My Clinical Notes

Overdoses

·        Must be excluded in coma of unknown origin.

·        Assay for identification, but normally to assess concentration levels (unless it will change your management! – e.g. paracetamol).

·        Epidemiology:

o       Most common ODs are: ethanol, paracetamol, salicylates (all of which cause metabolic derangements – Acid-base disturbance, hypokalaemia, hypoglycaemia) and benzodiazepines & tricyclics (which do not).

 

Salicylates (asprin)

• No antedote but measures can be taken to increase the drugs excretion
• Pathophysiology of salicylate poisoning
  • Respiratory alkalosis – due to an uncoupling of oxidative metabolism. This can result in increased renal secretion of HCO3-, Na, K and water resulting in dehydration and electrolyte imbalance
  • Non-respiratory acidosis due to;
    • Increased lipolysis resulting in ketone production
    • Inhibition of the TCA cycle causing increases in lactate and pyruvic acid
    • Increased proteolysis causing increased amino acids
  • Stimulation of chemoreceptor trigger zone resulting in vomiting
  • It can also cause hypo and hyperglycaemia
• Metabolised by hydrolysis to salicylic acid (the active form of the drug) and excreted unchanged into the urine
• If the urine is acidic, salicylic acid isn’t ionised so once filtered by the glomerulus it is reabsorbed by the tubules
• If the urine is alkaline, salicylic acid is ionised, tubular reabsorption is inhibited and excretion is enhanced
• Therefore treat with sodium bicarbonate infusions
  • Problems – dangerous, requires careful monitoring
  • Don’t give if the patient already has a systemic alkalosis or the urine pH is above 8
  • Potassium supplementation is required
  • Hypoglycaemia and dehydration must be corrected
  • Monitor fluid balance, BM, arterial pH and urine pH
• Also consider activated charcoal to reduce absorption
• If levels are very high and there is renal impairment – consider haemoperfusion or haemodialysis

 

Paracetamol

• Essential to measure plasma drug concentrations in suspected paracetamol poisoning as;
• A specific antedote to the hepatotoxic effect is available – N-acetylcysteine given IV (promotes glutathione synthesis)
• It is only useful is given within a defined period of time and if plasma concentrations have been reached
• The likelihood of hepatotoxicity cannot be predicted from the clinical picture at presentation
• Levels can only be interpreted once absorption and distribution are completed – 4 hours after ingestion
• Metabolism – when taken in toxic doses, a toxic metabolite is formed which is detoxified by conjugation with glutathione, when taken in excess, glutathione supplies are rapidly exhausted and the metabolite accumulates causing cell damage. The metabolite is toxic to the liver and kidneys
• Patients taking enzyme inducing drugs such as phenytoin, rifampacin, carbamazepine or alcohol or those that are malnourished e.g. anorexic or infected with HIV are more at risk of paracetamol toxicity
• Clinical features
  • <24hr – anorexia, vomiting, nausea
  • 24-48hr – abdominal pain, hepatic tenderness, prolonged PT, elevated plasma transaminases and bilirubin
  • >48hr – jaundice, encephalopathy, renal and hepatic failure
• Treatment graph;
  • Plots paracetamol concentration over time
  • There are 2 lines on it which indicate significant risk of hepatotoxicity
  • Normal treatment line: Give N-acetylecystine if above this line.
  • High Risk treatment line: Give N-acetylecystine if above this line and have any of the above risk factors.
  • Prognostic accuracy of treatment lines much reduced after 15 hours.
  • If unknown when patient last took drug simply treat if plasma levels fall above relevant treatment line
• Take serial measurements of plasma transaminases, renal function, prothrombin time and INR (prothrombin time and INR as the best markers of severity of liver failure)
• Treatment of paracetamol poisoning should include emergency measures;
  • Activated charcoal is only beneficial in the first hour
  • Kept patient hydrated with 5% dextrose as there is a tendency for hypoglycaemia with liver damage
  • Give Vitamin K prophylactically

 

Iron

• Can cause severe illness, particularly in children
• Causes necrosis of the GI mucosa resulting in haemorrhage, fluid and electrolyte loss
• Patients may develop encephalopathy, renal failure, circulatory collapse and acute liver failure
• Treatment is with desferroxamine, an iron chelating agent which promotes its excretion
• Assess by measuring free iron concentration

 

Carbon monoxide

• Causes hypoxia without cyanosis
• Carboxyhaemoglobin above 60% can cause respiratory failure and death
• Diagnosed by measuring carboxyhaemoglobin
• Can result in a metabolic acidosis – measure ABG
• Oxygen therapy can increase the washout of carboxyhaemoglobin

 

Methanol

• Broken down by alcohol dehydrogenase to form formic acid and formaldehyde
• This can lead to nerve damage, renal failure, hypoglycaemia, metabolic acidosis and rhabdomyolysis
• Also causes a raised serum amylase
• Measure methanol levels in the blood
• Treat with ethanol which inhibits alcohol dehydrogenase

 

Ethylene glycol (antifreeze)

• It is metabolized to various organic acids, including oxalic acid which combines with calcium to form insoluble calcium oxalate – the precipitates in the tissues and renal tubules
• Characterized by a severe acidosis and a hypoglycaemia
• Treated by giving a competitive inhibitor of alcohol dehydrogenase blocking the conversion of ethylene glycol to toxic metabolites
• Ethanol used to be used for this but now 4-methyl pyrazole is used

 

Ethanol

• Drug overdose is often complicated by simultaneous ingestion of alcohol
• It potentiates the action of many drugs
• Metabolic effects;
  • Hypertriglyceridaemia
  • Hypoglycaemia
  • Hypogonadism
  • Hyperuricaemia
  • A form of Cushing’s syndrome
  • Thiamine deficiency
  • Cutaneous hepatic porphyria
• Laboratory assays;
  • Direct assay of ethanol concentration
  • γ- glutamyl tranferase – not specific
  • Increased MCV – not specific
  • Carbohydrate deficient transferrin – both specific and sensitive

 

Iatrogenic toxicity

 

Lithium

• Has a low therapeutic ratio and there are wide interindividual differences in dose requirements – therefore measure levels if in any doubt
• It is nephrotoxic and excreted by the kidneys, therefore toxicity is self-perpetuating
• Renal handling of lithium is also related to sodium balance therefore diuretics can cause lithium retention

 

Digoxin

• Levels should be measured in the following situations;
• To assess compliance especially in the elderly
• In patients such as the elderly who have a reduced threshold for toxicity and premature infants with an increased elimination half life
• If dose is difficult to calculate because of an abnormal volume of distribution e.g. in obese or oedematous patients
• If excretion is impaired e.g. due to renal dysfunction
• If the patient is taking another drug which might reduce the rate of excretion
• Digoxin concentrations are difficult to interpret in the presence of conditions which alter the receptors sensitivity; e.g.
  • Hypokalaemia, hypercalcaemia, hypomagnesaemia
  • Hypoxia or acidosis
  • Hypothyroidism
• Measurement is with an immunoassay using antibodies which may cross react with certain endogenous compounds – called digoxin like immunoreactive substances
• Digoxin overdose/toxicity can be treated with administration of inactivating digoxin antibodies

 

Aluminium

• Toxicity is rare but has been described in renal patients
• Contamination of the water used in dialysis fluid has lead to cases of renal osteodystrophy and dialysis dementia
• Dialysis water is now usually treated to decontaminate aluminium
• Toxicity is also seen in individuals with high oral intake such as in aluminium containing antacids
• Diagnosed by measuring plasma aluminium levels
• Desferrioxamine can be used to chelate aluminium in toxicity

 

Rare causes of poisoning;

 

Lead

• Chronic poisoning is more common than acute
• Lead poisoning is a notifiable occupational disease
• Concentrated in erythrocytes
• Causes nausea, vomiting and severe abdominal colic. In the nervous system there may be encephalopathy, convulsions and impairment of consciousness
• Assay
  • Blood lead measurement
  • Non-specific measurements – protoporphyrin in erythrocytes (lead interferes with several steps in porphyrin synthesis)
• Acute lead poisoning can be treated with a chelating agent – DMSA or IV sodium calcium edentate to promote lead excretion

 

Mercury

• Poisoning may occur from organic or inorganic salts or elemental mercury vapour
• Acute toxicity – metallic taste, respiratory distress, nausea, vomiting
• Chronic features – renal dysfunction and neuropathy
• Diagnosed by mercury levels in the urine or blood, levels in hair can be used to establish chronic exposure
• Acute toxicity can be treated with dimercaprol-chelating agents which increase excretion in the urine and bile
• N-acetyl penicillamine has been used to chelate mercury following chronic exposure

 

Cadmium

• Industrial exposure
• Clinical features include hepatotoxicity, nephrotoxicity and bone disease
• Levels can be measured in the urine and blood

 

Organophosphates

• Irreversible AChE inhibitors, results in;
  • Miosis, accommodation, bronchoconstriction, excessive secretions, GI spasms/nausea/vomiting, bradycardia, hypotension, urinary incontinence, muscular fasciculation → weakness, restlessness, anxiety, insomnia, tremor, convulsions, respiratory depression circulatory collapse.
  • Death = respiratory failure.
• Treatment is via Pralodoxime (Highly nucleophilic. Splits phosphorous-enzyme bond. But only have a few hours to work before the bond is made permanent)
• Treatment is monitored using acetylcholinesterase activity – Red cell cholinesterase measured

 

Herbal drugs

• May contain steroids, metals and oestrogens

 

Arsenic

• Allosteric inhibitor of metabolic enzymes
• Uncouples oxidative phosphorylation resulting in decreased levels of ATP

 

Thallium

• Presents as nerve damage and hair loss
• Readily absorbed through the skin, has similar properties to K+ so enters cells disrupting cellular processes

 

Malignant hyperthermia

• An inherited myopathy characterized by a hypermetabolic state which is triggered when the patient is exposed to certain anesthetic agents
• Thought to be due to a reduction in calcium reuptake in skeletal muscles required for muscle relaxation
• Results in acidosis
• Some susceptible subjects in affected families have elevated plasma CK activity

 

Rhabdomyolysis

• Rapid breakdown of muscle leading to elevated muscle CK levels
• Can be due to;
  • Alcohol
  • Drugs such as statins, cocaine and ciclosporin

 

Ethicolegal Aspects

• Chain of Custody:
  • When calculating drug levels for medicolegal reasons, need to secure evidence of a chain of custody e.g. documentation
• Assays may differ from routine labs.
• Can only over-ride a non-consenting live patient if on order of a judge.

 

 

This entry was posted on Wednesday, March 26th, 2008 at 1:11 pm and is filed under Chemical Pathology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.