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ANTIDEPRESSANTS

POISONINGTCAS, SSRIS, MAOIS

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TRICYCLIC ANTIDEPRESSANT

SPOISONING

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TRICYCLIC ANTIDEPRESSANTS

Amitriptyline Amoxapine Bupropion Clomipramine Desipramine Dothiepin Doxepin Imipramine Lofepramine

Maprotiline Mirtazapine Nefazodone Nortriptyline Protriptyline Trazodone Trimipramine Venlafaxine

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TRICYCLIC ANTIDEPRESSANTS

TCAs are one of the most common causes of death from poisoning

In developed countries, accounting for 20-25% of fatal drug poisoning in the United Kingdom and United States.

Deaths normally occur outside of hospital The ingestion of 15-20 mg/kg or more of a

TCA is potentially fatal

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TOXIC DOSEFor all TCAs except desipramine, nortriptyline, trimipramine, and protriptyline, this dose is >5 mg/kg.

Despiramine , Nortriptyline, trimipramine>2.5 mg/kg

Protriptyline >1 mg/kg.6

TRICYCLIC ANTIDEPRESSANTS Narrow therapeutic index Therapeutic plasma Conc.< 300ng/ml Toxic plasma Conc.> 1000ng/ml Toxic Dose ≤10times of therapeutic dose

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1gr Amitriptyline was fatal in 1year child

1.5gr Desipramine was fatal in 4years old child.

TRICYCLIC ANTIDEPRESSANTSMECHANISM Blocking reuptake of noradrenaline and

serotonin

These effects are probably unimportant in overdose except in combined overdose with selective serotonin reuptake inhibitors (SSRIs) 8

TRICYCLIC ANTIDEPRESSANTSMECHANISM

The drugs are pharmacologically "dirty" and bind to many other receptors:

including histamine(H1 & H2) ( sedation)

Alpha 1 & 2 (vasodilatation, BP)

GABA-A (seizures ) muscarinic receptors

(anticholinergic effects )9

TCA TOXICITYIn overdose, the tricyclics produce rapid onset (within 1-2

hours) of:

Sedation and coma Seizures Hypotension Tachycardia, midriasis Broad complex dysrhythmias Anticholinergic syndrome

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TRICYCLIC ANTIDEPRESSANTSMECHANISM

The drugs block sodium and other membrane ion channels.

The influx of sodium is the major event responsible for the zero phase of depolarisation in cardiac muscle and Purkinje fibres.

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TRICYCLIC ANTIDEPRESSANTSMECHANISM The duration of phase 0 in the

heart as a whole is measured indirectly as the duration of the QRS complex on the ECG.

Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width.

Prolongation of the QRS is a reflection of TCA tissue concentrations and is predictive of both seizures and cardiac arrhythmias. 12

TRICYCLIC ANTIDEPRESSANTSMECHANISM

Other cardiac channel effects include reversible inhibition of the outward K+ channels responsible for repolarisation giving a mechanism for QT prolongation and arrhythmia generation

TCAs demonstrate a dose dependent direct depressant effect on myocardial contractility that is independent of impaired conduction

alter mitochondrial function and uncouple oxidative phosphorylation 13

TRICYCLIC ANTIDEPRESSANTSKINETICS Highly lipid soluble weak bases

Rapidly absorbed Anticholinergic effects may prolong absorption

High volume of distribution Death and toxicity mainly before redistribution (toxic

compartment) (heart, brain) Protein binding > 95%

May saturate increasing free fraction pH dependent Toxicity increase with acidosis Prolonged clinical course Alkalinisation causes significant decrease in the

percentage of free amitriptyline; with a drop of 20% when pH rises from 7.0-7.4 and 42% over a pH range of 7.4-7.8.

P450 Hepatic metabolism Saturable: long elimination half life Active metabolites

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TRICYCLIC ANTIDEPRESSANTS CLINICAL EFFECTS

Symptoms and signs depend upon the dose and the time since ingestion.

Patients who are asymptomatic at three hours post ingestion of normal release medication do not normally develop major toxicity

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TRICYCLIC ANTIDEPRESSANTS CLINICAL EFFECTS In acute TCA overdose there are three

major toxic syndromes.These are

Anticholinergic effectsCardiac toxicityCNS toxicity (sedation and seizures)

Death in TCA overdose is usually due to CNS and cardiotoxic effects.

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ANTICHOLINERGIC SYNDROME Anticholinergic Syndrome: Hot as hell Blind as a bat Red as a beet Dry as a bone Mad as a hatter (Thus, it is often useful to ask patients when they

regain consciousness whether they're hearing or seeing anything strange and reassure them that this is a drug effect)

A sensitive indicator for ingestion, but poor predictor for toxicity.

Full syndrome is rare

CARDIAC EFFECTS There is a wide spectrum of toxic effects

ranging from trivial to life threatening.

• Non-specific ST or T wave changes• Prolongation of QT interval• Prolongation of PR interval• Prolongation of QRS interval• Atrioventricular block• Brugada wave (ST elevation in V1-V3

and right bundle branch block)18

CARDIAC EFFECTS

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PREDICTING MAJOR COMPLICATION

QRS > 100 milliseconds or more in a limb lead is as good as TCA concentration

Ventricular arrhythmia Seizures R aVR > 3 mm R/S aVR > 0.7

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CARDIAC EFFECTS Arrhythmias

The most common arrhythmia is sinus tachycardia which is due to anticholinergic activity and/or inhibition of norepinephrine uptake by tricyclic antidepressants.

Hypotension: The blood pressure may be elevated in the

early stages after overdose, presumably due to the inhibition of norepinephrine uptake.

hypovolaemia, decreased peripheral resistance due to

alpha-adrenergic blockadeimpaired myocardial contractility and cardiac

output 21

CENTRAL NERVOUS SYSTEM EFFECTS

Low consciousness and coma because of a very rapid absorption of the drug

Hyperreflexic or have myoclonic jerks or any evidence of seizure activity

A number of TCAs (dothiepin, desipramine, maprotiline, bupropion and amoxapine) cause seizures more frequently. Thus, they may cause seizure at lower drug ingestions

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TREATMENT Supportive ABC ECG monitoring GI Decontamination If patients are alert and co-operative and

have ingested > 5 mg/kg, charcoal may be administered orally

If the patient is unconscious and requires intubation to protect the airway insert an orogastric tube, aspirate stomach contents then give activated charcoal 23

TREATMENT IV fluids (control BP)

Acidosis control with sodium bicarbonate (hypotensive patients, wide QRS, metabolic acidosisdysrrhythmia)

NaHCO3: drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning

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TREATMENT OF SPECIFIC COMPLICATIONS

Diazepam 5-20 mg IV: 1mg/min(.01-0.2mg/kg)

Phenobarbitone 15-18 mg/kg IV

Succinylcholine chloride 10-20mg IV slowly and maintain adequate oxygenation/ventilation)

Phenytoin should be avoided ( sodium-channel blocking)

Kinidine Procainamide Disopyramide Propranolol Atropine Physostigmine Flumazenil (seizure

risk) Ipecac

Seizures Contraindication:

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IFE decreased mortality from clomipramine toxicity by 80% when compared to placebo.

Yoav G, Odelia G, Shaltiel C. A lipid emulsion reduces mortality from clomipramine overdose in rats. Vet Hum Toxicol 2002; 44(1):30)

EKG Case reports

4 h later in case of suspected amitriptyline intoxication.

IFE decreased the frequency of recurrent ventricular arrhythmia in a case of suspected

imipramine overdose

Intravenous Lipid emulsions A new antidote

Serotonin Re-Uptake Inhibitors

SSRIs Citalopram Fluoxetine Fluvoxamine Paroxetine Serteraline

Serotonin Syndrome Excessive

serotonergic tone 5HT1A, 5HT2

Continuum of neuropsychiatric manifestations

Serotonin

Serotonin Syndrome: Major Criteria*

Confusion Elevated mood Coma Fever Diaphoresis

Chills Rigidity Hyperreflexia Myclonus Tremor

4 major, or 3 major and 2 minorBirmes P CMAJ 2003;168:1439-1442

Minor Criteria: Serotonin Syndrome Agitation Nervousness Insomnia Tachypnea Dyspnea Tachycardia

High or low BP

Akathisia Incoordination Mydriasis Diarrhea

4 major, or 3 major and 2 minorBirmes P CMAJ 2003;168:1439-1442

Fatal Serotonin Syndrome Abrupt onset

Autonomic instability

Hyperthermia, diaphoresis

Neuromuscular rigidity, movement disorder

Altered mental status

Absence of a neuroleptic or other cause

Serotonin Syndrome Most often iatrogenic

Resolution in 48-96 hours

Death from uncontrolled hyperthermia

Serotonin Syndrome: Therapeutic Goals Rapid identification of Hyperthermia

Continuous core temperature monitoring, aggressive cooling, benzodiazepines for sedation

Rule out other potential etiologies

Serotonin Syndrome Identification of serotonergic factors,

particularly the presence of monoamine oxidase inhibitors

?Role of serotonin antagonists (cyproheptadine 0.1mg/kg, max 0.25mg/kg/d)

Drugs Implicated in Serotonin Syndrome

MAO-Inhibitors SSRIs Clomipramine Venlafaxine Lithium

MDMA* L-Tryptophan* Meperidine* Dextromethorphan* Cocaine*

Citalopram SSRI with toxic

metabolite

In overdose can prolong QRS, QTc,

Seizures

Delay in onset

Catalano G. Clin Neuropharmacol 2001;24:158-62

Citalopram Overdose Immediate cardiac monitoring for QTc, IV

lines Assess and correct electrolytes, especially K+,

Ca2+, Mg2+

Decontamination Use of Mg2+ for torsade Admission of minimum 24 hours of cardiac

monitoring

MONO AMINE OXIDES

INHIBITORSMAOIS

Tranylcypromine (parnate)Phenelzine (nardil)IsocarboxazideSelegiline (MAO –B inhibitor)moclobemide

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KINETICS MAOIs are orally absorbed well peak plasma conc. within 2-3 hours. large volume of distribution (1-5 L/kg) highly protein bound. They are metabolized by oxidation and

acetylation in the liver excreted in the urine.

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MAOI TOXICITYMAOI poisoning is classified into the following 3

subtypes: Actual poisoning from an overdose is

uncommon. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion (morbidity)

Drug-food interaction is so-called tyramine reaction or cheese reaction.

rapid in onset(15-90 min after ingestion). Most symptoms resolve in 6 hours

Drug-drug interaction 41

SYMPTOMS AND SIGNS The symptoms and signs of all 3 categories

are quite similar and represent the effects of excessive catecholamine neurotransmitters.

MAOIs inhibit breakdown of the neurotransmitters norepinephrine, dopamine, and serotonin, resulting in

hypertension tachycardia tremors seizures hyperthermia

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PREHOSPITAL CARE

Prehospital care for MAOI toxicity may include the following:

Stabilization of vital signs - IV fluids Treatment of seizure activity -

Benzodiazepines Attention to airway maintenance Attention to temperature control

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EMERGENCY DEPARTMENT CARE Decontamination

Because of the potential for severe toxicity and lack of antidotes, an aggressive decontamination is very important.

Consider gastric lavage, particularly in patients with recent ingestion (within an hour).

Administer charcoal Because of its pharmacokinetics, extracorporeal removal,

such as hemodialysis or repeat dosed of activated charcoal, is likely less effective to reduce its level.

Control hyperthermic, rapidly (within 20-30 min)

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EMERGENCY DEPARTMENT CARE Fluid therapy (control dehydration from

hyperthermia).

Treating the associated hypertension is usually not necessary. It may actually be dangerous because of the

eventual hypotensive phase (avoid beta-blockers because they leave unopposed alpha-stimulation), which may exacerbate the clinical picture.

If deemed necessary, use of a short-acting antihypertensive agent, such as nitroprusside, nitroglycerine or phentolamine, is advisable.

IV benzodiazepines (useful for agitation and seizure control; they also may help control the hypertension).

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FERROUS POISOINING

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ARSENIC POISONING

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