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wikitox:2.1.11.9.2.1_tricyclic_antidepressants [2018/09/01 09:00] – created - external edit 127.0.0.1wikitox:2.1.11.9.2.1_tricyclic_antidepressants [2025/07/18 00:06] (current) – [LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP] kharris
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 Less than 10 % of TCA circulates as free drug, the rest is bound to circulating proteins (albumin and alpha1 acid glycoprotein) or dissolved in circulating free fatty acids. Alpha1 acid glycoprotein (AAG) has high and low affinity binding sites for TCA. AAG is a more important binding protein than albumin, additional AAG can reverse TCA toxicity whereas albumin has no affect. The “bound” fraction is sensitive to changes in pH with acidosis causing an increase in free fraction. Less than 10 % of TCA circulates as free drug, the rest is bound to circulating proteins (albumin and alpha1 acid glycoprotein) or dissolved in circulating free fatty acids. Alpha1 acid glycoprotein (AAG) has high and low affinity binding sites for TCA. AAG is a more important binding protein than albumin, additional AAG can reverse TCA toxicity whereas albumin has no affect. The “bound” fraction is sensitive to changes in pH with acidosis causing an increase in free fraction.
  
-[[:wikitox:alkalinisation|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. (Levitt et al., 1986)+[[:concept_serum_alkalinization|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. (Levitt et al., 1986)
  
 ==== Metabolism - Elimination ==== ==== Metabolism - Elimination ====
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 Most patients with significant ingestions of TCAs who are likely to have cardiac complications or seizures have a significantly impaired level of consciousness prior to those complications. Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug. Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity. Some patients who are likely to have seizures may be noted to have relatively brisk reflexes compared to the normal hyporeflexia seen with coma from other causes. This can be a marker of high seizure risk. Most patients with significant ingestions of TCAs who are likely to have cardiac complications or seizures have a significantly impaired level of consciousness prior to those complications. Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug. Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity. Some patients who are likely to have seizures may be noted to have relatively brisk reflexes compared to the normal hyporeflexia seen with coma from other causes. This can be a marker of high seizure risk.
  
-Seizures themselves are associated with an increased mortality. Acidosis affects the [[:wikitox:alkalinisation|partitioning of TCAs between the cell membrane and the Na+ channel binding site]] and increases TCA induced Na+ channel blockade. There may also be a small increase in free drug concentration from pH-mediated changes in protein binding but this is a less important effect.+Seizures themselves are associated with an increased mortality. Acidosis affects the [[:concept_serum_alkalinization|partitioning of TCAs between the cell membrane and the Na+ channel binding site]] and increases TCA induced Na+ channel blockade. There may also be a small increase in free drug concentration from pH-mediated changes in protein binding but this is a less important effect.
  
 A number of TCAs (dothiepin, desipramine, and amoxapine) cause seizures more frequently. Thus, they may cause seizure at lower drug ingestions with less ECG abnormalities and occasionally in conscious patients. A number of TCAs (dothiepin, desipramine, and amoxapine) cause seizures more frequently. Thus, they may cause seizure at lower drug ingestions with less ECG abnormalities and occasionally in conscious patients.
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 **Arrhythmias** \\ It is often very difficult to distinguish whether the patient is having a supraventricular arrhythmia with aberrant conduction or primary ventricular tachycardia. Most arrhythmias, especially if they are associated with low output, are treated in a standard cardiac arrest protocol manner. The main difference is the requirement for early and large doses of NaHCO3 (bicarbonate). Hypertonic saline can be considered in refractory cases. **Arrhythmias** \\ It is often very difficult to distinguish whether the patient is having a supraventricular arrhythmia with aberrant conduction or primary ventricular tachycardia. Most arrhythmias, especially if they are associated with low output, are treated in a standard cardiac arrest protocol manner. The main difference is the requirement for early and large doses of NaHCO3 (bicarbonate). Hypertonic saline can be considered in refractory cases.
  
-Arrhythmias are best treated by correction of hypoxia and acidosis. This is achieved by administering oxygen and by [[:wikitox:alkalinisation|]] with bolus injections of intravenous sodium bicarbonate (1 to 2 meq of 8.4%). Further doses of sodium bicarbonate may be given cautiously depending on clinical response to achieve an arterial pH of 7.5-7.55 but care is needed to avoid a sustained alkalosis as pH>7.65 is potentially fatal.+Arrhythmias are best treated by correction of hypoxia and acidosis. This is achieved by administering oxygen and by [[:concept_serum_alkalinization]] with bolus injections of intravenous sodium bicarbonate (1 to 2 meq of 8.4%). Further doses of sodium bicarbonate may be given cautiously depending on clinical response to achieve an arterial pH of 7.5-7.55 but care is needed to avoid a sustained alkalosis as pH>7.65 is potentially fatal.
  
 [[:wikitox:3.4.3.4_antiarrhythmics|Antiarrhythmic agents]] should be avoided unless arrhythmias are unresponsive to the aforementioned measures. In these situations, magnesium sulfate or lidocaine may be used to treat refractory ventricular arrhythmias. Class Ia (quinidine,disopyramide,procainamide) and class Ic antiarrhythmic drugs (flecainide,propafenone) are contraindicated as they may worsen sodium channel blockade and exacerbate arrhythmias. [[:wikitox:3.4.3.4_antiarrhythmics|Antiarrhythmic agents]] should be avoided unless arrhythmias are unresponsive to the aforementioned measures. In these situations, magnesium sulfate or lidocaine may be used to treat refractory ventricular arrhythmias. Class Ia (quinidine,disopyramide,procainamide) and class Ic antiarrhythmic drugs (flecainide,propafenone) are contraindicated as they may worsen sodium channel blockade and exacerbate arrhythmias.
  
-**//Bicarbonate//  ** \\ Both sodium loading and [[:wikitox:alkalinisation|]] have been show to be effective in reversing TCA induced conduction defects and hypotension (McCabe et al, 1998), both are supplied by hypertonic sodium bicarbonate. Sodium bicarbonate is the drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning (Albertson et al, 2001).+**//Bicarbonate//  ** \\ Both sodium loading and [[:concept_serum_alkalinization]] have been show to be effective in reversing TCA induced conduction defects and hypotension (McCabe et al, 1998), both are supplied by hypertonic sodium bicarbonate. Sodium bicarbonate is the drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning (Albertson et al, 2001).
  
 Treatment with plasma alkalinisation to a pH of 7.50 - 7.55 using sodium bicarbonate (to alter both pH and sodium) and/or hyperventilation is effective for all TCA induced arrhythmias. The initial treatment in critically ill patients is often titrated against clinical response with bolus injections of 1-3 mEq of sodium bicarbonate per kg body weight repeated at 3-5 minute intervals. When the clinical situation allows it, arterial blood pH should be checked. The target pH is 7.50 - 7.55, sustained elevations of pH greater than this are associated with impaired oxygen dissociation from hemoglobin. As the patient is usually ventilated the pH can be maintained with mild hyperventilation (pCO2 = 30 mmHg). Treatment with plasma alkalinisation to a pH of 7.50 - 7.55 using sodium bicarbonate (to alter both pH and sodium) and/or hyperventilation is effective for all TCA induced arrhythmias. The initial treatment in critically ill patients is often titrated against clinical response with bolus injections of 1-3 mEq of sodium bicarbonate per kg body weight repeated at 3-5 minute intervals. When the clinical situation allows it, arterial blood pH should be checked. The target pH is 7.50 - 7.55, sustained elevations of pH greater than this are associated with impaired oxygen dissociation from hemoglobin. As the patient is usually ventilated the pH can be maintained with mild hyperventilation (pCO2 = 30 mmHg).
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 ===== LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP ===== ===== LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP =====
  
- \\ Patients are medically fit for discharge if they have no symptoms or signs of toxicity (including no anticholinergic features such as tachycardia) and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool). \\  \\ Patients who still have an isolated tachycardia generally should be kept in hospital and observed. As the usually cause is volume depletion, IV fluid to ensure adequate volume replacement should be given. \\  \\ Patients with a QRS complex equal to or greater than 100 milliseconds should be monitored until this has returned to normal. \\  \\ Reports of occasional late cardiac arrests have occurred in patients with persistently abnormal ECGs. Continued drug absorption or exposure may be the cause for late deterioration in this group and markedly delayed toxicity (> 24 hours) has only been reported in patients who did not receive gastrointestinal decontamination or, more recently, in modified release amitriptyline overdose. \\  \\ Antiholinergic delirium is relatively common post resolution of acute toxicity, and serotonin syndrome may be seen where a serotonergic drug has been co-inigested. \\ Neurological sequelae and other end organ injury may occur as a consequence of hypotension and cellular hypoxia in the setting of cardiac arrest or profound toxicity. They are not expected as a consequence of elevated drug levels per se, and are not seen post resolution of lesser toxicity.+\\ 
 +Patients are medically fit for discharge if they have no symptoms or signs of toxicity (including no anticholinergic features such as tachycardia) and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool).\\ 
 +\\ 
 +Patients who still have an isolated tachycardia generally should be kept in hospital and observed. As the usually cause is volume depletion, IV fluid to ensure adequate volume replacement should be given.\\ 
 +\\ 
 +Patients with a QRS complex equal to or greater than 100 milliseconds should be monitored until this has returned to normal.\\ 
 +\\ 
 +Reports of occasional late cardiac arrests have occurred in patients with persistently abnormal ECGs. Continued drug absorption or exposure may be the cause for late deterioration in this group and markedly delayed toxicity (> 24 hours) has only been reported in patients who did not receive gastrointestinal decontamination or, more recently, in modified release amitriptyline overdose.\\ 
 +\\ 
 +Antiholinergic delirium is relatively common post resolution of acute toxicity, and serotonin syndrome may be seen where a serotonergic drug has been co-inigested.\\ 
 +Neurological sequelae and other end organ injury may occur as a consequence of hypotension and cellular hypoxia in the setting of cardiac arrest or profound toxicity. They are not expected as a consequence of elevated drug levels per se, and are not seen post resolution of lesser toxicity. 
 + 
 +===== Educational Resources ===== 
 + 
 +[[https://player.vimeo.com/video/551810770?h=3c44a8d9c0|Video: TCA overdose - Prof Nick Buckley - TA{MA ASM 2021]] 
 + 
 +[[https://player.vimeo.com/video/908030027?h=33d58b4b70|Video: Why all the bicarb? Pitfalls of overtreatment - A/Prof Katherine Isoardi - TAPNA ASM 2023]] 
  
 ===== REFERENCES ===== ===== REFERENCES =====