Transcript TRICYCLIC ANTIDEPRESSANTS

Tricyclic Antidepressant
Cardiotoxicity:
Beyond ABC to pH
Andrew Dawson
South Asian Clinical Toxicology
Research Collaboration
The Case

A 70 kg man presents on 1-2 hours following a
TCA overdose (3000 mg Amitryptilline)
– Unconscious
– Seizure
– BP 60 Systolic
TRICYCLIC ANTIDEPRESSANTS
Revise the pharmacology and
mechanisms
 Relate this to the clinical picture
 Advanced Treatment Options

KINETICS

Highly lipid soluble weak bases
– Rapidly absorbed


Anticholinergic effects may prolong absorption
High volume of distribution
– Death and toxicity mainly before redistribution
(toxic compartment)

Clinical Correlates
– asymptomatic at 3 hours remain well
 Liebelt
EL, et al Ann Emerg Med 1995; 26(2):195-201
– >15 mg/kg associated major toxicity
KINETICS

Protein binding > 95%
May saturate increasing free fraction
 pH dependent


P450 Hepatic metabolism
Saturable: long elimination half life
 Active metabolites


Clinical Correlates
Toxicity increase with acidosis
 Prolonged clinical course

Pharmacodynamically Promiscuous

Block re-uptake of noradrenaline and serotonin
Antagonists to H1 and H2 receptors,GABA
Alpha antagonists
Anticholinergic effects

Clinical Correlate



– Anticholinergic effects
– Hypotension
Anticholinergic Syndrome

Anticholinergic Syndrome:
–
–
–
–
–


Hot as hell
Blind as a bat
Red as a beet
Dry as a bone
Mad as a hatter
A sensitive indicator for ingestion, but
poor predictor for toxicity.
Full syndrome is rare
CNS Toxicity



Anticholinergic psychosis
Coma
Myoclonus and seizures
–
Seizures are strongly associated with
arrhythmia and acute deterioration and
increased mortality


Lancet 1994;343:159-62
J Tox - Clin Tox. 33(3):199-204, 1995
Fast Sodium Channel blockers &
pH

Slowing of the 0 phase of depolarisation
Rate dependent block
Ionized drug binds with the greatest affinity

Clinical Correlates


– Increasing conduction defects
– Impaired myocardial contractility
Predicting Major Complication


QRS > 100 milliseconds or more in a limb lead is as
good as TCA concentration
Ventricular arrhythmia



Sensitivity 0.79 (95% CI 0.58- 0.91)
Specificity 0.46 (95% CI 0.35- 0.59)
Seizures


Sensitivity 0.69 (95% CI 0.57- 0.78)
Specificity 0.69 (95% CI 0.58- 0.78)


RaVR > 3 mm


Bailey et al J Tox ClinTox 2004
Sensitivity 0.81
R/SaVR >.7

Sensitivity 0.75
CVS toxicity

Tachycardia:
Good indicator of TCA ingestion
 Caused by cholinergic blockade
 Catecholamine
 Anxiety


Hypotension
Vasodilation, hypovolaemia, alpha receptor blockade
 Serious myocardial depression (normally wide QRS)


Bradycardia:
generally associated major conduction block
 severe toxicity

HA

+
H
+A
Drugs and Receptors can be considered to be weak
acids or bases.
– Equilibrium influenced by external pH

The balance of the equilibrium can be expressed
by pKa
– The pKa is the pH where [ionised] = [non-ionised]
Henderson-Hasselbach
HA

+
H
+A
For basic compounds:
– pH = pKa + log (non-ionised/ionised)
– ionised/non-ionised = 10 (pKa – pH)
pKa
8.5
pH
6.9
7 7.1
ratio I/U 39.8 31.6 25.1
7.2
20.0
7.3 7.4 7.5
15.8 12.6 10.0
TCA: pH = 7.1
TCA: pH= 7.3

200 mEq
bicarbonate
TCA: pH =7.4

200 mEq
bicarbonate
pH: Local anesthetics Sodium
Channel Blocker


Non-ionised form to diffuse
Preferential binding of ionised form in the
channel
 Narahashi
T, Fraser DT. Site of action and active form of
local anesthetics. Neurossci Res, 1971, 4, 65-99

Demonstration pH sensitivity
– pH 7.2 to 9.6 unblock the channel
 Ritchie
JM, Greengard P. On the mode of action of local
anesthetics. Annu Rev Pharmacol. 1966, 6, 405-430
TCA & pH

Sodium channel Binding
– Ionisation trapping in the channel
– Receptor preferentially binds ionised drug

Other mechanisms
– Protein Binding

Phospholipid barrier
– non-ionised diffusion = more rapid redistribution

Sodium Loading
Protein Binding

Therapeutic concentrations
– pH shift 7.1 to 7.5



95% to 96% protein binding
Toxic concentrations protein binding is
saturated
pH change is effective in the absence of protein
Sasyniuk B ,Jhamandas V. J Pharmacol Exp Ther
1984;231:387-394
 Wang R,Schuyler J,Raymond R.The role of the cell
membrane bicarbonate exchanger in NaHCO3 therapy of
imipramine cardiac dysfunction J Toxicol Clin Toxicol
1997;35:533.

pH or sodium

Sodium loading has an additive effect
– Hypertonic saline (15meq/kg) > NaHCO3 >
Hyperventilation
McCabe. Ann Emerg Med .1998;32:329-333.

Bicarbonate via cell membrane exchanger
– block exchanger you lose the bicarbonate effect

Wang R,Schuyler J,Raymond R J Toxicol Clin Toxicol .
1997;35:533.
Risk?


Shift oxygen desaturation
curve
Cerebral blood flow &
hypocapnoea
– CBF varies linearly with PaCO2
( 20 - 80 mmHg)
– CBF change is 4% per mmHg
PaCO2

Sodium loading and
hypertonicity
Management CVS Toxicity

ABC
– Avoid acidosis
Volume replacement often large
 Ventilation to a low normal CO2


Decontamination
– Activated charcoal is indicated….mostly in the
same patients who intubation is indicated

Na Bicarbonate (AHA ACLS 2a)
– Dose: Repeated 3-5 minutes

1-3 meq/kg bolus (if not in shock)
 1-3

mls/kg of 8.4% solution
3-6 meq bolus (if in shock)
– Titrated by ECG
– Monitored ABG target pH 7.55 -7.6

? Refractory Hypotension
– Intropes with alpha effects: adrenaline
– 3 Case reports of hypertonic saline
– Cardiopulmonary bypass

Complex Ventricular Tachycardia
– Consider Magnesium
– Overdrive pacing
Conclusion



Manipulation of pH alters the kinetics and
dynamics of TCA
Recommendations are for bolus NaHCO3
Resuscitation should not be ceased until the
pH is corrected