Pharmacotherapy of Seizure Disorders Flashcards
Epilepsy drugs
Used for…/mechanism
phenytoin
Partial/Generalized/Mech
Partial:
Simple +
Complex +
Generalized:
Tonic-clonic: 1st line
Absence:
Status: 1st line for propylaxis
Mech: ↑Na channel inactivation
Epilepsy drugs
Used for…/mechanism
Carbamazepine
Partial/Generalized/Mech
Also used for…
Causes:
Partial
Simple: 1st line
Complex: 1st line
Generalized
Tonic-clonic: 1st line (with phenytoin)
Absence:
Also used for…
1st line for trigeminal neuralgia
Mech: ↑Na channel inactivation
Causes agranulocytosis
Epilepsy drugs
Used for…/mechanism
Lamotrogine
Partial/Generalized/Mech
Partial
Simple: +
Complex: +
Generalized
Tonic-clonic: +
Absence:
Status:
Mech: Blocks voltage gated Na channels
Epilepsy drugs
Used for…/mechanism
Gabapentin
Partial/Generalized/Mech
Also used for….
Partial
Simple: +
Complex: +
Generalized
Tonic-clonic: +
Absence:
Also used for….
Also used for peripheral neuropathy, bipolar disorder
Mech: Designed as GABA analog but primarily inhibits HVA Ca channels
Epilepsy drugs
Used for…/mechanism
Topiramate
Partial/Generalized/Mech
Partial
Simple: +
Complex: +
Generalized
Tonic-clonic: +
Absence:
Status:
Mech: Blocks Na channels,
↑ GABA action
Epilepsy drugs
Used for…/mechanism
Phenobarbital
Partial/Generalized/Mech
Partial
Simple: +
Complex: +
Generalized
Tonic-clonic: +
Absence:
Status: 1st line in pregnant women, children
Mech: ↑ GABAA action
Epilepsy drugs
Used for…/mechanism
Valproic Acid
Partial/Generalized/Mech
Partial:
Simple: +
Complex: +
Generalized:
Tonic-clonic: 1st line
Absence: +
Status: Also used for myoclonic seizures
Mech:
↑ Na channel inactivation
↑ GABA concentration
Epilepsy drugs
Used for…/mechanism
Ethosuximide
Partial/Generalized/Mech
Partial:
Simple
Complex
Generalized:
Tonic-clonic
Absence: 1st line
Status
Mech:
Blocks thalamic T-Type Ca channels
Epilepsy drugs
Used for…/mechanism
Benzodiazepines
Partial/Generalized/Mech
Partial
Simple
Complex
Generalized Tonic-clonic Absence Status: 1st line for acute also used for seizures of eclampsia (1st line is MgSO4)
Mech: ↑ GABAA action
Epilepsy drugs
Used for…/mechanism
Tiagabine
Partial/Generalized/Mech
Partial:
Simple: +
Complex: +
Generalized:
Tonic-clonic
Absence
Status
Mech: Inhibits GABA reuptake
Epilepsy drugs
Used for…/mechanism
Vigabatrin
Partial
Simple: +
Complex: +
Generalized:
Tonic-clonic
Absence
Status
Mech:
Irreversibly inhibits GABA transaminase → ↑ GABA
Epilepsy drugs
Used for…/mechanism
Levetiracetam
Partial:
Simple: +
Complex: +
Generalized:
Tonic-clonic: +
Absence
Status
Mech:
Unknown, may modulate GABA and glutamate release
Partial seizures
1st line drugs
Simple: carbamazepine
Complex: Carbamazepine
Generalized seizures
1st line drugs
Tonic Clonic: Phenytoin, carbamazepine
Absence: Ethosuximide
1st line for acute seizures/prophylaxis
Acute: benzodiazepines
Proph: Phenytoin
Epilepsy drug toxicities
benzos
Sedation
Tolerance
Dependence
Epilepsy drug toxicities
carbamazepine
Diplopia, ataxia, blood dyscrasias (agranulocytosis, aplastic anemia) liver toxicity teratogenesis induction of cytochrome P450 SIADH Steven-johnson syndrome
Epilepsy drug toxicities
Ethosuximide
GI distress Fatigue Headache Urticaria Steven Johnson syndrome
EFGH – ethosuximide, fatigue, GI, Headache
Epilepsy drug toxicities
Phenobarbital
Sedation
Tolerance
Dependence
Induction of cytochrome P450
Epilepsy drug toxicities
Phenytoin
Nystagmus Diplopia Ataxia Sedation Gingival hyperplasia Hirsutism Megaloblastic anemia Teratogenesis (fetal hydantoin syndrome) SLE-like syndrome Induction of P450
Epilepsy drug toxicities
Valproic Acid
GI distress
Rare but fatal hepatotoxicity (measure LFTs)
Neural tube defects in fetus (spinal bifida)
Tremor
Weight gain
Contraindicated in pregnancy
Epilepsy drug toxicities
Lamotrigine
Steven-Johnson syndrome
Epilepsy drug toxicities
Gabapentin
Sedation
Ataxia
Epilepsy drug toxicities
Topiramate
Sedation
Mental Dulling
Kidney Stones
Weight Loss
Stevens-Johnson syndrome
Prodrome of malaise and fever followed by rapid onset of erythematous/purpuric macules (oral, ocular, genital)
Skin lesions progress to epidermal necrosis and sloughing
Phenytoin
Mech/clinical use/toxicity
Mech
Use-dependent blockade of Na channels; ↑ refractory period; inhibition of glutamate release from excitatory presynaptic neuron
Clinical Use
Tonic clonic seizures
Also a class IB antiarrhythmic
Toxicity Nystagmus Ataxia Diplopia Sedation SLE-like syndrome Induction of cytochrome P450 Chronic use produces gingival hyperplasia in children, peripheral neuropathy, hirsutism, megaloblastic anemia (↓ folate absorption). Teratogenic (fetal hydantoin syndrome)
Barbiturates
Mech/clinical use/toxicity
Phenobarbital, pentobarbital, thiopental, secobarbital
Mech
Facilitate GABA A action by ↑ duration of CL- channel opening, thus ↓ neuron firing
Clinical Use
Sedative for anxiety, seizures, insomnia, induction of anesthesia (thiopental)
Toxicity
Dependence, additive CNS depression effects with alcohol, respiratory or CV depression (can lead to death)
DDI owing to induction of liver P450 enzymes
Treat overdose with sx management (assist respiration, ↑ BP)
Contraindicated in porphyria
Benzos
Mech/clinical use/toxicity
Diazepam, Lorazepam, Triazolam, Temazepam, oxazepam, midazolam, chlordiazepoxide, alprazolam
Mech
Facilitate GABA A action by ↑ frequency of Cl channel opening
↓ REM sleep
most have long half-lives and active metabolites
Clinical Use Anxiety Spasticity Status epilepticus (lorazepam and diazepam) Detox (esp alcohol – DT’s) Night terrors Sleepwalking General anesthetic (amnesia, muscle relaxant) Hypnotic (insomnia)
Toxicity
Dependence, additive CNS depression effects with alcohol. Less risk of respiratory depression and coma than with barbiturates
Tx overdose with flumazenil (competitive antagonist at GABA benzo rec)
Benzodiazepines
Short acting/most addictive
Short acting = TOM
Triazolam
Oxazepam
Midazolam
Also the highest addictive potential
GABA(A)-R
What binds to it
Benzos
Barbs
EtOH
AED
MOA
Benzos
Enhance GABA
AED
MOA
CBZ
Modulate Na channels
AED
MOA
Ethosuximide
Modulate Ca Channels
AED
MOA
felbamate
Enhance GABA
AED
MOA
Gabapentin
Modulate Ca Channels
AED
MOA
Lamotrigine
Modulate Na Channels
AED
MOA
Levetiracetam
Unknown
AED
MOA
Oxcarbazepine
Modulate Na channels
AED
MOA
Phenobarbital
Enhance GABA
AED
MOA
phenytoin
modulate Na Channels
AED
MOA
pregabalin
modulate Ca channels
AED
MOA
tiagabine
Enhance GABA
AED
MOA
Topiramate
Module Na channels
Enhance GABA
Inhibit excitatory NTs
AED
MOA
Valproate
Modulate Na channels
Modulate Ca channels
Enhance GABA
AED
MOA
Zonisamide
Modulate Na channels
Modulate Ca channels
Therapeutic targets by seizure type
Partial seizures
Focal but can become generalized
Effective drugs limit sustained repetitive discharges
Therapeutic targets by seizure type
Generalized seizures
May have brief impairment or loss of consciousness
Effective drugs reduce T-type Ca++ conductance
Therapeutic targets by seizure type
Generalized tonic-clonic
Tonic spasm followed by synchronous clonic jerking
Effective drugs limit sustained repetitive discharges
AED drug selection
Partial with or w/o generalization
1st line/2nd line/other drugs to consider/drugs to avoid
1st line: CBZ Oxcarbazepine Valproate Lamotrigine Phenytoin
2nd line: Topiramate Phenobarbital Levetiracetam (A) Zonisamide (A) Pregabalin (A) Gabapentin (A) Tiagabine (A)
Other drugs to consider:
Felbamate (R)
acetazolamide
Drugs to avoid: None
AED drug selection
Generalized tonic-clonic
1st line/2nd line/other drugs to consider/drugs to avoid
1st line: CBZ Oxcarbazepine Valproic Acid Lamotrigine Phenytoin
2nd line:
Topiramate
Levetiracetam (A)
Zonisamide (A)
Other drugs to consider:
Phenobarbital
acetazolamide
Drugs to avoid: Tiagabine
AED drug selection
Absence
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Ethosuximide
Lamotrigine
Valproate
2nd line:
Topiramate
Clonazepam
Other drugs to consider:
Levitiracetam
Drugs to avoid (could worsen seizure): CBZ Oxcarbazepine Gabapentin Tiagabine phenytoin
AED drug selection
Myoclonic
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Valproate
Topiramate
2nd line: Clonazepam Lamotrigine Levetiracetam Zonisamide (A)
Other drugs to consider:
Felbamate
Drugs to avoid: CBZ Oxcarbazepine Gabapentin Tiagabine pregabalin
AED drug selection
atonic
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Valproate
Lamotrigine
2nd line:
Clonzazepam
Topiramate
Zonisamide
Other drugs to consider:
Levetiracetam
Felbamate
Phenobarbital
Drugs to avoid:
CBZ
Oxcarbazepine
phenytoin
AED drug selection
tonic
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Lamotrigine
Valproate
2nd line:
Clonazepam
Topiramate
Other drugs to consider: Levetiracetam Zonisamide Phenobarbital Phenytoin Acetazolamide Felbamate (R)
Drugs to avoid:
CBZ
oxcarbazine
AED drug selection
Lennox-Gastaut
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Valproate
2nd line:
Topiramate
Lamotrigine
Zonisamide (A)
Other drugs to consider:
Felbamate
Drugs to avoid: None
AED drug selection
Infantile spasms
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
ACTH
Corticosteroids
2nd line:
Clonazepam
Valproate
Other drugs to consider: None
Drugs to avoid: None
AED drug selection
febrile
1st line/2nd line/other drugs to consider/drugs to avoid
1st line:
Phenobarbital
Valproate
2nd line: None
Other drugs to consider: none
Drugs to avoid:
Phenytoin
CBZ
AED drug selection
Neonatal seizures
1st line/2nd line/other drugs to consider/drugs to avoid
1st line: Phenobarbital
2nd line: Phenytoin
Other drugs to consider: None
Drugs to avoid: None
Pharmacokinetics of anti-epileptic drugs
Serum concentration monitoring
Used primarily as a guide to direct therapy
Useful in optimizing AED therapy, teasing out drug interactions, detecting noncompliance, and during pregnancy
Important to consider that individual patients determine their “therapeutic” and “toxic” concentrations
AED serum concentrations are not monitored with newer agents
Pharmacokinetics of anti-epileptic drugs
Important considerations
phenytoin
Phenytoin undergoes capacity-limited metabolism (elimination NOT proportional to serum concentration) and the capacity is reached at therapeutic concentrations
Phenytoin is highly protein bound to albumin (90%). The “free” phenytoin concentration (unbound) is a more accurate description of the therapeutic effects of this drug. Thus, changes in protein binding in certain disease states (renal or hepatic disease, burns, etc.) can effect the free concentration and the effect of the drug.
Pharmacokinetics of anti-epileptic drugs
Important considerations
CBZ
Carbamazepine undergoes “autoinduction” whereby it induces its own metabolism such that concentrations may be initially “therapeutic” only to be reduced once autoinduction occurs. This process begins within the 1st week after starting therapy and plateus at 2-3 weeks.
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pg. 481
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Pharmacokinetics of agents in status epilepticus
Onset of action/half-life/duration
diazepam
Onset of action
Half life
Duration of anti-seizure effect
0.5-2 min
24-57 hr
10-20min
Highly lipophilic; may be given rectally
Pharmacokinetics of agents in status epilepticus
Onset of action/half-life/duration
lorazepam
Onset of action
Half life
Duration of anti-seizure effect
2-3 min
8-25 hr
~6hr
DOC in SE – longer duration vs diazepam
Pharmacokinetics of agents in status epilepticus
Onset of action/half-life/duration
midazolam
Onset of action
Half life
Duration of anti-seizure effect
<5 min
1.5-4hr
5-10min
Pharmacokinetics of agents in status epilepticus
Onset of action/half-life/duration
Phenytoin
Onset of action
Half life
Duration of anti-seizure effect
15min
IV: 10-15hr
Similar to ½ life
Pharmacokinetics of agents in status epilepticus
Onset of action/half-life/duration
fosphenytoin
Onset of action
Half life
Duration of anti-seizure effect
10-30min
IV: 10-15hr
Similar to ½ life
Induction
Def/AED major inducers
Induction = increased synthesis of drug metabolizing isoenzymes in the liver resulting in an increase in the rate of metabolism of drugs that are substrates of those enzymes and thus the plasma concentration of those drug is decreased. If the affected drug has an active metabolite, induction can result in increased metabolite concentration and possibly an increase in drug toxicity. The time course of induction is dependent on the rate of enzyme synthesis and degradation and the time to reach steady state concentrations of the inducing drug. Thus the time course is generally gradual and dose-dependent.
AED MAJOR INDUCERS: CARBAMAZEPINE, PHENYTOIN, PHENOBARBITAL, FELBAMATE
Inhibition
Def/AED major inhibitors
Inhibition = drug or its metabolite blocks the activity of one or more drug metabolizing enzymes, resulting in a decrease in the rate of metabolism of the affected drug and thus higher plasma concentrations. Inhibition is competitive & dose-dependent and begins as soon as sufficient concentrations of the inhibitor are achieved. (can be seen within 24 hour of inhibitor administration)
AED MAJOR INHIBITORS: VALPROIC ACID
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AED
Lab tests
Baseline (i.e. prior to starting therapy) lab tests should include liver function tests (SGOT, SGPT, alkaline phosphatase), serum albumin, complete blood cell count with differential, urinalysis, serum creatinine (for renally eliminated drugs) and serum electrolytes. Additionally for carbamazepine should obtain baseline urinalysis and serum sodium; and for valproic acid obtain baseline serum ammonia.
In otherwise healthy and asymptomatic patients, routine laboratory monitoring after starting therapy is unnecessary with clinical laboratory tests only being repeated if indicated by the patient’s clinical condition. For patients with abnormal baseline laboratory tests, further workup is required to evaluate their cause and follow-up monitoring performed as indicated.
Phenytoin
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related: Ataxia Diplopia Nystagmus Sedation Drowsiness
Idiosyncratic: Acne Gum Hypertrophy Hirsutism Megaloblastic anemia Rash Lupus-like syndrome Behavior changes Metabolic bone disease Intellectual blunting
Pregnancy category: D -Fetal hydantoin syndrome -cleft lip and palate -mental retardation -low set ears -skeletal spinal abnormalities -heart malformation
Phenobarbital
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Sedation
Drowsiness
Ataxia
Idiosyncratic: Rash cognitive impairment Hyperactivity ADD Passive-aggressive Behavior (mood change) Intellectual blunting
Pregnancy category:
D
CBZ
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Diplopia
Nausea
Drowsiness
Idiosyncratic: Hyponatremia Leukopenia Aplastic anemia Rash
Pregnancy category: D -neural tube defects -minor craniofacial defects nail hypoplasia
Valproate
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related: GI upset Sedation Unsteadiness Thrombocytopenia Tremor
Idiosyncratic: Acute hepatic failure Acute pancreatitis Alopecia Weight gain Hyperammonemia
Pregnancy category: D -neural tube defects -fetal valproate syndrome (developmental delays, limb and digit abnormalities) -black box warning in pregnancy
Ethosuximide
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
GI upset
Drowsiness
Dizziness
Idiosyncratic:
Hiccups
Blood dyscrasias
Headache
Pregnancy category:
C
Felbamate
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
GI upset
Insomnia
Anorexia
Idiosyncratic:
Aplastic anemia
Hepatotoxicity
Weight loss
Pregnancy category: C
Gabapentin
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Sedation
Drowsiness
Ataxia
Idiosyncratic:
Weight gain
Aggressive behavior
Pedal edema
Pregnancy category: C
Lamotrigine
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Insomnia
Ataxia
Diplopia
Idiosyncratic:
Rash
Headache
Pregnancy category: C
Topiramate
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related: Slowed thinking Psychomotor slowing Speech/language problems Drowsiness Ataxia Dizziness
Idiosyncratic: Renal calculi Weight loss Glaucoma Paresthesia Metabolic acidosis
Pregnancy category:
C
Oxcarbazepine
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:Somnolence
Dizziness
Diplopia
Nausea
Idiosyncratic:
Hyponatremia
Rash
Pregnancy category: C
Tiagabine
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related: Dizziness Somnolence Blurred vision Depression Weakness Irritability Slowed thinking
Idiosyncratic:
Non-convulsive status
Mood instability
Pregnancy category: C
Zonisamide
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related: Sedation Dizziness Cognitive impairment GI upset
Idiosyncratic: Rash Weight loss Kidney stones Hypohidrosis
Pregnancy category: C
Levetiracetam
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Somnolence
Dizziness
Idiosyncratic:
Depression
Aggression
Infection
Pregnancy category: C
Pregabalin
Adverse drug rxns
Conc related/idiosyncratic/pregnancy category
Conc-related:
Somnolence
Dizziness
Blurred vision
Idiosyncratic: Weight gain Peripheral edema Increased CK Decreased platelet count
Pregnancy category: C
Concerns of long-term AED administration
Bone disorders
Bone Disorders: Bone disorders particularly osteoporosis have been associated with AEDs. Bone mineral density decreases leading to osteoporosis and fractures have been associated with some AEDS (phenobarbital, phenytoin, carbamazepine and valproate) in both women and men. The newer AEDs have not been systematically evaluated for these relationships. Potential mechanisms of osteoporosis development include increased catabolism of vitamin D, impairment of calcium absorption, impaired bone resorption and formation, hyperparathyroidism, vitamin K deficiency, and calcitonin deficiency. Osteoporosis is of particular concern in patients with epilepsy because of the increased risk of fractures during seizures. Experts recommend bone density testing every 5 years during AED treatment in men and premenopausal women and before AED initiation in postmenopausal women. Treatment with vitamin D at doses of 400-4000IU/day, calcium supplementation, bisphosphonates, or calcitonin may be necessary.
Concerns of long-term AED administration
Intellectual function
Recent studies have demonstrated that significant interference with higher cognitive functions; including attention span, concentrating ability, memory, information processing, motor speed and IQ; occurs during AED therapy
Concerns of long-term AED administration
cognition
Based on published data from prospective, chronic dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction. AEDs with traditional gamma-aminobutyric acid (GABA)ergic mechanisms have the most detrimental effects on cognitive function, possibly because they impair attention. A number of consistent risk factors have been established. Polypharmacy and high blood levels of an antiepileptic drug (AED) increase the risk of cognitive side effects.
Concerns of long-term AED administration
memory
Impaired memory is among the most common complaints of patients with epilepsy. Multiple factors contribute to memory impairment in patients with epilepsy.
AED therapy in pregnancy
AAN rec
Sex hormone fluctuations during maturation may exacerbate seizures at particular points during the life of women, eg. during menarche, menses, pregnancy, or later in the perimeno- pausal years.
American Academy of Neurology recommends monotherapy during reproductive years. There is a teratogenic potential of anti epileptic drugs. Ideally, in well-controlled seizures, taper and discontinue anti epileptic drugs before conception. Risk of continuing must be weighed against the benefits. Post partum adjustment of the anti epileptic drugs dose will be necessary if the dose was increased during pregnancy, and usually can be reduced by eight weeks after delivery. All women of child bearing years should receive folate supplementation (at leaset 1 mg/day) before and during the pregnancy.
AED
In-utero effects
In utero exposure to antiepileptic drugs (AEDs) can cause intrauterine growth retardation, congenital malformations, and cognitive dysfunction. The most common major malformations are cleft lip/palate, heart defects, neural tube defects, and urogenital defects. Current treatment guidelines advise use of AED monotherapy and folate supplementation beginning before and continuing throughout pregnancy. Prenatal screening for major malformations should be offered.
AED
Safety while breast feeding
Safety while breast-feeding is a common concern. Authorities recommend that it is safe with no risk of hematological or hepatotoxicity, although some sedation may occur with phenytoin, carbamazepine and phenobarbital. The efficacy of birth control pills is decreased by the use of enzyme-inducing anticonvulsants. Some prescribe estrogen/progesterone pill with higher hormonal doses or an alternative and preferred approach, is to use a second method of contraception.
AEDs that decrease effectiveness of oral contraceptives
CBZ Felbamate Oxcarbazepine Phenobarbital Phenytoin Primidone Topiramate (doses >200mg/day)
AEDs that do not decrease the effectiveness of oral contraceptives
Benzodiazepines Gabapentin Lamotrigine Levetiracetam Tiagabine Valproate Zonisamide
