• Discuss the possible mechanisms of action of lithium.

The suppression of IP₃ and DAG 2^nd messengers lead the decrease in the various enzymes that are needed for the conversion and recirculation of membrane phosphoinositide. This, in turn, has an effect of monoamine and cholinergic transmission.

• What is the therapeutic index of lithium and what is its clinical significance?

The therapeutic index of lithium is between 0.5 – 1.5 mM. this is clinically significant because if the therapeutic index exceeds 2, then it becomes toxic for the patient. The therapeutic index also gives an indication of the plasma levels. In the case of lithium, the plasma half-life is 20 hours which means that it can be prescribed twice daily.

• When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?

Lithium is used as a single drug in bipolar disorder (manic phase) and recurrent depression.

Lithium is used in combination for schizoaffective disorder, with antipsychotics as a combination.

• Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.

Diuretics (such as thiazides), NSAIDS (Diclofenac), ACE inhibitors (Enalapril) and Fluoxetine: increase lithium toxicity

Carbamazepine, calcium blockers, losartan, methyldopa, metronidazole, and phenytoin: neurotoxic effects

Caffeine: increases renal excretion of lithium

• Name the major side effects of lithium.

Tremors

Decreased thyroid function

Oedema

Polydipsia and polyuria (reversible)

• What is the status of the use of lithium during pregnancy and lactation?

Lithium should not be used during pregnancy as the renal clearance increases but then goes back to normal after delivery of the baby. This means that if the renal clearance during pregnancy is good, then after pregnancy it may become toxic as it decreases after giving birth.

Lithium should not be used in breastfeeding as it can be transferred to the nursing baby through breast milk. This can cause lithium toxicity in the baby.

• Name three other important indications for lithium.

Recurrent depression

Resistant schizophrenia

Aggressive behaviour

• Evaluate the following case and fully motivate your recommendations:
• Ms B. Polar (21 years, 60 kg) is a student and used the following medication for the past two months:

Camcolith 600mg bd. The plasma levels after two weeks were 0.8mmol/l. She sustained a muscle injury and has been using Indocid® 75mg nocte for the past 10 days. On questioning she reveals that “she had picked up a lot of weight” and is now using some of her mother’s “water pills” in the hope of losing a few of the extra kilos. However, she complains of fatigue, that she has difficulty in keeping her eyes open in class, remains thirsty and constantly feels shaky and nauseous.

Ms B. Polar’s are within the therapeutic index of lithium, which is very good. However, since she had a muscle injury, she was using Indocid® which is an NSAID. NSAIDs increase lithium toxicity by decreasing renal clearance. The wight gain in a side-effect of using lithium. The “water pills” are thiazide diuretics, which increase lithium toxicity by decreasing renal clearance. Fatigue, sedation, increased thirst, shakiness, and nausea are all side-effects of lithium use.