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USMLE - Pharm
Kaplan Section 4 Chapter 1 CNS Pharm - Sedative-Hypnotics & Anticonvulsants
| Question | Answer |
|---|---|
| In membrane depolarization, what is the direction of flow for Na and K? | inside of membrane is getter more positive, so Na is flowing IN and less K flowing OUT |
| In membrane hyperpolarization, what is the direction of flow for Cl and K? | inside of membrane is getter more negative, so Cl is flowing IN and more K flowing OUT |
| What are the two types of ion channels in the brain? | Voltage-gated (Na channels in propagation of AP's and presynaptic Ca channels for release of NTs) and transmitter-gated (direct coupling or G proteins) |
| Name two examples of voltage-regulated ion channels | 1. Na channels in axons (propagation of AP's), 2. Ca channels in presynaptic membranes |
| What are the voltage-gated ion channels in the CNS blocked by? | Anesthetics and some anticonvulsants --> dec neuronal excitability (CNS depression) |
| Name 4 examples of direct coupling NT-regulated ion channels | 1. GABA, 2. glutamate, 3. glycine, 4. Ach (N) |
| What are the direct coupling NT-regulated ion channels in the CNS blocked by? | 1. Anesthetics and 2. some anticonvulsants --> dec neuronal excitability (CNS depression). Also 3. cholinergic drugs and 4. sedative-hypnotics. |
| Name 2 groups of G-protein coupled NT-regulated ion channels | 1. amines (Ach, DA, NE, 5HT), and 2. peptides (endorphins) |
| What are the G-protein coupled NT-regulated ion channels in the CNS blocked by? | 1. analgesics, 2. antidepressants, 3. antipsychotics, 4. anxiolytics |
| Name the 2 excitatory NT's in the CNS | 1. glutamic acid, 2. Ach |
| Name the 2 NT's in the CNS that are both excitatory and inhibitory | 1. NE, 2. 5HT |
| Name the 3 inhibitory NT's in the CNS | 1. GABA, 2. DA, 3. Opioids |
| Glutamic acid. What type of channel? Which receptor? | 1. causes influx of cations --> excitatory, 2. direct coupling AND G-protein linked, 3. NDMA receptor |
| What drugs target the NMDA receptor? | This is the receptor for the NT, Glutamic Acid. Ketamine and PCP target this receptor. |
| GABA. What type of channel? | 1. causes hyper/repolarization --> Cl- IN and K+ OUT --> inhibitory, 2. direct coupling |
| What drugs target the GABA receptor? | 1. anticonvulsants, 2. sedatives, 3. hypnotics, 4. muscle relaxants |
| Ach. What type of channel? | 1. M1: Gq --> DAG --> decrease K+ going OUT --> depolarization --> excitatory. 2. M2: Gs --> inc cAMP --> increase K+ going OUT --> re/hyperpolarization --> inhibitory. 3. N: direct coupling --> Na+ IN --> excitatory. |
| What drugs target the Ach receptors (M1, M2, N)? | 1. Nicotine, 2. AchE inhibitors (Alzheimer's), 3. M blockers (Parkinson's) |
| Dopamine. What type of channel? | G-protein --> inhibitory (multiple subtypes). |
| What drugs increase the activity of Dopamine? | Drugs that increase dopamine activity (CNS stimulants, anti-Parkinson drugs) ultimately increase movement (dopamine receptors inhibit the globus pallidus internus, which inhibits movement; so inhibiting the inhibitor supports movement). |
| What drugs decrease the activity of Dopamine? | Antipsychotics -- ultimately work to slow activity of the brain. |
| What drugs affect the NE receptors in the CNS? | (both inhibitory and stimulatory) CNS stimulants, antidepressants, & some anxiolytics/sedatives (same as those that act on 5HT receptors) |
| What is special about the 5HT serotonin receptor? | this is the only one directly coupled to an ion channel. The other 5HT subtypes are coupled to second messengers. |
| What drugs affect the 5HT serotonin receptors in the CNS? | (both inhibitory and stimulatory) CNS stimulants, antidepressants, & some anxiolytics (same as those that act on NE receptors) |
| Opiods. What type of channel? | inhibitory, second messenger-coupled. |
| What drugs affect opioid receptors in the brain? | Opioid analgesics |
| Name 3 types of sedative-hypnotic drugs | benzodiazepines (BZ's), barbiturates, alcohols |
| What is the difference in the dose-response curve between BZ's vs. alcohols and barbiturates? | BZ's curve is flatter --> where an increase in dose doesn't have as much effect on the CNS (as opposed to alcohols and barbiturates, which have linear dose response relationships) -- BZ's plateau out before hitting the coma state |
| What is the mechanism of most sedative-hypnotic drugs? | GABA (inhibitory). |
| What is the difference between GABAa and GABAb? | Both are GABA receptors and lead to membrane hyperpolarization, but GABAa leads to increase Cl- IN, whereas GABAb leads to increase K+ OUT. |
| Wht drugs bind to the GABA receptor? | Sedative-hypnotics such as BZ's, alcohols, and barbiturates |
| What is the mechanism of BZ's? | Bind to GABAa --> increase FREQUENCY of Cl- ion channel opening |
| What is flumazenil? | BZ receptor antagonist -- decrease FREQUENCY of Cl- ion channel opening |
| What is the mechanism of barbiturates? | Bind to GABAa --> increase DURATION of Cl- ion channel opening |
| How does flumazenil block the effects of barbiturates? | It does not. It only blocks BZ action at the GABAa receptor, affecting the FREQUENCY of the Cl- ion channel opening. |
| What is the difference between the BZ1 receptor and the BZ2 receptor? | Both are receptors for benzodiazepines and are part of the GABAa receptor/Cl- channel complex. BZ1 mediates hypnotic actions; BZ2 plays role in memory, sensory-motor, and cognitive fxns. |
| What is zolpidem? | a non-BZ, but binds to the BZ1 receptor, used in sleep disorders |
| What is the advantage of using zolpidem? | More selective hypnotic than BZ's, less tolerance developed, and lower abuse and dependence than BZ's |
| How do you reverse the effects of zolpidem? | Use flumazenil (BZ1 receptor antagonist) |
| What drug is flumazenil comparable to? | Flumazenil (BZ antagonist) similar to naloxone (opioid receptor antagonist). Both are IV, short half-lives -- administered repeatedly, used in anesthesia to recover from CNS depressants (GABA/opioid agonists). |
| What is group of most commonly used drugs for the treatment of anxiety and sleep disorders? | Benzodiazepines (BZ's) |
| What are the side effects of BZ's? | Anterograde amnesia and dose-dependent CNS depression (sedation, disinhibition, nystagmus, ataxia, respiratory depression - high doses) |
| Where are BZ's metabolized? | Most in the liver --> form ACTIVE metabolites; 3 Out The Liver -- 3 undergo extrahepatic metabolism (no active metabolites) -- Oxazepam, Temazepam, Lorazepam |
| Can someone get addicted to BZ's? | Yes. Chronic use --> down-regulation of BZ receptors --> drug tolerance. Psychological and physical dependence occurs, but abuse and withdrawal are less intense than with EtOH or barbiturates. |
| What happens when a pt discontinues BZ's? | Rebound REM sleep (REM rebound is when your body starts making up all the REM sleep it didn't get); insomnia, and anxiety |
| Alprazolam -- what is it used for? Any special characteristics? | A BZ. Used for 1. anxiety (most commonly used anxiolytic), 2. panic, and 3. phobias |
| Diazepam -- what is it used for? Any special characteristics? | A BZ (longest acting BZ, forms THREE active metabolites). Used for 1. anxiety, 2. preop sedation, 3. muscle relaxation, 4. withdrawal states |
| Lorazepam -- what is it used for? Any special characteristics? | A BZ (no active metabolites, metabolized outside the liver). Used for 1. anxiety, 2. preop sedation, 3. status epilecticus (administered IV) |
| Midazolam -- what is it used for? Any special characteristics? | A BZ (shortest-acting BZ). Used for 1. preop sedation, 2. anesthesia (administered IV) |
| Temazepam -- what is it used for? Any special characteristics? | A BZ (slow oral absorption). Used for sleep disorders |
| Triazolam -- what is it used for? Any special characteristics? | A BZ (short-acting, possible early AM waking). Used for sleep disorders |
| Phenobarbital -- what is it used for? Any special characteristics? | A barbiturate (long-acting). Used for seizures |
| Thiopental -- what is it used for? Any special characteristics? | A barbiturate (short-acting). Used for IV anesthesthetic |
| What are the side effects of barbiturates? | 1. dose-dependent CNS depression -- can lead to nystagmus --> ataxia --> respiratory depression --> coma --> death (no plateau like BZ's), |
| What drug would you use if a patient OD's on barbiturates? | No specific antidote. |
| Where are barbiturates metabolized? | liver (induction of CYP450) -- some to active metabolites. |
| In what condition is barbiturate use contraindicated? Why? | Contraindicated in porphyrias because of increased heme synthesis. |
| Can someone get addicted to barbiturates? If so, what are the withdrawal sx's? | Tolerance and dependence can occur. Severe withdrawal: anxiety, agitation, hyperreflexia, seizures --> depression of vital functions |
| How would you manage someone with a barbiturate addiction? | treat with long-acting BZ (like diazepam) and dose-tapering. |
| What are Zolpidem and Zaleplon? | nonBZ's used in sleep disorders |
| What is the mechanism of Zolpidem and Zaleplon? | activate BZ1 receptors (although they are NOT BZ's) |
| What is Zaleplon? | a non-BZ, but binds to the BZ1 receptor, used in sleep disorders |
| What is the advantage of using Zaleplon? | More selective hypnotic than BZ's, less tolerance developed, and lower abuse and dependence than BZ's |
| How do you reverse the effects of Zaleplon? | Use flumazenil (BZ1 receptor antagonist) |
| What is Buspirone? | nonBZ used as anxiolytic, used for generalized anxiety states (takes 1 to 2 weeks to exert effects) |
| What is the mechanism of Buspirone? | Partial agonist at 5HTA receptors (no effect on GABA) |
| What are the advantages of Buspirone? | Non-sedating (for use as anziolytic), no ADDITIVE CNS depression like the other sedative-hypnotic drugs. Does not cause dependence. |
| Can you use Buspirone to reduce withdrawal sx's from other sedative-hypnotic drugs? | No, even though it doesn't cause dependence itself. |
| What drugs besides sedative-hypnotics can be used for sedation and sleep? | Antihistamines (i.e. hydroxyzine) and opioid analgesics. |
| What drugs would you use for status epilecticus? | BZ's Lorazepam & diazepam. Anticonvulsants: phenytoin or phosphenytoin (IV, so more water soluble) |
| What is the longest acting BZ? | Diazepam |
| What is the shortest-acting BZ? | Midazolam |
| What two BZ's are used for sleep disorders? | Temazepam and triazolam |
| What non-BZ's are used for sleep disorders? | Zolpidem and Zaleplon |
| What BZ has the slowest oral absorption? | Temazepam |
| What groups of drugs besides sedative-hypnotics can be used for anxiety characterized by panic and/or phobias? | SSRI's and TCA's (tricyclic anti-depressants) |
| What drug to use in patient with performance anxiety and social phobias? | Propranolol |
| What are the effects of ethylene glycol? | 1. CNS depression, 2. metabolic acidosis, 3. nephrotoxicity |
| What are the effects of methanol? | 1. severe anion gap metabolic acidosis, 2. ocular damage, 3. respiratory failure |
| What are the effects of methanol? | 1. NV, 2. headache, 3. hypoTN |
| How do you treat a Methanol OD? | fomepizole -- a long acting inhibitor of alcohol dehydrogenase (high Methanol levels will require hemodialysis) |
| How does EtOH affect folate? | Combines with folate to inactivate it --> too much EtOH leads to folate deficiency |
| How does EtOH affect thiamine? | Combines with thiamine to decrease availability --> too much EtOH leads to thiamine deficiency |
| What are the clinical manifestations of chronic alcoholism? | 1. hypoglycemia, 2. fatty liver and lipemia (excess lipids in the blood), 3. muscle wasting (poor food intake), 4. gout (lactate competes with urate for excretion) |
| What is the effect of fetal alcohol syndrome on the fetus? | 1. growth restriction, 2. midfacial hypoplasia, 3. microcephaly, 4. marked CNS dysfunction (frequent mental retardation) |
| What is disulfiram? | Drug that inhibits acetaldehyde dehydrogenase, which breaks down acetaldehyde (from EtOH) into acetic acid; prevents the formation of acetic acid. |
| What drugs have disulfiram-like effects? | Drugs that inhibit acetaldehyde dehydrogenase to prevent the formation of acetic acid: 1. metronidazole, 2. cefamandole, 3. cefoperazone, 4. cefotetan, 5. chlorpropamide |
| What is a seizure? | episodic electrical discharges in cerebral neurons associated with prolonged depolarization, during which sustained, high-frequency, repetitive firing (SHFRF) occurs. SHFRF is followed by prolonged hyperpolarization |
| Why do chronic alcoholics get gout? | Lactate competes with urate for excretion. |
| what is the goal of seizure management? | restoration of normal patterns of electrical activity |
| What are the mechanisms by which you can restore normal patterns of electrical activity in a seizure pt? (part 1) | 1. inhibition by stimulating GABA (causes hyperpolarization) -- barbiturates or BZ's. 2. block Na fast channels --> pervent Na influx --> prevent depolarization (anticonvulsants: carbamazepine, phenytoin) |
| What are the mechanisms by which you can restore normal patterns of electrical activity in a seizure pt? (part 2) | 3. block type T channels in thalamic neurons-->dec Ca INto presynaptic terminals-->block release of NTs (ethosuxamide, valproic acid), 4. dec glutamic acid (excitatory) fx: lamotrigine & topiramate block AMPA recptrs, felbamate blocks NMDA recptrs |
| What is the DOC for partial seizures (simple OR complex)? When would you avoid using these drugs? | Anticonvulsants: 1. valproic acid, 2. phenytoin, 3. carbamazepine -- except in pregnancy!!! |
| What to use for partial or tonic-clonic seizures in pregnant women? | phenobarbital |
| What is the DOC for general tonic-clonic seizures? When would you avoid using these drugs? | Anticonvulsants: 1. valproic acid, 2. phenytoin, 3. carbamazepine -- except in pregnancy!!! |
| What is the DOC for general absence seizures? When would you avoid using these drugs? | Anticonvulsants: 1. ethosuximide, 2. valproic acid. BZ: clonazepam. |
| In what situation would you want to use Clonazepam over the other anticonvulsants for general absence OR myoclonic seizures? | When you need marked sedation (anticonvulsant doses) |
| Phenytoin | Anticonvulsant. Blocks fast Na channels in inactivated state (state dependent) on axons --> decreased SHFRF. Also can be used as anti-arrhythmic and as back up in bipolar disorder. |
| What are the drug interactions of phenytoin? | Competition for plasma binding protein. Also induces CYP450. |
| Adverse effects of phenytoin | 1. sedation, 2. ataxia, 3. diplopia, 4. acne, 5. gingival overgrowth, 6. hirsutism, 7. osteomalacia, 8. hematotoxicity (granulocytopenia, megaloblastic anemia) |
| In what population in phenytoin contraindicated? | Pregnant woman. Teratogenic -- fetal hydantoin syndrome (cleft palate and lip). |
| Carbamazepine | Anticonvulsant. Blocks fast Na channels in inactivated state (state dependent) on axons --> decreased SHFRF. DOC for trigeminal neuralgia and as back up in bipolar disorder. |
| What are the drug interactions of phenytoin? | Is metabolized by CYP450 and also INDUCES CYP450 (induces its own metabolism) |
| Adverse effects of carbamazepine | 1. sedation, 2. ataxia, 3. diplopia (seizures in OD), 4. osteomalacia, 5. hematotoxicity (granulocytopenia, megaloblastic anemia, aplastic anemia) 6. inc ADH --> H2O retention, 7. exfoliative dermatitis |
| In what population in carbamazepine contraindicated? | Pregnant woman. Teratogenic -- craniofacial abnormalities and spina bifida. |
| Name all the older anti-convulsants (4) | Phunny (Pheny) Val's Ethos (character) requires CARBs and MArZiPan or else she convulses. Phenytoin, Valproic Acid, Ethosuximide, Carbamazepine. |
| Name all the newer anti-convulsants (6) | TIA's TOP MATE, GABby was a LAMO who FELl because she was convulsing VIGorously. Tiagabine, Topiramate, Gabapentin, Lamotrigine, Felbamate, Vigabatrin. |
| What is the mechanism of Ethosuxamide? What is it used for? | Blocks T-type Ca ion currents in thalamic neurons. Used only for absence seizures. |
| Adverse effects of ethosuximide | 1. GI distress, 2. fatigue, 3. lethargy |
| What does Mascha take for her trigeminal neuralgia? | Carbamazepine |
| Name the three actions of valproic acid | 1. block T-type Ca ion channels, 2. inhibits GABA transaminase --> more GABA --> more inhibition, 3. block Na axonal channels |
| What is GABA transaminase | enzyme that breaks down GABA to enter the TCA |
| What is valproic acid used for? | 1. All types of seizures except status epilepticus. 2. Backup for bipolar disorder. 3. migraines |
| Drug interactions of valproic acid | inhibits CYP450. Interacts with carbamazepine and phenytoin. |
| Adverse effects of valproic acid | 1. GI distress, 2. form toxic metabolite --> hepatotoxicity, 3. pancreatitis, 4. alopecia (hair loss), 5. tremor, 6. photosensitivity |
| In what population in valproic acid contraindicated? | Pregnant woman. Teratogenic -- spina bifida. |
| What happens when there is a sudden discontinuation of anticonvulsant meds? | abrupt withdrawal --> seizures |
| What should you especially ask women who are on anticonvulsants? | (make sure they're not pregnant first because it's teratogenic) Are you on OCP's? Anticonvulsants induce the CYP450 system, so drug metabolism is increased --> decreases efficacy of OCP's. |
| What is the mechanism of Felbamate? | Blocks Na and Ca channels; blocks glutamate receptors |
| For which diseases would you prescribe felbamate? | 1. partial seizures, 2. general myoclonic seizures (adjunct), 3. Lennox-Gastaut syndrome (child onset epilepsy) |
| Adverse effects of Felbamate | Aplastic anemia, acute liver failure |
| What is the mechanism of lamotrigine? | Blocks Na channels; blocks glutamate receptors |
| For which diseases would you prescribe lamotrigine? | General absence and partial seizures |
| Adverse effects of lamotrigine | 1. sedation, 2.ataxia, 3. diplopia, 4. Stevens Johnson Syndrome (skin damaged by hypersensitivity complexes) |
| What is Stevens Johnson Syndrome? | an immune-complex–mediated hypersensitivity complex that affects the skin and mucous membranes and is a severe expression of erythema multiforme |
| What is the mechanism of topiramate? | Blocks glutamate (AMPA) receptors; increases GABA effects --> increases inhibition |
| For which diseases would you prescribe topiramate? | Partial seizures |
| Adverse effects of topiramate | 1. sedation, 2.ataxia, 3. weight loss, 4. word-finding difficulty, 5. renal stones |
| What is the mechanism of gabapentin? | increases GABA effects --> increases inhibition |
| For which diseases would you prescribe gabapentin? | 1. partial seizures, 2. bipolar disorder, 3. migraine, 4. neuropathic pain |
| Adverse effects of gabapentin | 1. sedation, 2.ataxia, 3. cognitive change |
| What is the mechanism of Tiagabine? | Blocks GABA transporter (decreases the clearing away of GABA) --> increases GABA activity --> increase inhibition |
| For which diseases would you prescribe Tiagabine? | Partial seizures |
| Adverse effects of Tiagabine | 1. sedation, 2. dizziness, 3. "flu-like" sx's |
| What are the three new anticonvulsant drugs that you should use only for partial seizures? | Topiramate, tiagabine, and vigabatrin. |
| What is the mechanism of Vigabatrin? | inhibits GABA transaminase --> more GABA --> more inhibition |
| For which diseases would you prescribe Vigabatrin? | Partial seizures |
| Adverse effects of Vigabatrin | 1. depression, 2. psychosis, 3. visual dysfunction |
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christinapham
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