Discuss the possible mechanisms of action of lithium. 

The MoA of lithium salts is mediated by Lithium (Li) ions. The action involves the influence of IP3 and DAG 2nd messenger systems by inhibiting various enzymes which are very important for conversion and re-circulation of membrane phosphoinositides. (IP3 & DAG are essential in monoamine and cholinergic neurotransmission). 

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

Lithium has a very narrow therapeutic index of 0.5-1.5 mM. The clinical significance is that lithium can very easily lead to toxicities due to its narrow therapeutic index, thus dosing ought to be done with extreme vigilance and care and the patient’s blood levels must be closely monitored for any toxicity. 

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

Lithium can be used as monotherapy in bipolar disorder, as well as prophylaxis of manic and hypomanic episodes and during the treatment of acute manic episodes. 

Combination therapy: lithium can be used in combination with valproate, carbamazepine, risperidone and haloperidol for psychiatric symptoms. Lithium is also used in combination with clonazepam and lorazepam as mood stabilizers. 

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 should only be used in life-threatening emergencies when no other safer drug is available, since lithium has positive evidence of teratogenic effects when used during pregnancy. Lithium use should also be avoided during lactation and can be excreted in the breast milk, causing toxicities in the infant. 

Name 3 other important indications for lithium. 

Major depressive disorder, schizophrenia, used as a mood stabilizer during bipolar disorder and is also used in the treatment of Huntington’s disease. 

Recommendations for Ms B Polar’s case study: 

The adverse effects that Ms B Polar has been experiencing are commonly associated with lithium toxicity – even though her plasma lithium levels are within the therapeutic range (0.5-1.5 mmol/L), the combination of lithium with Indocid may cause these adverse effects. Since lithium and Indocid (a NSAID) cause a toxic drug interaction when administered together. Also the use of a diuretic (“waterpill”) in combination with lithium will decrease the renal clearance of lithium. 

I would suggest cessation of use of the diuretic and NSAID for the patient, or lower the dose of lithium or I would suggest an alternative drug to replace lithium.