Flashcards in Week 9 - Chapter 24 Drugs for Epilepsy (Anti-epileptic drugs) Deck (51):
Absence Seizures (Petit Mal)
Absence seizures are characterized by loss of consciousness for a brief time (10 to 30 seconds). Seizures usually involve mild, symmetric motor activity (eg, eye blinking) but may occur with no motor activity at all. The patient may experience hundreds of absence attacks a day. Absence seizures occur primarily in children and usually cease during the early teen years.
How do they work?
We have long known that AEDs can (1) suppress discharge of neurons within a seizure focus and (2) suppress propagation of seizure activity from the focus to other areas of the brain. However, until recently we didn't know how these effects were achieved. It now appears that nearly all AEDs act through five basic mechanisms: suppression of sodium influx, suppression of calcium influx, promotion of potassium efflux, blockade of receptors for glutamate, and potentiation of gamma-aminobutyric acid (GABA).
These seizures are characterized by sudden loss of muscle tone. If seizure activity is limited to the muscles of the neck, “head drop” occurs. However, if the muscles of the limbs and trunk are involved, a “drop attack” can occur, causing the patient to suddenly collapse. Atonic seizures occur mainly in children.
Breakthrough seizures, inappropriate alterations in effective therapy, therapeutic complacency, and toxic side effects may result if the clinical considerations of efficacy and adverse effects are not given priority in adjustments to AED dosage.
Complex Partial Seizure
These seizures are characterized by impaired consciousness and lack of responsiveness. At seizure onset, the patient becomes motionless and stares with a fixed gaze. This state is followed by a period of automatism, in which the patient performs repetitive, purposeless movements, such as lip smacking or hand wringing. Seizures last 45 to 90 seconds.
---In contrast to seizures, convulsion has a more limited meaning, applying only to abnormal motor phenomena, for example, the jerking movements that occur during a tonic-clonic attack. Accordingly, although all convulsions may be called seizures, it is not correct to call all seizures convulsions.
---Convulsions, characterized by a period of muscle rigidity (tonic phase) followed by synchronous muscle jerks (clonic phase).
The term epilepsy refers to a group of chronic neurologic disorders characterized by recurrent seizures, brought on by excessive excitability of neurons in the brain. Symptoms can range from brief periods of unconsciousness to violent convulsions. Patients may also experience problems with learning, memory, and mood, which can be just as troubling as their seizures.
Fever-associated seizures are common among children ages 6 months to 5 years. Febrile seizures typically manifest as generalized tonic-clonic convulsions of short duration. Children who experience these seizures are not at high risk of developing epilepsy later in life.
Seizures are initiated by synchronous, high-frequency discharge from a group of hyperexcitable neurons, called a focus. A focus may result from several causes, including congenital defects, hypoxia at birth, head trauma, brain infection, stroke, cancer, and genetic disorders. Seizures occur when discharge from a focus spreads to other brain areas, thereby recruiting normal neurons to discharge abnormally. The overt manifestations of any particular seizure disorder depend on the location of the seizure focus and the neuronal connections to that focus. The connections to the focus determine the brain areas to which seizure activity can spread.
Gamma- aminobutyric acid (GABA)
Several AEDs potentiate the actions of GABA, an inhibitory neurotransmitter that is widely distributed throughout the brain. By augmenting the inhibitory influence of GABA, these drugs decrease neuronal excitability and thereby suppress seizure activity. Drugs increase the influence of GABA by several mechanisms. Benzodiazepines and barbiturates enhance the effects of GABA by mechanisms that involve direct binding to GABA receptors. Gabapentin promotes GABA release. Tiagabine inhibits GABA reuptake, and vigabatrin inhibits the enzyme that degrades GABA, and thereby increases GABA availability.
Generalized Seizures (6 types)
Generalized seizures may be convulsive or nonconvulsive. As a rule, they produce immediate loss of consciousness.
1) Tonic-Clonic Seizures
2) Absence Seizures (Petit Mal)
- loss of consciousness for a brief time (10 to 30 seconds), involve mild, symmetric motor activity (eg, eye blinking), may have hundreds a day, primarily in children to early teens
3) Atonic Seizures
- sudden loss of muscle tone (neck muscles = "head drop", limbs/trunk = "drop attack" leading to collapse), occurs mainly in children
4) Myoclonic Seizures
5) Status Epilepticus
6) Febrile Seizures
- fever-associated, common among children 6 months to 5 years ,manifest as short generalized tonic-clonic convulsions, children who have this are not at high risk for developing epilepsy later in life
Gingival hyperplasia (excessive growth of gum tissue) is characterized by swelling, tenderness, and bleeding of the gums. In extreme cases, patients require gingivectomy (surgical removal of excess gum tissue). Gingival hyperplasia is seen in about 20% of patients who take phenytoin. Can risk be reduced? Yes. Evidence indicates that supplemental folic acid (0.5 mg/day) may prevent gum overgrowth. In addition, risk can be minimized by good oral hygiene, including dental flossing and gum massage. Patients should be taught these techniques and encouraged to practice them.
Fetal hydantoin syndrome, characterized by growth deficiency, motor or mental deficiency, microcephaly, craniofacial distortion, positional deformities of the limbs, hypoplasia of the nails and fingers, and impaired neurodevelopment.
It's a side affect of Phenytoin during pregnancy.
Lennox-Gastaut Syndrome (Mixed Seizures)
Lennox-Gastaut syndrome is a severe form of epilepsy that usually develops during the preschool years. The syndrome is characterized by developmental delay and a mixture of partial and generalized seizures. Seizure types include partial, atonic, tonic, generalized tonic-clonic, and atypical absence. 218In children with Lennox-Gastaut syndrome, seizures can be very difficult to manage.
- sudden muscle contraction that lasts for just 1 second, may be limited to one limb (focal myoclonus) or entire body (massive myoclonus)
-a period of central nervous system (CNS) depression resulting from marked impairment of consciousness during Tonic-clonic seizures.
Secondarily Generalized Seizures
These seizures begin as simple or complex partial seizures, and then evolve into generalized tonic-clonic seizures. Consciousness is lost. These seizures last 1 to 2 minutes.
Seizure is a general term that applies to all types of epileptic events and is not synonymous with convulsions.
Simple Partial Seizure
These seizures manifest with discrete symptoms that are determined by the brain region involved. Hence, the patient may experience discrete motor symptoms (eg, twitching thumb), sensory symptoms (eg, local numbness; auditory, visual, or olfactory hallucinations), autonomic symptoms (eg, nausea, flushing, salivation, urinary incontinence), or psychoillusory symptoms (eg, feelings of unreality, fear, or depression). Simple partial seizures are distinguished from complex partial seizures in that there is no loss of consciousness. These seizures persist for 20 to 60 seconds.
Neuronal action potentials are propagated by influx of sodium through sodium channels, which are gated pores in the cell membrane that control sodium entry. For sodium influx to occur, the channel must be in an activated state. Several AEDs, including phenytoin, carbamazepine, valproic acid, and lamotrigine, reversibly bind to sodium channels while they are in the inactivated state, and thereby prolong channel inactivation--> delaying return to the active state-->decrease the ability of neurons to fire at high frequency-->seizures are suppressed.
- seizure that persists for 15 to 30 minutes or longer or a series of recurrent seizures during which the patient does not regain consciousness, can be life threatening
- major convulsions, period of muscle rigidity (tonic phase),muscle jerks (clonic phase), cause urination, but not defecation.
Phenytoin [Dilantin, Phenytek] is our most widely used AED, despite having tricky kinetics and troublesome side effects. The drug is active against partial seizures as well as primary generalized tonic-clonic seizures. Phenytoin is of historic importance in that it was the first drug to suppress seizures without depressing the entire CNS. Consequently, phenytoin heralded the development of selective medications that could treat epilepsy while leaving most CNS functions undiminished.
Mechanism of action?
At the concentrations achieved clinically, phenytoin causes selective inhibition of sodium channels. Specifically, the drug slows recovery of sodium channels from the inactive state back to the active state. As a result, entry of sodium into neurons is inhibited, and hence action potentials are suppressed. Blockade of sodium entry is limited to neurons that are hyperactive. As a result, the drug suppresses activity of seizure-generating neurons while leaving healthy neurons unaffected.
Phenytoin has unusual pharmacokinetics that must be accounted for in therapy.
- varies between the different oral formulations of phenytoin. With the oral suspension and chewable tablets absorption is relatively fast, whereas with the extended-release capsules absorption is delayed and prolonged. Phenytoin can be administered IV to treat generalized convulsive SE, but other drugs are preferred.
- capacity of the liver to metabolize phenytoin is very limited. Doses needed to produce therapeutic effects are only slightly smaller than the doses needed to saturate the hepatic enzymes that metabolize phenytoin. Consequently, if administered in doses only slightly greater than those needed for therapeutic effects, the liver's capacity to metabolize the drug will be overwhelmed, causing plasma levels of phenytoin to rise dramatically.
-treat all major forms of epilepsy except absence seizures. The drug is especially effective against tonic-clonic seizures, and is a drug of choice for treating these seizures in adults and older children.
-active against certain types of dysrhythmias.
Effects on the CNS
- when doses are excessive, toxicity can occur, Nystagmus (continuous back-and-forth movements of the eyes), sedation, ataxia (staggering gait), diplopia (double vision), and cognitive impairment.
- (excessive growth of gum tissue) is characterized by swelling, tenderness, and bleeding of the gums.
- morbilliform (measles-like) rash
Effects in Pregnancy
- Phenytoin is a teratogen. It can cause cleft palate, heart malformations, and fetal hydantoin syndrome
- when administered by IV injection (to treat Status Epilepticus), cardiac dysrhythmias and hypotension may result
Purple Glove Syndrome
- rare condition characterized by swelling and discoloration of the hands and arms.
Carbamazepine [Tegretol, Tegretol-XR, Tegretol CR image, Carbatrol, Epitol, Equetro] is a cornerstone of epilepsy therapy. The drug is active against partial seizures and tonic-clonic seizures but not absence seizures.
Mechanism of Action
Carbamazepine suppresses high-frequency neuronal discharge in and around seizure foci. The mechanism appears to be the same as that of phenytoin: delayed recovery of sodium channels from their inactivated state.
- effective against tonic-clonic, simple partial, and complex partial seizures. Not effective against absence, myoclonic, or atonic seizures.
- manic-depressive illness
Trigeminal and Glossopharyngeal Neuralgias
-neuralgia is a severe, stabbing pain that occurs along the course of a nerve
-Absorption of carbamazepine is delayed and variable. Levels peak 4 to 12 hours after dosing. Overall bioavailability is about 80%. The drug distributes well to tissues.
-Elimination is by hepatic metabolism. Carbamazepine is unusual in that its half-life decreases as therapy progresses. During the initial phase of treatment, the half-life is about 40 hours. With continued treatment, the half-life decreases to about 15 hours because carbamazepine, like phenytoin and phenobarbital, induces hepatic drug-metabolizing enzymes. By increasing its own metabolism, carbamazepine causes its own half-life to decline.
- visual disturbances (nystagmus, blurred vision, diplopia), ataxia, vertigo, unsteadiness, and headache. Minimal when compared to phenytoin and phenobarbital Hematologic Effects
- Carbamazepine-induced bone marrow suppression can cause leukopenia, anemia, and thrombocytopenia. However, serious reactions are rare.
- the drug is teratogenic
- can inhibit renal excretion of water, apparently by promoting secretion of antidiuretic hormone.
-morbilliform rash (10% incidence), photosensitivity reactions, SJS, and TEN.
Valproic acid [Depakene, Depakote, Depakote ER, Depacon, Stavzor, Epival image] is an important AED used widely to treat all major seizure types. Although generally very safe, valproic acid has caused rare cases of severe hepatotoxicity and pancreatitis, both of which can be fatal. Also, the drug is highly teratogenic, and should not be used during pregnancy unless it is the only AED that will work. In addition to its use in epilepsy, valproic acid is used for bipolar disorder and migraine headache.
Mechanism of action
Valproic acid appears to act by three mechanisms. First, it shares the same mechanism as phenytoin and carbamazepine: suppression of high-frequency neuronal firing through blockade of sodium channels. Second, it suppresses calcium influx through T-type calcium channels. Third, it may augment the inhibitory influence of GABA.
Valproic acid is readily absorbed from the GI tract and is widely distributed throughout the body. The drug undergoes extensive hepatic metabolism followed by renal excretion.
Therapeutic responses are often seen at plasma levels of 50 to 100 mcg/mL. However, the correlation between plasma levels and therapeutic effects is not very narrow.
-drug is a first-line drug for all partial and generalized seizures.
- Like carbamazepine, can provide symptomatic control in patients with bipolar disorder (manic-depressive illness).
Valproic acid is generally well tolerated and causes minimal sedation and cognitive impairment. Gastrointestinal effects are most common. Hepatotoxicity and pancreatitis are rare but serious. Owing to teratogenic effects, valproic acid should be avoided during pregnancy.
Ethosuximide [Zarontin] is the drug of choice for absence seizures, the only indication it has. Absence seizures are eliminated in 60% of patients, and, in newly diagnosed patients, practical control is achieved in 80% to 90%. In a trial reported in 2010, which compared ethosuximide with lamotrigine and valproic acid, ethosuximide was more effective than lamotrigine, and better tolerated than valproic acid; seizure reduction with ethosuximide and valproic acid was the same.
Mechanism of action
Ethosuximide suppresses neurons in the thalamus that are responsible for generating absence seizures. The specific mechanism is inhibition of low-threshold calcium currents, known as T currents. Ethosuximide does not block sodium channels and does not enhance GABA-mediated neuronal inhibition.
Ethosuximide is well absorbed following oral administration. Therapeutic plasma levels range between 40 and 100 mcg/mL. The drug is eliminated by a combination of hepatic metabolism and renal excretion. Its half-life is 60 hours in adults and 30 hours in children. Ethosuximide does not induce drug-metabolizing enzymes.
Adverse effects and drug interactions
Ethosuximide is generally devoid of significant adverse effects and interactions. During initial treatment, it may cause drowsiness, dizziness, and lethargy. These diminish with continued use. Nausea and vomiting may occur and can be reduced by administering the drug with food. Rare but serious reactions include systemic lupus erythematosus, leukopenia, aplastic anemia, and Stevens-Johnson syndrome.
Phenobarbital, one of our oldest AEDs, is effective and inexpensive, and it can be administered just once a day. Unfortunately, certain side effects—lethargy, depression, learning impairment—can be significant. Hence, although phenobarbital was used widely in the past, it has largely been replaced by newer drugs that are equally effective but better tolerated.
Phenobarbital belongs to the barbiturate family. However, in contrast to most barbiturates, which produce generalized depression of the CNS, phenobarbital is able to suppress seizures at doses that produce only moderate disruption of CNS function. Because it can reduce seizures without causing sedation, phenobarbital is classified as an anticonvulsant barbiturate (to distinguish it from most other barbiturates, which are employed as sedatives or “sleeping pills”).
Mechanism of Antiseizure Action
Phenobarbital suppresses seizures by potentiating the effects of GABA. Specifically, the drug binds to GABA receptors, causing the receptors to respond more intensely to GABA itself.
Phenobarbital is administered orally, and absorption is complete. Elimination occurs through hepatic metabolism and renal excretion. Phenobarbital has a long half-life—about 4 days. As a result, once-daily dosing is adequate for most patients. In addition to permitting once-daily dosing, the long half-life has another consequence: 2 to 3 weeks are required for plasma levels to reach plateau. (Recall that, in the absence of a loading dose, an interval equivalent to four half-lives is required to reach plateau.)
- effective against partial seizures and generalized tonic-clonic seizures but not absence seizures. Intravenous phenobarbital can be used for generalized convulsive SE, but other antiseizure drugs are preferred.
Sedation and Induction of Sleep.
- drowsiness, sedation, irritable, hyperactive, depression, agitation, confusion
Exacerbation of Intermittent Porphyria.
- buildup of natural chemicals that produce porphyrin in your body
Use in Pregnancy.
- fetal malformation
Other Adverse Effects.
- interfere with the metabolism of vitamins D and K. Disruption of vitamin D metabolism can cause rickets and osteomalacia.
Gabapentin [Neurontin] has a broad spectrum of antiseizure activity. However, its only FDA-approved use in epilepsy is adjunctive therapy of partial seizures (with or without secondary generalization). The AAN/AES guidelines also recommend the drug for monotherapy of partial seizures. Gabapentin also has approval for treating postherpetic neuralgia. Interestingly, more than 80% of prescriptions are written for off-label uses, including relief of neuropathic pain (other than postherpetic neuralgia), prophylaxis of migraine, treatment of fibromyalgia, and relief of postmenopausal hot flashes. However, benefits in these disorders are modest, at best. Gabapentin does not appear effective in bipolar disorder.
Mechanism of Action
Gabapentin's precise mechanism of action is unknown. The drug is an analog of GABA, but does not directly affect GABA receptors. Rather, it may enhance GABA release, thereby increasing GABA-mediated inhibition of neuronal firing.
Gabapentin is rapidly absorbed following oral dosing and reaches peak plasma levels in 2 to 3 hours. Absorption is not affected by food. However, as the dosage gets larger, the percentage absorbed gets smaller because, at high doses, the intestinal transport system for uptake of the drug becomes saturated. Gabapentin is not metabolized and is excreted intact in the urine. Its half-life is 5 to 7 hours.
Unlike most AEDs, gabapentin is devoid of significant interactions. It doesn't induce or inhibit drug-metabolizing enzymes, and doesn't affect the metabolism of other drugs. As a result, gabapentin is well suited for combined use with other AEDs.