• Discuss the possible mechanisms of action of lithium.

Lithium influences the 2^nd messaging systems of IP3 and DAG by decreasing the enzymes that are important in the conversion and the re-circulation of membrane phosphoinositides. The influence of IP3 and DAG also has an effects on monoamine and cholinergic neurotransmission, because IP3 and DAG are very important on these neurotransmission processes.

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

The therapeutic index for Lithium is very small, 0.5-1.5mM and also toxicity when the plasma levels exceed 2mM, this causes that it is very important that patients that are receiving Lithium treatment should go for routine bloodwork to ensure that the plasma levels are still safe and effective. They should also be educated on the signs and symptoms of Lithium toxicity, that they can identify it themselves.

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

Lithium is used as mono-therapy when only the mood stabilizing effects, for Bipolar Mood Disorder, are preferred for long-term and there are no episodes of acute mania.

It would be used in combination with anti-psychotics when there are episodes of acute mania.

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

Diuretics, NSAIDs, ACE inhibitors and fluoxetine all causes an increase in Lithium plasma levels, which then increases the chance for Lithium toxicity.

Neurotoxicity can be caused when used in combination with carbamazepine, Calcium-blockers, Lorsartan, Methyldopa, Metronidazole and Phenytoin.

Lithium used in combination with Traditional Anti-psychotic drugs worsens the prevalence of EPS.

• Name the major side effects of lithium.
• Tremors, sedation, ataxia, aphasia
• Muscle weakness, fatigue
• Polidypsia, poliuria, nocturia
• Nephrogenic diabetes insipidus (Li+ interferes with kidney’s ability to concentrate urine)
• Thyroid enlargement
• Leucocytosis
• Edema
• Weight gain
• Acne, alopecia
• Sexual dysfunction

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

Lithium has to be used in the lowest possible dose when used during pregnancy to reduce the effects of Lithium on the baby. It is however, completely contraindicated during breastfeeding.

• Name three other important indications for lithium.

Depression, Schizophrenia as well as Huntington’s Disease.

• 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.

The symptoms that she is experiencing are all associated with Lithium toxicity. I would recommend that she would completely stop to use the diuretics (the water-pills) as well as either reduce the dose of Indocid or replace it with a non-NSAID analgesics (Paracetamol) as both of these medications increases the Lithoum levels which causes an increase in toxicity. I would also recommend that she reduce the dosage of Camcolith she takes as the weight gain is also a symptom of Lithium toxicity. To assist her in losing the weight she has gained, I would recommend she follow a diet for weight loss, as the use of diuretics without the proper indications could have serious side effects.