is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not recommended in TCA poisoning. If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA). Interactions The TCAs are highly metabolised by the cytochrome P450 (CYP) hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity. Drugs that prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties. Pharmacology The majority of the TCAs act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, with the sole exception of amineptine, the TCAs have weak affinity for the dopamine transporter (DAT), and therefore have low efficacy as dopamine reuptake inhibitors (DRIs). Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders. In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2 (5-HT2A and 5-HT2C), 5-HT6, 5-HT7, α1-adrenergic, and NMDA receptors, and as agonists at the sigma receptors (σ1 and σ2), some of which may contribute to their therapeutic efficacy, as well as their side effects. The TCAs also have varying but typically high affinity for antagonising the H1 and H2 histamine receptors, as well as the muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These