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Q1)Cardiovascular toxicity

Anticholinergic effects and inhibition of neuronal reuptake of catecholamines result in tachycardia and mild hypertension.

2. Peripheral alpha-adrenergic blockade causes vasodilation and contributes to hypotension.

3. Membrane-depressant (quinidine-like) effects cause myocardial depression and cardiac conduction disturbances by inhibition of the fast sodium channel that initiates the cardiac cell action potential.

Metabolic or respiratory acidosis may contribute to cardiotoxicity by further inhibiting the fast sodium channel.

CNS toxicity: these result in part from anticholinergic toxicity (eg, sedation and coma)

Seizures are probably a result of inhibition of reuptake of norepinephrine or serotonin in the brain or other central effects.

Q2) Describe the three major clinical features of TCA overdose.

1- anticholinergic effects:

- Can present with dilated pupils, tachycardia, diminished or absent bowel sounds, and urinary retention.

-Myoclonic or metonymic jerking is common with anticholinergic intoxication and may be mistaken for seizure activity.

2- cardiovascular effects:

A) typical electrocardiographic, e.g:

* sinus tachycardia with pro- longation of the PR, QRS, and QT intervals.

* Various degrees of atrioven- tricular (AV) block may be seen.

B) Sinus tachycardia accompanied by QRS interval prolongation may resem- ble ventricular tachycardia.True ventricular tachy- cardia and fibrillation may also occur.

*Atypical or polymorphous ventricular tachycardia (torsade de pointes) associated with QT interval prolongation may occur with therapeutic dosing, but is actually un- common in overdose.

*Development of bradyarrhythmias usually indicates a severely poisoned heart and carries a poor prognosis.

C)Hypotension caused by venodilation is common and usually mild. In se- vere cases, hypotension results from myocardial depression and may be refractory to treatment; some patients die with progressive intractable cardiogenic shock. Pulmonary edema is also common in severe poisonings.

3- seizures:  are common with tricyclic antidepressant toxicity and may be recurrent or persistent. The muscular hyperactivity from seizures and myoclonic jerking, combined with diminished sweating, can lead to severe hyperthermia, resulting in rhabdomyolysis, brain damage, multisystem failure, and death.

Q3) Patients who are initially awake may abruptly lose consciousness or develop seizures without warning because of the delay owing to slow and erratic gut absorption.
Q4)  include sinus tachycardia with prolongation of the PR, QRS, and QT intervals. Various degrees of atrioventricular (AV) block may be seen

Q5) Most of these drugs are ex- tensively bound to body tissues and plasma proteins, resulting in very large volumes of distribution so plasma levels of free drug wont br a good representation of the actual drug

Q6) Plasma levels of some of the tricyclic antidepressants can be measured by clinical laboratories.

Therapeutic concentrations: less than 0.3 mg/L (300 ng/mL)

Electrolyte, blood urea nitrogen (BUN), and creatinine levels

Anion gap (see the Anion Gap calculator)

Complete blood cell count (CBC)

Alcohol level

Arterial blood gases (ABGs) for evaluation of acidosis or hypoxia

Q7)  sodium bicarbonate is the specific antidote for patients with QRS interval prolongation or hypotension

Q8) Sodium bicarbonate may reverse membrane-depressant effects by increasing extracellular sodium concentrations( which is inhibited by TCA) and by a direct effect of pH on the fast sodium channel( maintain arterial pH- bcz TCA cause metabolic or respiratory acidosis which furthers inhibits fast sodium channels and worsens cardiotoxicity)
Q9) it may aggravate conduction disturbances, causing asystole. it further impairs myocardial contractility, worsen hypotension, and contribute to seizures
Q10) Explain the emergency and supportive measures to treat TCA

overdose.

1- Maintain an open airway and assist ventilation if necessary.

2-Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur.

Note: Do not use pro- cainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia, because these drugs may aggravate cardiotoxicity.

3- Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes.

4- Mechanical support of the circulation (eg, cardiopulmonary bypass) may be useful (based on anecdotal reports) to stabilize patients with refractory shock, allowing time for the body to eliminate some of the drug.

5- If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker such as pancuronium to prevent hyperthermia, which may induce further seizures, and lactic acidosis, which aggravates cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures, but has no effect on brain seizure activity. After paralysis, ECG monitoring is necessary to determine the efficacy of anticonvulsant therapy.

6- Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.

Q11)Prehospital:Administer activated charcoal if available. Do not induce vomiting because of the risk of abrupt onset of seizures.

2-  Hospital. Administer activated charcoal. Perform gastric lavage for large ingestions (eg, > 20–30 mg/kg). but if the doses is less no need for GI emptying

overdose,  erratic absoprtion, so when its sudenly abrobed.. loss of conciousess
Q12)  extensive tissue and protein binding with a resulting large volume of distribution, dialysis and hemoperfusion are not effective.

qt prolongation is VERY RELABLE IN TCA TOX!!!!!

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10) Explain the emergency and supportive measures to treat TCA overdose. 1. Maintain an open airway and assist ventilation if necessary . Caution: Respiratory arrest can occur abruptly and without warning. 2. Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur. Note: Do not use procainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia, because these drugs may aggravate cardiotoxicity. 3. Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes. 4. Mechanical support of the circulation (eg, cardiopulmonary bypass) may be useful (based on anecdotal reports) to stabilize patients with refractory shock, allowing time for the body to eliminate some of the drug. 5. If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker such as pancuronium to prevent hyperthermia, which may induce further seizures, and lactic acidosis, which aggravates cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures, but has no effect on brain seizure activity. After paralysis, ECG monitoring is necessary to determine the efficacy of anticonvulsant therapy. 6. Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.11) Which methods of decontamination are useful in TCA overdose? 1. Prehospital. Administer activated charcoal if available. Do not induce vomiting because of the risk of abrupt onset of seizures. 2. Hospital. Administer activated charcoal. Perform gastric lavage for large ingestions (eg, > 20–30 mg/kg). Gastric emptying is probably not necessary for smaller ingestions if activated charcoal can be given promptly.12) Why the routinely used methods to enhance elimination of poisons such as hemodialysis and hemoperfusion are ineffective to treat TCA overdosed patient?Owing to extensive tissue and protein binding with a resulting large volume of distribution, dialysis and hemoperfusion are not effective. Although repeat-dose charcoal has been reported to accelerate tricyclic antidepressant elimination, the data are not convincing.

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10) Explain the emergency and supportive measures to treat TCA overdose. 1. Maintain an open airway and assist ventilation if necessary . Caution: Respiratory arrest can occur abruptly and without warning. 2. Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur. Note: Do not use procainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia, because these drugs may aggravate cardiotoxicity. 3. Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes. 4. Mechanical support of the circulation (eg, cardiopulmonary bypass) may be useful (based on anecdotal reports) to stabilize patients with refractory shock, allowing time for the body to eliminate some of the drug. 5. If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker such as pancuronium to prevent hyperthermia, which may induce further seizures, and lactic acidosis, which aggravates cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures, but has no effect on brain seizure activity. After paralysis, ECG monitoring is necessary to determine the efficacy of anticonvulsant therapy. 6. Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.11) Which methods of decontamination are useful in TCA overdose? 1. Prehospital. Administer activated charcoal if available. Do not induce vomiting because of the risk of abrupt onset of seizures. 2. Hospital. Administer activated charcoal. Perform gastric lavage for large ingestions (eg, > 20–30 mg/kg). Gastric emptying is probably not necessary for smaller ingestions if activated charcoal can be given promptly.12) Why the routinely used methods to enhance elimination of poisons such as hemodialysis and hemoperfusion are ineffective to treat TCA overdosed patient?Owing to extensive tissue and protein binding with a resulting large volume of distribution, dialysis and hemoperfusion are not effective. Although repeat-dose charcoal has been reported to accelerate tricyclic antidepressant elimination, the data are not convincing.

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1) What are the primary mechanisms of toxicity in TCA overdose?
A. Cardiovascular effects. Several mechanisms contribute to cardiovascular
toxicity:
1. Anticholinergic effects and inhibition of neuronal reuptake of catecholamines
result in tachycardia and mild hypertension.
2. Peripheral alpha-adrenergic blockade causes vasodilation and contributes
to hypotension.
3. Membrane-depressant (quinidine-like) effects cause myocardial depression
and cardiac conduction disturbances by inhibition of the fast sodium
channel that initiates the cardiac cell action potential. Metabolic or respiratory
acidosis may contribute to cardiotoxicity by further inhibiting the fast
sodium channel.
B. Central nervous system effects. These result in part from anticholinergic
toxicity (eg, sedation and coma), but seizures are probably a result of inhibition
of reuptake
2) Describe the three major clinical features of TCA overdose.
A. Anticholinergic effects include sedation, delirium, coma, dilated pupils, dry
skin and mucous membranes, diminished sweating, tachycardia
B. Cardiovascular toxicity manifests as abnormal cardiac conduction, arrhythmias,
and hypotension.
C. Seizures
3) Explain why patients with TCA overdose who often appear awake may abruptly lose consciousness or develop seizures without warning.
may be delayed owing to slow and erratic gut absorption. Patients who are initially awake may abruptly lose consciousness or develop seizures without
warning.
4) What ECG findings are typical of TCA overdose?
typical electrocardiographic findings include sinus tachycardia with prolongation of the PR, QRS, and QT intervals. Various degrees of atrioventricular (AV) block may be seen. Prolongation of the QRS complex to 0.12 seconds or longer is a fairly reliable predictor of serious cardiovascular and neurologic toxicity (except in the case of moraine, which causes seizures and coma with no change in the QRS interval).

2. Sinus tachycardia accompanied by QRS interval prolongation may resemble ventricular tachycardia (see Figure I–4, p 12). True ventricular tachycardia and fibrillation may also occur. Atypical or polymorphous ventricular tachycardia (torsade de pointes; see Figure I–7, p 15) associated with QT interval prolongation may occur with therapeutic dosing, but is actually uncommon in overdose.
5) Why the plasma levels of TCAs are not used in the emergency management of TCA poisoning?
Generally, plasma levels are not used in emergency management because the QRS interval and clinical manifestations of overdose are reliable and more readily available indicators of toxicity.
6) Which laboratory tests are useful to diagnose TCA overdose?
1.      Plasma levels of some of the tricyclic antidepressants can be measured by clinical laboratories. Therapeutic concentrations are usually less than 0.3 mg/L (300 ng/mL). Total concentrations of parent drug plus metabolite of 1 mg/L (1000 ng/mL) or greater are usually associated with serious poison- ing. Generally, plasma levels are not used in emergency management be- cause the QRS interval and clinical manifestations of overdose are reliable and more readily available indicators of toxicity.

2. Most tricyclics are detectable on comprehensive urine toxicology screen- ing.

3. Others: electrolytes, glucose, BUN, creati- nine, CPK, urinalysis for myoglobin, arterial blood gases or oximetry, 12-lead, ECG and continuous ECG monitoring, and chest x-ray hy the plasma���Bf3�

7) What is the specific antidote for TCA overdose?
1.     sodium bicarbonate (see p 419), 1–2 mEq/kg IV, and repeat as needed to maintain the arterial pH between 7.45 and 7.55. Sodium bicarbonate may reverse membrane-depressant effects by increasing extracellular sodium concentrations and by a direct effect of pH on the fast sodium channel.

8) What are the possible mechanisms of therapeutic effect of sodium bicarbonate in TCA overdose?
Sodium bicarbonate may reverse membrane-depressant effects by increasing extracellular sodium concentrations and by a direct effect of pH on the fast sodium channel

9) Physostigmine, (an anticholinesterase inhibitor), is routinely used in the clinic to reverse anticholinergic effects. However, the use of Physostigmine during TCA overdose is strongly discouraged despite the toxicity caused by anticholinergic effects of TCAs. Why?
Although physostigmine was advocated in the past, it should not be routinely administered to patients with tricyclic antidepressant poisoning; it may aggravate conduction disturbances, causing asystole, further impair myocardial contractility, worsening hypotension, and contribute to seizures.
10) Explain the emergency and supportive measures to treat TCA overdose.

11) Which methods of decontamination are useful in TCA overdose?
1.      Prehospital. Administer activated charcoal if available. Do not induce

vomiting because of the risk of abrupt onset of seizures.

2.      Hospital. Administer activated charcoal. Perform gastric lavage for large ingestions (eg, > 20–30 mg/kg). Gastric emptying is probably not neces-

sary for smaller ingestions if activated charcoal can be given promptly.

12) Why the routinely used methods to enhance elimination of poisons such as hemodialysis and hemoperfusion are ineffective to treat TCA overdosed patient?

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Q1)Mechanism of toxicity.
A. Cardiovascular effects. Several mechanisms contribute to cardiovascular
toxicity:
1 Anticholinergic effects and inhibition of neuronal reuptake of catecholamines  result in tachycardia and mild hypertension.
2. Peripheral alpha-adrenergic blockade causes vasodilation and contributes  to hypotension.
3. Membrane-depressant (quinidine-like) effects cause myocardial depression and cardiac conduction disturbances by inhibition of the fast sodium channel that initiates the cardiac cell action potential. Metabolic or respiratory acidosis may contribute to cardiotoxicity by further inhibiting the fast  sodium channel.
B. Central nervous system effects. These result in part from  anticholinergic toxicity (eg, sedation and coma), but seizures are probably a result of inhibition of reuptake of norepinephrine or serotonin in the brain or other central effects.

Q 2)anticholinergic effects, cardiovascular effects, and seizures

Cardiovascular toxicity manifests as abnormal cardiac conduction, arrhythmias, and hypotension.
1. Typical electrocardiographic findings include sinus tachycardia with prolongation of the PR, QRS, and QT intervals. Various degrees of atrioventricular (AV) block may be seen. Prolongation of the QRS complex to 0.12 seconds or longer is a fairly reliable predictor of serious cardiovascular and neurologic toxicity (except in the case of moraine, which causes seizures and coma with no change in the QRS interval).
2. Sinus tachycardia accompanied by QRS interval prolongation may resemble  ventricular tachycardia ). True ventricular tachycardia and fibrillation may also occur. Atypical or polymorphous ventricular tachycardia (torsade de pointes; associated with QT interval prolongation may occur with therapeutic dosing, but is actually uncommon  in overdose. Development of bradyarrhythmias usually indicates a severely poisoned heart and carries a poor prognosis.
3. Hypotension caused by venodilation is common and usually mild. In severe cases, hypotension results from myocardial depression and may be refractory to treatment; some patients die with progressive intractable cardiogenic shock. Pulmonary edema is also common in severe poisonings.
C. Seizures are common with tricyclic antidepressant toxicity and may be recurrent or persistent. The muscular hyperactivity from seizures and myoclonic
jerking, combined with diminished sweating, can lead to severe hyperthermia   resulting in rhabdomyolysis, brain damage, multisystem failure, and death.

Q3 Symptoms usually begin within 30–40 minutes of ingestion  but may be delayed owing to slow and erratic gut absorption.

Q4 sinus tachycardia with prolongation of the PR, QRS, and QT intervals

Q5 plasma levels are not used in emergency management because the QRS interval and clinical manifestations of overdose are reliable and more readily available indicators of toxicity.

Q6 electrolytes, glucose, BUN, creatinine, CPK, urinalysis for myoglobin, arterial blood gases or oximetry, 12-lead ECG and continuous ECG monitoring, and chest x-ray

Q7 . Sodium bicarbonate may reverse membrane-depressant effects by increasing extracellular
sodium concentrations and by a direct effect of pH on the fast sodium channel.

Q9 it may aggravate conduction disturbances, causing asystole, further impair myocardial contractility( so this increase parasympathetic ), worsening hypotension, and contribute to seizure

NOTE SSRI is not toxic like TCA