Neurologic Toxicity Dr. Peters (video) Flashcards
What magnifies the effect of antipsychotic overdoses?
they are taken with other agents - layering effect
-long-acting depot formulations, complex regimen
What are the symptoms you might see with Antipsychotic toxicity?
NMS
AMS
Qt or QRS prolongation
Hypotension
Tachycardia
Sedation
What the is duration of symptoms?
12-48 hours
What are Extra Pyramidal symptoms
What are the antidotes?
affects motor system
-involuntary movements
-muscle stiffness, and tremor
Antidotes:
-Benztropine (anticholinergic)
-diphenhydramine
What are the symptoms of NMS?
-Hyperpyrexia up to 42.2C (108F)
-Lead Pipe rigidity
-AMS (delirium/coma)
When does NMS usually occur?
How long does it usually last?
What leads to death?
-it occurs 3-9 days after initiating therapy or adding a 2nd agent
-can continue for 5-10 days
-rhabdomyolysis from lead pipe rigidity
-multisystem organ failure
-respiratory failure
-arrhythmias
How do you manage NMS?
-d/c the offending agent
-rapid external cooling
-Benzos: lorazepam for fast onset
What is Dantrolene and how does it work?
acts on the skeletal muscle
-prevents the increase in myoplasmic calcium that activates the process associated with hyperthermia
What is Bromocriptine and how does it work?
by D2 agonism
(more helpful later in the course of treatment than in the acute phase)
What causes Serotonin Syndrome?
excessive stimulation of the post-synaptic receptors in the CNS
-it is a toxic hyper-serotonergic state
What are the triad of symptoms of Serotonin Syndrome?
-AMS
-Autonomic instability
-Neuromuscular abnormalities (myoclonus)
When does serotonin syndrome usually develop?
rapidly
within 6h of an increase in the causing medication
(usually not caused by a single agent, but multiple serotonergic agents)
Know the various ways that serotonin can become a problem – the pharmacology
direct agonists
-Bupropion
-Lithium, LSD
-Sumatriptan
increases the release of serotonin
-Amphetamine, Cocaine, NMDA
-Mirtazapine
inhibitor of serotonin uptake
-MAOI
-Linezolid
Reduced uptake of serotonin
-SSRI, SNRI
-TCA
-Trazodone, Dextromethorphan
What’s the MOA for cyproheptadine?
-1st gen histamine antagonist
-non specific 5-HT1a and 5-HT2A receptor antagoist
Compare and contrast Serotonin Syndrome and NMS.
Serotonin Syndrome
-low fever
-lasting less than 24h
-responds to cyproheptadine and Benzos
-myoclonus, hyperreflexia (more in lower limbs)
NMS
-higher fever
-lasting more than 24 h
-responds to bromocriptine and dantrolene
-diffuse lead pipe rigidity
What’s the MOA of VPA toxicity?
-increases GABA availability to neurons (more inhibitory effect)
-blocks voltage-gated Na-channels (suppresses neuronal firing)
What’s the therapeutic drug conc of VPA?
50-100 mcg/ml
What are the alterations in kinetics with overdose?
peak concentration takes more time
-up to 18 hours
-protein-binding decreases - 35% protein bound in toxicity
-elimination is prolonged by 2-3 fold, half-life greater than 30h
-ß-oxidation results in CoA-metabolites that removes CoA-supplies in the mitochondria
-> without CoA substrates, other fatty acids accumulate - causing hepatic steatosis
-omega-oxidation produces hepatotoxin -> hyperammonemia (CNS effects)
How do patients present with VPA toxicity?
-CNS depression, lethargy due to hyperammonemia encephalopathy
-bone marrow suppression -> thrombocytopenia
What happens with hyperammonemia in VPA toxicity?
seizures due to osmotic shifts
also hyperammonemia encephalopathy
How does VPA impact bone marrow?
bone marrow suppression
How do you monitor VPA toxicity?
VPA serum concentration
BMP
LFTs (liver injury, omega oxidation)
Ammonia
Blood gas
Consider EEG for monitoring for seizures
How do you manage VPA overdose?
- supportive care: ABC (airway, breathing, circulation)
may use Levocarnitine
How does Levocarnitine work for VPA toxicity?
thought to help with ß-oxidation and improve urea cycle function, helps with hyperammonemia
Why can dialysis work for VPA overdose?
-bc it is a small molecule
-it is less protein-bound in overdose, so has a high free-fraction
How do carbapenems interact with VPA?
DDI that decreases VPA concentration
MOA not well known, assumed MOA:
-reduced intestinal absorption
-reduced enterohepatic recirculation
-shift of VPA to erythrocytes
How long does it take for VPA levels to decrease once carbapenems are given?
within hours of Carbapenem administration
How long does it take to recover drug levels after using a carbapenem is used?
no recovery for 7 days)
What aspect of VPA toxicity will not be managed with a carbapenem?
does NOT help with hyperammonemia (still need to use Levocarnitine, Arginine or HD)
What are the 3 classifications of Lithium toxicity and what types of patients fall in each category?
Acute
Chronic
Acute-on-chronic
How is lithium eliminated?
95% renal
halflife of 12-58 hours (hard to predict the pharmacokinetics)
Who are the patients affected by the acute toxicity of Lithium?
-not already on therapy
-low Lithium concentration
-example kids accidentally take their parents Lithium meds
What happens with large ingestions of Lithium in the stomach?
Acute Lithium toxicity
formation of a bezoars
-delays absorption for 48-72 hours (3 days)
How long does it take to reach equilibrium in the CNS in acute toxicity of Lithium?
can take up to 24h to reach equilibrium in the CNS
-so serum concentration may be elevated but they don’t experience symptoms yet, bc it has not reached the brain
What symptoms do you see in acute toxicity?
-N/V, diarrhea, epigastric pain
-CNS (early phase is often mild due to limited CNS distribution)
drowsiness, tremor,
Hyperreflexia !!
muscle weakness
Ataxia
later could be severe: coma, seizure, myoclonus
Who are the patients affected by the chronic toxicity of Lithium?
patients on Lithium therapy
How does chronic Lithium toxicity occur?
accidental toxicity often secondary to
-dose adjustments
-DDI
-decreased renal elimination or AKI
What drug interactions cause an increase in lithium toxicity?
ACE, thiazides, NSAIDs (via AKI) increase Li+
How does this toxicity present in chronic toxicity?
enhanced CNS distribution (more symptoms: drowsiness, ataxia, seizure) as compared to serum concentrations (might be at goal)
What life-threatening symptoms occur?
Chronic toxicity
-Hypotension
-Respiratory failure
-Dysrhythmias
if levels exceed 3 meq/L
What happens with long-standing Lithium toxicity?
Chronic toxicity
Syndrome of Irreversible Lithium toxicity (due to damage to the cerebellum)
long-lasting effects of:
-tremor, EPS
-gait difficulties
-nystagmus
-dysarthria
-cognitive deficits
Who are the Acute-on-chronic patients?
patients on chronic therapy and now exposed to excess Lithium, either by accident or intentionally
What is monitored with lithium toxicity?
-Serial lithium serum concentration
-Serial BMP (to monitor for AKI/resolution, as well as hypernatremia)
-Close monitoring for respiratory depression/CNS depression requiring intervention
How do you manage lithium toxicity?
- Manage ABC first (airway, breathing, circulation)
- normal saline at 1.5-2x maintenance, then adjust to 0.45% saline for maintenance fluids
Why do we avoid diuresis and alkalization therapy?
it can cause lithium retention
(alkalisation is good for salicylate toxicity)
What is the rebound phenomenon with HD in lithium toxicity?
Lithium is dialyzable but it is controversial due to tissue distribution
-when pulling Li+ out of the serum during HD, the Li+ will move from the tissue into the serum
-peak concentration 6-12 after HD, worsening of clinical status
