Anticonvulsants Toxicology Flashcards
What is a seizure?
- A seizure is a sudden, uncontrolled burst of electrical activity in the brain.
- It can cause changes in behavior, movements, feelings and levels of consciousness. Most seizures last from 30 seconds to two minutes.
What are generalized seizures?
Happen in both sides (hemispheres) of the brain. Tend to cause more severe effects and symptoms
What are focal seizures?
Aka partial seizures - happen in only one hemisphere. Symptoms only happen in a specific part or on one side of the body. Can sometimes spread and become generalized
What are the different types (names only) of generalized seizures? (Just know the one)
- Absence seizures**
Focal seizures can occur in the 4 lobes of the brain. Should know what happens in:
Frontal seizure
Temporal lobe seizure
Occipital seizure
Parietal lobe seizure
Frontal seizure - motor phenomena
Temporal lobe seizure - auditory or sensory (smell or taste) phenomena
Occipital seizure - positive or negative visual phenomena
Parietal lobe seizure - contralateral altered sensation (dysaesthesia)
What are the 2 big neurotransmitters to know for seizures?
- Glutamate = excitatory
- GABA = inhibitory
Very simply - CBZ and phenytoin work by?
Blocking the voltage gated Na+ channel (stopping glutamate release/binding)
Very simply - barbiturates work by?
Behaving like GABA (enhancement of inhibitory transmission)
What 3 barbiturate drugs should you know?
-one drugs
1. Phenobarbitone
2. Mephobarbitone
3. Primidone
What are 3 hydantoin drugs you should know?
- Phonations
- Mephenytoin
- Phenytoin
Carbamazepine is a part of which chemical class?
Iminostilbene
Absorption of CBZ is ____ and _______________.
Why? (2)
Slow and unpredictable
- Delay owing to anticholinergic effects
- Some evidence of enterohepatic recirculation (extending duration)
What is the Vd of CBZ?
0.8-2 L/kg
What is the plasma protein binding of CBZ?
~76%
Is CBZ suitable for dialysis? Why or why not?
No - because of high Vd and 76% PPB
(This is in normal circumstances though, remember that)
What enzyme metabolizes CBZ?
CYP3A4
CBZ-10, 11-epoxide is the metabolite of CBZ, it is _______ and _____
active; toxic
CBZ-10, 11-epoxide is metabolized by _______ _________
Epoxide hydrolase
The unique theing about CBZ’s metabolism is?
Autoinduction (induce their own CYP enzymes)
St. John’s Wort is a CYP3A4 ________
inducer
Is the TI of CBZ narrow or wide?
Narrow - 20 to 50 umol/L
What are the 2 neurologic toxicity symptoms of CBZ?
- Nystagmus
- Ataxia
(Funnily enough, these occur within therapeutic range)
Aside from neurologic toxicity, CBZ can also affect what 2 systems?
- Respiratory
- Cardiovascular
Chronic (toxic) use of CBZ can lead to?
SIADH
CBZ toxicity can be diagnosed based off labs. What 2 things are there to note about CBZ levels here?
- Serial levels (b/c of erratic absorption) and delayed presentation of cardiac symptoms - remember, slow and unpredictable absorption
- Co-ingestants
- VPA and lamotrigine are enzyme inhibitors of epoxide hydrolase, therefore accumulation of the 10-11 epoxide active metabolite = toxicity that will not show up as CBZ levels (false negative)
How is CBZ toxicity managed? (5)
- No antidote
- Supportive care
- ABCs
- BZDs for refractory seizures - IV fluids to correct electrolytes and treat hypotension
- Protect airway
- Sodium bicarb may be administered if the QRS duration > 100 ms
Can you use SDAC in CBZ toxicity?
Yeah it binds. 1-2 hour window.
You can do hemodialysis in CBZ overdose why?
B/c the proportion of free drug increases, theoretically making this approach more effective - so use it in overdose if needed
The prodrug of phenytoin is?
Fosphenytoin
- 1.5mg fosphenytoin = 1mg phenytoin
- Faster infusion rate (at 3x)
IV phenytoin if released quickly causes…
local tissue damage (alkaline), cardiotoxicity
How common is death/severe morbidity in phenytoin toxicity?
Rare if good supportive care
Describe the distribution of phenytoin (2)
- Rapidly distributed to all tissues
- Extensive PPB (88-93%)
- Be mindful when looking at serum levels as they not may represent total drug
- Therapeutic range but patient may exhibit clinical signs/symptoms of toxicity
- At risk: neonates, elderly –> hypoalbuminemia
Phenytoin is 95% metabolized ___________
hepatically
Drugs that alter CYP function and increase plasma phenytoin concs include: (10)
- Amiodarone
- Cimetidine
- Cotrimoxazole (antibiotic)
- Disulfiram
- Fluconazole (antifungal)
- Metronidazole
- Chloramphenicol
- Sodium valproate
- 5-fluorouracil
- Sulphonamides
What is important to know about phenytoin elimination? Specifically when it comes to enzyme saturation
Enzyme is saturated as high concentration, so shift from first to zero order kinetics at higher concentration of the drug
Toxic effects of phenytoin after __ umol/L
80
For phenytoin, should know the toxic effects at the following dose ranges:
80-120
120-160
160-200
>200
80-120 - nystagmus
120-160 - ataxia
160-200 - lethargy, confusion
>200 - seizures, coma
What are the neurologic toxicity symptoms of phenytoin? (4)
- Drowsiness, lethargy
- Tremor
- Irritability/agitation
- Peripheral neuropathy (chronic use)
What are the CV toxicity symptoms of phenytoin? (3)
- Bradycardia
- Hypotension
- Cardiac arrest; critically ill are at most risk
Phenytoin has some CV toxicity symptoms related to IV phenytoin total dose, rate of infusion. How to avoid? What causes cardiotoxicity? What is essential to monitor?
- The rate of fosphenytoin IV administration should not exceed 150 mg phenytoin equivalents (PE)/minute in adults.
- Cardiotoxicity from Fosphenytoin (follow the administration guidelines carefully)
- Cardiorespiratory monitoring is essential during and after the infusion
How is phenytoin toxicity managed? (2)
- ABCs
- Supportive/symptomatic care:
- Mainstay of treatment
- If hypotension from IV = reduce infusion rate, IV fluids, vasopressors
- Airway protection
True or False? Phenytoin has no antidote
True
SDAC in phenytoin toxicity. Yay or nay?
Nay - no evidence it does anything
Hemodialysis for phenytoin toxicity. Yay or nay
Nay - no evidence supporting it. Very highly plasma protein bound too
Why did BZDs for the most part replace barbiturates?
BZDs replaced barbiturates because of safer profile in terms of respiratory depression; however, they can cause some respiratory depression.
What is the antidote to benzos?
Flumazenil
What is the MOA of benzos?
Act by stimulating GABA-A receptor. Thereby, opening the Cl channel in the receptor complex. Increased conductance of Cl ions across the nerve cell membrane
Describe benzo absorption
What is the Tmax
Lipo or hydrophilic?
- Rapid and complete orally
- Tmax = 1-3 hours
- Relatively lipophilic - meaning faster onset and longer duration of action
What is the Vd of benzos?
How protein bound is it?
0.75-1.5 L/kg
Highly protein bound
Benzos are metabolized where?
The liver
Mortality from pure benzo overdose is rare. Toxicity depends on: (4)
- Co-ingestant; especially if CNS depressants- ethanol, opioids
- BZD: shorter acting BZD are associated with more toxicity events/clinical complications.
- Route of administration: IV admin more likely to cause significant toxicity leading to apnea/death
- Tolerance skews the course.
What patient history is needed for benzo toxicity?
- As per usual? (idk what that means ngl)
- Co-ingestants
- Duration of BZD use - chronic use causes tolerance
What labs are taken to diagnose benzo toxicity? (5)
- Urine levels (tox screen)
- These urine drug screens commonly test for substances that are metabolized to oxazepam and nordiazepam.
- False-negative if not metabolized to oxazepam/nordiazepam (i.e., clonazepam, alprazolam, and lorazepam). - Serum levels - Not indicated in the acute setting because symptoms are severe and results are not immediately available
- Arterial blood gas- If chance of respiratory depression
- Glucose
- Chest x-ray- If respiratory compromise and aspiration risk due to CNS depression
How do we manage benzo toxicity?
Can we do SDAC?
Gastric lavage?
MDAC?
Hemodialysis?
- Symptomatic/supportive care
- O2, assisted ventilation
- Fluids if hypotensive - Decontamination
- SDAC (maybe)
– If within 1h of ingestion
– May require intubation, harder to manage
- Gastric lavage (no) - Elimination
- MDAC (not been studied; no)
- Hemodialysis (ineffective - PPB, lipophilicity; no
What is the MOA of flumazenil?
Selective competitive antagonist of GABA receptor; out-competes benzodiazepine at recognition site on receptor complex, thereby reversing benzodiazepine (GABAmimetic drugs) effect on central nervous system.
Onset of action of flumazenil is?
1-2 minutes
What are some possible side effects of using flumazenil in benzo toxicity? (3)
- Seizure
- Dysrhythmias possible with mixed overdose (with other CNS depressants)
- Re-sedation - due to modulation of GABA receptor
What are the pros (1) and cons (2) of flumazenil?
Pro:
- Adverse effects minimal
Cons:
- Seizure risk
- Withdrawal risk
Flumazenil is effective at ___ depression but not ___________ depression
CNS; respiratory
Flumazenil is ideal for?
BZD-naive and single BZD-ingested pts
What is the MOA of barbiturates? (3)
- Enhance the binding of GABA to GABA-A receptors
- Prolonging duration of channel opening
- Narrow TI
The toxicokinetic profile of carbamazepine is characterized by:
A. Delayed absorption
B. Tmax as early as 1 hr after a large dose
C. Increased protein binding with increasing dose level
D. Increased renal elimination
A
Which of the following symptoms are associated with phenytoin toxicity?
A. Nystagmus
B. Drowsiness
C. Slurred speech
D. All of the above
D
Which symptom is most likely associated with serum phenytoin concentrations of 80-120umol/L?
A. Nystagmus
B. Seizures
C. Slurred speech
D. Lethargy
A
In what clinical scenario may hemodialysis be effective for phenytoin toxicity?
A. Older patient with hypoalbuminemia
B. Child with immature CYP enzymes
C. Benzodiazepine-tolerant individuals
D. Otherwise healthy adult
A
What is the active intermediate metabolite of carbamazepine?
A. Carbamazepine 10, 11 epoxide
B. Trans-CBZ-diol
C. Oxazepam
D. Carbamazepine 1, 5 epoxidas
A
As carbamazepine plasma levels increase above the therapeutic range, first signs of toxicity include _______ followed by_______ at higher levels and finally______ at very high concentrations
A. nystagmus, sinus tachycardia, coma
B. bradycardia, ataxia, respiratory depression
C. respiratory depression, miosis, seizures
D. rapid speech, QT prolongation, respiratory depressio
A
Beverly is a poorly nourished patient on multiple medications for a seizure disorder. She is experiencing nausea and vomiting for 72 hours and did not take her medication today. Today her abdomen is tender in the right upper quadrant. Blood levels of phenytoin were measured and found to be very elevated. Her serum albumin is low and her liver enzymes are slightly elevated. Which of the following is a reasonable course of action for elimination of phenytoin in this patient?
A. hemodialysis
B. multidose activated charcoal
C. flumazenil
D. whole bowel irrigation
A
May, age 57, presents to the ED with probable carbamazepine toxicity. She is conscious and has fair mental status, but is suffering from ataxia, dizziness and a racing heart. Her last dose was about 3 hours ago. What should the primary treatment be?
A. Flumazenil
B. Hemodialysis
C. Single dose activated charcoal/MDAC
D. Whole bowel irrigation
C
What is the main reason that different benzodiazepines vary so much in their half-lives?
A. Lipophilicity
B. Plasma protein binding
C. Enterohepatic recirculation
D. Autoinduction
A
Why might clonazepam toxicity result in a false-negative urine test?
A. Clonazepam is not metabolized into oxazepam and nordiazepam, which are the compounds measured in a urine test
B. Clonazepam results in severe anticholinergic effects which delay its detection in the plasma
C. Clonazepam is overshadowed by other, more recognizable and/or hazardous drugs of abuse in the urinalysis
D. Clonazepam is metabolized into nordiazepam, which is not detected in the urine test
A
Benzodiazepines undergo Phase I metabolism via ______, and Phase II metabolism via ______.
A. Hydroxylation, glucuronidation
B. Glucuronidation, hydroxylation
C. Oxidation, hydroxylation
D. Sulfate conjugation, glucuronidation
A
A 39 year old man presents with generalised tonic-clonic seizures. His medical history is significant for epilepsy treated successfully with carbamazepine for the past 15 years. He recently started taking another medication but he cannot recall the name. which of the following drugs is the patient also taking?
A. St. John Wort
B. Paracetamol
C. Lincomycin
D. Vitamin D
A
Answer:
- Carbamazepine is metabolized by the cytochrome P 450 3A4 system. Inducers of this cytochrome, such as St. Johns wort, phenobarbital, rifampin, rifabutin, theophylline, efavirenz, nevirapine, pioglitazone, and theophylline, can decrease levels of carbamazepine.
- Inhibitors such as macrolides, some protease inhibitors, azole antifungals, verapamil, diltiazem, cimetidine, amiodarone, SSRIs, and ginkgo Biloba can increase levels.
- The patient’s seizures were induced because of low levels of carbamazepine secondary to St. John
