1. Discuss the possible mechanisms of action of lithium.

Lithium is a monovalent cation that is able to mimic the role of Na+ in excitatory tissues, and it therefore is able to move across voltage-gate Na+ channels which are responsible for action potential generation. In this way Lithium is able to adjust the balance between excitatory and inhibitory neurotransmitters and decreases glutamate (Excitatory Neurotransmitter) activity.

Lithium also inhibits IMPase= decrease in free inositol

Decrease in inositol= decrease in second messenger PIP2= Decrease in release of IP3 and DAG

Decrease in PIP2 dependent pathways= mood stabilising effect ( PIP2 activity increased during manic episodes)

https://slideplayer.com/slide/7027021/

https://www.slideshare.net/drashutoshtiwari/mood-stabilisers-antimanic-drugs

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

Lithium has a very small therapeutic index  (0.5-1.5 mM; >2 mM toxic), it is therefore very important to carefully monitor the concentration in blood plasma to prevent toxicity. Serum levels need to be monitored at regular intervals: 1 week after each dose increment, then at one month, 3 months and 6 monthly during maintenance

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

Monotherapy: Used for prophylaxis of manic and hypomanic episodes and for treatment of acute mania.

Combination therapy with antipsychotics: treatment of resistant depression and aggressive behaviour.

Combination with antipsychotics and benzodiazepine: treatment severely manic patient

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

• Lithium + Neuroleptic (Phenothiazine)= Increased EPS
• Lithium + Xanthines (Theophylline, Caffeine) = Increased renal excretion of Lithium
• Lithium + SSRI (Fluoxetine) = Increased Lithium plasma levels

5. 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

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

Category D drug. Teratogenic effects and excreted in high concentrations in breast milk

7. Name three other important indications for lithium.

• Recurrent depression
• Augmentation in Acute major depression
• Bipolar disorder

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= Lithium Carbonate

• 20mg/kg/day = 1200mg
• Dosage is correct.

• Plasma levels = within therapeutic range (0.5-1.5), but plasma levels have not been recently tested= need to be tested at regular intervals
• Indocid = NSAID= decrease renal excretion of lithium = increase toxic effects
• Water pills= diuretics= Diuretics may increase serum concentration and predispose to lithium toxicity

Adverse effects

• Fatigue and tiredness= Adverse effects of Lithium
• Thirst= due to renal adverse effects of lithium use
• Shaky =Tremor= normal side effects of Lithium that occurs at therapeutic dosages.
• Nauseous= GIT effects of Lithium
• Weight gain= adverse effect of Lithium use

Fatigue, Tiredness, thirst (Dehydration) and nausea are all early symptoms of Lithium toxicity.

The combination of Lithium with a NSAID and a diuretic causes an increase in Lithium Serum levels. Lithium has a very small Therapeutic index, therefore small increases in blood serum levels can lead to toxic effects. The effects she is experiencing may very likely be due to toxic levels of Lithium within the blood.

I recommend that stops taking the NSAID and Water pills immediately, and that her serum levels are tested. The toxic effects she is experiencing such as the tiredness, fatigue, thirst and nausea should decrease once her serum levels have been restored to therapeutic levels. Her Shakiness (Tremors) can be treated with the use of Propranolol or atenolol. I also recommend that she drinks lots of water and oral rehydrate solutions to treat potential dehydration. For the muscle injury she can use Paracetamol and Cyclobenzaprine to treat the pain.

Brand, L. 2021. Anti-psigoriese middels. Leergedeelte 9. [PowerPoint Presentation]. Study Unit 9, FKLG 312. Potchefstroom, NWU