Transcript Review of Neuro-Psychiatric Medication Overdoses

Review of Neuro-Psychiatric
Medication Overdoses
Dennis P. McKenna
Albany Medical Center Hospital
Lecture will offer review of the following:
 Tricyclic Antidepressants
 SSRIs
 Other antidepressants
 Lithium
 Benzodiazepines
 Antipsychotics
Tricyclic Antidepressants
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TCAs introduced 1958
First TCA OD in 1959
Leading cause of poisoning deaths due to ingestion
50 deaths for every one million prescriptions
2.6% mortality for patients who reach hospital
First Generation Cyclic Antidepressants
Doxepin – Sinequan
Amitriptyline – Elavil
Nortriptyline – Pamelor
Imipramine – Tofranil
Desipramine - Norpramin
Tricyclic Antidepressants
 Block the reuptake of NE, Dopamine and Seratonin at the
central presynaptic terminal
 Increases synaptic catecholamines
 ODTransient HTN cathecholamine depletion and
relative hypotension
 Block fast inward sodium channels with resultant QRS
widening
 Negative inotropy contributes to hypotension
 Anticholinergic effects
 Alpha adrenergic blockage contributes to hypotension
 Antihistamine effects contribute to sedation
Tricyclic Antidepressants
Physical Exam:
High BP Normal BP Low BP
Tachycardia
Increase Temp
Decreased RR
Anticholinergic signs: Dilated pupils; dry, hot and flushed
skin; decreased bowel sounds; urinary retention
Neurologic: Myoclonus or seizures
Mental status changes from lethargy to coma
Tricyclic Antidepressants
Diagnosis
 Boehnert and Lovejoy, NEJM, 1985
49 patients with known TCA OD
QRS >100 msec, 1/3 had seizures
QRS > 160 msec, ½ had ventricular dysrhythmias
QRS< 100 msec, no signif toxicity
 Niemann and Bessen
Terminal 40 msec right axis deviation between 130 to 270
degrees, QT prolongation and sinus tachycardia had PPV
66% and NPV 100% in setting of O.D.
Tricyclic Antidepressants
Treatment of Acute Toxicity
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Intubate and hyperventilate (if clinically indicated)
IVF (crystalloid)
Syrup of ipecac contraindicated
Orogastric lavage
Activated charcoal 1 gm/kg, followed by
0.5 gm/kg Q2 hr
 Diazepam and Lorazepam for seizures.
Phenytoin is contraindicated
Tricyclic Antidepressants
Treatment of Acute Toxicity(cont)
 Sodium Bicarbonate
If QRS >100msec NaHCO3 1-2 mEq/Kg bolus, then drip
Repeat EKG and look for QRS narrowing
 Pressors
NE preferred to Dopamine if fluid fail to raise BP
 Flumazenil SZs
Tricyclic Antidepressants
If stable initially:
 Orogastric lavage vs. activated charcoal
 EKG, continuous monitoring
 Can be medically cleared in 6 hrs if:
Normal VS
No anticholinergic signs
Normal mental status
Tricyclic Antidepressants
Disposition
Admit any patient with:
 QRS > 100 msec. Consider ICU on HCO3 ggt
 Any patient with a seizure
 Any patient in need of medical (or psych) support
Home management :
 Accidental pediatric exposures should be referred to ED
 Syrup of ipecac always contraindicated
Other Antidepressants
Selective Serotonin Reuptake Inhibitors (SSRI)
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Introduced 1980s
By 1994 became largest class of medicine Rx for
depression
Also used to treat OCD, obesity, Etohism
Decreased side effect profile and safer in OD
Inhibit seratonin reuptake
Potentiate the activity of neuronally released seratonin
Unlike TCAs, SSRIs have little interaction with other
receptors such as adrenergic, cholinergic, GABA or Na
SSRIs
Available agents
Fluoxetine – Prozac
Paroxetine – Paxil
Sertraline – Zoloft
Toxicity profile
 Nausea, vomiting, blurred vision, lethargy and
sedation
 No evidence of seizures
 Serotonin syndrome
Treatment of SSRI Overdose
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Mainly supportive
Must rule out other concomitant OD
Must rule our significant TCA OD (EKG)
Dextrose and Thiamine if patient has AMS
Administer activated charcoal and cathartic if
significant ingestion
 Observe in ED for 6 hrs on cardiac monitor prior
to medical clearance
 Small, unintentional OD may be observed at home
Other antidepressants
Buproprion
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Unrelated to all antidepressants
Unicyclic antidepressant
Seizures are common
Rx seizure with supportive care and BZs and Barbituates
Trazadone
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Peripheral seratonin agonist
CNS depression is the most common adverse side effect
May cause hypotension
Does not cause seizures or arrhythmias
Lithium
 First used in England to treat gout
 Early 20th century used to as salt substitute
in patients with CHF
 Banned by FDA in 1949
 Reintroduced to treat Bipolar in 1970
Lithium
Neuropharmacology
 Antimanic effetcs
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Moderatly attenuates Dopamine and NE through
decreased turnover
 Antidepressant effects
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Increases synthesis and turnover of 5-HT in presynaptic
neurons
 In 1994 there were 5341 acute or chronic
exposures
 Resulted in 13 Fatalities
 75-90% of all patients on Li therapy at risk for
signs/symptoms of toxicity
Lithium
 Absorption
Peaks in 1-2 hrs in regular release
Delayed to 6-12 hrs following SR
 Distribution
* No protein binding
Slow distribution half-life
* Final VD 0.8 L/kg – Readily dialyzable
 Elimination
All renal
 Therapeutic Serum Concentrations (Check 12 hrs after last dose)
Goal for acute mania 0.7-1.2 mEq/L
Goal for maintenance 0.5-0.8 mEq/L
Side Effects at Therapeutic Doses
 Fine Tremor
If persists may need treatment with BZ
 GI
N/V/D. May indicate high level
 Hypothyroidism
 Renal
Li produces concentration defect that cause
polyuria and polydypsia
 Weight gain
 Rare cardiac conduction abnormalities
 Teratogenicity
Side Effect of Overdose
Toxicity by degrees
 Mild – Apathy, lethargy, weakness, tremor, GI sxs
 Moderate – Coarse tremor, slurred speech, ataxia,
confusion, hyperreflexia, clonus, nonspecific EKG changes
 Severe – Seizures, coma, cardiovascular collapse, EPS,
generalized fasiculations
Poor correlation with serum levels.
Toxicity does not occur until Li in cells
 Acute OD – High levels with less sxs
 Chronic OD – More sxs with lower levels
 Acute on chronic OD – Intermediate finding
Factors predisposing to Chronic Toxicity
 Dehydration
 Sodium depletion
 High lithium dose after control of mania
 Renal dysfunction
 Drug interactions
e.g. NSAIDs, Diuretics, ACEI,
Antipsychotics, SSRIs, Tegretol
Evaluation and Therapy
 Normal saline hydration
 Orogastric lavage if early or WBI if >2-4 hrs since
ingestion
 No role for charcoal in Li OD (unless concomitant OD)
 Li level and repeat in 2 hrs for acute, 6 hrs for chronic
 Obtain serum electrolyte and check renal function
 Frequently reassess neuro function
Hemodialysis in Li Toxicity
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Recommended for Li level 4-4.5 mEq/L (Acute)
Recommended for Li level > 2.5 mEq/L (Chronic)
Any patient with renal failure
Watch for rebound Li levels after HD
No real current indication for PD (no more
effective than normal kidneys)
Seratonin Syndrome
 Usually occurs in patients concomitantly ingesting
MAOIs and seratonergic agents
 Reported to occur after single doses, high
therapeutic doses or ODs
 Characterized by agitation, hyperthermia,
myoclonus and seizures
 Mainstay of Rx is BZs, hydration and cooling
Benzodiazepines
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Diazepam introduced for seizure control in 1965
15 different BZs available in U.S. market
Triplicate in NYS
Today used principally as anxiolytics to produce
sedation
Temazepam (Restoril) and Triazolam (Halcion) used
for sleep
Clonazepam (Klonopin) used as chronic
anticonvulsant therapy
Benzodiazepines
 Most administered oral or IV
 Midazolam (Versed) and Lorazepam (Ativan) have
salts that are water soluble given IM
 BZs have erratic IM absorption
 Midazolam eliminated more quickly (pre-op and
pre-induction agent)
 Lorazepam less lipophilic, therefore less distribution
into fat stores and longer half life (seizure control)
Adverse effects of Benzodiazepines:
 Hailed for their safety when first marketed
 Most concerning is respiratory depression
 Weakness, HA, blurred vision, vertigo,
Nausea, Diarrhea and Chest Pain
 Coingestion with alcohol is severe
 Intensity of CNS toxicity increase with age
 May cause paradoxical CNS effects (e.g. Halcion)
Adverse effects of Benzodiazepines
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Deaths due to BZs alone are very rare
Most obtunded patients arouse in 12-36 hrs
Duration of coma in elderly may be prolonged
No specific systemic injury
Tolerance to BZs exist
Abrupt withdrawal of long-term use of BZ can
lead to withdrawal may require hospitalization
Flunitrazepam (Rohypnol)
 Legal in Caribbean, Mexico and Europe
 Illegal in U.S.
 Used recreationally and criminally
 Cause profound CNS depression without
alterations in VS if not used with alcohol
 Long duration of action
 Partial amnestic properties
Flumazenil
 Competitively occupy the BZ receptor
 Capable of reversing most BZ effects
Consensus group:
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Not substitute for primary emergency care
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Hypoxia and hypotension should be corrected first
Small, titrated doses should be used
Avoid in patients with h/o seizure or TCA OD
Should not be used by inexperienced physicians
Flumazenil
 Indications: Pure BZ OD in individual who has
CNS depression
Normal VS
Normal EKG
Otherwise normal neurologic exam
 Contraindications to use of Flumazenil
Prior seizure history or current Rx for seizures
H/O ingestion of substance capable of provoking seizures
or cardiac dysrthmias
Long-term use of BZs
EKG evidence of TCA ingestion
Abnormal VS
Antipsychotics
Psychotropics first introduced 1950s
“Neuroleptic” = “Antipsychotics” or “tranquilizing”
 Suppress extrapyramidal movt
 Suppress spontaneous and complex behavior
 N.B. Clozapine has minimal EPS, therefore it is an
antipsychotic without truly being a “neuroleptic”
Antipsychotics
Classes of Neuroleptics – Structurally unrelated
 Phenothiazines
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Aliphatic, e.g. Thorazine
Piperazine, e.g. Stelazine, Compazine, Prolixin, Trilafon
Piperidine, e.g. Mellaril
Thioxanthenes, e.g. Navane
Butyrophenones, e.g. Haldol
Dibenzodiazepines, e.g. Clozaril
Benzisoxazoles, e.g. Risperdal
Indoles
Dibenzoxazepines
Antipsychotics
Therapeutic mechanism
Neuroleptic activity:
Positive symptoms (Hallucinations, Delusions,
Thought disorder) respond best to dopaminereceptor blockade of the limbic system
Antipsychotic activity:
Negative symptoms (Blunted affect, Apathy,
Social withdrawal) respond best to agents
with Serotonin antagonist activity
Pharmakokinetics
 Can be given PO, IM or IV
 GI absorption diminished
 IM absorption variable
 Peak levels early (2-4 hrs), Plateau for 3-4 hrs
 Large volumes of distribution
 Breakdown products in urine for up to 6 weeks
Pharmakokinetics
 Little correlation between dose, serum level and
neuroleptic effect
 Optimum neuroleptic effect requires 1 month therapy
 Tolerance does not occur for months
 Significant Dopamine inhibition Parkinson-like
syndrome and extrapyramidal effects
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Ameliorated with anticholinergics (Artane, Cogentin,
Benadryl)
 Chronic useTarditive Dyskinesia
Acute Overdose
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Some solid forms of phenothiazines are radiopaque
CNS Depression and Coma in large doses
Seizure possible, but uncommon
Hypotension secondary to alpha adrenergic blockade
Sinus tachycardia secondary to hypotension
Quinidine-like QT and PR prolongation
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Mostly with Mellaril
 Acute dystonia
 Neuroleptic Malignant Syndrome
Management of Acute Overdose
 Stabilization, ABCs
 Fluid resuscitation with crystalloid
 Catecholamines should be limited.
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If use—NE, Levophed
Avoid Epi and Dopamine because will lead to vasodilation
Check for polysubstance OD
Emesis, lavage, MDAC and catharsis
Avoid syrup of ipecac
Cardiotoxicity – Treat like TCAs
Dystonia – IV diphenhydramine, then PO for 2-3 days
Management of Acute Overdose
 Admit
 Large ingestions
 Seizures
 Hypotension
 EKG abnormalities
 Discharge
 Decontamination
 Normal mental status
 No life-threatening events
 Medically and psychiatrically stable
 6 hours observation
Neuroleptic Malignant Syndrome
 First described 1968
 Characterized by hyperthermia, muscle rigidity, AMS
and autonomic instability
 Rare – 0.02% to 2.4%
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Most common with Thorazine, Haldol
Greater anti Dopamine activity
Idiosyncratic reaction
Pathophysiology is central dopamine blockade
In essence, severe form of extrapyramidal reaction
Neuroleptic Malignant Syndrome (cont.)
 Hyperthermia not responsive to antipyretics
 No specific lab test
 Metabolic acidosis, Elevated LFTs, Leukocytosis
 Essential in Hx to have recent change in neuroleptic dose
 Medical etiologies need to be excluded
 NMS primarily involves CNS
 No derangement in Ca transport in skeletal muscle
 Clinically indistinct from Malignant Hyperthermia (MH)
 MH is hereditary disorder
 Defect in skeletal muscle metabolism of Ca
 Responds almost immediately to Dantrolene
Treatment of NMS
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Discontinuation of agent
Rapid external cooling
Ice and IV BZs
Several agents with limited success
 Bromocriptine, Dantrolene
 Clinical course lasts about 10 days
 Do not reintroduce neuroleptic agents while NMS
symptoms present
 If necessary, wait additional 1-2 weeks to restart
 Should be different class, with less EPS
e.g. Clozapine