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TOX: Lithium, Dilantin, Carbamezapine & Valproic Acid

R2 Topic Presentation January 2013
by

Janet Ferguson

on 4 December 2013

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Transcript of TOX: Lithium, Dilantin, Carbamezapine & Valproic Acid

Janet Ferguson
PGY2 Emergency Medicine Anticonvulsants Cases Approach to the Poisoned Patient Cases! ? Questions ? Valproic Acid
(Depakene) Carbamazepine
(Tegretol) Phenytoin/Fosphenytoin
(Dilantin) History History Lithium Toxicity Pharmacology: Mechanism of Action: poorly understood 75-90% of patients on lithium will have toxicity at some point in their lifetime 1965 1938
1997 1965 Airway
Breathing
Circulation No! Lithium, Carbamazepine, Phenytoin & Valproic Acid Toxicity Decontamination
Elimination
Find an antidote G = "Get them outta here" (disposition) Why is this important? Patients with unintentional and intentional overdoses will present to the Emergency Department It is our job to have an approach to the management of these patients Specific antidotes exist for certain medications and it is our job to know them and to be able to administer them safely Self Quiz Take 2 minutes to complete the following table: Lithium Phenytoin Carbamazepine Valproic Acid Antidote? Decontamination or Elimination Method of Choice? Predominant symptoms in toxicity? Approach to the Poisoned Patient (Hint: it's almost the same as EVERY other patient we see) Key points on history: WHAT was ingested
TIME of ingestion
AMOUNT ingested

Objectives: After this talk you should...
Have a general approach to the poisoned patient
Be familiar with the clinical presentations of lithium, carbamazepine, phenytoin and valproic acid toxicity
Be aware of the decontamination and elimination strategies for each drug
Know which drugs have antidotes
ODORS Bitter Almonds
Carrots
Fishy
Fruity
Garlic
Glue
Pears
Rotten Eggs
Shoe Polish
Wintergreen Cyanide Winter Hemlock (cicutoxin) Zinc or Aluminum Phosphide Ethanol, Acetone, Isopropyl Alcohol, Cholorform Arsenic, DMSO, Organophosphates, Yellow Phosphorus, Tellurium, Selenium Toluene, other solvents Chloral hydrate, Paraldehyde Disulfiram, Hydrogen Sulfide, N-acetylcysteine, DMSA Nitrobenzene Methyl salicylate Antidotes Universal Antidotes:
"DONT"
Dextrose
Oxygen
Naloxone
Thiamine 1800's MOST EFFECTIVE mood stabilizer in the treatment of bipolar disorder 1949 Monovalent cation: competes with other cations (eg. Na, K, Mg, Ca) displacing them from both intracellular and extracellular sites
*ECG findings of hypokalemia -modulates intracellular second messengers (inositol triphosphate)
-affects neurotransmitter production and release Pharmacokinetics: Absorption
Distribution
Metabolism
Excretion Pharmacology Pharmacokinetics Absorption
Distribution
Metabolism
Excretion Carbamazepine Toxicity Clinical Presentation Management Clinical Pearls Clinical Presentation Management Clinical Pearls Pharmacology Pharmacokinetics Absorption
Distribution
Metabolism
Excretion Phenytoin Toxicity Clinical Presentation Management Clinical Pearls Pharmacology Pharmacokinetics Absorption
Distribution
Metabolism
Excretion Valproic Acid Toxicity Clinical Presentation Management Clinical Pearls 26 year-old male, brought in by EMS
N/V/D
2 hours ago swallowed 180 x 450g of sustained release lithium carbonate tablets
suicidal intent

HR=60 (occasional brady's to 40), BP=115/70
GCS 15 rapid, peaks in 1-4 hours, SR preps 6-12 hours 7 deaths /5674 reported cases in 2006
4 deaths /6492 reported cases in 2008 Neuromuscular blocking agents may result in a prolonged neuromuscular blockade when given to patients receiving long-term lithium therapy. no protein binding, rapidly distributed throughout ECF with slower redistribution into tissues (brain) >95% freely filtered by kidneys, reabsorption in proximal tubule, elimination half life 24 hours (longer in chronic use) none Who is at risk for lithium toxicity?
-any patient with renal impairment *CRITICAL FACTOR
-advanced age (decreased GFR)
-thiazide diuretics, NSAIDs, ACE-inhibitors
-hyponatremia, dehydration Acute Chronic Narrow therapeutic index therefore treat patient based on symptoms, not levels

However, rule of thumb:
Consider hemodialysis when levels reach
4 mEq/L in acute toxicity
and
2.5 mEq/L in chronic toxicity SILENT= Syndrome of Irreversible Lithium Effectuated Neurotoxicity

Def’n: persistent neurologic dysfunction attributed to lithium toxicity persisting 2 months after lithium cessation

FEVER = poor prognosis

DDx:Serotonin Syndrome and Neuroleptic Malignant Syndrome Narrow Therapeutic Index: 0.6-1.2 mmol/L Decontamination? Charcoal NOT effective, Gastric Lavage useless
Whole bowel irrigation for SR preparations Elimination? Antidote? None ABC's Hemodialysis effective but reserved for 3 types of patients... IV, Cardiac Monitor, Fluid resuscitation 2 x maintenance with NS Rule of 25!!!
>25 g = likely a severe ingestion Many of the test tubes used to collect blood for testing contain lithium salts of heparin.

Use gold-topped or red-top tubes for blood clotting, without heparin.








There is enough Lithium in the mint-top tubes to generate 1.2 to 2.5 mmol/L lithium (upper range of therapeutic to critical levels) and any circulating Lithium in the patient would only elevate this level higher. Significant arrythmias are rare! Seizure = excessive neuronal activity in brain incidence of epilepsy in Canada = 0.6% Lithium DIRTY DRUG ALERT! -sodium channel blocker
-interferes with muscarinic/nicotinic acetylcholine, NMDA and CNS adenosine receptors
-actions:
anticholinergic
antiarrhythmic
antidepressant
sedative
neuromuscular-blocking properties
central antidiuretic effects (SIADH)
block synaptic transmission through trigeminal nucleus lipophilic, slow, unpredictable, peaks 8-24 hrs 0 deaths/2330 reported exposures in 2008
69 had significant adverse outcome 80% protein bound, small volume of dist'n metabolized by liver cytochrome P-450 isoenzymes to active metabolite (10,11-epoxide) NOTE: potent P450 inducer therefore speeds own elimination, elimination half life 6-20 hours in acute ingestion, 5-12 hours in chronic COMA Symptoms: predominately neurological (cerebellar) 70% excreted in the urine as epoxidated, hydroxylated or conjugated metabolites; the remaining 30% is excreted in the faeces. Don't copy me Therapeutic range = 4-12mg/L ABC's IV, continuous cardiac monitoring, sodium bicarb if QRS>100msec Serum levels are available for ALL of the medications discussed today !! Decontamination? Elimination? Antidote? >12mg/L - Nystagmus and ataxia
>20mg/L - Drowsiness and anticholinergic delirium
>40mg/L - Coma, seizures and cardiac conduction AbN
What dose do we need to worry about?
< 50mg/kg - Mild - Moderate: mild CNS and anticholinergic effects
> 50mg/kg - Severe: Fluctuating mental status, agitation, coma AC and MDAC = classic indication Hemodialysis effective, however MDAC equivalent None Patients can be sent home/medically cleared when:
awake and alert
no conduction AbN
serum levels show a decline over hours Na Carbamazepine = CYP inducer and metabolized by CYP
CHECK DRUG INTERACTIONS
That may have been the cause for toxicity! Phenytoin = CYP inducer and metabolized by CYP
CHECK DRUG INTERACTIONS
That may have been the cause for toxicity! The diluent used in IV prep (propylene glycol) is responsible for the myocardial depression and decreased peripheral vascular resistance causing hypotension slow, variable, and often incomplete, especially after an overdose, levels peak 3-12 hours large volume of dist'n, extensively protein bound (to albumin), only free form is active, following standard 20mg/kg dose therapeutic levels in 12 min (IV) or 6 hours (PO) metabolized by liver cytochrome P-450 isoenzymes, metabolites inactive however one thought to be responsible for hypersensitivity reaction 5% excreted unchanged in urine, elimination half life prolonged with higher serum levels from 6-24 hours up to 20-60 hours 4 deaths / 2395 reported exposures in 2007 >15mg/L = nystagmus
>30mg/L = ataxia, poor coordination
>50mg/L = lethargy, slurred speech, extrapyramidal side effects Who is at risk for phenytoin toxicity?

Anyone with low albumin
Uremia
Hyperbilirubinemia
increased amount of free drug circulating

Drug interactions galore!!
over 14 million hits on google search
Cytochrome system strikes again Therapeutic range = 10-20mg/L Nystagmus Ataxia RARE PO = Never
IV = Yes, but.... ABC's Decontamination? Elimination? Antidote? IV, cardiac monitors (for IV only), supportive care AC
MDAC controversial Initially = hemodialysis no go, highly protein bound
New techonology = maybe now? IV infusion-related hemodynamic instability?
-effects are transient and resolve in 30-60 min
-stop infusion, give 500cc bolus of NS
-re-start infusion at 1/2 initial rate Fosphenytoin = soluble, doesn't contain propylene glycol or ethanol, safer and can be used IV or IM None Coming soon!
"Free phenytoin" levels in the SHR 100% absorbed from GI tract, peak 4-6 hours, 16-24 hours in SR preps Mechanism of action is unclear
-increases GABA 90% protein bound, however more unbound as levels increase bc protein binding sites saturated metabolized in the liver (glucuronic acid conjugation and mitochondrial beta oxidation)
enters mitochondria by using L-carnitine as a cofactor <5% excreted unchanged in urine, elimination half life 8-21 hours, prolonged in overdose Metabolites of VPA are active but are not measured on serum screen, contribute to CNS depression
Remember this when the patient isn't getting better but serum levels are normal! 26 deaths / 8705 reported cases in 2005
404 major adverse outcomes

prevalence increasing as more use in bipolar disorder DEPLETES CARNITINE ABC's Therapeutic range = 50-100mg/L >150 mg/L = adverse reactions
>800 mg/L = neurotoxicity Valproate-induced hyperammonemic encephalopathy:
impaired consciousness with confusion or lethargy, focal or bilateral neurologic signs, and increased seizure frequency
not necessarily associated with increased levels of valproic acid, may be related to elevation of ammonia and other metabolites
mechanism unclear What dose do we typically worry about in acute overdose?
>400mg/kg
>1000mg/kg = multi-organ failure Decontamination? Elimination? Antidote? YES!!!
L-carnitine IV, cardiac monitors, supportive care Valproate is eliminated partly as ketone bodies and may cause a positive test result for ketones in the urine or blood. AC
MDAC or WBI with large ingestions or SR preps some evidence, hemodialysis will reduce serum levels and clear ammonia so try in severe cases Seizing in the summer? NO NO NO L-CARNITINE ACUTE = GI
CHRONIC = NEURO NEURO
Anticholinergic
"TCA-LIKE" NEURO NEURO
METABOLIC
RESP DEPRESSION
HYPOTENSION WBI AC
MDAC! AC
?MDAC/WBI IF BIG OD AC
MDAC/WBI IF BIG OD Management Priorities? ECG = N
Labs = N
except Creat 114 Initial Lithium Level 5.57mmol/L
(Normal range 0.6-1.4mmol/L). ABC (NS 2 x maint)
D = WBI only
E = HD in 3 patients
severe neurotoxicity (ie. seizing)
inability to tolerate fluid resusc
renal impairment
F = None
8 hours later ... confused, restless and continually trying to climb out of bed. He appears to be hallucinating and is picking at imaginary objects in the air. His pupils are fixed and dilated. He has a marked sinus tachycardia (140bpm), with low BP (90/62). His skin is flushed and warm. Mucous membranes are dry. Temperature is 38 C. A catheter has been inserted for urinary retention after a bladder scan showed 850ml in his bladder. 32 year-old male, brought in by EMS
nystagmus, ataxia, lethargic
1.5 hours ago swallowed 35 x 100 mg tabs of Dilantin SR
States he took them because his "head hurt"

HR=75, RR=14, BP=117/82, O2=100%RA
GCS = 14 (loses point for eyes open to command) Management Priorities? ECG = N
Labs = N ABC
D = consider AC, but out of window
E = not for him, neurologically stable (severe cases only)
F = None Initial Phenytoin 32.5 umol/L
normal range 40-80 umol/L Repeat level 4 hours later = 79.2 umol/L
4 hours later = 82.4 umol/L
4 hours later = 76.9 umol/L 30 year-old male, brought in by family
confusion, disorientation, lethargy
PMHx: Epilepsy
family found 75 x 500 mg tabs of VPA missing
presumed time of ingestion = 15 hours ago

HR=79, BP=118/59
GCS13 VPA level 391 g/ml (therapeutic range 50–100 g/ml)
Ammonia 256 mol/l (normal range 10–47 mol/l) Management Priorities? ABC
D = AC
given in this case bc unsure of time of ingestion
E = poor evidence, can do HD if ammonia high
F = L carnitine! ECG = N
Labs = N except... 41 year-old male, brought in by police
ataxic and drowsy
states he swallowed an unknown amount of diazepam prior to arrest
VS normal
GCS = 14 Toxidrome? Ingestion? Management Priorities? Intubated and sent to ICU He had taken 25 x 400mg Tegretol CR tablets
(= 10g carbamazepine or ~140mg/kg)
Carbamazepine level added onto his admission bloods confirmed ingestion, with a serum level of 39 mg/L. (therapeutic range = 4-12 mg/L) Physical Exam:

Vitals x 6
Toxidrome? Investiations: Tox labs
Serum level of the drug
(and other potential coingestants)
ECG
Urine tox if altered or mixed picture Received L-Carnitine 1 g IV q8h x 24 hrs
VPA down into therapeutic range 13 hours later
Ammonia down in therapeutic range 22 hours later Anticholinergic! Carbamazepine! ABC = needs sedation for delirium
D = MDAC
E = MDAC > HD
F = none
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