Transcript tricyclic antidepressants

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ANTIDEPRESSANTS
POISONING
TCAS, SSRIS, MAOIS
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Dr K.Naseri
Pharm D, PhD of Pharmacology
TRICYCLIC
ANTIDEPRESSANTS
POISONING
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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 DOSE
For
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.
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TRICYCLIC ANTIDEPRESSANTS
Narrow therapeutic index
 Therapeutic plasma Conc.< 300ng/ml
 Toxic plasma Conc.> 1000ng/ml
 Toxic Dose ≤10times of therapeutic dose



1gr Amitriptyline was fatal in 1year
child
1.5gr Desipramine was fatal in 4years
old child.
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TRICYCLIC ANTIDEPRESSANTS
MECHANISM


Blocking reuptake of noradrenaline and
serotonin
These effects are probably unimportant in
overdose except in combined overdose with
selective serotonin reuptake inhibitors (SSRIs)
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TRICYCLIC ANTIDEPRESSANTS
MECHANISM

The drugs are
pharmacologically "dirty"
and bind to many other
receptors:




including histamine(H1 & H2)
( sedation)
Alpha 1 & 2 (vasodilatation,
iBP)
GABA-A (seizures )
muscarinic receptors
(anticholinergic effects )
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TCA TOXICITY
In 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 ANTIDEPRESSANTS
MECHANISM
 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 ANTIDEPRESSANTS
MECHANISM
 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.
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TRICYCLIC ANTIDEPRESSANTS
MECHANISM


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
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TRICYCLIC ANTIDEPRESSANTS
KINETICS

Highly lipid soluble weak bases

Rapidly absorbed


High volume of distribution


Death and toxicity mainly before redistribution (toxic
compartment) (heart, brain)
Protein binding > 95%



Anticholinergic effects may prolong absorption
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 effects
 Cardiac toxicity
 CNS 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)
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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 blockade
impaired myocardial contractility and
cardiac output

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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

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TREATMENT



IV fluids (control BP)
Acidosis control with
sodium bicarbonate
(hypotensive patients,
wide QRS, metabolic
acidosisa dysrrhythmia)
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
Seizures




Diazepam 5-20 mg
IV: 1mg/min(.010.2mg/kg)
Phenobarbitone 15-18
mg/kg IV
Succinylcholine
chloride 10-20mg IV
slowly and maintain
adequate
oxygenation/ventilati
on)
Phenytoin should be
avoided ( sodiumchannel blocking)
Contraindication:
Kinidine
 Procainamide
 Disopyramide
 Propranolol
 Atropine
 Physostigmine
 Flumazenil (hseizure

risk)

Ipecac
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Intravenous Lipid emulsions
A new antidote

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
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
 Chills
 Elevated mood
 Rigidity
 Coma
 Hyperreflexia
 Fever
 Myclonus
 Diaphoresis
 Tremor
4 major, or 3 major and 2 minor
Birmes P CMAJ 2003;168:14391442
Minor Criteria: Serotonin
Syndrome
 Agitation
 High or low
 Nervousness
BP
 Akathisia
 Incoordination
 Mydriasis
 Diarrhea
 Insomnia
 Tachypnea
 Dyspnea
 Tachycardia
4 major, or 3 major and 2 minor
Birmes P CMAJ 2003;168:14391442
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
 MDMA*
 SSRIs
 L-Tryptophan*
 Clomipramine
 Meperidine*
 Venlafaxine
 Dextromethorphan*
 Lithium
 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
INHIBITORS
MAOIS
Tranylcypromine (parnate)
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Phenelzine (nardil)
Isocarboxazide
Selegiline (MAO –B inhibitor)
moclobemide
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 TOXICITY
MAOI 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
(hmorbidity)

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
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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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