorders.
• The goal of pharmacologic treatment is to control seizures with minimal medication-related adverse effects.
• 70% of epilepsy patients become seizure-free with a single antiepileptic drug.
• Options for the other 30% include switching drugs, combining drugs, or surgical procedures like vagal nerve stimulation or laser ablation.
• Antiepileptic drug selection is individualized and tailored to the patient.
• Criteria include efficacy, tolerability, safety, ease of use, administration frequency, and pharmacokinetics.
• Drug choices have increased dramatically with fewer side effects.
• Dose-related side effects can limit antiepileptic drug use.
• Side effects are associated with higher plasma concentrations, but toxicity levels vary.

Classification of Epileptic Seizures

• Partial seizures (beginning locally): simple partial (consciousness not impaired), complex partial (consciousness impaired), partial evolving to secondary generalized seizures
• Generalized seizures (convulsive or nonconvulsive): absence (petit mal), myoclonic, clonic, tonic, tonic-clonic
• Unclassified seizures

Pharmacokinetics

• Antiepileptic drugs are administered once daily or more frequently.
• Sustained release and combination preparations are preferred for ease of use and side effect profile.
• Absorption from the gastrointestinal tract is slow and may be incomplete, especially for gabapentin.
• Protein binding varies greatly (0% for gabapentin to over 90% for phenytoin).
• Hepatic and renal disease may necessitate dose adjustment.
• Medications relying on renal excretion (gabapentin, pregabalin, levetiracetam, vigabatrin, zonisamide) should be dosed according to renal function.
• The remainder of medications are hepatically metabolized and should be dosed according to the patient's degree of liver dysfunction.
• Antiepileptic drug clearance and elimination half-time range from hours (carbamazepine, valproate, primidone, gabapentin) to days (phenytoin, lamotrigine, phenobarbital, zonisamide).
• All antiepileptic drugs, except gabapentin, levetiracetam, and vigabatrin, may be associated with pharmacokinetic drug interactions that alter plasma drug concentrations of concomitantly administered drugs.
• Drug interactions should be anticipated in all patients receiving antiepileptic drugs and subsequently receiving any other drugs.

Drug Interactions Related to Protein Binding

• Medications that compete for protein binding sites of highly protein-bound antiepileptic drugs (phenytoin, valproate, carbamazepine) can displace the bound drug and lead to increases in the plasma concentration of pharmacologically active drug.
• Commonly used protein-bound medications include thyroxine and salicylates.
• Albumin is the principal binding protein for antiepileptic drugs.
• Hypoalbuminemia, accompanying renal or hepatic disease or malnutrition, can increase unbound antiepileptic drug concentrations, resulting in toxicity.
• In pregnancy, hypoalbuminemia due to increasing central volume offsets the dilutional effect.

Drug Interactions Related to Accelerated Metabolism

• Enzyme-inducing antiepileptic drugs that accelerate metabolism (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, topiramate, primidone) may accelerate estrogen and progesterone metabolism and render oral contraceptives ineffective at usual doses.
• Patients on antiepileptic drugs have increased dose requirements for thiopental, propofol, midazolam, opioids, and nondepolarizing neuromuscular-blocking drugs.
• Possible explanations for altered dose requirements during anesthesia include increased hepatic P450 enzyme activity, altered receptor number/responsiveness, and interactions with endogenous neurotransmitters.

Principles of Dosing

• The initial dose should be high enough to expect a clinical effect, but low enough to avoid significant side effects.
• Gradual dose titration is recommended in all but emergency situations.
• The clinical response guides dose adjustment, as there is variability in clinical response over a wide range of dosages.
• A common cause of ineffectiveness is failure to achieve a high enough plasma concentration.
• Noncompliance is a particular concern in specific patient populations including adolescents and the elderly.
• Plasma drug concentrations should be maintained in a therapeutic range with equal doses administered at intervals equivalent to less than one elimination half-time of the drug.
• Dosing at one-half the drug's elimination half-time ensures a single missed dose will not result in the plasma concentration dropping below therapeutic levels.

Plasma Concentrations and Laboratory Testing

• Phenytoin is regularly monitored due solely to its nonlinear saturation dose kinetics.
• Titration based on clinical effectiveness is advised as routine laboratory monitoring of plasma concentrations is not recommended for other medications.
• Some patients may respond at low plasma concentrations while others need high plasma concentrations.
• If a patient does not respond as expected, plasma drug concentration investigation can aid in determining compliance and potential pharmacokinetic interactions.

Mechanism of Seizure Activity

• Seizure activity often has a localized origin.
• High frequency and synchronous firing in a seizure focus is most often unknown.
• Neurons in a chronic seizure focus has hypersensitivity to stimuli.
• The spread of activity is restrained by normal inhibitory mechanisms.
• If the spread is extensive the whole brain is activated and a tonic-clonic seizure ensues.
• If the spread is localized the seizure displays signs characteristic of the anatomic focus.
• Once initiated, a seizure is maintained by excitatory impulses.

Mechanism of Drug Action

• Presumed antiepileptic drugs control seizures by decreasing neuronal excitability or enhancing neurotransmission inhibition.
• Achieved by altering membrane currents or by affecting inhibitory neurotransmitters.
• Drugs delay sodium channel reactivation (phenytoin, carbamazepine, primidone, valproate, lamotrigine) during high-frequency neuronal firing which produces an inhibitory effect on creation of action potentials
• Some drugs(phenytoin, carbamazepine, valproate, lamotrigine, zonisamide) act on both calcium channels and sodium
• Other drugs (ethosuximide, phenobarbital) act selectively at calcium ion channels.
• Drugs (phenobarbital, benzodiazepines) alter synaptic function act primarily by enhancing γ-aminobutyric acid (GABA)-mediated neuronal inhibition.

Major Antiepileptic Drugs

• Drugs used to treat patients with epilepsy are carbamazepine, clobazam, eslicarbazepine, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin primidone, rufinamide, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.
• Since 2005 number of agents has more than doubled which offers broader therapeutic fewer drug interactions, broader spectrums of activity, and unique mechanisms of action
• Benzodiazepines (diazepam, lorazepam, midazolam) are used for short-term treatment of acute seizures or status epilepticus.
• Clonazepam can treat epilepsy, but tolerance and sedation are a common side effects.
• Felbamate is reserved for use due to its side effect profile.
• Drugs used in the treatment of partial seizures are carbamazepine, lamotrigine, oxcarbazepine, topiramate, zonisamide, and phenytoin.
• Valproate, lamotrigine, and topiramate are the antiepileptic drugs useful for treatment of patients with generalized seizures.
• Ethosuximide, lamotrigine, or valproate are effective in treatment of patients with generalized nonconvulsive seizures, especially absence seizures

Adverse Side Effects

• Antiepileptic drugs may produce adverse side effects.
• Newer agents have a more favorable side effect profile.
• Effects are dose-related (sedation, lethargy, neurotoxicity) or idiosyncratic (hypersensitivity, hepatotoxicity, aplastic anemia).

Maternal Epilepsy

• Enzyme inducing antiepileptic drugs can result in unintended pregnancy that render oral contraceptives less effective.
• Seizures during pregnancy may result in fetal harm making seizure control during this period imperative.
• Monotherapy with the lowest dose possible is the guiding principle
• Fetal organogenesis is complete by 8 weeks making this important to discontinue teratogenic drugs prior
• Valproate taken during pregnancy have more than double the risk of giving birth to a fetus with malformations.
• Antiepileptics to avoid during pregnancy include phenytoin and phenobarbital.

Carbamazepine

• Iminostilbene derivative is effective for nonconvulsive and convulsive partial and generalized seizures.
• May be useful for trigeminal neuralgia and glossopharyngeal neuralgia.
• Like phenytoin, carbamazepine maintains sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential.
• Only available Orally

Carbamazepine Pharmacokinetics

• Oral absorption is rapid, with peak plasma concentrations occurring 2 to 6 hours after ingestion.
• Plasma protein binding is 70% to 80%.
• The plasma elimination half-time is 8 to 24 hours.
• Requires a dosage increase in 2-4 weeks

Carbamazepine Side Effects

• Toxicity is similar to phenytoin.
• Frequent side effects Nausea diplopia.
• Aplastic anemia, and cardiac dysrhythmias are rare but life-threatening.
• Monitor bone, Cardiac, liver and renal function.
• High plasma levels result in hyponatremia.
• Skin rash occurs in approximately 10%.
• Accelerates hepatic oxidation and conjugation of other lipid-soluble drugs.
• The most common interaction is with oral contraceptive pills, and most women require an increase in the daily dose of estrogen.
• Accelerates the metabolism of valproic acid, ethosuximide, corticosteroids, anticoagulants, and antipsychotic drugs.

Eslicarbazepine

• Approved for use for partial-onset seizures.
• Mechanisms involve stabilization of the inactive state of voltage-gated sodium channels
• Has >90% absorption following oral use.
• Most common side effects are dizziness.

Ethosuximide

• Drug of choice for suppression of absence (petit mal) epilepsy.
• Decreases calcium conductance in thalamic neurons

Ethosuximide Pharmacokinetics

• Available only in oral form.
• Peak plasma concentrations occur in 1 to 7 hours after oral administration.
• The drug is excreted unchanged in urine.

Ethosuximide Side Effects

• The Toxicity is low.
• May include gastrointestinal intolerance, lethargy and dizziness.

Felbamate

• Only used in Intractable epilepsy.
• Used principally for poorly controlled partial and secondarily generalized seizures
• Its is associated with the Lennox-Gastaut syndrome.

Felbamate Pharmacokinetics

• Oral absorption is prompt but the elimination half-time is prolonged.
• Undergoes minimal metabolism being mostly excreted unchanged.

Felbamate Side Effects

• Serious side effects include aplastic anemia and hepatotoxicity.
• Concurrent carbamazepine or phenytoin may decrease plasma concentrations of felbamate.
• Potent inhibitor of P450 enzymes, it can slow the metabolism of phenytoin.
• decrease the dose by 20% if needed

Gabapentin

• GABA analogue but is not a GABA receptor binder.
• Mechanism likely involves voltage-gated calcium channel inhibition.
• Limited epilepsy treatment efficacy.

Lacosamide

• Indicated for partial-onset seizures.
• Its mechanism is though voltage-gated sodium channels.
• Is able to effectively stabilize highly excitable neurons.

Lacosamide Side Effects

• Low risk for drug interactions.
• Most common side effects are nausea, vomiting, diarrhea, dizziness, headaches and drowsiness

Lamotrigine

• Novel anticonvulsant drug of the phenyltriazine lass.
• Effective when used alone or in combination in adults and children.
• Lennox-Gastaut syndrome with some side affects.

Lamotrigine Pharmacokinetics

• Its well absorbed after oral administration.
• Drugs that decrease the elimination half-time of lamotrigine includes phenobarbital, phenytoin.
• Valproic acid increases the elimination half life.

Lamotrigine Side Effects

• Common Side effects include headache, nausea, vomiting, drowsiness.
• Tremor is also a problem.

Levetiracetam

• Available in oral and IV preparations.
• Effective in juvenile myoclonic epilepsy, partial and generalized convulsive seizures, generalized tonic-clonic, and the partial seizures.
• Binds to presynaptic calcium channels, reducing synaptic neurotransmitter release.
• Side effect are minor consisting of sedation, asthenia, anxiety, and headache.

Oxcarbazepine

• Keto analogue of carbamazepine.
• Provides equivalent seizure control but has less side effects.
• Does not induce hepatic microsomal enzymes.
• Safer when used with combination.

Perampanel

• Indicated for patients suffering partial seizures.
• Involves the selective noncompetitive antagonism of a-amino-3-hydroxy-5-methyl-4
• isoxazolepropionic acid receptor.
• Black box warning exists that some patients may experience suicidal or homicidal thoughts.

Phenobarbital

• Long acting barbiturate
• Effective against seizure types in general.
• Cognitive and behavioral side effects often limits the use of this.
• Appears to exert antiepileptic through potentiation of inhibitory neurotransmitter GABA

Phenobarbital Pharmacokinetics

• Slow but Nearly complete and well absorbed orally.
• Peak concentrations occurring approximately 12-18 hours after a single dose.
• The usual maintenance dose is 20 to 60 hours.
• Side effects such a Sedation make the toxic threshold less impactful.

Phenytoin

• A hydantoin
• Effective for the management of partial and generalized seizures
• Available in oral and IV preparations.
• Does not possess Sedation when administered.
• Has a high therapeutic index

Phenytoin Mechanism of Action

• Neuronal excitability regulator.
• Stabilizing through sodium and calcium management

Phenytoin Pharmacokinetics

• Its poor water solubility may result in slow and variable absorption from the gastrointestinal tract
• Doses that exceed 500 mgs should be avoided
• It can precipitate at the injection site after IM injections making it unadvised.

Phenytoin Pharmacokinetic

• Control of Seizures plasma concentration should be between 10 to 20 Micrograms per mL
• 90% bound to plasma albumin
• metabolized to inactive by hepatic microsomal enzymes.

Phenytoin Side Effects

• These includes CNS toxicity.
• Peripheral neuropathy may be observed in long term
• Gingival hyperplasia is observed often in those whom are chronically treated.

Primidone

• Metabolized to phenobarbital
• It has better properties compared to the usage of Barbiturates

Rufinamide

• Used as combination therapy with Lennox-Gastaut Syndrome.
• Binds from 30% to 40%
• Has Liver via carboxylesterase-mediated

Stiripentol

• A unique chemical structure
• Approved for Treatment of Drave syndrome
• Rapid crosses the blood-brain barrier and enters into the brain

Tiagabine

• It is often used as an ajunctive theraoy for complex partial seizures.
• Potent inhibitor of a GABA uptake.
• Can cause mental deression.

Topiramate

• Is effective towards partial, generalized tonic-clonic, and absense seizures.
• Its a weak inhibitor that can provide control across specific receptor subtypes.
• Its may have the effect of carbonic anhydrate.

Valproic Acid

• Effective in all primary generalized and all convulsive epilepsies.
• Also has some effectiveness for the treatment of nonconvulsive partial seizures.
• This drug limits the neuronal firing through the blocking of sodium channels.

Valproic Acid Pharmacokinetics

• Administration through enterically coated formulations can aid in its ease of delivery.
• Absorption is prompt, and peak plasma is in four and one fourth hours.
• Binds to plasma protein at around 80%
• More than 70% is recovered as inactive glucuronide.

Valproic Acid Side Effects

• Anorexia, nausea, and some vomitting.
• Weight gain is common during treatment.
• Liver toxicity can result.

Vigabatrin

• Used to treat Refractory partial seizures.
• Its Mechanism is in part used by irreversibly inhibiting the GABA transaminase.
• Significant visual loss is observed during the treatment of this drug.

Zonisamide

• For management of secondarily generalized seizures.
• Modulation of Calcium Is one of its most powerful utilities.
• Adverse side effects including Sedation and dizziness.

Benzodiazepines

• Are used for Muscle Relaxation, sedation and anti convulsant effects.
• They Potentiate GABA-mediated neuronal inhibition.

Clonazepam

• Clonazepam is generally added to other drug therapy and is used as a first- line drug only for myoclonic seizures.
• personality changes may be seen within the treatment of clonazepams.

Diazepam

• used for treatment of status epilepticus and local anesthetic-induced seizures
• Has active Metabolites

Lorazepam

• Has shorter elimination half-time of around 8 to 24 hours
• used to treat status epilepticus

Clobazam

• Clobazam is used for complex partial, tonic-clonic, and myoclonic seizures primarily as a second-line agent

Treatment of Status Epilepticus

• Maintain The airway when a patient is under the influence of drugs.
• The initial therapy includes a benzodiazepine administered under a health profession such as Diazepam, Lorazepam and midalzolam
• In the aence of In IV an injection of Diazepam may be needed

Drugs Used for Treatment of Parkinson's Disease

• Aimed at managing debilitating symptoms.

Levodopa

• Cornerstone of symptomatic therapy.
• Crosses the blood-brain barrier and is converted to dopamine by decarboxylase enzyme.

Levodopa Pharmacokinetics

• Dopamine administration is crucial but it must be introduced into the brain.
• It must be often Administered to maintain A therapeutic concentration

Levodopa Metabolism

• Approximately 95% of Orally Administered Levodopa Is Rapidly Decarboxylated to Dopamine During the Passage Through the Liver
• Levodopa may cause Dyskinesias Fluctuations Motor Involuntary Dysfunction
• Nausea can be relieved by medication

Levodopa Side Effects

• Most Common includes the nausea and hypotension.
• Those whom are long term are prone to Dyskinesias, confusion and psychosis

Cardiovascular Changes

• Those receiving the treatment will be more like to be subjected to reflect Alpha and Beta Adrenergic responses, most notably with Norepinephrine and the transient flusing of the skin

Orthostatic Hypotension

• Orthostatic hypotension can Be avoided by having an increased fluid and sodium intake, elevating the head of the patient’s bed, and compression stockings

Cardiac Dysrhythmias

• Rare but have Still been noted with Levadopa therapy especially with the cardiac dyshythmias.

Abnormal Involuntary Movements

• Is common among with Parkinson's and tremor problems Fluctuations In mobility are characterized by increasing bradykinesia at the end of an interval between doses.

Psychiatric Disturbances

• Confusion visual hallucinations, and paranoia may affect the natural disease The psychiatric disturbances tend to be nocturnal emphasizing the possible value of decreasing or discontinuing last evenening dose of levodopa

Laboratory Measuements

• Urinary metabolites of levodopa may generate false positive tests for ketoaccidosis These Metabolites Also Color the urine red and then black out on exposure to oxygen

Drug Interactions Antipsychotic Drugs

• Drugs should not be administered to patients with known or suspected Parkinson disease Infection administration it can be noted that the body may produce severe skeletal muscle rigidity and pullmonary edema

Monoamine Oxidase Inhibitors

• The results It to these drugs Can Exaggerate the peripheral and CNS Effects of the Alpadopa

Anticholinergic Dugs

• Symptoms May Be alleviated.

Pyridoxine

• Can abolish the therapeutic potency of Levedopa

Peripheral Decarboxylasse Inhibitors.

• With more levedopa, escape Metabolism to dopamine within the peripheral circulation and is available to enter the sens, side effects related to systemic concentrations and the dopamine are decreased when lovedopa is administered a peripheral decarbinlace Inhibitor Several combinations of love and a peripheril carboxylase Inhibitor are available as a lovedopa documentation strategy

Catechol 0 Methyl Iransferases Inhibitors

• The Cont is partially responsible for the peripheral breakdown of the According another lovedo augmentation strategy consists of blocking the cont enzyme activity in the gastrointestinal tract with toullophone or entacapon

Synthetic Dopamine Agonists

• Synthetic Dopamine Agents require neither transformation nor facilitated transport across with the block through the brain barriers Available drugs include the norgoal alkyloids

Anticholinergic Drugs

• Are used to treat for a number of symptoms those with parkinsons

Amantadine

• Is an antiviral drug that may be used as an antiviral, and helps with patient.
• Unlike Anticholinergics Amantadine may improve both skeletal and muscle rigidity.

Monoamine Oxidase Type B Enzyme Inhibitors

• Its also used for treatment of A number of conditions