Treatments

Question 1

What is the underlying principal of deciding which AED to start?

Answer 1

Choice of anticonvulsant therapy is based upon effectiveness of each drug in the reduction of specific seizure types (ie, generalized vs complex partial vs absence) and also least risk of side effects.

Question 2

What is considered the safest option in pregnancy in regards to AEDs?

Answer 2

Treatment should be continued if seizure frequency is a greater risk to pregnancy than medication risk.

Lamotrigine has recently been given a pregnancy category C rating, making it the safest selection for patients with refractory epilepsy in pregnancy,

The approximate relative risks of the other AEDs listed compared to lamotrigine were 1.2 for levetiracetam; 1.5 for carbamazepine; 1.5 for phenytoin; 2.2 for topiramate; and 5.1 for valproic acid.

Question 3

Which AED is considered safest in liver disease?

Answer 3

Levetriacetam is considered the safest in the setting of liver disease.

Question 4

Which seizure types is sodium valproate most effective for?

Answer 4

Valproic acid has a particular efficacy in absence seizures and juvenile myoclonic epilepsy. It also has the least risk of skin hypersensitivity.

Question 5

Which AED is used in the acute treatment of neonatal seizures?

Answer 5

Phenobarbital is used in

the acute treatment of neonatal seizures.

Question 6

What is initial management for children with cryptogenic complex partial seizures

Answer 6

Carbamazepine is the initial monotherapy for a child with cryptogenic complex partial seizures.”

Question 7

What is seizure risk after unprovoked generalised first seizure? Do you start treatment?

Answer 7

A single unprovoked generalized seizure in a patient with a normal neurological examination and a
normal evaluation. The etiology is likely idiopathic, and his risk for recurrent seizure is low (about 30% over the
next 5 years); therefore, observation is warranted.

Question 8

List the AEDs which do not have an effect on steroid hormone contraception? Which drugs have high rate of contraceptive failure?

Answer 8

Levetiracetam, gabapentin, tiagabine, vigabatrin, zonisamide, and topiramate (<200 mg) all appear to have no effect on steroid hormone concentration, such as oral contraceptive concentration.

Contraceptive failure
Phenytoin, phenobarbital, carbamazapine and oxcarbazepine all induce cytochrome P450 reducing OCP levels

Lamotrigine (LTG) is primarily metabolized by hepatic glucuronidation. Oral hormone contraception (OHC) induces this system and may result in a significant lowering of serum LTG levels. Therefore, the risk of breakthrough seizures is increased and LTG dosing often needs to be concomitantly increased. LTG has no effect on OHC metabolism and does not increase the risk of OHC failure.

Valproate does not affect hormonal contraception but should be avoided secondary to birth defects.

Question 9

What is gabapentin and inducer/inhibitor of?

Answer 9

“Gabapentin is neither an enzyme inducer nor inhibitor and is not associated with significant interactions with
other medications.”

Question 10

Which AEDs affect weight?

Answer 10

Weight loss: Topiramate

Weight gain: pregabalin, carbamazepine, gabapentin, and valproate

Question 11

A patient has a single seizure (GTC) with morning myoclonus. Would you start treatment?

Answer 11

Yes. (Juvenile myoclonic epilepsy). Although he has had only one seizure, he has morning myoclonic seizures and is at high risk for recurrence of seizures. He should be started on an anticonvulsant at this time.”

Question 12

What is the drug of choice for generalised tonic clonic seizures and myoclonus? What should be avoided?

Answer 12

“Valproate is the drug of first choice for treating generalized tonic-clonic seizures and myoclonus.

Juvenile myoclonic epilepsy may be aggravated by carbamazepine, oxcarbazepine and phenytoin.

Question 13

Can tramadol cause seizures?

Answer 13

Tramadol is a synthetic, centrally acting analgesic with weak mu receptor activity. Tramadol also inhibits reuptake of norepinephrine and seratonin. Seizures have been reported in patients receiving the drug in overdose and, rarely, at the recommended dose. It is important to consider tramadol as a possible cause of seizures even when used at recommended doses.

Question 14

What are some of the side effects of Sodium Valproate? (13)

Answer 14

Hepatic dysfunction, pancreatitis
weight gain, 
alopecia, 
tremor / reversable parkinsonism 
ataxia
high risk of teratogenesis. 
Rash / urticaria / pruritis
Decreased BMD
Dysmenorrhoea
Thrombocytopenia, haemorrhage
Hyperammonaemia
Hyponatraemia
hair thining
PCOS
RARE: severe skin reaction (incl DRESS), hypothyroidism, myelodysplastic syndrome; 

NOTE- hyponatremia is not a SE of valproate

Question 15

Which AEDs are associated with major congenital malformations?

Answer 15

Valproate, phenobarbital, carbamazepine and phenytoin are all associated with MCM.
Valproate, in particular, should be avoided during the first trimester and is associated with a higher risk of congenital malformations when used in polytherapy and at higher doses.”

Question 16

What is a serious SE from Carbamazepine? RFs?

Answer 16

Stevens-Johnson syndrome is a fatal skin reaction to carbamazepine.

Asian descent increases the risk to 5%
- Need to screen for HLAB* 1502 allele prior to starting therapy in Asian descent.

Question 17

What can be used to reverse sedation associated with benzos?

Answer 17

Flumazenil

Question 18

Which drugs inhibit carbamazepine metabolism?

Which drugs do carbamazepine increase metabilism of?

Answer 18

Phenytoin, cimetidine, diltiazem, erythromycin, verapamil, fluoxetine, and isoniazid.

carbamazapine can accelerate hepatic breakdown of a number of drugs, including oral contraceptives, sodium valproate, ethosuximide, corticosteroids, anticoagulants, antipsychotics, cyclosporine, and methylphenidate.

Question 19

What is the mechanism of action of vigabatrin?

Answer 19

“Vigabatrin enhances GABAergic transmission by inhibiting GABA transaminase, thus increasing GABA
concentration at the synapse.

Question 20

What is the mechanism of action of sodium valproate?

Answer 20

Valproate — is a broad-spectrum antiseizure drug

It has multiple cellular mechanisms of action:
- suppress high frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels,

• increases brain gamma-aminobutyric acid (GABA) concentrations at clinically relevant doses,
• acts against T-type calcium currents,

Question 21

What is the mechanism of action of lamotrigine?

Answer 21

Lamotrigine — The cellular mechanism of action of lamotrigine (LTG) is not completely understood, and it may have multiple effects.

One mechanism -inhibit voltage gated sodium channels

may selectively influence neurons that synthesize glutamate and aspartate,

Question 22

What is the mechanism of action of carbamazepine?

Answer 22

DRUGS THAT AFFECT VOLTAGE-DEPENDENT SODIUM CHANNELS —
CBZ binds to voltage-dependent sodium channels, probably after they change from the activated to the inactivated state. This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains.

Question 23

What are some of the SE of carbamazapine?

Answer 23

Common systemic side effects of CBZ include
nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and fluid retention

Patients who develop a rash with CBZ are more likely to develop one with oxcarbazepine, lamotrigine, phenytoin or phenobarbital and vice versa

Neurotoxic side effects include drowsiness, dizziness, blurred or double vision, lethargy, and headache. Hyponatremia related to CBZ and oxcarbazepine is discussed separately.

life-threatening adverse events: Stevens-Johnson syndrome and bone marrow suppression.

Leukopenia: 7% adults. May be transient or persistent. Does not normally require immediate discontinuation. onset is typically within the first three months of treatment.

Aplastic anemia (pancytopenia) is a rare, idiosyncratic, non-dose-related side effect that is most likely to occur within the first three or four months after initiating CBZ therapy.

Question 24

What is the mechanism of action of levetiracetam?

Answer 24

Levetiracetam — The mechanism of action of levetiracetam (LEV) is unknown. However, LEV binds to the synaptic vesicle protein SV2A, which has been linked in animal models to epilepsy

Question 25

List the drugs that affect voltage dependent sodium channels?

Answer 25

Carbamazepine
Phenytoin
Lamotrigine
Oxcarbazepine
Zonisamide
Lacosamide
Rufinamide
Eslicarbazepine

Question 26

Side effects of lamotrigine?

Answer 26

Systemic side effects of LTG include rash and nausea

A benign rash may develop in up to 10 percent of patients during the initial one to two months of therapy and necessitates discontinuation of the drug.

The risk of developing a life-threatening rash such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema is approximately 1 in 1000 adults;

LTG is also rarely associated with acute multi-organ failure, hypersensitivity reactions and disseminated intravascular coagulation.

Neurotoxic side effects are predominantly dizziness and somnolence.

Question 27

What is the mechanism of action of zonisamide?

Answer 27

Zonisamide — primary mechanism of action appears to be to blocking both voltage-dependent sodium channels and T-type calcium channels.

Zonisamide is a broad spectrum agent

Zonisamide is metabolized primarily in the liver by CYP and non-CYP transformations but is not a CYP inducer

Question 28

Side effects of zonisamide?

Answer 28

The most commonly reported side effects of zonisamide are somnolence, ataxia, anorexia, confusion, abnormal thinking, nervousness, fatigue, and dizziness;

Most of these are self-limited

Zonisamide is a weak carbonic anhydrase inhibitor. Nephrolithiasis was reported in 4 percent of patients in an early clinical trial, but later studies found a much lower risk

Question 29

What is the mechanism of action of lacosamide?

Answer 29

Lacosamide —selectively enhances slow inactivation of voltage-dependent sodium channels; this results in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide is also known to interfere with the activity of the collapsing response mediator protein-2 (CRMP- 2), a cell protein involved in neuronal differentiation and axonal guidance. The nature of the interaction between lacosamide and CRMP-2 and its role in seizure control are unclear. Lacosamide is Food and Drug Administration approved as an adjunct for partial- onset seizures in patients aged 17 years and older. It is available in oral and IV formulations. It is eliminated primarily by renal excretion and has little drug–drug interaction with other antiepileptic medications. Dizziness and nausea are the most common side effects.

Question 30

Side effects of lacosamide?

Answer 30

Lacosamide tends to be well tolerated.

Dizziness, nausea, vertigo, abnormal coordination and ataxia are the most frequently reported side effects

Dose-dependent PR interval prolongations on electrocardiogram in some studied patients suggest caution in prescribing lacosamide to those with known conduction problems (eg, atrioventricular block, sick sinus syndrome without a pacemaker, Brugada syndrome), severe ischemic or structural heart disease,

Question 31

List the drugs that affect calcium currents?

Answer 31

DRUGS THAT AFFECT CALCIUM CURRENTS
Ethosuximide

Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized

Ethosuximide is effective for the treatment of absence seizures; it has no activity against generalized tonic-clonic or focal seizures.

Question 32

First line treatment for childhood absence seizures?

Answer 32

Ethosuximide

Question 33

List the drugs that effect GABA activity

Answer 33

Increasing GABAergic tone generally has an anticonvulsant effect. Thus AEDs can work by lowering GABA metabolism (by GABA-T), reducing reuptake of GABA, increasing production of GABA (by GAD)

DRUGS THAT AFFECT GABA ACTIVITY
Phenobarbital
Tiagabine
Vigabatrin
Benzodiazepines
- Clobazam
- Others

Question 34

What is the mechanism of action of phenobarbital?

Answer 34

Phenobarbital binds to the GABA(A) receptor, improving the effect of GABA by extending the duration of GABA-mediated chloride channel openings.

Phenobarbital is metabolized primarily in the liver by the CYP system and 25 percent is excreted renally as unchanged drug. It is a potent and broad spectrum inducer of CYP and UGT-glucuronidation (table 2).

Question 35

Side effects of vigabitran?

Answer 35

Permanent vision loss with this medication.
As many as 30 to 50 percent of adults with long-term exposure to VGB have developed irreversible concentric visual field loss of varying severity that is often asymptomatic .

mean time to onset of about five years

Vigabatrin has also been reported to produce MRI abnormalities, specifically hyperintense lesions on T2-weighted images with restricted diffusion on diffusion weighted imaging in the basal ganglia, thalamus, brainstem, and dentate nucleus of the cerebellum

Other frequent adverse events with VGB include drowsiness, fatigue, headache, and dizziness [137]. Depression and weight gain can occur. Severe hypersensitivity reactions and angioedema have also been reported

Question 36

Mechanism of action of Benzodiazepines?

Answer 36

Benzodiazepines bind to the GABA(A) receptor and facilitate the attachment of GABA to its binding site on the receptor. The inhibitory action of endogenous GABA is magnified because benzodiazepines increase the occurrence of chloride channel openings.

Question 37

Drugs that affect glutamate receptors?

Answer 37

DRUGS THAT AFFECT GLUTAMATE RECEPTORS

Perampanel

Question 38

Mechanism of action of perampanel

Answer 38

erampanel — Perampanel is an orally active, noncompetitive AMPA-type glutamate receptor antagonist. It appears to inhibit AMPA-induced increases in intracellular calcium, reducing neuronal excitability

Question 39

Side effects of perampanel?

Answer 39

The most common side effects observed in randomized trials include dizziness, somnolence, headache, fatigue, irritability, gait disturbance, falls, nausea and weight gain (table 5A) [163,164,170,171]. Labelling information includes a boxed warning of serious neuropsychiatric effects including alteration of mood and aggression [121]. In a pooled analysis of the safety data from three randomized trials, the risk of psychiatric adverse effects was dose-dependent and was increased compared with placebo for both overall psychiatric symptoms (22, 17 and 12 percent for perampanel 12 mg, 8 mg, and placebo) as well as for more narrowly-defined symptoms of hostility/aggression (6, 3, and 0.7 percent) [172]. A majority of patients with psychiatric adverse effects continued on study, some with dose reductions, and the proportion of patients with a psychiatric adverse effect who discontinued therapy completely was relatively low (14 percent). A smaller randomized trial in adolescents found similar results [173].

Question 40

Side effects of perampanel?

Answer 40

The most common side effects observed in randomized trials include dizziness, somnolence, headache, fatigue, irritability, gait disturbance, falls, nausea and weight gain

boxed warning:
serious neuropsychiatric effects including alteration of mood and aggression

Question 41

Drugs with multiple mechanisms of action?

Answer 41

DRUGS WITH MULTIPLE MECHANISMS OF ACTION
Valproate
Felbamate
Topiramate

Question 42

Why is oxcarbazepine thought to have less SE than carbamazepine?

Answer 42

Oxcarbazepine is a derivative of carbamazepine and shares many similarities with carbamazepine, including its mechanism of action, ability to induce hepatic metabolism of oral contraceptives and other drugs, risk of hyponatremia, and indication for treatment of partial epilepsy.

Unlike carbamazepine, oxcarbazepine is reduced
to 10-monohydroxy-carbamazepine and does not undergo oxidation to an epoxide. This may explain its fewer side effects as compared to carbamazepine.”

Question 43

What is used to treat cerebral cysticercosis?

Answer 43

Cysticercosis is caused by the larval stage of the pork tapeworm Taenia solium. Clinical syndromes related to this parasite are divided into neurocysticercosis (NCC) and extraneural cysticercosis.
Neurocysticercosis, in turn, is divided into parenchymal and extraparenchymal forms.

Treatment is first based on seizure control and then consideration of anti-parasitic treatments.

The potential benefit of antiparasitic therapy is hastened resolution of active cysts, decreased risk for seizures, and decreased recurrence of hydrocephalus

The potential risk of treatment with antiparasitic therapy is exacerbation of neurologic symptoms due to increased inflammation around the degenerating cyst, particularly in patients with a large number of lesions. Thus, corticosteroids should be routinely administered together with antiparasitic therapy.

Antiparasitic treatment = praziquantel or / and albendazole

“Praziquantel is effective in treating cerebral cysticercosis. Active uninflamed cysts are responsive. Praziquantel will produce inflammation and edema as it kills the larva, which may temporarily result in symptoms such as headache.”

Question 44

Fetal vitamin K deficiency - when does it occur and how is it treated?

Answer 44

Fetal vitamin K deficiency with hemorrhagic complications occurs in 10% of neonates born to mothers receiving antiepileptic drugs that induce liver metabolism of vitamin K, including phenobarbital and phenytoin.

Women taking enzyme-inducing antiepileptic drugs should be treated with vitamin K1, 10 mg to 20 mg daily
during the last month of pregnancy. Infants should receive 1 mg intramuscularly at birth and, if needed, fresh frozen plasma.”

Question 45

Which AEDs are predominantly renally cleared?

Answer 45

gabapentin

phenybarbital

Question 46

Which AEDs are predominantly hepatically cleared?

Answer 46

phenytoin

Question 47

Common side effects of topiramate?

Answer 47

“The common side effects seen with topiramate are CNS related, including dizziness, confusion, drowsiness, paresthesias, impaired memory, and nervousness. Weight loss is common.

Painful angle-closure glaucoma has been reported.

Renal stones occur in about 1.5% of the study patients.

Question 48

Half life and excretion of phenybarbital?

Answer 48

“Phenobarbital has a plasma half-life of 53 to 118 hours (mean: 79 hours).

For children and newborns the plasma half-life is 60 to 180 hours (mean: 110 hours).

Phenobarbital is metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine a

Approximately 25% to 50% of a dose of phenobarbital is eliminated unchanged in the urine

Question 49

Common side effects of topiramate?

Answer 49

“The common side effects seen with topiramate are CNS related, including dizziness, confusion, drowsiness, paresthesias, impaired memory, and nervousness. Weight loss is common.

Painful angle-closure glaucoma has been reported.

Renal stones occur in about 1.5% of the study patients. Topiramate increases the risk for calcium kidney stones by making it easier for calcium to bind with phosphate (forming calcium phosphate stones). There is no contraindication to administer topiramate to a patient with history of calcium oxalate stones.”

Question 50

Grapefruit juice interaction?

Answer 50

Grapefruit juice leads to inhibition of CYP3A4, predisposing to increased plasma levels and toxicity of carbamazepine.

Question 51

Inducers of vitamin D metabolism?

Answer 51

The AEDs most commonly associated with altered bone and mineral metabolism and decreased bone density are those that induce the cytochrome P450 enzyme system (phenytoin, primidone, carbamazepine, and phenobarbital)

Induction of the cytochrome P450 system by AEDs leads to increased catabolism of vitamin D to inactive metabolites. Decreased availability of active vitamin D metabolites leads, in turn, to decreased gastrointestinal absorption of calcium, hypocalcemia, and a rise in circulating PTH. PTH increases the mobilization of bone calcium stores and subsequent bone turnover.

Question 52

What is the MOA of topiramate? What are the side effects of topiramate? What is its clearance?

Answer 52

Topiramate is a carbonic anhydrase inhibitori. Topiramate is a broad-spectrum antiepileptic used for partial GTC and absence seizures and for LGS. It has multiple mechanisms of action, including voltage-dependent sodium channel antagonism, enhancement of GABA activity through a nonbenzodiazepine site on GABAA receptors, and antagonism of AMPA/kainate glutamate receptors. It is predominantly excreted unchanged in urine with minimal liver metabolism.
Topiramate is associated with weight loss. Additional side effects of topiramate include drowsiness, word-finding difficulties, cognitive impairment, confusion, impaired memory, paresthesias, dizziness, nervousness, painful angle-closure glaucoma, and kidney stones.

Question 53

What does gabapentin induce/inhibit? what is its MOA

Answer 53

Gabapentin is neither an enzyme inducer nor inhibitor, so it has less potential interactions with other medications. It can be used as adjunctive therapy for partial seizures with or without secondary generalization.

Unknown MOA as an anticonvulsant. Its principal proposed mechanism of action, however, is through an interaction with the alpha2-δ subunit of presynaptic L- type voltage-regulated calcium channel.

Gabapentin can worsen generalized epilepsy, especially myoclonic epilepsy

Question 54

How is gabapentin absorbed and how is it excreted?

Answer 54

Gabapentin is absorbed by an active transporter in the intestine. When the transporter becomes saturated, the absorption of gabapentin becomes nonlinear (i.e., a smaller percentage is absorbed at higher doses).

Gabapentin is renally excreted, and essentially no metabolism occurs before excretion.

Question 55

Side effects of gabapentin

Answer 55

The most common side effects
of gabapentin include fatigue, headache, nausea, dizziness, and ataxia. There are no significant drug interactions or idiosyncratic reactions. The other medications listed interact with the metabolism of various other drugs.

Question 56

What are the differences between fosphenytoin and phenytoin? WHat are the benefits and SE of fosphenytoin

Answer 56

Fosphenytoin is an IV prodrug of phenytoin. It is composed of a disodium phosphate ester that is water soluble and less alkaline than phenytoin. It does not include propylene glycol and ethyl alcohol as a solvent vehicle as is the case with IV phenytoin.

Fosphenytoin can be loaded at a faster rate, but because the fosphenytoin needs to be converted into phenytoin in plasma, the rate of rise of serum levels is approximately equal to that of phenytoin. Compared to phenytoin, fosphenytoin is not associated with purple glove syndrome; it can be given more rapidly intravenously, its administration is associated with a lower occurrence of cardiovascular side effects, such as hypotension, and it can be given intramuscularly

The most common side effects of IV fosphenytoin include pruritus, as well as the other less problematic and typical phenytoin side effects, such as dizziness, nystagmus, and drowsiness.

Question 57

What is purple glove syndrome?

Answer 57

Purple glove syndrome may ensue when phenytoin infiltrates into the subcutaneous tissue, resulting in swelling, pain, and discoloration of the extremity because of blood vessel leakage.

Question 58

Which drugs are associated with worsening myoclonic seizures?

Answer 58

Lamotrigine, gabapentin, carbamazepine, pregabalin, and vigabatrin are known to exacerbate some myoclonic epilepsies

Question 59

Which common AED is a liver enzyme inhibitor?

Answer 59

Valproic acid is the only antiepileptic medication listed that is a hepatic enzyme inhibitor. Concurrent use of valproic acid with medications that undergo the same hepatic enzyme metabolism may result in dangerously elevated serum levels of these medications because their metabolism is inhibited. An example would be concurrent valproic acid and warfarin use, which could result in elevated international normalized ratio (INR) levels and, thus, increased bleeding risk.

Question 60

Name some hepatic inducers?

Answer 60

Phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine and topiramate (at higher doses) are all hepatic enzyme inducers. These increase the metabolism of the OCP

Question 61

What has been associated with aggravation of absence seizures on rare occasions?

Answer 61

he use of lamotrigine, Phenytoin, carbamazepine, gabapentin, have been associated with aggravation of absence seizures on rare occasions.

Question 62

What order kinetics does the metabolism of phenytoin follow?

Answer 62

It is important to understand that phenytoin exhibits nonlinear (zero- order) kinetics, as the metabolic pathways responsible for its metabolism become saturated. This means that when the dose of phenytoin is increased beyond a certain point, its plasma concentration at steady state will no longer increase in a proportionate manner. Rather, small dose changes may result in a large/toxic increment in plasma concentrations. In general, phenytoin approaches zero-order kinetics at total levels of >10 to 15 g/mL, and small dose increments can potentially cause large increases in the serum level.

Question 63

What are the se of phenytoin?

Answer 63

Idiosyncratic reactions caused by phenytoin include aplastic
anemia, Stevens–Johnson syndrome, and hepatic failure. Other side effects include thrombocytopenia, lymphadenopathy, gingival hyperplasia, acne, coarse facial features (also called “phenytoin facies,” from hypertrophy of subcutaneous facial tissue), hirsutism, purple glove syndrome (with intravenous administration), nystagmus, ataxia, dysarthria, diplopia, nausea, dizziness, and drowsiness. Phenytoin can also cause folate deficiency and increased vitamin D metabolism, resulting in premature osteoporosis. Chronically, its use has been associated with a usually mild peripheral neuropathy and with cerebellar but not cortical atrophy. Acutely, the IV form can cause phlebitis, pain, burning, hypotension, and cardiac conduction abnormalities. Phenytoin is a liver enzyme inducer, so it can increase metabolism of many other drugs.

Question 64

How do valproate and lamotrigine interact?

Answer 64

Valproic acid significantly increases the half-life of lamotrigine by 24 to 48 hours. Initiation of as little as 500 mg of valproic acid in chronic lamotrigine users may necessitate an immediate 50% reduction in the dose of lamotrigine.

Question 65

What is the metabolism of carbamazepine?

Answer 65

Carbamazepine undergoes liver metabolism with renal excretion of metabolites, so caution is advised with kidney or liver failure. Carbamazepine is also a hepatic enzyme inducer and undergoes autoinduction. The dose must be titrated up gradually to allow tolerance to develop to its CNS side effects, to avoid early toxicity, and to achieve an optimal therapeutic level as carbamazepine “autoinduces” the hepatic enzymes responsible for its own metabolism. If carbamazepine is started at too high of a dose, or titrated too fast, the result would be elevated carbamazepine levels with accompanying toxicity early on, as the hepatic enzymes responsible for carbamazepine’s metabolism have not been fully activated (autoinduced) yet. It is, therefore, important to remember that carbamazepine’s half-life decreases from 30 hours to 10 to 20 hours after the first few days to weeks of use. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Plasma concentrations decrease in the first 1 to 2 months, and during this time, the dose of carbamazepine should be gradually increased. Therefore, carbamazepine would not be a good option if quick control of new-onset, frequent seizures was desired. Of note, oxcarbazepine does not undergo autoinduction and can be titrated faster.

Question 66

What is oxcarbazepine? WHat are the differences with carbamazepine?

Answer 66

Oxcarbazepine is a structural derivative of carbamazepine and is reduced to 10-monohydroxy-carbamazepine and unlike carbamazepine does not undergo oxidation to epoxide. Carbamazepine on the other hand is oxidized to 10,11-carbamazepine epoxide, which is the principal metabolite of carbamazepine. It is important to remember that the 10,11- carbamazepine epoxide is pharmacologically active and responsible for many of the side effects seen with carbamazepine use Because of these differences, oxcarbazepine has less side effects, overall, as compared to carbamazepine. Oxcarbazepine has less liver enzyme induction, no autoinduction (and can thus be titrated more rapidly), and is used for the same seizure types as carbamazepine, having the same mechanism of action, metabolic pathways, and side effect profile. Approximately 30% of patients who have a history of a rash with carbamazepine will also develop a rash when exposed to oxcarbazepine..

Question 67

What is the MOA of benzos? What is their excretion and metabolism?

Answer 67

Benzodiazepines are broad-spectrum antiepileptic medications used most commonly for partial GTC, absence, and myoclonic seizures, as well as status epilepticus. They work as GABAA agonists. Binding to the GABAA receptor leads to subsequent activation of chloride channels and, as a result, hyperpolarization of the neuronal membrane and decreased neuronal excitability. Benzodiazepines, in general, undergo liver metabolism and renal excretion of their metabolites.

Question 68

What is the MOA of rufinamide? WHat is it approved for? What is its clearance?

Answer 68

Rufinamide modulates the activity of neuronal sodium channels, resulting in prolongation of the inactive state of the channel. It is Food and Drug Administration approved for the adjunctive treatment of seizures associated with LGS in pediatric patients 1 year of age and older, and in adults.
Rufinamide undergoes extensive metabolism, with only 4% excreted as parent drug. Rufinamide is primarily metabolized via enzymatic hydrolysis of the carboxylamide group to form carboxylic acid. This metabolic route is not CYP 450 dependent. There are no known active metabolites. Elimination of rufinamide is predominantly via urine. Plasma half-life of rufinamide is approximately 6 to 10 hours. Rufinamide shows little or no inhibition of most CYP 450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Rufinamide is a weak inducer of the CYP 3A4 enzyme.

Question 69

How is phenytoin metabolised? What interactions does it have?

Answer 69

Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes to inactive metabolites, which are then excreted in the urine. Phenytoin follows zero-order kinetic metabolism (discussed in questions 26 to 28).

There is a long list of medications that could potentially interact with the metabolism of phenytoin, either increasing or decreasing its serum levels. Fluconazole and trimethoprim are substrates of the same CYP 450 pathway and can, therefore, raise levels of this AED

Question 70

Explain differences in pharmacology in the elderly.

Answer 70

Absorption, distribution, metabolism, and excretion of AEDs are altered in the elderly. These patients tend to have lower gastric acidity, making the weakly basic drugs less easily absorbed and weakly acidic drugs more easily absorbed. Gastric emptying may be slowed and intestinal villi height may be reduced, making the absorption surface smaller. Given that lean body mass decreases with aging, total body water mass decreases, making the volume of distribution of hydrophilic drugs smaller. The proportion of fat also decreases with age, reducing lipophilic drug distribution volume. The metabolism of drugs is also affected, and hepatic metabolism decreases, given the reduction in liver volume, hepatic flow, and bile flow. Renal blood flow and glomerular filtration rate are lower in the elderly, and, therefore, renal excretion is also decreased. Hepatic synthesis of protein is lower, and the free fraction of drug that binds to protein tends to increase. Therefore, the measurement of free drug levels is recommended if available for that specific drug. The therapeutic window is also smaller in elderly patients. These patients tend to have multiple comorbidities and are usually on multiple medications that could potentially interact with AEDs. Therefore, careful selection of drugs and monitoring for side effects are strongly recommended in this group of patients.

Question 71

What is an important SE to consider in levetiracetam?

Answer 71

Many antiepileptic agents produce cognitive and behavioral side effects, with levetiracetam being notorious for doing so. This medication in general has few side effects and does not interact with other medications; however, it can produce significant behavioral problems and emotional lability, sometimes agitation and even aggressiveness. Levetiracetam should be used carefully in the elderly and in patients with psychiatric disorders, with alternative medications used when possible.