Cyclic Antidepressant Toxicity

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Cyclic Antidepressant Toxicity

• Dawn R. Ruskosky, Pharm.D.
• Florida Poison Information Center Jacksonville

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Cyclic Antidepressants

• Catastrophic Deterioration!!

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Cyclic AntidepressantsMechanisms of Toxicity

• Fast sodium channel blockade
• Catecholamine reuptake inhibition
• Anticholinergic effects
• Blockade of alpha receptors
• GABA antagonism

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Fast Sodium Channel BlockadeQuinidine-like
effect

• QRS duration prolongation
• QT prolongation
• PR prolongation
• Ventricular dysrhythmias
• Terminal 40 msecond shift

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Reuptake Inhibition

• Hypertension initially
• Hypotension results

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Anticholinergic Effects

• Tachycardia
• Decreased bowel sounds
• Urinary retention
• Red as a beet
• Mad as a hatter
• Hot as Hades
• Dry as a bone
• Blind as a bat

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Alpha Blockade

• Hypotension
• GABA Antagonism
• Seizures

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Pediatric Population

• Low capacity for binding to albumin
• increased free drug
• Small fat stores
• more free drug available
• Small dose for toxicity
• 5 mg/kg/24 hrs therapeutic

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Cyclic AntidepressantsEKG Criteria (Adults)

• Marshall and Forker (1983)
• QRSgt 0.1sec assume potentially fatal ingestion
• Boehnert and Lovejoy (1985)
• QRSgt 0.1sec higher prob. of seizures
• QRSgt 0.16sec higher prob. of seizures and
  arrhythmias
• Niemann, et al. (1986)
• Terminal 40 ms shift present in all pts evaluated
  that were TCA

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Cyclic AntidepressantsEKG Criteria (Adults)
Continued

• Foulke and Albertson (1987)
• QRS lt 0.1sec cannot be used as a lone indicator
  of safety
• Wolfe, Caravati, and Rollins (1989)
• terminal 40 msec was a sensitive indicator of
  whether TCAs on board
• Liebelt, Francis, and Woolf (1995)
• RaVR gt 3mm and QRSgt 0.1 in sensitivity
• R/SaVR gt 0.7 had a higher PPV

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Pediatric PopulationEKG Criteria Differences

• Berkovitch, et al (1995)
• terminal 40msec had a sensitivity of 38 and
  specificity of 74
• QRS, QTc, and PR interval did not differ
  significantly from controls

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Serum AlkalinizationModalities

• Hyperventilation
• tolerance
• requires intubation
• Sodium Bicarbonate
• prefered method
• sodium load

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Serum AlkalinizationIndications

• Hypotension
• EKG abnormalities
• QRS prolongation
• arrhythmias
• Seizures
• CNS depression requiring intubation
• not a strict indication

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Serum Alkalinization SurveyEmpiric Alkalinization

• 84 centers surveyed
• 53 responded (63)
• Of those, 33 (62) use a QRSgt 0.1
• 13 (25) use a QRSgt 0.12
• 3 (6) use a QRSgt 0.14

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Serum AlkalinizationMechanism

• Cyclics are approx. 96 protein bound
• When pH increased (7.45-7.55), protein binding
  increases to approx. 98
• decreasing active drug to 1/2
• Alkalinization of sodium channel
• resets channel
• extracellular sodium load (bicarb)

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Cyclic AntidepressantsInitial Management

• ABCs
• Decontamination
• ? lavage ?
• activated charcoal
• MDAC
• Alkalinization (if required)

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While Alkalinizing..

• Hypotension
• Trendelenburg, a fluid bolus
• dopamine inconsistent
• norepinephrine agent of choice
• Seizures
• benzodiazepines
• barbiturates
• phenytoin had increased incidence of VT in animal
  studies

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While Alkalinizing.cont.

• Arrhythmias
• ACLS protocol
• consider magnesium
• avoid class 1a agents

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Serum AlkalinizationMonitoring Parameters

• Dont hang the bag and walk away
• Monitor serum pH every hour until within range,
  then back off
• can use VBGs
• Monitor potassium closely
• drops while on bicarb
• Monitor serial EKGs

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Remember!!!!!!!!

• Serum Alkalinization Antidote
• Urinary Alkalinization Elimination Enhancement

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Urinary AlkalinizationSalicylates and
Phenobarbital

• Unionized form of drug passes across membranes to
  be reabsorbed
• When urine pH increased, ionized form of drug
  increases
• Cannot traverse biological membranes
• Trapped in the urine to be eliminated

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Urinary AlkalinizationProcedure

• Sodium bicarbonate utilized
• Acetazolamide alkalinizes urine, but causes
  acidosis in serum
• would increase salicylate penetration to brain
• not recommended
• Goal is a urine pH of 7.5-8

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Any Questions???