Receptor Fun
What receptor antagonism MUST you have for antipsychotics to be effective?
Dopamine (D2)
True or false, Overdoses of antipsychotics are rarely fatal?
True
Death most frequently from respiratory arrest, arrhythmia or aspiration induced resp failure.
How do you treat acute dystonic reactions?
Anticholinergic medications
- Relief within 10 mins
- Benztropine, diphenhydramine - may need repeat dosing
- If resistant can trial benzo
Name 4 symptoms of a carbamazepine overdose
- Ataxia, abnormal movements (choreoathetosis, dystonia..etc), coma (can be cyclical), seizures
- resp failure
- Cardiac conduction defects (tachy, RBB), hypotension
- Anticholinergic toxidrome (early)
True or false - Phenytoin commonly causes cardiac toxicity - why or why not?
Does inhibit myocardial sodium channels but is a type 1B (like lidocaine) - unbinds rapidly during repolarization/diastole thus no QRS prolonging
Instead typically = nystagmus, ataxia, CNS depression, N/V
What is the mechanism of VPA?
VPA increases the apoenzyme of glutamic acid decarboxylase, the enzyme that synthesizes GABA.
Name a general benefit of atypical antipsychotics?
- Less EPS
- Lower propensity to cause TD
How long should you monitor a patient with antipsychotic overdose at minimum?
Typically 6 hours or until asymptomatic
Name 4 symptoms of a VPA overdose
CNS: drowsiness can progress to coma rapidly (levels >5000), seizures, delayed cerebral edema, hyperammonia
CVS: Hypotension
GI: Hepatotoxicity (rarely severe)
Metabolic: Metabolic acidosis, hypoglycemia, hypocalcemia, hypophosphatemia, hypernatremia
Heme: Thrombocytopenia
In which scenario would you consider giving flumazenil for a benzodiazepine overdose?
- Competitive antagonist of GABAa receptor
- Known benzo naive + no proconvulsant agents + no history of seizure + no suspicion of proarrhythmic + significant benzo toxicity
- May precipitate withdrawal or seizure, perhaps arrhythmias, lasts 1-2h
How is aripiprazole unique?
Dopamine (D2) and serotonin partial antagonism
- Reduce dopaminergic neurotransmission when it's excessive and enhance
dopaminergic activity when it's deficient.
Can EPS be a presenting symptom for an overdose?
Yes, especially true in children - acute dystonia, parkinsonism, akathisia
If you really wanted to tell if a patient took olanzapine vs quetiapine what investigation could you order?
Urine General Tox Panel (the only 2 antipsychotics it tests for)
MDAC
Link the antiepileptic to it's overdose effect
- Drugs: Keppra, Lamotrigine, Topiramate
- Effect: QRS prolongation and serotonin toxicity, generally asymptomatic, NAGMA
- Lamotrigine = QRS prolongation and serotonin toxicity
- Keppra = generally asymptomatic, rarely CNS depression
- Topiramate = NAGMA (similar to acetazolamide structure), can also cause seizures
Name 5 receptor or channel actions of antipsychotics
- Alpha-1 adrenergic antagonism
- Alpha-2 receptor antagonism
- H1 histamine antagonism
- M receptor antagonism (anticholinergic)
- Serotonin blockade (primarily, but 5HT1a agonism)
- GABAa blockade
- Blockade of channels: Sodium, potassium, calcium
Link the medication to a particular symptoms in overdose
Medications = clozapine, Haloperidol, chlorpromazine
Effect = Torsades de pointes, seizure, anticholinergic
- Torsades de pointes = haloperidol
- Seizure = clozapine (10%)
- Anticholinergic = chlorpromazine (also clozapine and to an extent olanzapine)
Generally speaking, how do you treat antipsychotic overdoses?
- Activated Charcoal
Supportive care
- Intubation as required for low GCS or respiratory depression
- Fluid and inotropes for hypotension
- Typical treatment for seizures (no phenytoin), QRS/QTC prolonging, ?physostigmine
Name a particularity about carbamazepine pharmacokinetics/toxicokinetics
Absorption - peak concentration can be delayed 96h (due to slow dissolution from tablet and anticholinergic effect)
Distribution - protein binding 70-80%
Metabolism - Metabolized by CYP3A4, active metabolite
Excretion- time dependent elimination (induces it's own metabolism), half life average 36h, but varies 16-24h, 28% excreted into feces
Name an antiepileptic which can mimic brain death
- Baclofen
- Barbiturates
- Carbamazepine and VPA in case reports
State the clinical effects of the following and an antipsychotic that has particular action
- Alpha-1 adrenergic antagonism
- Alpha-2 receptor antagonism
- H1 histamine antagonism
- M1 receptor antagonism
- Alpha-1 adrenergic antagonism - hypotension (olanz, cloz, risp)
- Alpha-2 receptor antagonism - sympathomimetic effects (cloz, risp)
- H1 histamine antagonism- CNS depression, low BP (cloz, quet, olanz)
- M1 receptor antagonism- anticholinergic (cloz, olanz)
List 10 symptoms of an antipsychotic overdose
CNS - confusion, agitation, delirium, hyperthermia (or hypo), lethargy, slurred speech, ataxia, sialorrhea (cloz), EPS
CVS - Hypotension, hypertension, tachycardia, conduction disturbances (QTC, QRS), atrial, ventricular dysrhythmias
Resp - depression, acute pulmonary edema (rare)
GU - Urinary retention
Are most antipsychotics dialyzable, why or why not?
Highly lipophillic, protein bound and large volume of distribution (distribute to the brain and other tissues)
How should you treat a patient with hyperammonemia and encephalopathy in the context of a VPA overdose?
L-carnitine - (more beta-oxidation and is used to shuttle fatty acids into mitochondria) may also help with hepatotoxicity
?Carbapenems - stops reverse glucuronidation
Dialysis
For which antiepileptics do extrip guidelines recommend dialysis for in certain situations, name 3
Baclofen - In severe toxicity with kidney impairment
Barbiturates - If prolonged coma expected, shock post fluid resus of if despite MDAC toxicity persists
Carbamazepine - If multiple seizures, life threatening arrhythmias, suggested if coma, or high levels despite MDAC
Gabapentin - Severe toxicity and kidney impairment
Phenytoin - Severe toxicity
VPA - Level >9000 (consider 6250), shock, cerebral edema, consider if coma, high ammonia, pH<7.1
Name a medication used to treat NMS
- Dantrolene (direct skeletal muscle relaxant)
- Bromocriptine or amantadine (dopamine agonist)