1. Tricyclic Antidepressants (TCAs) lecture 9 by Dr. Magdy M.Awny

2. Examples of TCA Clinical Uses Of TCAs .Pediatric enerusis
.Severe depression
.Panic disorders, phobia
.Bulimia nervosa (uncontrolled constant eating followed by vomiting)
.Pediatric enerusis
TCA overdose:
60% likely intentional
90% of TCA suicides do not reach hospital but die at home
Examples of TCA
Imipramine Tofranil®
Desipramine
Trimipramine
Clomipramine Anafranil®
Amitriptyline Tryptizol®
Nortriptyline
protriptyline

3. Therapeutic mechanism
At low therapeutic dose or at the beginning of toxicity…….TCAs Inhibit neuronal reuptake of catecholamines especially NE, 5HT so increase their level in synapse

4. At high toxic dose TCA can block -Histamine receptors……sedation
-Muscarinic receptors…… antimuscarinic effects,
-α adrenergic receptors …….VD (orthostatic hypotension)
GABA-A receptor antagonist……..seizures
Sodium channel blockage
Potassium Channel Blockade

5. Pharmacokinetics Peak levels occur 2-6 hours post ingestion
Lipophilic….easily crosses BBB
Highly bound to plasma protein
Hemodialysis, hemoperfusion and forced diuresis are ineffective
Enter enterohepatic circulation
Hepatic metabolism…..active metabolites
Renal excretion
Half life
Therapeutic: on average 24 hours
Overdose: up to 72 hours

6. Manifestations of TCA toxicity
Peripheral anticholinergic
CNS manifestations
CVS effects

7. Anticholinergic Effects
Due to muscarinic receptor blockade
Eye…..
GIT……
Heart……
Secretions……
Urinary tract …….
Body temp…….

8. CNS manifestations
(due to central anticholinergic effects and H blockage )
Delirium
Sedation
Stupor
Coma
Respiratory depression
Myoclonic twitching
Seizures & hyperthermia
Choreoathetoid movements (dancing movements of upper limbs)

9. CVS manifestations sympathomimetic effects: resulted in hypertension
as TCAs at low dose or initially during toxicity they
block neuronal reuptake of NE so ↑ NE in synapse→→
VC (α effect), ↑HR (sinus tachycardia “Beta effect”)→ ↑BP
sympatholytic effects: resulted in hypotension
as TCAs at high dose or later during toxicity they
-block alpha-receptor →Vasodilation
-Has direct depressant action on myocardium (Na+ channel
blockade)→↓contractility→↓ cardiac output→ ↓BP

10. TCAs mediated Sodium Channel Blockade Impairs sodium entry
Arrhythmogenic action due to (quinidine-like or anticholinergic effects)
TCAs mediated Sodium Channel Blockade Impairs sodium entry
into myocardial cells →
Prolongs depolarization (Phase 0), ↓ contractility (-ve inotropy)
↓conduction velocity may →AV block
Prolonged PR
Widens QRS
Bradycardia as TCA depress phase 4 (May be attenuated by antimuscarinic effect)
Potassium Channel Blockade
Prevents potassium efflux during repolarization
QT interval prolongation
More pronounced with bradycardia
Tachycardia prevents severe QT prolongation

11. TCA induced acidosis causes arrhythmia (VT either monomorphic or polymorphic “torsades de-points”).
where respiratory depression result in accumulation of CO2
(respiratory acidosis), ↓ utilization of O2 →hypoxia →
Anerobic metabolism →metabolic acidosis
Also hypotension causes tissue hypoperfusion →hypoxia
On conclusion
acidosis inhibit Na/K ATPase pump → hyperkalemia……arrhythmia

13. Toxicity Life threatening Ingestions greater than 10mg/kg in adults
Pediatrics more susceptible to antimuscarinic effects
Manifest symptoms within 6 hours
High risk for TCA toxicity
▪ Co-ingestion with other cardiac or CNS depressants
▪ Prior heart disease
▪ Geriatrics
Most fatalities ingest more than 1 gram
Fatalities occur in initial hours usually before arrival to hospital

14. Clinical Features Mild/Moderate Toxicity Severe Toxicity Drowsiness
Confusion
Slurred speech
Ataxia
Dry skin/mucous membranes
Tachycardia
Urinary retention
Myoclonus
Hyperreflexia
Hypertension
Severe Toxicity
Coma
Conduction delays
Hypotension
Respiratory depression
Ventricular tachycardia
Seizures
Pulmonary edema
High degree AVB

15. Diagnosis ICU Suspect in: Rapidly presenting coma
Cardiovascular collapse
Anticholinergic toxidrome
Generalized seizure
Characteristic ECG findings
▪ 1st degree AVB
▪ Widened QRS
▪ Prolonged QT
ICU

16. Treatment GI Decontamination
Emesis not recommended in unconscious pt
Gastric lavage within first few hours after toxic ingestion
Activated Charcoal
1-2gm/kg PO, repeated dose (0.5-1g/kg) 2-4 hrs of first dose with cathartic
Elimination enhancement …….. Not effective
Lipophilic
Highly distributed “vd L/kg)
Highly bound to plasma proteins up to 95%
So TCAs elimination not affected by hemodialysis, hemoperfusion or even multiple doses of charcoal.
Also urinary excretion of TCAs or their metabolites (demethylated cpd) is < 10% so enhancing renal excretion is not effective

17. Adjunctive Treatments
Sodium Bicarbonate Therapy (1-3 mEq/kg, bolus injection as the initial management)
Indications
Widened QRS
Refractory hypotension (trendlenburg, I.V saline,….)
Ventricular dysrhythmias or conduction abnormality
Improves
▪ Conduction ▪ Contractility ▪ correct acidosis
Hypokalemia is an expected complication
Supplementation usually required
NaHCO3 →↑pH →↑non ionized fraction of TCAs→→
↑protein binding→↓active free fraction→ facilitate
dissociation of TCAs from !fast Na channel (recovered)
also increased extracellular sodium reverses the effect on
conduction velocity and QRS duration

18. Treatment Seizures Hypotension
Benzodiazepines are drug of choice (diazepam 5-10mg i.v
Hypotension
Vasopressor e.g. Norepinephrine used with caution as TCA block amine pump so may increase Arrhythmogenic potential of theses agents

19. Treatment Dysrhythmias Antidotes
Prolonged QRS or ventricular dysrhythmias
1st line drug is bicarbonate therapy
2nd line drug is lidocaine
- torsade de pointes is best treated with overdrive cardiac
pacemaker insertion
Antidotes
There are no readily available specific antidotes for the most serious manifestations.

20. Case study
A.B is a 24-year- female with a 4 months history of depression who was found unresponsive at home. The paramedics discovered empty bottles of amitriptyline (Elavil)100 mg and trazodone (desyrel) 100mg. Vital signs was BP 80/55 mm Hg, pulse 160/min and irregular, respiration 6 /min and temperature 99.9˚ F. physical examination showed dry mucous membranes, dilated pupils, absent bowel sounds and a distended urinary bladder. During transport to hospital the patient had severe episodes of myoclonic jerking of her arms.
1-Characterize the toxicity of the antidepressant compounds.
A.B has anticholinergic manifestations e.g. tachycardia, fever,……
CNS manifestations include coma, respiratory depression, fever and myoclonus
2-what initial management would you recommend for A.B?
Emesis ……..
hypotensive and unresponsive and should be admitted to ICU
should be placed in trendlenburg position and resuscitated with
saline to restore cardiac output

21. 3-What antiarrhythmic treatment would be most appropriate for A.B?
a-bolus injections of 1-3mEq/kg sod bicarbonate as the initial management of
TCA-induced conduction abnormality and vent arrhythmia
b-if no response after bicarbonate therapy or hyperventilation→
antiarrhythmic therapy is indicated
4-while in the emergency department, A.B had a tonic-clonic seizures, which lasted about one minute and spontaneously subsided. What treatment is indicated? If A.B develop persistent tonic clonic seizures, they may be controlled initially with 5-10 mg IV diazepam
5- 30 hrs after admission A.B. was alert and her vital signs were BP 110/70 mmHg, pulse 65/min, respiratory rate 20/min and temperature 98.6 F. her ECG has returned to normal 12 hrs after admission and remained stable. What is A.B’s risk for developing delayed arrhythmia?
It is highly unlikely that she will develop arrhythmia following discharge since she is alert and her ECG has been stable for 12 hrs.