Chapt. 24: AntiSeizure Drugs Flashcards
List the drugs used for Tonic-clonic & Partial seizures.
Carbamazepine, Lamotrigine, Phenytoin, Valproic Acid
List the drugs used for Absence Seizures.
Clonazepam, Ethosuximide, Valproic Acid
List the drugs used for Myoclonic Seizures
Clonazepam, Lamotrigine, Valproic Acid
List the “Back-up and Adjunctive Drugs” used to treat Seizures.
Felbamate, Gabapentin, Lamotrigine, Levetiracetam, Phenobarbital, Tiagabine, Topiramate, Vigabatrin, Zonisamide.
Anti-seizure drugs are commonly used for _____ periods of time.
Long
Why is consideration of the pharmacokinetics of anti seizure drugs so important?
Because they are typically used for long periods of time, so it is important for avoiding toxicity and drug interactions.
Which is a primary example of an antiseizure drug that requires determination of plasma levels and clearance in order to achieve for optimum therapy.
Phenytoin
Why is Phenytoin different than most antiseizure drugs?
Determination of plasma levels and clearance in individual patients may be necessary for optimum therapy.
Antiseizure drugs are not well absorbed orally; thus, they have poor bioavailability. (T/F)
False.
In general, antiseizure drugs are well absorbed orally and have good bioavailability.
Where are most anti seizure drugs metabolized and which drugs are an exception to this?
Most antiseizure drugs are metabolized by hepatic enzymes.
Exceptions: gabapentin and vigabatrin
Is it true that some antiseizure drugs produce active metabolites?
Yes.
Most antiseizure drugs are metabolized by hepatic enzymes and in some cases active metabolites are formed.
How is resistance to anti seizure drugs expressed?
Resistance to antiseizure drugs may involve increased
expression of drug transporters at the level of the blood-brain barrier.
In which instances would plasma concentration of anti seizure agents reach toxic levels?
In the presence of drugs that inhibit antiseizure drug
metabolism or displace anticonvulsants from plasma protein binding sites.
What effect does Rifampin have on anti seizure drug metabolism?
Rifampin induces hepatic drug-metabolizing enzymes, so may result in plasma levels of the antiseizure agents that are inadequate for seizure control.
There are two specific anti seizure drugs that are capable of inducing hepatic drug metabolism; which drugs are they?
Carbamazepine and Phenytoin
The oral bioavailability of phenytoin is distinct. (T/F)
False.
Oral bioavailability is variable because individual differences in first-pass metabolism.
Rapid-onset and extended-release forms are available. Phenytoin metabolism is nonlinear; elimination kinetics shift from first-order to zero-order at moderate to high dose levels.
The drug binds extensively to plasma proteins (97–98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete
for binding (eg, carbamazepine, sulfonamides, valproic acid).
Explain the “order” of Phenytoin metabolism and elimination.
Phenytoin metabolism is nonlinear; elimination kinetics shift from first-order to zero-order at moderate to high dose levels.
What is the relationship between phenytoin and its plasma concentration and protein binding characteristic?
The drug binds extensively to plasma proteins (97–98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, carbamazepine, sulfonamides, valproic acid).
What are some drugs that effect plasma concentrations of phenytoin?
Free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, carbamazepine, sulfonamides, valproic acid).
How is the metabolism of phenytoin enhanced?
In the presence of inducers of hepatic metabolism:
Phenobarbital and Rifampin
How is the metabolism of phenytoin inhibited?
By other drugs, such as Cimetidine or Isoniaside
What is the “self inducing” effect of Phenytoin?
Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine.
What is Fosphenytoin?
Fosphenytoin is a water-soluble prodrug form of phenytoin that is used parenterally.
What are Seizures?
Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
What are Partial Seizures (Simple)
Consciousness preserved; manifested variously as convulsive jerking, paresthesias, psychic
symptoms (altered sensory perception, illusions, hallucinations, affect changes), and autonomic
dysfunction
What are Partial Seizures (Complex)
Impaired consciousness that is preceded, accompanied, or followed by psychological symptoms
What are Tonic-Clonic Seizures (Generalized)
Tonic phase (less than 1 min) involves abrupt loss of consciousness, muscle rigidity, and respiration
arrest; clonic phase (2–3 min) involves jerking of body muscles, with lip or tongue biting, and fecal
and urinary incontinence; formerly called grand mal
What are Myoclonic Seizures?
Single or multiple myoclonic muscle jerks
What is Status Epilepticus
A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it is a
life-threatening emergency
What is the Pharmacokinetics of Carbamazepine.
Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs including clonazepam, lamotrigine, and valproic acid.
Carbamazepine may increase the clearance of which type of drugs?
anticonvulsant drugs including clonazepam, lamotrigine, and valproic acid.
Which drugs inhibit Carbamazepine metabolism?
propoxyphene, valproic acid
How does Oxcarbazepine effect Carbamazepine?
Oxcarbazepine is related to Carbamazepine but is less likely to be involved in drug interactions.
How does Valproic Acid interact with Phenytoin?
Competes for phenytoin plasma protein binding sites.
Valproic Acid inhibits metabolism of which drugs?
carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine.
What is significant regarding biotransformation of Valproic Acid?
Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug.
Why are gabapentin, pregabalin, levetiracetam, and vigabatrin considered unusual?
They are unusual in that they are eliminated by the kidney, largely in unchanged form…and have no drug-drug interactions.
Which drugs are eliminated by the kidneys in an uncharged form?
Gabapentin, pregabalin, levetiracetam, and vigabatrin
Which drugs undergo both hepatic metabolism and renal elimination of intact drug?
Tiagabine, topiramate, and zonisamide
How is Lamotrigine eliminated?
Via hepatic glucuronidation.
What is the general effect of antiseizure drugs?
to suppress repetitive action potentials in epileptic foci in the brain.
What are the 3 main MOA’s of antiseizure drugs?
Sodium Channel Blockade, GABA-Related Targets, Calcium Channel Blockade,
What are the 4 main anti seizure drugs that block voltage-gated sodium channels in neuronal membranes?
Phenytoin, carbamazepine, lamotrigine, and zonisamide
The blockage of voltage gated sodium channels in neuronal membranes is “rate-dependent;” what does this mean?
The rate is dependent on the frequency of neuronal discharge.
The blockage of voltage gated sodium channels in neuronal membranes results in what?
The prolongation of the inactivated state of the Na+ channel and the refractory period of the neuron.
At high doses, phenobarbital and valproic acid may exhibit what kind of effects?
Acting as a sodium channel blocker.
benzodiazepines interact with specific
receptors on the _________.
GABAA receptor–chloride ion channel macromolecular
complex.
When is the frequency of chloride ion channel opening is increased?
In the presence of benzodiazepines
What effect do benzodiazepines have on GABA?
These drugs facilitate the inhibitory effects of GABA.
How does the GABA effect of Phenobarbital and other Barbiturates differ from that of Benzodiazepines
Like Benzodiazepines, Phenobarbital and other barbiturates also enhance the inhibitory actions of GABA but interact with a different receptor site on chloride ion channels that results in an increased duration of chloride ion channel opening.
What is the enzyme that terminates the action of GABA?
How is the enzyme inactivated?
GABA aminotransaminase (GABA-T). Irreversibly inactivated by Vigabatrin at therapeutic plasma levels and can also be inhibited by Valproic Acid at very high concentrations.
What effect does the drug Tiagabine have in neurons and glia?
Tiagabine inhibits a GABA transporter (GAT-1) in neurons and glia prolonging the action of the neurotransmitter.
How is Gabapentin related to GABA?
Gabapentin is a structural analog of GABA, but it does not activate GABA receptors directly.
Besides Gabapentin, what other drugs facilitate the inhibitory actions of GABA?
felbamate, topiramate, and valproic acid.
What are T-type Calcium Channels?
Low-voltage activated calcium channels that open during membrane depolarization.
How does Ethosuximide work?
Ethosuximide inhibits low-threshold (T type) Ca2+ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge.
How do Valproic Acid, Gabapentin and Pregabalin relate to Ethosuximide?
They all exhibit a similar effect as Ethosuximide; meaning they inhibits low-threshold (T type) Ca2+ currents,
especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge.
What are the mechanisms of Valproic Acid?
Calcium channels: inhibits low-threshold (T type) Ca2+ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge.
Neuronal membrane hyperpolarization, possibly by enhancing K+ channel permeability.
What is the action of Phenobarbital?
Acts on both sodium channels and GABA-chloride channels.
Also acts as an antagonist at some glutamate receptors.
Felbamate blocks ______ ______ receptors.
Glutamate NMDA
What is the action of Topiramate?
Blocks sodium channels and potentiates the actions of GABA and may also block glutamate receptors.
Which of the mechanisms of action of antiseizure drugs
have theoretical implications regarding their activity in
cardiac arrhythmias?
Find the Answer
Recall any clinical uses of antiseizure drugs in the
management of cardiac arrhythmias?
Find the Answer
What is most important for prescribing the most appropriate antiseizure drug?
Diagnosis of a specific seizure type
What are the basis’ on which anti seizure drugs are chosen?
Established efficacy in the specific seizure state that has been diagnosed
Prior responsiveness of the patient
Anticipated toxicity of the drug.
What are the categories of seizures used to establish clinical use of anti-seizure drugs?
Generalized Tonic-Clonic (Gand Mal) Partial Seizure Absence Seizure Myoclonic and Atypical Absence Syndromes Status Epilepticus
What are the 3 drugs of choice for generalized tonic-clonic (grand mal) seizures. What are the 2 lesser used?
Choice: Valproic acid, carbamazepine, and phenytoin.
Lesser: Lamotrigine and Topiramate
Which drug continues to be a primary drug in Generalized Tonic-Clonic (Grand Mal) seizures in infants.
Phenobarbital (or primidone); is now considered to be an alternative agent in adults
What are the drugs of first choice for partial seizures?
Carbamazepine (or oxcarbazepine) or
lamotrigine or phenytoin.
What are some alternative drugs for Partial Seizures?
Felbamate, phenolbarbital, topiramate, and valproic acid. Many of the newer anticonvulsants can be used adjunctively, including gabapentin and pregabalin,
a structural congener.
What are the preferred drugs for Absence Seizures and why? Side Effects?
Ethosuximide (GI Side Effects) or valproic acid because they
cause minimal sedation.
When is Valproic Acid particularly useful?
For Absence seizures in patients who have concomitant
generalized tonic-clonic or myoclonic seizures.
What other drugs are less used for Absence Seizures?
Clonazepam: effective but causes sedation and tolerance.
Lamotrigine, levetiracetam, and zonisamide
are also effective
Myoclonic seizure syndromes are usually treated with which drugs?
Valproic acid
Lamotrigine approved for adjunctive use, but commonly used as monotherapy.
Clonazepam; high doses cause drowsiness Levetiracetam, topiramate, and zonisamide are also used as backup drugs in myoclonic syndromes.
Felbamate has been used adjunctively with the primary drugs but
has both hematotoxic and hepatotoxic potential.
Which drugs are used as “back up” drugs in myoclonic syndromes?
Levetiracetam, topiramate, and zonisamide
Felbamate as adjunct with primary drugs but
has both hematotoxic and hepatotoxic potential.
Which drugs are typically used for Status Epilepticus?
IV Diazepam or Lorazepam, phenytoin, phenobarbital (especially in children).
Which 2 drugs are usually effective in terminating
attacks and providing short-term control.
IV diazepam or lorazepam
What drug is used for prolonged therapy in Status Epilepticus and why?
IV phenytoin has often been used because it is
highly effective and less sedating than benzodiazepines or barbiturates.
Which is safer in the treatment of Status Epilepticus, Phenytoin or Fosphenytoin?
Fosphenytoin is safer due to its water solubility.
Phenytoin may cause cardiotoxicity, possibly due to its solvent, propylene glycol.
Which drug is especially used for Status Epilepticus in children?
Phenobarbital.
How are severe cases of status epileptics treated, that are unresponsive to typical drug therapy?
General anesthesia
Which anti seizure drugs are also used for management of bipolar disorder?
Valproic acid, carbamazepine, lamotrigine
Which anti seizure drug is now used as first-line drug for treatment of mania?
Valproic Acid
_______ is the drug of choice for trigeminal neuralgia, and its cogeneration _______ may provide similar analgesia with fewer adverse effects.
Carbamazepine; oxcarbazepine
When are Gabapentin and Pregabalin used for pain?
Pain of neuropathic origin, including postherpeutic neuralgia.
Which 3 anti seizure drugs may have some use in migraine treatment?
Gabapentin, Topiramate and phenytoin
Children born of mothers taking anticonvulsant drugs have increased risk of ________?
congenital malformations
Neural tube defects are associated with use of which anti seizure drug?
Valproic Acid and Carbamazepine
Which anti seizure drug can cause craniofacial anomalies and spina bifida?
Carbamazepine
The use of phenytoin by pregnant women has been related to what?
Fetal hydantoin syndrome
Overdosage of anticonvulsants commonly results in _________ and _______.
CNS depression; respiratory depression
How is management of anticonvulsant overdose achieved?
Primarily supportive: airway management, mechanical ventilation.
When is Flumazenil used?
In the treatment of benzodiazepines overdose
What are the life-threatening toxic effects of Valproic Acid?
Fetal hepatotoxicity, with greatest risk to children under the age of 2 and patients taking multiple anticonvulsant drugs.
What are the toxic effects of Lamotrigine?
What factors increase this risk?
Skin rashes and life-threatening Steven-Johnson syndrome or toxic epidermal necrolysis.
Risk increased in children (1-2% incidence), especially if also taking Valproic Acid
Severe skin reactions can result from taking which anticonvulsants?
Lamotrigine and Zonisamide
Which drug has been limited to use solely in severe, refractory seizure states, and why?
Felbamate, due to reports of aplastic anemia and acute hepatic failure
Withdrawal from anti seizure drugs can be accomplished acutely due to decreased risk of subsequent seizures? (T/F)
False.
Withdrawal from antiseizure drugs should be accomplished gradually to avoid increased seizure frequency and severity.
Which is achieved easier and why? Withdrawal from anti-absence drugs from partial or generalized tonicclonic seizure drugs?
Anti-absence drugs is more easily accomplished.
Adverse effects and complications of antiepileptic drugs:
Benzodiazepines
Sedation, tolerance, dependence
Adverse effects and complications of antiepileptic drugs:
Carbamazepine
Diplopia, cognitive dysfunction, drowsiness, ataxia; rare occurrence of severe blood dyscrasias and Stevens-Johnson syndrome; induces hepatic drug metabolism; teratogenic potential
Adverse effects and complications of antiepileptic drugs:
Ethosuximide
Gastrointestinal distress, lethargy, headache, behavioral changes
Adverse effects and complications of antiepileptic drugs:
Felbamate
Aplastic anemia, hepatic failure
Adverse effects and complications of antiepileptic drugs:
Gabapentin
Dizziness, sedation, ataxia, nystagmus; does not affect drug metabolism (pregabalin is similar)
Adverse effects and complications of antiepileptic drugs:
Lamotrigine
Dizziness, ataxia, nausea, rash, rare Stevens-Johnson syndrome
Adverse effects and complications of antiepileptic drugs:
Levetiracetam
Dizziness, sedation, weakness, irritability, hallucinations, and psychosis have occurred
Adverse effects and complications of antiepileptic drugs:
Oxcarbazepine
Similar to carbamazepine, but hyponatremia is more common; unlike carbamazepine, does not induce drug metabolism
Adverse effects and complications of antiepileptic drugs:
Phenobarbital
Sedation, cognitive dysfunction, tolerance, dependence, induction of hepatic drug metabolism; primidone is similar
Adverse effects and complications of antiepileptic drugs:
Penytoin
Nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral neuropathy, osteoporosis, induction of hepatic drug metabolism
Adverse effects and complications of antiepileptic drugs:
Tiagabine
Abdominal pain, nausea, dizziness, tremor, asthenia; drug metabolism is not induced
Adverse effects and complications of antiepileptic drugs:
Topiramate
Drowsiness, dizziness, ataxia, psychomotor slowing and memory impairment; paresthesias, weight loss, acute myopia
Adverse effects and complications of antiepileptic drugs:
Valproic Acid
Drowsiness, nausea, tremor, hair loss, weight gain, hepatotoxicity (infants), inhibition of hepatic drug metabolism
Adverse effects and complications of antiepileptic drugs:
Vigabatrin
Sedation, dizziness, weight gain; visual field defects with long-term use, which may not be reversible
Adverse effects and complications of antiepileptic drugs:
Zonisamide
Dizziness, confusion, agitation, diarrhea, weight loss, rash, Stevens-Johnson syndrome
