1. Discuss the possible mechanisms of action of lithium.

The MOA of lithium is not well defined.

The drug inhibits several enzymes involved in the recycling of neuronal membrane phosphoinositides.

This action may result in depletion of the second messenger source, phosphatidylinositol bisphosphate (PIP2), which, in turn, would decrease generation of inositol trisphosphate (IP3) and diacylglycerol (DAG).

These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors.

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

0.5 – 1.5 mM; >2 mM is toxic.

Lithium is used to stabilize mood swings of bipolar disorders, and sometimes used for people with depression who are not responding to other medications.

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

Monotherapy: lithium is used for bipolar disorders

Combination therapy with lithium: valproate and carbamazepine for psychiatric symptoms.

Olanzapine and quetiapine for acute mania

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

• Dehydration, diuretics (e.g. thiazides), NSAID’s, ACE inhibitors and fluoxetine all increase lithium ion levels and causes toxicity.
• Theophylline, caffeine increase the renal excretion of lithium ions.
• Neurotoxic effects when lithium is used in combination with carbamazepine, calcium ion blockers, losartan, methyldopa, metronidazole and phenytoin.
• Traditional Anti-Parkinson’s drugs worsen EPS in combination with lithium.  

5. Name the major side effects of lithium.

• Tremors
• Sedation
• Ataxia
• Aphasia
• Muscle weakness
• Fatigue
• Polidipsia
• Poliuria
• Nocturia
• Nephrogenic diabetes insipidus (lithium ions interferes with kidney’s ability to concentrate urine)
• Thyroid enlargement
• Leucocytosis
• Edema
• Weight gain
• Acne
• Alopecia
• Sexual dysfunction

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

Not safe for use during pregnancy and breastfeeding.

The risks to your baby breastfeeding are heart defects. Taking lithium in early pregnancy can increase the risk that your baby's heart might not develop properly.

7. Name three other important indications for lithium.

• Bipolar disorders.
• Schizophrenia.
• Depression.

8. 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.

Camcolith 400 mg tablets contain lithium carbonate, which is used to treat and prevent mania or mania depressive illness and depression in adults. For acute symptoms the target plasma therapeutic concentration is 8-12 mEq/L (mmol/L) and maintenance is 0.4-0.7 mEq/L (mmol/L). The plasma levels of Ms Polar is 0.8 mmol/L which is higher than the maintenance plasma therapeutic concentration of lithium. This can be due to changes in body water of Ms Polar, due to use of NSAID such as Indocid®.

Indocid® is used for pain, swelling and joint stiffness caused by arthritis or gout. It is an anti-inflammatory drug (NSAID).

Indocid®can increase the lithium ion levels and cause adverse side effects, such as weight gain, fatigue, sedation, polydipsia (thirsty) and tremors.

The “water pill” which is a diuretic, she is taking will not help to elevate her symptoms, it will in fact worsen her symptoms, since diuretics increase the lithium ion levels and will cause adverse side effects. .

Therefore, Ms Polar must be prescribed another anti-psychotic drug that does not cause drug interactions with her NSAID and she must stop taking the “water pill”.

Reference list:

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

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

Katzung, B.G., Kruidering-Hall, M. & Trevor, A.J. 2015.  Katzung and Trevor’s Pharmacology Examination and Board Review. 11^th ed. California, San Francisco: McGraw-Hill Companies, Inc.