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#Blog 13:

Discuss the possible mechanisms of action of lithium.

• Mechanism of action: mediated by Li+
• Influences IP3 & DAG 2nd messenger systems by ↓ various enzymes which are very important for conversion and re-circulation of membrane phosphoinositides
• IP3 & DAG is NB in monoamine and cholinergic neurotransmission

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

The therapeutic index of lithium is 0,5-1.5mM > 2mM toxic. Li+has a very small index and thus the dosing of lithium should be done very carefully.Thw blood levels must be monitored very closely to prevent lithium toxicity that include:

• 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

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 monotherapy for the prophylaxis of manic and hypomanic episodes and treatment of an acute manic episodes. Lithium is used in combination with antidepressant for the treatment of resistant or recurrent unipolar depression, but you should be careful with the monotherapy because this can cause mania.

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

• Dehydration, diuretics (e.g. thiazides), NSAIM’s, ACE I’s & fluoxetine ↑ Li+ levels, toxicity
• Theophylline, caffeine ↑ renal excretion of Li+
• Neurotoxic combination with carbamazepine, Ca2+ blockers, losartan, methyldopa, metronidazole and phenytoin
• Traditional APD’s worse EPS in combination with Li+

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 been associated with an increased incidence of congenital cardiovascular abnormalities, but the incidence is very low and when the risk-benefit has been considered it may be continued. Lithium is excreted into the breastmilk in high concentrations and thus breastfeeding is not recommended.

Name three other important indications for lithium.

• Mood stabilizers

• lithium salts
• Valproate
• Carbamazepine

• Anti psychotic (acute mania)
• Anti-depressants (NB: can cause mania!)

• SSRI’s, Bupropion, MAOI’s, Lamotrigin

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.

• Indocid is an NSAIM (non-steroidal anti-inflammatory agent) and it will increase the lithium levels of the drug already given (CAMCOLIT), and the patient then has a risk for lithium toxicity.
• My recommendation will be to give another anti-inflammatory drug rather than an NSAIM to avoid toxicity. An indication that lithium toxicity is already present in the patient is her complaint of mass gain and because she drinks water pellets (diuretics) for it, lithium levels will increase further and her mass admissions will not be treated but exacerbate due to toxicity. The fatigue, thirsty feeling, nausea and tremors are all due lithium toxicity.
• My recommendation is to stop all current therapy and for now consider another drug for her bipolar disorder. A drug such as valproate will be recommended to treat bipolar disturbance in our patient with current lithium toxicity.