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USMLE - Pharm

Kaplan Section 4 Chapter 1 CNS Pharm - Sedative-Hypnotics & Anticonvulsants

QuestionAnswer
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
Created by: Missy Kratz Missy Kratz on 2008-02-13



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