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HY points followed by a quiz at the end
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Hypnotics (sleep-inducing agents)
Benzodiazepines
MOA of benzos?
- Agonize GABAA receptor and cause ↑ frequency of chloride channel opening.
Short-acting benzos: Midazolam
Intermediate-acting benzos: Alprazolam, Clonazepam, Lorazepam
Long-acting benzos: Chlordiazepoxide, Diazepam
When are they the answer for USMLE?
- Used for acute anxiety and/or acute insomnia
- 38F + mother recently diagnosed with breast cancer + recently sent kid off to college + stressed at work + having trouble sleeping; next best step in pharmacologic therapy? –> answer = clonazepam (answer on NBME)
- Never give benzos for chronic use (cause dependence).
- Social phobia if patient has asthma
- 35M + needs to give presentation on stage in front of people; next best step in pharmacologic therapy? –> answer = propranolol.
- 35M + needs to give presentation on stage in front of people + has history of asthma; next best step in pharmacologic therapy? –> answer = clonazepam (highly efficacious in social phobia).
- Psych NBME for 2CK has two nearly identical Qs back-to-back; one has asthma; the other doesn’t; propranolol is correct in the non-asthma vignette; clonazepam is correct in patient with asthma Hx.
- Alcohol withdrawal / delirium tremens
- 44M + in hospital for past 48 hours following surgery + now is tremulous + tachy + high BP; next best step in pharmacologic therapy? –> answer = diazepam, lorazepam, or chlordiazepoxide.
- 44M + cut down to 2 beers a day from 12 beers a day + tremulous and tachy; next best step? –> answer = diazepam, lorazepam or chlordiazepoxide –> can get delirium tremens even when not cutting down fully (oh wow).
- Panic attack
- 17M + footballer + tachy + feels like he’s going to die + breathing rapidly; next best step in pharmacologic therapy? –> benzodiazepine (used for panic attack) –> should be noted that before benzos, breathing into paper bag is correct if listed (the aim is to calm their respirations).
- 17M + has third panic + now completely resolves; how to best prevent future attacks pharmacologically? –> answer = SSRI, not benzo.
- SSRIs = Tx for panic disorder (prevents recurrent attacks; used between attacks); benzo = Tx for panic attack (acute).
- Status epilepticus (seizure lasting >5 minutes)
- Diazepam is usually used, but can be other benzos.
- Sequence is: benzo first; if not successful, use phenytoin; if not successful, use barbiturates; if not successful, use general anaesthesia. In other words: diazepam –> (fos)phenytoin –> phenobarbital –> propofol.
Adverse effects of benzos?
- Respiratory depression with a normal A-a gradient (arterial oxygen is low because the patient is hypoventilating, so alveolar oxygen is also low).
- 19M + found unconscious with bottle of diazepam; which combination of findings best reflects this patient’s current status? –> answer = high pCO2, low pH (respiratory acidosis), normal bicarb (not enough time to change), normal, not high, A-a gradient.
- Anterograde amnesia (can’t remember new things).
- Dependence (don’t give to patients for chronic use).
Treatment for benzo overdose?
- Flumazenil (GABAA receptor antagonist).
- Some literature says don’t give in the emergency setting because it can precipitate seizures in those who are benzo-dependent, but a 2CK NBME Q has flumazenil as the answer in this setting.
Barbiturates (phenobarbital, thiopental)
MOA of barbiturates?
- Agonize GABAA receptor and cause ↑ duration of chloride channel opening.
When are barbiturates the answer for USMLE?
- Truthfully, not often. USMLE wants you to know that they cause respiratory depression, similar to benzos and opioids. So the same concepts hold true as far as patients who have high CO2 and low O2 with a normal A-a gradient.
- Used for status epilepticus after phenytoin, as per above:
- Sequence is: benzo first; if not successful, use phenytoin; if not successful, use barbiturates; if not successful, use general anaesthesia. In other words: diazepam –> (fos)phenytoin –> phenobarbital –> propofol.
- Treatment for overdose is supportive (ABCs). Flumazenil is for benzos only.
- Have rare uses such as Criger-Najjar syndrome type II (you won’t get asked, but students sometimes ask me about this one).
- Contraindicated in porphyrias (i.e., acute intermittent porphyria; porphyria cutanea tarda). Barbiturates upregulate δ-ALA synthase → increased production of heme precursors → patients with porphyrias who lack conversion enzymes will get precursor overload and become symptomatic.
Non-benzo hypnotics (Zolpidem, Zaleplon)
MOA of zolpidem and zaleplon?
- Agonize GABAA receptor at location distinct from benzos.
When are zolpidem and zaleplon the answer on USMLE?
- Can be used for acute insomnia.
- Answer on one of the 2CK Psych forms for insomnia (benzo wasn’t listed, but of course other Qs will have benzo used acutely).
- If you then say, “But if USMLE listed both, which one is it then?” My response is: USMLE won’t list both like that. If they ever did, it would probably be in the context of a patient with history of substance dependence, where benzo would be a bad choice, even if acutely.
Anti-epileptic agents that block Na+ channels
Block sodium channels + ↑ GABA
- TV (television) –> Topiramate, Valproic acid
- Weird mnemonic, but it’s better than nothing and helps some students. Watching TV at night can put you to sleep (GABA).
- “TV…okay…well those are the ones that block sodium channels and increase GABA.”
- Topiramate + valproic acid used for tonic-clonic seizures.
When is topiramate the answer on USMLE?
- Topiramate I’ve never seen as an answer. Just know it as a common med + its MOA.
When is valproic acid the answer?
- First-line med for myoclonic seizures (twitching of limb + no loss of consciousness + no prodrome).
- Teratogen (causes neural tube defects –> stop drug before getting pregnant; if Hx of taking valproic acid, patients need 10x dose of folic acid prior to + during early pregnancy (400 ug –> 4mg/day). Other anti-epileptics (i.e., carbamazepine, phenytoin) can also cause neural tube defects, but the association is notably associated with valproic acid.
- These agents cause folate (B9) deficiency via decreasing intestinal absorption.
- 39M + taking valproic acid + Q shows you image of hypersegmented neutrophil; what’s he deficient in? –> answer = B9, not B12. Hypersegmented neutrophils + ↑ MCV are of course seen in both B9 and B12 deficiencies.
- Weird HY detail about valproic acid is that it is the answer for patients with absence seizures who’ve also had a history of other seizures. For example:
- 5M + stares off blankly into space during class + EEG shows 3Hz spikes; Tx? –> answer = ethosuximide (used for absence seizures in isolation; blocks thalamic T-type calcium channels).
- 5M + stares off blankly into space during class + EEG shows 3Hz spikes + had tonic-clonic seizure several months back; Tx? –> answer = valproic acid (kid also has Hx of tonic-clonic seizure, so valproic acid is correct over ethosuximide. Oh wow.)
Only block sodium channels
- Carbamazepine, Lamotrogine, Phenytoin
- “TV are the ones that block sodium channels and increase GABA, so these are the ones that only inhibit sodium channels. Meaning, because they’re not TV (putting people to sleep at night), they don’t affect GABA.”
When is carbamazepine the answer?
- First-line for trigeminal neuralgia.
- For diabetic neuropathic pain, use TCAs (i.e., amitriptyline) first-line. However in elderly (where we want to avoid TCAs), carbamazepine + gabapentin can be combined first-line (on FM form for 2CK).
- Standard first-line Tx for tonic-clonic seizures (as are valproic acid, phenytoin, and others).
When is lamotrogine the answer?
- Is notably associated with Stevens-Johnson syndrome (SJS).
- SJS can occur with any number of agents, but for some reason lamotrogine is known to have a strong association.
- And of course know its MOA (blocks sodium channels).
When is phenytoin the answer?
- Causes fetal hydrantoin syndrome in neonates born to mothers taking it while pregnant –> fingernail hypoplasia + any number of miscellaneous findings, e.g., facial and organ system defects. Carbamazepine and valproic acid can also cause fetal hydrantoin syndrome in theory, but the association is classically phenytoin.
- Can cause neural tube defects similar to valproic acid and carbamazepine (due to B9 deficiency).
- Standard first-line Tx for tonic-clonic seizures (as are valproic acid, carbamazepine, and others).
- Used after benzos in the treatment of status epilepticus (use benzo, then phenytoin, then barbiturate, then propofol).
- Can cause purple glove syndrome (PGS) –> swollen purple extremities in patients receiving high-dose phenytoin. Weird, but Google it.
Anti-epileptic agents that block Ca2+ channels
Ethosuximide
MOA of ethosuximide?
- Blocks thalamic T-type calcium channels.
When is ethosuximide the answer on USMLE?
- For absence seizures in kids who don’t also have other types of seizures. Once again:
- 5M + stares off blankly into space during class + EEG shows 3Hz spikes; Tx? –> answer = ethosuximide (used for absence seizures in isolation; blocks thalamic T-type calcium channels).
- 5M + stares off blankly into space during class + EEG shows 3Hz spikes + had tonic-clonic seizure several months back; Tx? –> answer = valproic acid (kid also has Hx of tonic-clonic seizure, so valproic acid is correct over ethosuximide. Oh wow.).
Gabapentin
MOA of gabapentin?
- Inhibits high-voltage-activated calcium channels.
- Used for neuropathic pain (e.g., due to injuries, stroke).
- Choose TCA (i.e., amitriptyline) over gabapentin first-line for diabetic neuropathic pain if not elderly. In elderly, use gabapentin + carbamazepine, OR just nortriptyline (TCA that can be used in elderly). This is on FM 2CK form.
Levetiracetam
MOA of levetiracetam?
- Blocks pre-synaptic calcium channels. May increase GABA.
Other (lower-yield) anti-epileptic agents
Vigabatrin
MOA of vigabatrin?
- Inhibits GABA transaminase → ↑ GABA.
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