4. Drug Overdose: Prescribed and Therapeutic Drugs

(TCAs) such as amitriptyline and imipramine serotonin re-uptake inhibitors (SSRIs) such as fluoxetine (Prozac), paroxetine (Seroxat), sertraline (Lustral), citalopram (Cipramil) and escitalopram (Cipralex)

SSRIs are relatively selective for 5-HT uptake, have fewer anticholinergic side effects than TCAs and are safer in overdose They can cause a ‘serotonin syndrome’ if used in combination with drugs such as monoamine oxidase inhibitors. Its features include hyperthermia, muscular rigidity and cardiovascular collapse.

TCAs are tertiary amines and are related chemically to phenothiazines. They act by blocking the re-uptake of amines, primarily noradrenaline and 5-HT competitive inhibition of a transport protein binding site They have minimal influence on dopaminergic synapses but do affect muscarinic ACh and histamine receptors.

major problems are cardiovascular and neurological. Ventricular arrhythmias are common and are associated particularly with QT interval prolongation. In high doses they appear to block a specific cardiac potassium channel (the HERG channel) Ventricular fibrillation may supervene. Other potential arrhythmias include heart block and ventricular tachycardia

agitation and excitability, grand mal convulsions and coma. The muscarinic effects resemble those of atropine poisoning, with flushing, dry mouth, mydriasis and gastrointestinal stasis. Features of poisoning with SSRIs are analogous, but are generally less severe.

Largely supportive. Benzodiazepines may abort convulsions. Cardiac arrhythmias should be treated only with extreme caution, if at all, because the combination of effects can be fatal. Magnesium is probably the least dangerous treatment, although intravenous lidocaine and amiodarone have been used. ECG monitoring is mandatory for at least 24 hours after ingestion. Induced alkalosis (plasma pH > 7.5) by the use of hyperventilation a nd intravenous NaHCO3 may reduce the amount of free drug that is present. NaHCO3 - 1-2mEq/Kg

Mechanisms: paracetamol probably acts as an inhibitor of central prostaglandin synthesis, although its exact subcellular mechanism of action remains unclear. peripheral anti-inflammatory action is conflicting absorbed from the small intestine liver enzymes which catalyze the normal conjugation pathways rapidly become saturated. A dose of 8–10 g in adults is toxic. The alternative metabolic pathway via mixed function oxidases produces a metabolite (N-acetyl-p-benzoquinine imine) which is toxic to cells both of the liver and of the renal tubules normally conjugated with glutathione, but will accumulate when glutathione stores are depleted to cause centrilobular hepatic necrosis and renal tubular damage.

Features of overdose: nausea and vomiting occur early; symptoms and signs of hepatic failure appear later. Management: definitive early treatment is with agents that will replenish glutathione stores and prevent hepatic damage. Methionine, which is a glutathione precursor, can be given orally, although the more common treatment is intravenous N-acetylcysteine. Fulminant hepatic failure can be treated only by hepatic transplantation.

Mechanism of action: benzodiazepines facilitate the opening of GABA-activated chloride channels and thereby enhance fast inhibitory synaptic transmission within the CNS. They bind to a separate receptor, which effects an allosteric change that increases the affinity of GABA for the GABAA receptor.

Features of overdose: these drugs are relatively safe in overdose because, taken alone, they cause profound sedation but without respiratory depression, haemodynamic instability or secondary toxicity. In combination with other CNS depressants, however, they may be associated with marked respiratory depression.

: flumazenil (Anexate) is a specific benzodiazepine antagonist which displaces benzodiazepines from the binding sites and reverses their effects. The effective duration of action of flumazenil is shorter than that of many of the drugs which it antagonizes, and so the dose (typically up to 500 μg intravenously) may need to be repeated. The incautious use of flumazenil may also unmask convulsions caused, for example, by TCAs, otherwise suppressed by the benzodiazepine overdose

Tramadol has relatively low activity at μ-receptors, but it also acts by inhibiting the re-uptake of noradrenaline and 5-HT within the CNS Features of overdose: although activity at μ-opioid receptors is weak, after overdose patients may demonstrate typical features of sedation and respiratory depression. Of greater interest are the signs of a ‘serotonin syndrome’, which include agitation, tachycardia and hypertension, diaphoresis and muscular rigidity.

Management: in general, the treatment of a tramadol overdose is supportive. Naloxone can be used to treat the opioid side effects, but the optimal management of a serotonin syndrome remains uncertain. The 5-HT2A antagonist cyproheptadine has been used, as have drugs such as dantrolene, propranolol and diazepam

included because alcohol ingestion frequently complicates overdose with other drugs. TCAs, for example, can dangerously enhance the depressant effects of acute alcohol intake. Mechanism of action: ethanol facilitates the opening of GABA-activated chloride channels to increase fast inhibitory synaptic transmission within the CNS. It also acts to inhibit the NMDA receptor.

included because alcohol ingestion frequently complicates overdose with other drugs. TCAs, for example, can dangerously enhance the depressant effects of acute alcohol intake. Mechanism of action: ethanol facilitates the opening of GABA-activated chloride channels to increase fast inhibitory synaptic transmission within the CNS. It also acts to inhibit the NMDA receptor.

: disinhibition is followed by CNS depression. The features of acute intoxication are too well known to warrant detailing. An important complication that must not be missed, however, is the effect of acute alcohol on glucose metabolism. large volumes of alcohol are at risk of profound hypoglycaemia. The metabolism of alcohol to acetaldehyde is catalysed by alcohol dehydrogenase in a reaction which produces NADH from NAD+. This effectively depletes NAD+, which is an important co-factor (a hydrogen acceptor) in the gluconeogenetic conversion of lactate to pyruvate (C3H6O3 → C3H4O3; NAD+ → NADH + H+).

Management: at lower blood concentrations (up to 10 mg dl–1) the metabolism of alcohol follows first order kinetics, but at higher levels it demonstrates zero order kinetics. Management is of alcohol overdose is supportive as there is no means of accelerating its breakdown.

The administration of activated charcoal is rarely initiated by anaesthetists, but as it is routine first-line management following the ingestion of numerous toxins and drugs taken in overdose, the substance may form part of the discussion. Mechanism of action: activated charcoal adsorbs some, but not all, chemicals and drugs. (Adsorption describes the capacity of solid substances to attract to their surfaces atoms, ions and molecules from a gas, liquid or solution with which they are in contact. Adsorption can be physical, in which the bonding is by relatively weak Van der Waals forces, or chemical. The nature of the chemical bond varies with the adsorbate.) Charcoal is described as ‘activated’ because the addition of acid and steam to carbonaceous materials results in the formation of ultrafine particles with a large surface area (around 50–70,000 m2 per 50 g dose).

Efficacy: it may reduce the absorption of some substances by up to 60% and continues to be effective throughout its transit through the bowel. This can be accelerated by the addition of sorbitol, which acts as a hyperosmotic laxative. There are, however, some potential toxins and drugs which are not adsorbed by activated These include alcohols such as ethyl alcohol (alcohol), methyl alcohol (as used in antifreeze) and isopropyl alcohol (as used in hand gels); lithium; heavy metals such as lead and iron and the metalloid arsenic; strongly acidic and basic compounds; and many petroleum- and plant-derived hydrocarbons