Therapy of Epilepsy Flashcards
What happens in epilepsy?
Disrupted regulation of electrical activity in the brain = Synchronized and excessive neuronal discharge
What is critical to selection of appropriate pharmacotherapy for epilepsy?
Accurate classification and diagnosis of seizure type, including mode of seizure onset.
Aims of Drug therapy in Epilepsy?
1) Reducing the frequency of seizures
2) Minimizing adverse effects of anti-seizure drugs
3) Addressing coexisting health and social conditions
4) Enhancing quality of life (QOL)
Seizures that do NOT constitute epilepsy are those provoked by:
1) Infections
2) Fever (febrile seizures)
3) Drug overdose
4) Alcohol
5) Barbiturate or benzodiazepine withdrawal
6) Brain hemorrhage
7) Hypocalcemia
8) Hypoglycemia
9) Uremia
10) Eclampsia
What is the mainstay of epilepsy treatment?
Anti-seizure drug (ASD) therapy
Are Anti-seizure drugs (ASD) curative?
No, symptomatic and preventative only
How long are ASDs taken for?
Life-long
What do you do if the therapeutic goal for epilepsy is NOT achieved with monotherapy?
1) Add a second antiseizure drug (ASD), with a different mechanism of action
2) Switch to an alternative single ASD
What should you emphasize in epilepsy treatment?
Treat with a single drug!
What does the epilepsy drug treatment of first-choice depend on?
1) Type of epilepsy
2) Patient characteristics
What should you do once the proper ASD is selected?
Patient education and understanding of the treatment plan
What is the single most common reason for ASD treatment failure?
Medication non-adherence
Up to __% of patients with epilepsy are nonadherent to therapy.
60%
Reasons for ASD non-adherence:
1) Financial constraints
2) Complexity of the drug regimen
3) Frequent uncontrolled seizures
How should you stop ASD treatment?
Gradually, in order to avoid recurrence of seizures.
Sudden ASD withdrawal can be associated with:
Status Epilepticus
Withdrawal seizures are more common with which drugs?
1) Benzodiazepines
2) Barbiturates
Which patient characteristics must be considered before starting ASD treatment?
1) Age
2) Gender
3) Medical conditions
What should we keep in mind when giving ASDs to children?
They are more susceptible to neuropsychiatric adverse effects
What should we keep in mind when giving ASDs to Women of child-bearing potential?
They should not receive teratogenic ASDs
What should we keep in mind when giving ASDs to the elderly?
They are more susceptible to adverse effects on cognition
What if a patient has co-morbid conditions (migraine, tremor, or neuropathy)?
They may benefit from the use of an ASD that can also treat the
other condition
What should you pay EXTREME attention to when giving ASDs?
1) Drug-drug interactions with other drugs
2) Drug-drug interactions among ASDs themselves
What are the steps when giving ASDs?
1) Select one ASD, start with a low dose, and gradually titrate to a moderate dose goal, taking into account the patient’s response to treatment.
2) If there is NO adequate response at that dose, attempt increasing the dose.
3) If the first ASD monotherapy is still ineffective, or if the patient experiences intolerable adverse effects, adding a second ASD with a different mechanism of action and then tapering and discontinuing the first ASD is appropriate.
4) If the second ASD is ineffective, combination therapy may be indicated (although NOT
desirable).
A patient takes 1 ASD at a moderate dose, yet there is no therapeutic response. What is the next step?
Increase the dose
A patient takes 1 ASD at a moderate dose, yet has extreme side effects. What is the next step?
Add a second ASD with a different mechanism of action, then slowly taper off the first ASD.
A patient takes 1 ASD at a high dose and has previously tried 2 other ASDs, yet there is still no response. What is the next step?
ASD combination therapy
You have an elderly patient who is sensitive to falls, sedation, and neuro-cognitive adverse effects. How do you start ASD therapy?
Start at much lower initial dose and then titrate slowly (weeks –months), with a lower maximum dose goal.
You have a patient with multiple recent seizures (higher frequency). How do you start ASD therapy?
A therapeutic dose needs to be reached much more quickly, and a more rapid titration over days instead of weeks is appropriate.
Which ASDs have strong enough evidence to be labeled as effective, or as probably effective as initial monotherapy in certain seizure types?
1) Carbamazepine
2) Ethosuximide
3) Gabapentin
4) Levetiracetam
5) Oxcarbazepine
6) Phenytoin
7) Valproic acid
8) Zonisamide
ASD resistance is defined as:
Failure of two tolerated and appropriately chosen ASD (as monotherapy or in combination) to achieve sustained seizure freedom.”
Approximately 65% of patients can be maintained on one ASD and considered well controlled, although NOT necessarily ____.
Seizure free
The percentage of patients who are seizure-free on one drug after 12 months of treatment for only generalized tonic-clonic seizures is:
50%
The percentage of patients who are seizure-free on one drug after 12 months of treatment for only focal seizures is:
25%
The percentage of patients who are seizure-free on one drug after 12 months of treatment for those with mixed seizure types is:
25%
Of the 35% of patients with unsatisfactory control on monotherapy, __% will be well
controlled with a two-drug combination.
10%
____ are common and serious complicating factor in ASD selection.
Pharmacokinetic interactions
Which ASD drugs are considered enzyme inducers?
1) Carbamazepine
2) Lamotrigine
3) Phenytoin
4) Phenobarbital
5) Vigabatrin
Which ASD drugs are considered enzyme inhibitors?
1) Valproic acid
2) Topiramate
Knowledge of the presence of ____ of ASDs is important as they affect duration of action of the drug.
Active metabolites
Why is knowledge of the presence of active metabolites of ASDs important?
They affect duration of action of the drug
Which ASDs have active metabolites?
1) Carbamazepine
2) Primidone
Which ASDs have toxic metabolites?
Valproic acid
What are some common adverse effects shared by ASDs?
1) CNS adverse effects:
a) Sedation
b) Dizziness
c) Blurred or double vision
d) Difficulty in concentration
e) Ataxia
2) Impairment of cognition
3) Osteomalacia and osteoporosis
Which ASD causes more cognitive impairment than any other ASDs?
Barbiturates
What do barbiturates do in children?
Paradoxically cause hyperactivity
Which newer ASD causes substantial cognitive impairment?
Topiramate
How can ASD adverse effects be avoided?
By titrating the dose upward very slowly
How can ASD adverse effects be improved?
1) By decreasing the dose
2) By switching from polytherapy to monotherapy
Which ASDs interfere with vitamin D metabolism and/or absorption?
1) Phenytoin
2) Phenobarbital
3) Carbamazepine
4) Oxcarbazepine
5) Valproic acid
Patients receiving ASDs that interfere with Vitamin D metabolism/absorption should also receive:
1) Supplemental vitamin D and calcium
2) Bone mineral density testing
Why do we monitor the older ASDs?
To optimize therapy for an individual patient !NOT!! as a therapeutic end point in itself!!!
The serum concentration of ASDs should be always interpreted in association with:
Clinical response
Which seizure type needs higher concentrations of ASDs?
Focal dyscognitive seizures
Serum levels can also be useful:
1) To document lack or loss of efficacy
2) To document non-adherence
3) To determine how much room there is to increase a dose based on expected toxicity
4) In patients with significant renal or hepatic dysfunction
5) In those taking multiple drugs
6) In women who are pregnant or taking OCPs
When should ASD monitoring be performed?
ONLY at steady-state
What is Carbamazepine’s active metabolite?
10,11-epoxide
What is Clobazam’s active metabolite?
N-desmethylclobazam
What is Eslicarbazepine’s active metabolite?
Oxcarbazepine
What is Ezogabine’s active metabolite?
N-acetyl metabolite
What is Oxcarbazepine’s active metabolite?
10-hydroxycarbazepine
What is Primidone’s active metabolite?
Phenobarbital
Which 4 ASDs are highly protein bound?
1) Perampanel
2) Phenytoin
3) Tiagabine
4) Valproic acid
Clinical response is more important than the serum drug concentrations and involves:
1) Identifying the type and number of seizures
2) Identifying drug adverse effects
Evaluation of therapeutic outcomes includes:
1) Clinical response
2) Severity and frequency of seizures
3) Ascertain if the patient is truly seizure free
4) Monitor patient long-term for co-morbid conditions, social adjustment (including Quality-Of-Life assessments), drug interactions, and adherence.
5) Screen periodically for co-morbid neuropsychiatric disorders (depression and
anxiety).
The most important aspect of ASD use is:
Individualization of therapy
The following should be considered together in personalized pharmacotherapy:
1) Seizure type
2) Concomitant medical problems (hepatic function, renal function, psychiatric diseases, other neurologic problems, …).
3) Concurrent medications
4) Patient specific characteristics (age, gender, child-bearing ability, and ethnicity)
The elderly are often on polytherapy which may contribute to:
1) Increased sensitivity to neuro-cognitive effects
2) Increased possibility of drug-drug interactions with ASDs that affect CYP450
Which ASDs affect CYP450?
1) Carbamazepine
2) Phenytoin
3) Valproic acid
What should we consider when giving drugs to the elderly?
1) They are often on polytherapy
2) Hypoalbuminemia
3) Body mass changes
4) Compromised renal or hepatic function
Why is hypoalbuminemia an issue when giving ASDs?
Because it may cause problems with highly protein bound ASDs
Why are body mass changes (increase in fat to lean body mass or decrease in body water) an issue when giving ASDs?
They can affect the drug volume of distribution and elimination half-life.
Which ASD is considered the medication of choice in the elderly?
Lamotrigine
Why is Lamotrigine considered the medication of choice in the elderly?
Because it has equal efficacy to carbamazepine and gabapentin, and is better tolerated
What can change the volume of distribution in neonates and infants?
1) Increase in the total body water to fat ratio
2) Decrease in serum albumin and α1-acid glycoprotein
Children up to the age of 3 years have decreased ____ of ASDs, especially in neonates.
Renal elimination
Is hepatic activity higher or lower than adults in neonates?
Lower
Is hepatic activity higher or lower than adults in children (>2 years)?
Higher
Does a 4 year old child need higher or lower ASD dosing compared to adults?
Higher
Does an infant need higher or lower ASD dosing compared to adults?
Lower
What are “Catamenial seizures”?
Seizures that happen:
1) Just before menstruation
2) During menstruation
3) At the time of ovulation
What can cause “Catamenial seizures”?
1) Slight increase of estrogen relative to progesterone
2) Progesterone withdrawal
Treatment of “Catamenial seizures”?
Conventional ASDs
When do seizures tend to improve in women?
Menopause
How do enzyme-inducing ASDs cause menstrual irregularity, infertility, sexual dysfunction, and polycystic ovarian syndrome (PCOS)?
1) By increasing the metabolism
of estrogen, progesterone, and testosterone
2) By increasing production of sex hormone binding globulin = decreases the free fraction of these hormones
What are the ASD hormonal adverse effects in women?
1) Menstrual irregularity
2) Infertility
3) Sexual dysfunction
4) Polycystic ovarian syndrome (PCOS)
Why shouldn’t women take enzyme-inducing ASDs with OCPs?
Leads to OCP failure due to increased metabolism of ethinyl estradiol (and progestin).
____ may affect sex hormone concentrations, causing hyper-androgenism and polycystic changes.
Valproic acid
Men with epilepsy have reduced ___.
Fertility
Which ASDs are associated with sperm abnormalities in men?
1) Carbamazepine
2) Oxcarbazepine
3) Valproic acid
Which ASD is associated with testicular atrophy (=reduced testosterone levels) in men?
Valproic acid
True or False: ASDs have no affect on libido and sexual function in both men and women.
FALSE; they have an effect in both.
Carbamazepine mechanism of action?
Enhances fast inactivation of voltage-gated Na+ channels.
Carbamazepine’s place in therapy?
FIRST-LINE in many seizure types:
focal onset seizures, generalized tonic-clonic seizures, and mixed seizure types.
Carbamazepine should NOT be given in which type of seizure?
Absence seizures
Carbamazepine induces the metabolism of:
1) Primidone
2) Phenytoin
3) Ethosuximide
4) Valproic acid
5) Clonazepam
Which drugs decrease the steady-state concentration of Carbamazepine by enzyme induction?
1) Phenytoin
2) Phenobarbital
Which drugs inhibit Carbamazepine clearance and increase its steady-state levels?
1) Propoxyphene
2) Troleandomycin
3) Valproic acid
Which enzyme, if inhibited, may potentially increase Carbamazepine serum concentrations?
CYP3A4
Which Carbamazepine adverse reactions are concentration-dependent?
1) Diplopia
2) Dizziness
3) Unsteadiness
4) Drowsiness
5) Nausea
Which Carbamazepine adverse reactions are idiosyncratic?
1) Blood dyscrasias
2) Steven-Johnson syndrome
3) Epidermal necrolysis
Which Carbamazepine adverse reactions are chronic?
1) Hyponatremia
2) Metabolic bone disease
What should you monitor with chronic use of Carbamazepine?
Serum calcium and Vitamin D
Phenytoin mechanism of action?
Inhibits voltage-gated Na+ channels
Phenytoin’s place in therapy?
1) Focal onset seizures
2) Generalized tonic-clonic seizures
What does giving Phenytoin at very high concentrations (>50
µg/mL) do?
Exacerbates seizures
What should you know when
interpreting serum phenytoin concentrations?
1) The patient’s serum albumin level
2) Renal function
Phenytoin distributes to:
Breast milk
Does Phenytoin cross the placenta?
YES
Phenytoin displays ___ pharmacokinetics, (or zero-order kinetics).
Michaelis–Menten
Phenytoin displays __(zero/first) order kinetics.
Zero
Phenytoin is an inducer of:
1) CYP450
2) UGT isozymes
What do UGT isozymes do?
Conjugate drugs with glucuronic acid
Phenytoin ___(increases/decreases) folic acid absorption.
Decreases
Should you give folic acid supplementation with Phenytoin? Why or why not?
No, it can reduce Phenytoin concentration and result in loss of efficacy.
Which drugs can displace phenytoin from binding sites on plasma proteins?
1) Phenylbutazone
2) Sulfonamides
Does hypoalbuminemia result in decreased total plasma drug concentration or free concentration of Phenytoin?
Total plasma drug concentration
In which 2 cases should total Phenytoin levels NOT be increased due to fear of intoxication?
1) When taking Phenylbutazone or Sulfonamides
2) Hypoalbuminemia
Which drugs induce the
metabolism of phenytoin?
1) Phenobarbital
2) Carbamazepine
Which drug inhibits the metabolism of phenytoin?
Isoniazid
Which Phenytoin adverse reactions are concentration-dependent?
1) Diplopia
2) Blurring of vision
3) Nystagmus
4) Ataxia
5) Dizziness
6) Somnolence
7) Incoordination
8) Sedation
9) Behavioral changes
10) Cognitive impairment
11) Fatigue
Which Phenytoin adverse reactions are idiosyncratic?
1) Blood dyscrasias
2) Steven-Johnson syndrome
3) Epidermal necrolysis
4) Pseudolymphoma
Which Phenytoin adverse reactions are chronic?
1) Cerebellar syndrome
2) Connective tissue changes
3) Skin thickening
4) Folate deficiency
5) Gingival hyperplasia
6) Hirsutism
7) Coarsening of facial features
8) Acne
9) Metabolic bone disease
Valproic acid mechanism of action?
May potentiate postsynaptic GABA responses
Valproic acid place in therapy?
1) First-line therapy for generalized seizures, including myoclonic, atonic, and absence seizures.
2) Migraine headaches
3) Bipolar disorders
The primary pathway of valproic acid metabolism is:
β-oxidation, then glucuronidation
What is Valproic acid’s metabolite?
4-ene-VPA
Valproic acid is toxic with enzyme ____(inducing/inhibiting) drugs.
Enzyme-inducing
4-ene-VPA can cause:
Hepatotoxicity
Is Valproic acid teratogenic?
Yes, it crosses the placenta
Which drugs fight for plasma proteins with Valproic acid?
1) Free fatty acids
2) Phenytoin
3) Aspirin
Valproic acid inhibits which enzymes?
1) CYP450 isozymes
2) Epoxide hydrolase
3) UGT isozymes
Valproic acid inhibits the metabolism of:
1) Phenobarbital
2) Phenytoin
3) Carbamazepine
4) Lamotrigine
Oral contraceptives may ___(decrease/increase) the clearance of valproic acid .
Increase
Meropenem can __(decrease/increase) valproic acid levels
Decrease
Which Valproic acid adverse reactions are concentration-dependent?
1) GI upset
2) Sedation
3) Unsteadiness
4) Tremor
5) Thrombocytopenia
Which Valproic acid adverse reactions are idiosyncratic?
1) Acute hepatic failure
2) Acute pancreatitis
3) Alopecia
Which Valproic acid adverse reactions are chronic?
1) Polycystic ovary syndrome
2) Weight gain
3) Menstrual cycle irregularities
4) Hyperammonemia
Ethosuximide mechanism of action?
Inhibition of T-type Ca2+ channels
Ethosuximide’s place in therapy?
First-line treatment for absence seizures
Ethosuximide has a __(narrow/wide) spectrum of activity.
Narrow
Which Ethosuximide adverse reactions are concentration-dependent?
1) Ataxia
2) Drowsiness
3) GI upset
4) Unsteadiness
5) Hiccoughs
___ may inhibit Ethosuximide’s metabolism.
Valproic acid
Which Ethosuximide adverse reactions are idiosyncratic?
1) Blood dyscrasia
2) Rash
Which Ethosuximide adverse reactions are chronic?
1) Behavioral changes
2) Headache
Lamotrigine mechanism of action?
1) Inhibits voltage-gated Na+ channels
2) Modulates high voltage-gated Ca2+ channels
3) Modulates hyperpolarization-activated cation channels
4) Attenuates release of glutamate and to a lesser extent, GABA and dopamine.
Lamotrigine place in therapy?
1) Monotherapy and adjunctive treatment in patients with focal onset seizures, as a first- or
second-line therapy.
2 Used in primary generalized tonic-clonic seizures and for primary generalized seizures of Lennox-Gastaut Syndrome (LGS)
Lamotrigine’s half-life is prolonged in:
Renal failure
Is Lamotrigine dialyzable?
YES
___ inhibits Lamotrigine’s metabolism.
Valproic acid
___ increases Lamotrigine’s CNS adverse effects.
Carbamazepine
Why do oral contraceptives reduce Lamotrigine’s serum concentrations?
Because of induction of glucuronidation by ethinyl estradiol
Which Lamotrigine adverse reactions are concentration-dependent?
1) Diplopia
2) Dizziness
3) Unsteadiness
4) Headache
Which Lamotrigine adverse reactions are idiosyncratic?
1) Generalized erythematous and morbilliform rash
2) Steven-Johnson syndrome
Topiramate inhibits which enzymes?
1) Carbonic anhydrase
2) CYP2C19
Topiramate place in therapy?
1) Monotherapy or adjunctive therapy for focal onset seizures in patients 2 years or
older.
2) Tonic–clonic seizures in primary generalized epilepsy and generalized seizures in
patients with Lennox-Gastaut Syndrome (LGS).
3) Benefits patients with co-morbidities (migraines, obesity).
Topiramate increases ___ serum concentrations due to inhibition of CYP2C19.
Phenytoin
Topiramate may increase the clearance of ___ and the formation of its metabolites.
Valproic acid
Topiramate increases the clearance of ___ at doses higher than 200 mg/day.
Ethinyl estradiol
Topiramate should be adjusted in:
Renal impairment
Which Topiramate adverse reactions are concentration-dependent?
1) Difficulty concentrating
2) Psychomotor slowing
3) Speech or language problems
4) Somnolence
5) Fatigue
6) Dizziness
7) Headache
Which Topiramate adverse reactions are idiosyncratic?
1) Metabolic acidosis
2) Acute glaucoma
3) Oligohydrosis (deficient sweating)
Which Topiramate adverse reactions are chronic?
1) Kidney stones
2) Weight loss
Gabapentin mechanism of action?
1) Elevates human brain GABA levels
2) Binds to the α2δ subunit of Ca2+ channels = analgesic effects
Gabapentin’s place in therapy?
1) Focal-onset seizures with or without secondary generalization in patients 3 years and older.
2) Useful in treating epilepsies with neuropathic pain.
Which Gabapentin adverse reactions are concentration-dependent?
1) Dizziness
2) Somnolence
3) Fatigue
4) Ataxia
Bioavailability of Gabapentin is reduced 20% by:
Aluminum antacids
Which Gabapentin adverse reactions are idiosyncratic?
Pedal edema
Which Gabapentin adverse reactions are chronic?
Weight gain
Levetiracetam mechanism of action?
Binds to synaptic vesicle protein SV2A in presynaptic terminals and inhibits neurotransmitter release.
Levetiracetam’s place in therapy?
Adjunctive therapy in focal-onset seizures in patients 12 years of age or older, myoclonic seizures, and primary generalized seizures
Levetiracetam is mainly eliminated by:
Kidneys
Levetiracetam’s dose should be reduced by 50% in:
Severe liver cirrhosis
Levetiracetam is significantly excreted into:
Breast milk
Which Levetiracetam adverse reactions are concentration-dependent?
1) Sedation
2) Behavioral disturbances
Which Levetiracetam adverse reactions are idiosyncratic?
Psychosis
Zonisamide mechanism of action?
1) Inhibits slow Na+ channels
2) Inhibits T-type Ca2+ channels
3) Inhibits glutamate release
4) Weak carbonic anhydrase inhibitory effect
Zonisamide’s place in therapy?
Adjunctive treatment of focal-onset seizures and may be considered first-line.
Can Zonisamide be given in pregnancy and lactation?
NO, it crosses the placenta
Which Zonisamide adverse reactions are concentration-dependent?
1) Dizziness
2) Sedation
3) Cognitive impairment
4) Nausea
Which Zonisamide adverse reactions are idiosyncratic?
1) Rash
2) Metabolic acidosis
3) Oligohydrosis
Which Zonisamide adverse reactions are chronic?
1) Kidney stones
2) Weight loss
