Toxicology ProgramPsychiatric drug poisoning

Dr HT Fung

TMH AED

15 Jun 2005

F/18

• Depression

• DO

• Confused

• BP 101/62

• P 143

• Pupils 5 mm NR

Poison DDx?

Mechanism?

Tx?

QRS 0.1 s

QTc 0.58 s

- conduction

- inotropy

-1 block

-NE depletion

-Adenosine

-Nitric oxide

BP 90/60, why?

Adenosine

Kalkan 2004

Nitric oxide

Tuncok 2002

BP 96/60

Tx?

NaHCO3

• Na load, pH, hypokalemia QRS, BP

• Till hypernatremia, pH > 7.55

GP I: pH 7.48-7.55

GP II: pH >7.55

Anderson 1987

Alkalemia mortality

Hypertonic saline

QRS (ms) SBP (mmHg)

Control 144 54

HTS (15 mmol/kg)

80 134

NaHCO3

(3 mmol/kg)

105 85

HV (pH 7.5-7.6) 125 60

James 1998

If pH 7.56, Na 140, Tx?

Hypertonic saline

• NaHCO3 = HTS > HV in QRS & BP improvement in rats (Pentel 1984)

• NaHCO3 > HTS in improving amplitude & conduction velocity of action potential of dogs’ cardiac fibers (Sasyniuk 1984)

• Cases: 200 ml 7.5 % NaCl (Patrick 2003), 170 mM NaCl (Hoegholm 1991)

HyperventilationCase 1 Case 2 Case 3

pH 7.65 7.46 7.61

pCO2 14 mmHg 28 mmHg 23 mmHg

QRS Pre-Tx 0.2 s 0.146 s 0.136 s

Post-Tx 0.14 s

at 90 min

0.117 s

at 25 min

0.115 s

at 4.5 h

Bessen 1985

If Na 151, pH 7.48, Tx?

Hyperventilation

• 2 cases:

• Hyperventilation + NaHCO3

• pH 7.83 & 7.66

• pCO2 11 & 20 mmHg

• Arrest

• Keith 1992

If QRS 0.8 s, BP 88/59, Na 146, pH 7.56, Tx?

• Norepinephrine preferred to dopamine

• ? Epinephrine preferred to norepinephrine

E > NE in survival

Epinephrine

Norepinephrine

Control

Time (min)

Cu

mm

ulat

ive

surv

ival

(%

)

Knudsen 1997

E > NE in QRS

Norepinephrine

Epinephrine

Knudsen 1997

Duration (min) in sinus rhythm: E > NE

0

5

10

15

20

25

Control

Norepinephrine

Epinephrine

Knudsen 1997

NE > E in BP

Time (min)

10 20 30 40

Blo

od p

ress

ure

(mm

Hg)

Norepinephrine

Epinephrine

Knudsen 1997

F / 30

• Obsessive compulsive disorder

• Drug overdose• Mute, dull, GCS 424• P 92, BP 138/86• Pupils 6 mm reactive• Sweating• ? Sympathomimmetic

toxidrome

• Answer: Mirtazepine• Block central 2 > 1,

also 5HT, H1• Release 5HT, NE

SSRI toxicity

Setraline Paroxe-tine

Fluvoxa-mine

Fluoxe-tine

Citalo-pram

Seizures (%)

2 2 1 1 2

QTc (%) 40 40 24 36 68

Serotonin syndrome (%)

20 18 17 1 9

Isbister 2004

Other atypical antidepressants

• Multiple sites of action on 5HT, NE, D, etc

• Receptor antagonists, reuptake inhibitors, release neurotransmitters

• Drowsiness, anxiety, tachycardia

• Could be seizures, QRS / QTc, serotonin syndrome

• Mirtazapine, venlafaxine, nefazodone

Priapism

• Trazodone, chlorpromazine, thioridazine, etc

• Low flow• Painful• USG• Blood gas

Priap

us

Priapism Tx

• Aspiration• Epinephrine 1 in

1,000,000 1-10 ml• Methylene blue 50 mg• R-TPA 15 mg• Surgical shunt

Thioridazine – the most cardiotoxic neuroleptic

QTc > O.45 s QRS > 0.1 s Arrhythmias

Thioridazine 60% 23% 5%

Chlorpromazine 34% 15% 0%

Other neuroleptics

19% 6% 0%

Buckley 1995

Atypical antipsychotics – 5HT / D2 block

(EPS)

(+ve s/s)(Temp)

(--ve s/s)

Olanzapine overdose

GCS 92%

• Agitation 42%

• Convulsion 4%

• Tachycardia 23%

• Hypotension 4%

• QTc > 0.45 s 4%

• Miosis 31%

Palenzona 2004

F / 36• Depression, recently unemployed• Anxious, labile mood x 2/7• Psychiatric opinion: acute stress reaction• While pending home: incoherent speech,

irritable, sweating• Computer search: on long term psychiatric

medications, attended another ED 3/7 ago x chronic LBP

Dx? Serotonin syndrome?

M / 65

• Depression, dementia, parkinsonism

• R AMA x # NOF

• Post-op D2, 38.50C, GCS 14/15, limbs rigid, some abdominal rigidity

Dx? Neuroleptic malignant syndrome?

Sternbach criteria

• Serotonergic agent• No neuroleptics• Rule out others• > 3 of: - mental changes - shivering - agitation - tremor - myoclonus - diarrhea - hyperreflexia - incoordination - diaphoresis - fever

Sternbach 1991

Hunter criteria

• Serotonergic agent

• Any 1 of:• Inducible clonus & agitation or diaphoresis• Ocular clonus & agitation or diaphoresis• Tremor & hyperreflexia• Hypertonic & > 380C & ocular clonus or induci

ble clonus

Dunkley 2003

Levenson JL

• 3 major, or 2 major & 4 minor• Major: fever, rigidity, CK• Minor: HR, abnormal BP, RR, GCS, diaph

oresis, WBC

• Neuroleptic use

• Rule out others

Levenson 1985

DSM IV

• Fever & rigidity & > 2 of:

• Diaphoresis, dysphagia, tremor, incontinence, GCS, HR, BP changes, CK, WBC

S.S. N.M.S.Rapid onset ++ --Rigidity + +++ CK + +++ HR + ++ RR + ++ WBC +++ +Behavior +++ ++Clonus / shivering / tremor / reflex

+++ --

Fever / GCS ++ ++

Wappler 2001

L-tryptophan

MAOI

SSRI

Li

Amphatemines

5-HT agonistsSer

oton

in s

yndr

ome

D2 receptors X by neuroleptics

Sudden withdrawal of L-dopa NMS

Tx of serotonin syndrome

• Cyproheptadine 4 mg up to 0.5 mg/kg/d

• Methylsergide 2 mg up to 6 mg/d

• Propanolol 1 mg IV + repeat

• Chlorpromazine 25 – 100 mg IM + repeat

• Benzodiazepine

• Dentrolene

Tx of NMS

• Bromocriptine 7.5 mg/d – 45 mg/d, faster resolution, effect after h – 1 d

• Dentrolene 2 – 3 mg/kg Q 10 min up to 10 mg/kg/d, faster resolution

• ECT 84% good response

• Carbidopa / levodopa

• Benzodiazepine

M / 42

• Schizoaffective disorder, hypertension

• On Li2CO3, lisinopril

• Tremor, nausea x 2/7• Causes of s/s?

• Side effects• Acute poisoning• Acute on chronic

poisoning• Chronic poisoning• Drug interaction

Taken 10 more tablets of Li2CO3 in last 2 days

• Serum Li 3.6 mmol/L• Tremor gets coarse, a

taxia, hypertonic• Tx?

• WBI• NS IV• Na polystyrene sulpho

nate• HD• CAVHDF• CVVHDF

Na polystyrene sulphonate

• Case:• Acute on chronic Li overdose• Na polystyrene sulphonate 150 g/d• Li t½ 12 h

• Hypokalemia

• No rebound

Roberge 1993

Carbamazepine

• Anticholinergic - anticholinergic & delayed s/s, seizures• Membrane stabilization - QRS• Adenosine A1 / A2 - seizures• Active metabolites - prolonged s/s• MDAC• HP, HD

Carnitine

Carnitine

CoAAcyl-CoA

Acetyl-CoA

Kreb’s cycle Carbamyl phosphate synthetase

NH3 accumulation

Glutamate synthesis

Ketoglutarate depletion

oxidation

VA

4-en-VA

VA

Cyt

opl a

smM

itoc

hond

ria

Inhibit

VALPROIC ACID TOXICITY

X

X

XX

X

Tx of VA poisoning

• L-carnitine 50 mg/kg Q 3-4 h

• Naloxone 2 mg • Displace GABA• Enkephalin antagonist

• MDAC

• HP

• HD, CVVHDF

St. John’s Wort

• Hyperforin inhibits reuptake of D, 5HT, NE

• Hyperricin inhibits MAO

• ? Risk if together with atypical antidepressants, MAOI &

noradrenergic agents

• No reports of overdose

TCM

• 甘逐 – ‘ laxative’

• 天南星 – ‘ mucolytic’

• 朱砂 – ‘ sedative’