DNAP707_Anticonvulsants_2024.ppt

DNAP707: Pharmacology for Nurse Anesthetists Anticonvulsant Drugs Jill Bettinger, Ph.D. Dept. of Pharmacology and Toxicology [email protected] Seizures ehavioral consequence of a transient episode of abnormal electrical activity in the brain. Disordered synchronous and rhythmic firing of neurons....

DNAP707: Pharmacology for Nurse Anesthetists Anticonvulsant Drugs Jill Bettinger, Ph.D. Dept. of Pharmacology and Toxicology [email protected] Seizures ehavioral consequence of a transient episode of abnormal electrical activity in the brain. Disordered synchronous and rhythmic firing of neurons. Primarily arise from cerebral cortex. 10% of Americans experience a seizure in their lifetimes ny causes, some unknown: brain injury (stroke, head injury, tumor) infection (meningitis, etc.) electrical shock fever (febrile seizures in young children) kidney or liver failure sodium or glucose imbalance malignant hypertension drug abuse withdrawal from alcohol or other depressant drugs genetic predisposition epilepsy Epilepsy Repeated, unpredictable seizures Many causes, most unknown Prevalence in children decreasing, but prevalence in elderly increasing ~3% of Americans will be diagnosed with epilepsy in their lifetimes brain injury (traumatic or illness) stroke or transient ischemic attack disease progression (Alzheimer’s) metabolism disorders blood vessel abnormalities certain medications genetic contributions Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized EXTREMELY important to diagnose correctly as different drugs are effective for different types of seizures. Absence Myoclonic Tonic-Clonic Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized Begin focally in a cortical site Absence Myoclonic Tonic-Clonic Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized Diverse manifestations determined by the region of cortical involvement. drugline.org Absence Myoclonic Tonic-Clonic Seizure Types Seizures Focal Generalized Focal Aware Impaired consciousness lasting 30 sec – 2 min Focal with Impaired often associated with Awareness purposeless movements. Absence Consciousness preserved Myoclonic Consciousness altered Focal to Bilateral Tonic-Clonic Most originate in the temporal lobe Tonic-Clonic Can be difficult to control. Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized Loss of consciousness. Involve both hemispheres widely from the outset. Abrupt onset associated with staring and cessation of ongoing activities. Typically last 30 seconds or less. Absence Myoclonic Tonic-Clonic Seizure Types Seizures Focal Focal Aware Generalized Loss of consciousness. Consciousness preserved Focal with Impaired Awareness petit mal seizures Consciousness altered Focal to Bilateral Tonic-Clonic Absence Myoclonic Brief (less than 30 sec), associated with bilaterally synchronous, 3/second spike-and-wave EEG pattern. Tonic-Clonic Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized Brief (1 second) shocklike contraction of muscles. May be generalized or restricted to one extremity. Absence Myoclonic Tonic-Clonic Seizure Types Seizures Focal Focal Aware Consciousness preserved Focal with Impaired Awareness Consciousness altered Focal to Bilateral Tonic-Clonic Generalized Loss of consciousness. Absence grand mal seizure Sustained contraction Myoclonic of muscles (tonic) throughout the body, Tonic-Clonic followed by periods of rhythmic limb movement (clonic). Typically last 1-2 minutes Seizure Types atus Epilepticus ergency situation. Hypoxia can result; ~20% morbidity. izure that lasts more than 5 minutes or multiple prolonged seizures without full recovery between episodes. th convulsive (usually) and non-convulsive (rarely) types of seizure n cause permanent neuronal changes and brain damage. eatments include diazepam or lorazepam or, more aggressively, the induction of anesthesia. % of emergency hospital visits ANTI-EPILEPTIC DRUGS (AED) rent treatment goal is to treat symptoms. PROPHYLAXIS, NO CURE hanisms of action: Diverse, but all prevent xcessive discharge of affected neurons, prevent spread of excessive activity to ormal neurons. s control seizures in 60-80% of patients. Epilepsy Mechanisms Electroencephalograph (EEG) analysis demonstrated t epilepsy is a disorder of neuronal activity. 1. Enhanced excitatory activity Ionic: Na+, Ca2+ currents Neurotransmitter: glutamate 2. Reduced inhibitory activity Ionic: Cl-, K+ currents Neurotransmitter: GABA Action Potentials K+ channel opens in response to voltage (and Ca2+) change All Na+ channels open; massive membrane depolarization action potential Na+ channel inactivation gate CLOSED Na+ influx outpaces K+ efflux; membrane potential increases Balance between Na+ influx and K+ efflux Inactivation gate OPEN action potential possible Inactivation gate CLOSED NO action potential ANTI-EPILEPTIC DRUGS mechanisms of action lation of cation channels (Na+, K+, Ca2+) : prolong inactivation, K+: positive modulation, Ca2+: inhibit nce GABA transmission (inhibitory) ivate GABAA, decrease GABA metabolism, inhibit GABA reuptake late synaptic transmission on SV2A, act on Ca2+ channels (with a2d subunit) ease glutamate transmission (excitatory) rease AMPA currents Mechanism of action: Blockade of Na+ channels Na+ channels open during action potential Close into by INACTIVE STATE that requires a recovery peri Action potentials INHIBITED These drugs promote the inactive state of the Na+ channel. control carbamazepine phenytoin Mechanism of action: Blockade of Na+ channels Na+ channels open during action potential Close into by INACTIVE STATE that requires a recovery peri Action potentials INHIBITED These drugs promote the inactive state of the Na+ channel. PHENYTOIN (Dilantin) Widely used to treat partial AND tonic-clonic seizures. Effective for all types except ABSENC Side Effects: nausea, vomiting, rashes control carbamazepinephenytoin darkening of skin, abnormal hair growth, constipation. also alters metabolism of drugs (warfarin oral contraceptives Mechanism of action: Blockade of Na+ channels Na+ channels open during action potential Close into by INACTIVE STATE that requires a recovery peri Action potentials INHIBITED These drugs promote the inactive state of the Na+ channel. CARBAMAZEPINE (Tegretol) Related to tricyclic antidepressants. WIDELY used to treat partial AND tonic-clonic seizures. Effective for all types except ABSENCE control carbamazepinephenytoin Also used to treat BIPOLAR DISORDER Side Effects: dry mouth, potentially f skin reactions. Mechanism of action: UNCERTAIN, but probable blockade of Na+ channels in vitro pharmacological data suggest that it inhibits voltagesensitive Na+ channels. (this leads to a decrease in glutamate) LAMOTRIGINE (Lamictal) Used to treat partial seizures; effective against more types than phenytoin Side Effects: potentially fatal skin reactions, headaches, insomnia, acne (more common in women). OXCARBAZEPINE (Trileptal) Used to treat partial seizures Side Effects: dizziness, fatigue, nau tremor, ataxia. ANTI-EPILEPTIC DRUGS mechanisms of action lation of cation channels (Na+, K+, Ca2+) : prolong inactivation, K+: positive modulation, Ca2+: inhibi nce GABA transmission (inhibitory) ivate GABAA, decrease GABA metabolism, inhibit GABA reuptake late synaptic transmission on SV2A, act on Ca2+ channels (with a2d subunit) ease excitation rease AMPA currents Action Potentials GABA receptors are Cl- channels, when activated, they counter depolarization of the neuron, making it harder to reach the threshold for an AP echanism of action: Potentiation of GABA Cl- channel GABAA receptors are ion channels that allow influx of Cl- ions i neurons. Causes increase in negative charge inside cell. Potentiation of this Cl- influx = HYPERPOLARIZATION Inhibits activity of the neuron. These drugs potentiate GABAA receptors. echanism of action: Potentiation of GABA Cl- channel BARBITURATES Phenobarbital (Luminal) Primidone (Mysoline)- this one is metabolized to Phenobarbitol enhances length of opening of GABAA receptors used to treat complex and simple and tonic-clonic seizures Major side effect is sedation, but tolerance develops to the sedation w/ tolerance to the anticonvulsant effec Produces physical dependence echanism of action: Potentiation of GABA Cl- channel am BENZODIAZEPINES Clonazepam (Klonopin) Clorazepate (Tranxeme)- only two in approved for long term treatment seizures enhances frequency of opening of GABAA receptors used to treat absence and myoclonic seizures Major side effect is sedation. Produces physical dependence (Versed) is rapid onset; used in emergency treatment of Status E echanism of action: NOT CLEAR, but increase levels of GABA in brain which activates GABAA Cl- channels VALPROIC ACID (Valparin) (Depakene) (Depakote) etc. inhibits GABA-transaminase (GABA-T degrades GABA) increases GABA concentrations So probably enhances opening of GABAA receptor Cl- channels, also seems to act to promote inactive state of Na+ channels also likely to act on T-type Ca2+ chan UNUSUAL: used to treat partial, tonic-clonic, absence and myoclonic seizures Side effects: hepatic toxicity & failure fatal pancreatitis (mostly in children) teratogenic: neural tube defects (spina bifida) Mechanism of action: PROBABLY through irreversible inhibition of GABA transaminase VIGABATRIN (Sabril) Binds to and inactivates GABA-T, which is the enzyme responsible for metabolizing and eliminating GABA. Inhibition of GABA-T probably results in increases in GABA in brain. Irreversible inhibition, so the duratio action depends on how fast GABA-T is synthesized. Side effects: permanent vision damage i 30-60% of people. Mechanism of action: PROBABLY through inhibition of GABA reuptake carrier TIAGABINE (Gabitril) Binds to GABA recognition sites on th GAT-1 GABA reuptake transporter. This prevents presynaptic uptake o released GABA, this probably results in increases in GABA in brain. Side effects: confusion, sedation, slurring of speech, paresthesias Summary so far: Decreasing excitation (Na+ channels) Increasing inhibition (GABA signaling) ANTI-EPILEPTIC DRUGS mechanisms of action lation of cation channels (Na+, K+, Ca2+) : prolong inactivation, K+: positive modulation, Ca2+: inhibit nce GABA transmission (inhibitory) ivate GABAA, decrease GABA metabolism, inhibit GABA reuptake late synaptic transmission on SV2A, act on Ca2+ channels (with a2d subunit) ease excitation rease AMPA currents Mechanism of action: Limit voltage-regulated Ca2+ channel activity ABSENCE seizures: reciprocal firing in thalam and cortex Thalamic neurons have a large amplitude low-thresho (“T”) voltage-regulated Ca2 current. Uses T type Ca2+ channels Mechanism of action: Limit voltage-regulated Ca2+ channel activity ABSENCE seizures: reciprocal firing in thalam and cortex Thalamic neurons have a large amplitude low-thresho (“T”) voltage-regulated Ca2 current. NISAMIDE (Zonegran): vitro studies show that it reduces T-currents. y also block Na+ currents. Mechanism of action: Limit voltage-regulated Ca2+ channel activity ABSENCE seizures: reciprocal firing in thalam and cortex Thalamic neurons have a large amplitude low-thresho (“T”) voltage-regulated Ca2 current. IMIDE (Zarontin): Mechanism of action controversial. , in vitro studies suggested that it blocks T-currents. Has d. Current thought is that it physically blocks the channels ANTI-EPILEPTIC DRUGS mechanisms of action ulation of cation channels (Na+, K+, Ca2+) + : prolong inactivation, K+: positive modulation, Ca2+: inhibi ance GABA transmission (inhibitory) tivate GABAA, decrease GABA metabolism, inhibit GABA reuptake ulate synaptic transmission t on SV2A, act on Ca2+ channels (with a2d subunit) rease excitation crease AMPA currents Mechanism of action: UNKNOWN but probably acting on SV2A in synapses IRACETAM (Keppra) sm of action not elucidated. Eliminates burst firing without al neuronal excitability. This suggests that it may prevent agation of seizure firing patterns. n shown to bind to the SV2A protein in synaptic vesicles, an kinetics suggest that this binding is involved in the anti-s vity of the drug. fects: headache, infection, asthenia (general weakness), olence, dizziness ANTI-EPILEPTIC DRUGS mechanisms of action ulation of cation channels (Na+, K+, Ca2+) + : prolong inactivation, K+: positive modulation, Ca2+: inhibi ance GABA transmission (inhibitory) tivate GABAA, decrease GABA metabolism, inhibit GABA reuptake ulate synaptic transmission t on SV2A, act on Ca2+ channels (with a2d subunit) rease excitation crease AMPA currents UNKNOWN Mechanism of action: UNKNOWN APENTIN (Neurotonin) nism of action not elucidated. However, it does appear to in vels of GABA. also used to relieve nerve pain GABALIN (Lyrica) nism of action not clear, but it does bind to a subunit of t ltage-gated Ca2+ channel. Probably acts through this effect. neither of these drugs is subject to metabolism, and they d duce hepatic enzymes, and no significant drug interactions h en reported. Mechanism of action: UNKNOWN IRAMATE (Topamax) nism of action not elucidated. possible mechanisms: ocks voltage-dependent Na+ channels hances GABA signaling at some subtypes of GABA A receptor tagonizes the AMPA glutamate receptor hibits carbonic anhydrase enzyme (catalyzes reversible conve of CO2 to H2O + bicarbonate + protons, involved in acid bala effects: weight decrease, fatigue, insomnia, memory problems Mechanism of action: UNKNOWN BAMATE (Felbatol) nism of action not elucidated. es block the glycine binding site of NMDA receptor effects: VERY SERIOUS: hepatoxicity, aplastic anemia. y used for refractory seizure control Major Side Effects eral: nduction of hepatic cytochrome P450 enzymes. drugs induce liver enzymes: rbamazepine Oxcarbazepine enytoin Vigabatrin Phenobarbital Lamotrigine t is an acceleration of metabolism of some drugs, including hoxusimide Tiagabine Topiramate lproate Zonisamide ases effectiveness of some lipid soluble drugs: al contraceptives, anticoagulants, immunosuppressants. tion of cytochrome P450s associated with Vitamins D & K defi is effect requires approximately 7 days to occur or disappea Major Side Effects actions: (anorexia, nausea). Minimized when taken with food ution when combining with other drugs with GI effects SAIDs, opioids) ive CNS depression: some AED produce sedation that is additi th other CNS depressants ogenic effects: Many traditional AED generate a greater risk congenital malformations of a variety of types.