False: Azapropazone, diclofenac, ibuprofen, indomethacin, mefenamic acid and other NSAIDs reduce the excretion of lithium and raise serum lithium levels by up to 23% and hence increase the risk of toxicity. This is due to inhibition of the renal prostaglandin PGE2, resulting in reduced renal blood flow and reduced lithium clearance. Lithium levels should be monitored frequently when using this combination (Bazire 2005, p. 324; BNF 2005, Appendix 1).

False: Antimuscarinic agents may slow down the absorption of benzodiazepines but the amount absorbed remains the same (Bazire 2005, p. 271).

True: Pharmacokinetic interactions occur when one drug interferes with the disposition of another drug during absorption, distribution or elimination. Many antidepressants, anticonvulsants and warfarin which are highly bound to plasma proteins may displace each other, leading to increased plasma free concentrations of others. Sodium valproate may displace phenytoin from its protein binding sites. SSRIs may displace warfarin, a highly protein bound drug with a narrow therapeutic index (Anderson & Reid 2002, p. 31; Gelder et al 2000, p. 1282; King 2004, p. 67).

True: Doxazosin is an antihypertensive that selectively blocks α₁ receptors. Reboxetine is a potent inhibitor of the noradrenaline transporter. It has a mild sympathomimetic effect and causes only small increases in heart rate and blood pressure. In hypertensive patients whose α₁ receptors are already blocked by doxazosin, even these small increases would not occur (King 2004, p. 215).

True: Disulfiram inhibits the metabolism of warfarin. Prothrombin time can rise by about 10%, necessitating reduction in the dose of warfarin (Bazire 2005, p. 356; BNF 2005, Appendix 1).

True: Enalapril is an angiotensin-converting enzyme inhibitor (ACEI). Lithium should be used with caution in patients receiving NSAIDs, ACEIs and angiotensin 2 antagonists because these drugs may elevate lithium levels. This is due to the inhibition of renal prostaglandin PGE2 resulting in reduced renal blood flow and reduced lithium clearance. Lithium levels should therefore be carefully monitored in patients receiving these drugs, especially in the elderly. ACEIs in combination with lithium may increase the risk of renal failure (Bazire 2005, p. 322; BNF 2005, Appendix 1).

False: Fluoxetine increases the levels of drugs metabolized by CYP 2D6 and, to a lesser extent, those metabolized by CYP 3A4. Lithium is not metabolized in the body. It is eliminated solely by renal clearance. Therefore, lithium levels are unaffected by the co-administration of enzyme inducers or inhibitors.

However, fluoxetine may cause lithium toxicity, without increasing lithium levels. Serotonin syndrome, confusion and seizures have been reported (Bazire 2005, p. 323; BNF 2005, Appendix 1).

False: Atropine and opiates inhibit gastrointestinal motility, slow absorption, reduce peak concentrations and impair efficacy of analgesics and antibiotics. Metoclopramide stimulates gastric emptying and facilitates absorption of analgesics in the management of acute pain. Charcoal binds with phenobarbitone and TCAs and reduces their absorption in poisoning (King 2004, p. 602).

False: There is no firm evidence that >20 mg haloperidol + lithium combination is specifically associated with increased risk. However, there is no good evidence supporting the use of haloperidol in doses exceeding 20 mg/day either!

A few cases of reversible neurotoxicity have been reported, but these may have been undiagnosed NMS. There have also been unconfirmed reports of encephalopathy, severe EPS, neurotoxicity, irreversible brain damage and increase in lithium-induced neurological adverse effects, etc. When high doses of both drugs are used, there is a risk of missing signs of impending toxicity (Bazire 2005, p. 322; BNF 2005, Appendix 1; Kaplan et al 2000, p. 144).

True: Hypertensive crisis results from the direct absorption of pressor amines, e.g. tyramine, phenylethylamine and histamine, formed as part of the bacterial decarboxylation of the amino acid constituents of certain protein-containing foods. Normally these amines are neutralized by MAO in the gut wall. MAOIs inhibit MAO and hence this protective action is lost. This allows the free passage of these enzymes into the systemic circulation. The foods with the highest amount of these amines include pickled herring, yeast extracts, e.g. Marmite, fish and meat extracts, e.g. Bovril, certain vegetable items, e.g. broad bean pods and banana skins, and matured cheese (Gelder et al 2006, p. 550; Johnstone et al 2004, p. 278).

False: Lithium should be used with caution in patients receiving NSAIDs, ACE inhibitors, and angiotensin 2 antagonists. They inhibit renal prostaglandin PGE2 resulting in reduced renal blood flow, reduced excretion, elevated lithium levels and lithium toxicity. Lithium levels should therefore be carefully monitored in patients receiving these drugs. ACE inhibitors in combination with lithium may increase the risk of renal failure (King 2004, p. 660).

False: Imipramine does not inhibit MAO and hence it is safe with tyramine rich foodstuffs.

False: Probenecid was developed to inhibit renal tubular secretion of penicillin. Thiazide diuretics reduce the renal clearance of lithium and can cause toxicity.

True: MAOIs decrease plasma pseudocholinesterase activity. Hence, they can prolong muscle relaxation and muscle paralysis with muscle relaxants such as suxamethonium and d-tubocurarine (BNF 2005, Appendix 1; Stein & Wilkinson 1998, p. 188).

True: For example, adding soluble insulin to protamine zinc insulin can result in the added insulin binding to the excess protamine, thus reducing the immediate effect of the dose.

False: Pharmacodynamic interactions occur where two drugs act on the target site of clinical effect. Interaction by mixing in a syringe is an example of pharmaceutical interaction. It is a physiochemical interaction between drugs on a chemical, not on a pharmacological, level. An example is the formation of a complex between thiopentone and suxamethonium, which should not therefore be mixed in the same syringe. These types of interactions are best avoided by giving drugs as bolus injections where appropriate, making up infusions immediately before use and avoiding mixing drugs before administration except where this is known to be safe (Gelder et al 2000, p. 1282).

True: The combination of TCAs and irreversible MAOIs can cause serotonin syndrome as well as potentially lethal hypertension and CNS excitation. TCAs should not be given for 2 weeks after stopping MAOIs and MAOIs should not be started until 2 weeks after stopping TCAs (BNF 2005, Appendix 1; King 2004, pp. 193, 630; Gelder et al 2000, p. 1302).

True: Opioids, alcohol, anxiolytics, hypnotics and over-the-counter cold medications have additive CNS depressant and sedative effects when co-administered with TCAs.

Moreover, amitriptyline and clomipramine increase the bioavailability of morphine and potentiate its analgesic effect. Desipramine blood levels can double with methadone (Bazire 2005, p. 294, 359; BNF 2005, Appendix 1; Kaplan et al 2000, p. 248).

True: Combination of tricyclic antidepressants and sympathomimetic agents such as noradrenaline can cause hypertension and arrhythmias. The mechanism is summation (Bazire 2005, p. 640; BNF 2005, Appendix 1; Kaplan et al 2000, p. 248).

False: Carbamazepine induces the hepatic microsomal enzymes and thereby lowers the efficacy of several drugs, including oral contraceptives. In contrast, valproate, lithium, lamotrigine, and topiramate have no effect on oral contraceptives. Of note, carbamazepine may also cause false negative pregnancy tests (Bazire 2005, p. 351).

False: Pharmacodynamic interactions occur when two drugs interact at the same site of action. Pharmacokinetic interactions occur when one drug interferes with the disposition of another. Pharmacokinetic interaction may occur at absorption, distribution, metabolism or excretion. Thus decreased absorption is a pharmacokinetic interaction (Gelder et al 2000, p. 1282; King 2004, p. 60).

False: Pharmacodynamic interactions occur when two drugs interact at the same site of action. Pharmacokinetic interactions occur when one drug interferes with the disposition of another drug during absorption, distribution or elimination. Induction of liver microsomal enzymes can affect the elimination of some drugs and is therefore a pharmacokinetic interaction (Gelder et al 2000, p. 1282).

True: Phenobarbitone induces the CYP 3A4 enzyme which metabolizes oral contraceptives. This interaction may result in contraceptive failure (Bazire 2005, p. 339).

True: The SSRIs inhibit CYP 2D6 and 3A4 in a dose-related way. Fluoxetine, paroxetine and fluvoxamine cause significant inhibition at therapeutic doses. Citalopram and sertraline cause little clinically significant 2D6 inhibition. TCAs are hydroxylated and thus inactivated by 2D6 and 3A4. Hence, SSRIs increase plasma levels of TCAs. Fluoxetine may double or triple tricyclic levels (Bazire 2005, p. 295; Taylor et al 2005, p. 138).

False: St John’s wort (Hypericum perforatum) induces hepatic cytochrome P450 enzymes CYP 1A2 and CYP 3A4. This increases the metabolism and reduces the plasma concentrations and efficacy of theophylline, cyclosporine, warfarin, digoxin, the HIV-1 protease inhibitor indinavir, some anaesthetics and oral contraceptives (Bazire 2005, p. 315; King 2004, p. 233).