FRCA Notes

Drug Toxicity

This non-exhaustive page covers toxicity associated with overdose (accidental or otherwise) of other therapeutic substances.

Resources

Salicylate Toxicity

  • Clinical features relate to the ingested dose

>150mg/kg (mild toxicity)

  • Respiratory: tachypnoea, respiratory alkalosis due to direct respiratory centre stimulation
  • Cardiovascular: sweating, tachycardia
  • Neurological: retained consciousness, tinnitus, blurred vision, hyperthermia from uncoupling syndrome
  • Gastrointestinal: nausea, vomiting
  • Renal: HAGMA, impaired renal excretion of salicylate due to acidosis

>200mg/kg

  • Peripheral vasodilation
  • Agitation
  • Petechial haemorrhage

>500mg/kg

  • Pulmonary oedema
  • Profound cardiovascular collapse
  • Renal failure
  • Seizures
  • Encephalopathy
  • Coma
  • Coagulopathy - hypoprothrombinaemia causing abnormal bleeding

Salicylate levels

  • Early salicylate levels may be unreliable, especially if enteric-coated formulations are used
  • Therefore take levels at least 2-4hrs post-ingestion
  • Toxbase suggests serial measurements every 2hrs in those who are symptomatic or with a plasma level >200mg/ml

  • Issues include:
    1. Salicylate is highly protein bound and therefore the level won't correlate with the bioavailable fraction
    2. The level does not correlate with the degree of toxicity
    3. Salicylate becomes ion trapped in the CNS, which won't be detected by plasma levels

Decontamination

  • If within 1hr of ingestion of >125mg/kg salicylate, consider activated charcoal (e.g. 25-50g) with repeat dosing if indicated e.g. by rising salicylate levels
  • Toxbase suggest gastric lavage is indicated if >500mg/kg has been ingested, it is within 1hr of ingestion and the expertise to provide it is present
  • Whole bowel irrigation for ingestion of prolonged-release preparations is reportedly successful in animal models

Urine alkalinisation

  • Urinary alkalinisation with IV sodium bicarbonate in moderate-severe cases, even if respiratory alkalosis
  • E.g. an initial dose of 1.5L 1.26% NaHCO3 over two hours
  • The target urine pH is 7.5-8.5
  • Check urine pH hourly

  • Raising urine pH from 5 to 8 increases excretion by 20x
  • Helps prevent movement of salicylate into the CNS

  • Haemodialysis may be needed, especially in large overdoses or where further bicarbonate isn't possible

Potassium

  • Target potassium levels 4 - 4.5mmol/L
  • Check K+ level 2hrly
  • Potassium supplementation aids urine alkalinisation
    • If the patient is hypokalaemic, potassium is reabsorbed at the expense of hydrogen ions in the DCT
    • Ensuring adequate potassium prevents this

Digoxin Toxicity

  • Plasma digoxin levels >2.5μg/L are associated with toxicity
  • Serious problems, however, tend not to occur until a concentration of >10μg/L
  • Toxic effects do not correlate well with plasma level, although an ingested dose of >30mg is invariably fatal unless DigiFab is used

Interactions

  • Digoxin toxicity can be the result of various drug interactions
  • Some drugs enhance digoxin absorption, thus increasing plasma levels:
    • Macrolide antibiotics
    • Proton pump inhibitors

  • Some drugs inhibit clearance of digoxin by inhibiting P-glycoprotein
    • Non-DHP calcium channel blockers
    • Spironolactone
    • Amiodarone
    • Quinidine

Exacerbating factors

  • The effects of digoxin toxicity may be exacerbated by physiological disarray such as:
    • Hypokalaemia
    • Hypomagnesaemia
    • Hypocalcaemia
    • Acidosis


Cardiac Non-cardiac
Bradycardia Nausea & vomiting
AV block Abdominal pain
Ventricular ectopics Diarrhoea
Tachyarrhythmia Weakness
Ventricular bigeminy (highly suggestive) Confusion
Xanthopsia i.e. yellow-tinged vision
Hyperkalaemia


Decontamination/enhanced eliminiation

  • Avoid gastric lavage/use with caution as may increase vagal tone and worsen bradycardia
  • Equally, decontamination with cholestyramine is not well described unless renal clearance is affected e.g. those with renal failure
  • As digoxin is a large molecule, and has extensive tissue distribution, haemodialysis is also ineffective

Managing dysrhythmia

  • Ensure electrolytes are normalised:
    • Hyperkalaemia can occur (secondary to Na+>/K+ ATPase inhibition) - treat as usual
    • Hypokalaemia may exacerbate effects and should also be corrected
    • Correct hypomagnesaemia
    • Correct acidosis

  • For bradyarrhythmias, atropine or pacing is preferred to catecholamine, which may precipitate ventricular arrhythmias

  • For ventricular arrhythmias consider management with either:
    • Phenytoin
      • Limited role in management of arrhythmias associated with digoxin toxicity
      • Class 1b anti-arrhythmic properties by blocking Na+ channels
      • Depresses pacemaker activity and increases conduction through the conducting system
    • Lidocaine

DigiFab

  • Monovalent IgG antibodies that bind digoxin with 100-1000x higher affinity than the Na+>/K+ ATPase, effectively removing it from the circulation
  • Each 40mg dose of Fab binds 500micrograms of digoxin
  • The Fab-digoxin complex is excreted in the urine, increasing the renal clearance of digoxin by 20-30%

  • Generally indicated if there are:
    • Digoxin plasma levels >20μg/L
    • Life-threatening arrhythmias
    • Refractory hyperkalaemia

  • Caution as:
    • Digoxin assays will still measure digoxin bound by the Fab fragments, so serum digoxin levels will remain high after administration
    • May need to therefore resist the urge to give more as hypersensitivity reactions on re-exposure to Fab a second time have been described

Theophylline Toxicity

  • Theophylline (or aminophylline) therapy usually targets a therapeutic plasma concentration of 10 - 20μg/ml
  • The therapeutic window is narrow, however, as once the level is:
    • >20μg/ml: drug toxicity occurs
    • >35μg/ml: hepatic enzyme saturation occurs and drug kinetics change from first-order to zero-order (non-linear, saturation) kinetics
    • >100μg/ml: there is risk of seizures, coma and death

Cardiovascular

  • Tachycardia (either SVT in children or VF in adults)
  • Hypertension due to positive inotropy followed by hypotension
  • Widened pulse pressure due to peripheral vasodilation ('inodilator' effect)

Neurological

  • An array of 'positive' features occur:
    • Elevated mood
    • Agitation, anxiety
    • Hallucinations
    • Tremors
    • Insomnia
    • Seizures

Musculoskeletal

Biochemical

Too much Not enough
Hyperglycaemia Hypokalaemia
Hypercalcaemia Hypomagnesaemia
Hyperlactataemia Hypophosphataemia


  • Activated charcoal, with repeated doses suggested if severe clinical features or plasma concentration greater than 40 mg/L

Cardiovascular

  • May need vasopressor (noradrenaline) to combat vasodilation causing hypotension

  • SVT
    • Toxbase suggests leaving it be unless haemodynamic compromise
    • Tends to be adenosine-resistant as theophylline acts as an adenosine antagonist
    • Calcium channel blockers may be effective

  • Ventricular arrhythmias
    • Ventricular arrhythmias can be managed with β-blocker or amiodarone
    • Esmolol may be preferable as the β2-antagonism can somewhat counteract the peripheral vasodilation seen in theophylline toxicity

Neurological

  • Benzodiazepines are first line for agitation and for seizures (if they occur)
  • Seizures tend to be refractory to other anti-epileptics and barbiturates are second line (i.e. avoid phenytoin etc.)

Biochemical

  • Correct electrolyte disturbances
  • Consider dialysis