Question

Manic patient on lithium (therapeutic level) is started on a COX inhibitor for osteoarthritis and develops lithium toxicity symptoms. What is the mechanism?

• A. Action on glutathione of RBC
• B. Inhibition of renal prostaglandin synthesis decreasing GFR and lithium clearance
• C. Inhibition of hepatic microsomal enzymes
• D. Increased renal tubular secretion

Hint:

Lithium is cleared only by the kidney, and NSAIDs lower renal prostaglandins and GFR.

Answer 1

The Correct Option is B

Step 1: Understanding the question:
A manic patient is stable on lithium with a therapeutic blood level. A COX inhibitor (an NSAID) is added for osteoarthritis. Soon lithium toxicity symptoms appear. We need the mechanism.
Lithium has a narrow therapeutic range. Any drug that raises the blood level even a little can push the patient into toxicity.

Step 2: Recall how the body handles lithium:
Lithium is not metabolised. It is not bound to plasma proteins. Almost all of it leaves the body through the kidney.
It is filtered at the glomerulus. About 70-80% of the filtered lithium is reabsorbed in the proximal tubule, along with sodium and water. So anything that lowers filtration or increases sodium retention in the proximal tubule raises the lithium level.

Step 3: Link COX inhibitors to the kidney:
Prostaglandins (PGE2 and PGI2) made in the kidney dilate the afferent arteriole. They keep renal blood flow and GFR up, especially when the kidney is under stress.
A COX inhibitor blocks prostaglandin synthesis. The afferent arteriole narrows, renal blood flow and GFR fall, and the proximal tubule reabsorbs more sodium and lithium.
The net result is lower lithium clearance, a higher blood level, and toxicity. Tremor, vomiting, diarrhoea, ataxia and confusion are the usual symptoms.

Step 4: Check option (A) Action on glutathione of RBC:
Lithium does not act through red cell glutathione. Glutathione related hemolysis is seen with drugs like primaquine in G6PD deficiency. This has no link with lithium handling. So (A) is wrong.

Step 5: Check option (B) Inhibition of renal prostaglandin synthesis decreasing GFR and lithium clearance:
This matches the mechanism described above. NSAIDs reduce renal prostaglandins, GFR falls, and lithium clearance falls. So (B) is TRUE.

Step 6: Check option (C) Inhibition of hepatic microsomal enzymes:
Lithium is not metabolised by the liver, so liver enzyme inhibition cannot change its level. Enzyme inhibition matters for drugs like warfarin or theophylline. So (C) is wrong.

Step 7: Check option (D) Increased renal tubular secretion:
Increased secretion would remove more lithium and lower its level, which would reduce toxicity. The patient has toxicity, so the effect must be the opposite. So (D) is wrong.

Final Answer:
NSAIDs lower renal prostaglandins, which lowers GFR and lithium clearance, so lithium builds up. This is option (B). Thiazides, ACE inhibitors and low sodium intake raise lithium levels in a similar way.