Unit 3 Anticonvulsant Drugs Flashcards
Seizures
Sudden, transient episodes of brain dysfunction
Altered behavior due to abnormally excessive, synchronous, & rhythmic firing of hyper-excitable neurons in brain
Convulsions
Activation of motor neurons leading to involuntary contractions of skeletal muscle
Characteristic of seizures
Causes of seizures
CNS injury
Congenital abnormalities in brain
Genetic factors
Infections, hypoglycemia, hypoxia, toxic and metabolic disorders
Epilepsy
Chronic neurological disorder characterized by recurrent sizures
Primary (idiopathic) epilepsy
Unknown origin
Secondary epilepsy
identifiable cause (trauma, tumor, infection, etc.)
Most common partial seizure
Complex partial (temporal lobe)
Most common generalized seizure
Tonic-clonic (grand mal)
Simple Partial seizure
least complicated/severe
Minimal spread
No loss of consciousness, limited motor or sensory (one limb or muscle group)
Complex Partial seizure
Starts in a small brain area (temporal or frontal lobe) & quickly spreads to other areas (limbic system)
Altered consciousness with potential automatisms (don’t realize they are doing something)
Partial becoming generalized seizure
partial seizures that spread throughout brain & progress to generalized
Absence (petit mal) seizure
Generalized
Sudden onset & abrupt cessation (10-45 sec)
Brief loss of consciousness
Typical in children
Tonic-Clonic (grand mal) seizure
Generalized
Tonic spasms & major convulsions of entire body (bilateral)
Loss of consciousness
4 stages: Aura - sense of impending seizure
Tonic phase - muscle tensing & rigidity of all extremities, tremor
Clonic phase - convulsions due to rapid & repeating muscle contractions & relaxing Stuporous state & sleep
Atonic seizure
Generalized
Common in children
Loss in muscle tone
Status Epilepticus
Continuous or very rapid recurring seizures
Medical emergency requires immediate therapy
Epilepsy treatment options
Antiepileptic medications, surgery, vagus nerve stimulation
Antiepileptic medication goal
Restore normal patterns of electrical activity Inhibit seizures (& try to prevent from recurring), partially effective as prophylaxis, not a cure for seizures
Partial seizure with or without secondarily generalized anticonvulsant drugs
Carbamazepine (CBZ), Phenytoin (PHT), Valproate (VPA)
Drugs used for tonic clonic seizure (grand mal), tonic seizures, atonic seizures
Carbamazepine, Phenytoin, Valproate
Drugs used for Absence seizures (petit mal)
Ethosuzimide (ETH), Valproate
Drugs used for myoclonic seizures
Clonazepam, valproate
Drugs used for Status Epilepticus
Diazepam, Larazepam, Phenytoin, Fosphenytoin
Anticonvulsant drugs can inhibit firing by
- Decrease excitatory effects of glutamate & repetitive firing of neurons (block VG Na channels, etc.)
- Increase inhibitory effects of GABA
- Alter neuronal activation by altering movement of ions across neuronal membrane
Presynaptic targets diminishing glutamate release
Inactivation of VG Na channels, Inactivation of VG Ca channels, increase of K channel opening, SV2A synaptic vesicle proteins, CRMP-2
Postsynaptic targets diminishing glutamate release
Blockade of AMPA receptors, blockade of NMDA receptors
Anti-seizure agents bind to Na channel in what state?
Inactive state
Prevent conversion back to resting state to prolong inactivation & decrease firing
Targets increasing effects of GABA
Inhibition of GABA transporters (block GABA reputake), inhibition of GABA-transaminase (block GABA metabolism), Potentiates activation of GABAa receptors, GABAb receptors, Synaptic vesicular proteins
Anticonvulsant side effects
Sedation, diplopia, nystagmus, ataxia, GI upset
Abrupt withdrawal has potential for seizures, decrease efficacy of oral contraceptives, teratogenic, phenobarbital considered safest during pregnancy
Reduced activity of Ca channels in anticonvulsant agents
Reduce Ca influx - decreased transmitter release & prevent excitability
Effective against absence seizures (petiti mal) because of reduced pacemaker current
Phenytoin
Original drug - Hydantoins
Absorption varies, poorly soluble in aqueous
Metabolized in liver, dose-dependent (zero-order) elimination (can saturate enzyme system)
Fosphenytoin
Hydantoin
Newer, more soluble prodrug of phenytoin used for parenteral routes (IV & IM)
Phenytoin MOA
Block & prolong inactivated state VG Na channel -> decreases synaptic release of glutamate & block high-frequency neuron firing
Enhance release of GABA
Prevent seizure propagation
Phenytoin Clinical uses
Generalized tonic-clonic seizures (grand mal), Partial seizures, Status epilepticus
Phenytoin side effects
Sedation, ataxia, nystagmus, diplopia, cardiac dysrhythmias, hirsutism, gingival hyperplasia, osteomalacia, megaloblastic anemia, fetal hydantoin syndrome (cleft palate & lip, teratogenic)
Carbamazepine
Tricyclic compound
MOA: same as phenytoin, inhibition of VG Na channels
Well absorbed, hepatic metabolism (P450s)
Oxacarbazepine
Newer, similar to carbamazepine
Shorter half-life, but active metabolite has long duration & fewer drug interactions
Carbamazepine clinical uses
General clonic-tonic seizures, partial seizures, trigeminal neuralgia (drug of choice), bipolar disorder
Carbamazepine side effects & toxicity
CNS depression, osteomalacia, aplastic anemia, megaloblastic anemia
SIADH (syndrome of inappropriate ADH secretion; fluid retention & hyponatremia), Teratogenic (spina bifida & cleft lip/palate)
Carbamazepine drug itneractions
Phenytoin, valprate, phenobarbital
Phenobarbital
Barbiturate
MOA: enhances phasic GABAa receptor responses (increase opening time of Cl channel)
Phenobarbital clinical uses
Tonic-clonic, partial, myoclonic, generalized, neonatal (common drug of choice), & status epilepticus
Primidone
Metabolized by liver to phenobarbital & phenyl ethyl malonic acid
Ethosuximide
MOA: block presynaptic T-type Ca channel
Metabolized by liver
Ethosuximide clinical use
Absence seizures (petit mal) Drug of choice
Valproic acid
Least sedating
MOA: similar to phenytoin, inhibit presynaptic T-type Ca channels (block neuronal firing), inhibition of GABA transaminase
Valproic acid clinical uses
Partial seizures, tonic-clonic, absence seizure (drug of choice), bipolar disorder
Valproic acid adverse effects
Hepatotoxic syndrome, Teratogenic risk, GI upset, thrombocytopenia, pancreatitis, alopecia
Diazepam
Benzodiazepines
Used for status epilepticus (initial stop, not long term treatment) & seizure clusters
MOA: potentiate GABAa responses by increasing frequency of channel opening
Has sedative effects & can develop tolerance
Lorazepam
Benzodiazepines
Similar to diazepam but has longer duration of action - can be used to prevent status epilepticus
Gabapentin
Newer agent, amino acid, analog of GABA
Minimal hepatic metabolism (short 1/2 life)
MOA: block presynaptic VG Ca channels
Gabapentin clinical uses
Tonic-clonic, partial, generalized, Neuropathic pain (fibromyalgia, etc.)
Pregabalin
similar to gabapentin, GABA analog
Lamotrigine
Similar to carbamazepine
MOA: block presynaptic VG Na & Ca channels
Lamotrigine clinical uses
partial seizures, generalized seizures, tonic-clonic, absence
Lamotrigine adverse effects
Rash (especially if used with valproate), headache, ataxia, Stevens-Johnson syndrome
Felbamate (other agent)
Block Na channels & glutamate receptors
Used in seizure states (often as adjunct)
Cause aplastic anemia, hepatic failure
Topiramate (other agent)
Can cause sedation, confusion, parasthesias, anorexia
Interacts with zonisamide
Tiagabine (other agent)
Specifically designed as an inhibitor of GABA uptake
Partial seizures
Can cause sedation, dizziness, headache, tremor
Goal of muscle relaxants
Normalize muscle excitability without causing profound decreased muscle function
muscle spasticity
exaggerated muscle stretch reflex that occurs following injury to CNS
muscle spasm
increase in muscle tension seed after musculoskeletal injuries & inflammation (local, not CNS)
Diazepam
Increases central inhibitory actions of GABA on alpha motor neurons in spinal cord (increase frequency of chloride ion influx)
Treat muscle spasms (exertion, MS, cerebral palsy, injury)
Limitations - CNS depression
Baclofen
GABAb receptor agonist - increased K conductance, hyperpolarization, reduction in Ca influx, reduction in excitatory transmitter release
Reduces muscle spasticity with MS, spinal & brain injury
As effective as diazepam, but causes less sedation
