• Discuss the possible mechanisms of action of lithium.

The mechanism of action of Lithium are mediated via Lithium ions that influence multiple neurotransmission process. It influences both the adenylyl cyclase & phospholipase C protein couples messenger systems. Influences IP₃ & DAG and Camp 2^ND messengers by decreasing the various enzymes which are important for the conversion and the re-circulation of membrane phosphoinositides. IP₃ and DAG are important in monoamine and cholinergic transmission.

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

Very small therapeutic index (0.5-1.5 Mm) to produce therapeutic benefits in this range. This implies that plasma monitoring is very important as if the values are below 0.5 then there will be sub therapeutic effects and pharmacological treatment is not effective. If ranges of above 2 Mm are reached then toxicity occurs and leads to various adverse effects and which are dangerous and potentially harmful

 

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

Monotherapy for bipolar disorder and acute manic episodes lithium is indicated.

In rapid cycling lithium can be considered as monotherapy

Combination therapy: lithium and antidepressants for severe depressant episodes and initial treatment with SSRI can cause manic episode this reduces the occurrence.

Lithium and valproate when there is no or partial response to monotherapy

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

1. Lithium toxicity is reached in combination with drugs that interfere with the electrolyte-water balance of the body such as diuretics (thiazides), NSAID’s and fluoxetine
2. Increased renal excretion of lithium which means a decreased efficacy of he drug when it is administered with antacids (Na-bicarbonate), theophylline and caffeine
3. Neurotoxic in combination with carbamazepine, Ca blockers, losartan (ACE inhibitor), methyldopa, metronidazole and phenytoin

• Name the major side effects of lithium.

Acute toxicity: GI disturbances including nausea, vomiting and diarrhoea

Neurological toxicity: tremor, sedation, ataxia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrotic diabetes insipidus, thyroid enlargement, leucocytosis, edema, weight gain, acne, alopecia, sexual dysfunction

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

Cautionary use in pregnancy, should not be used especially during the first semester. It crosses the placental barrier which can cause the foetus to show lethargy and flaccid muscle tone. Contraindicated during breastfeeding as it is secreted in breast milk

• Name three other important indications for lithium.

Depression, schizophrenia and mania

• 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 NSAID. 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 indocid (NSAID) % diuretic she has been using are increasing her lithium plasma levels which are contributing to the side effects experienced such as the weight gain, fatigue, nausea, shakiness and polydipsia and muscle injury. Especially because within the first 2 weeks she already reached 0.8mmol/l the half-life can lead to accumulation when administered with NSAIDs & diuretics.

The recommendation I would make would be to stop using the NSAID as well as the ‘water pills” immediately and then to check and monitor her plasma levels weekly until a stable plasma level is obtained. Her symptoms have to be monitored when she is not on any concurrent treatment that can affect her lithium levels to establish if a lower dosage will reduce some of her symptoms.

As B Polar is still very young and of child bearing potential I would recommend to switch her to an alternative treatment now like Lamotrogine since this is also safe in pregnancy if she chooses to want children in the near future especially since lithium is not recommend during pregnancy and breastfeeding. Regarding her weight gain that clearly is bothering her I would recommend healthy eating plan and more frequent exercise to start with and then later additional therapy if required.

Brand, L.Prof.  2021.  Study Unit 9:Anti-psychotic Drugs and Lithium.  Unpublished lecture notes on efundi, FKLG 312.  Potchefstroom: NWU.  [PowerPoint presentation]