Discuss the following:

(a)            electrolyte abnormalities produced during the use of loop diuretics.

(b)            adverse effects of isoniazid and rifampicin.

(c)        the pharmacological basis of NSAID-induced gastric ulcer and its management.

Suggested Answer:

(a)

Loop diuretics inhibits active reabsorption of sodium and chloride ions in the thick ascending limb of the Loop of Henle, reducing the kidney’s ability to concentrate urine and can lead to up to 25% of the filtered sodium being excreted.

Due to their efficacy in removing salt and water from the body, hypovolaemia, hypochloremia and hyponatraemia may result from chronic use. Prevention of sodium reabsorption at the Loop of Henle causes more sodium to reach the distal tubule where it is reabsorbed at the expense of potassium which is excreted. Hence hypokalaemia can also result. Prolonged hypokalaemia can lead to a state of metabolic alkalosis. Other electrolyte abnormalities are hypocalcaemia, hypomagnesemia and hyperuricaemia.

(b)

Isoniazid is a structural analogue of pyridoxine and a cornerstone of anti-TB therapy. It is selectively effective against Mycobacterium tuberculosis because it prevents the synthesis of mycolic acid which is unique to mycobacterial cell walls. Hence it is bactericidal against actively multiplying bacilli but is bacteriostatic against nondividing cells.

Isoniazid is readily absorbed from the GI tract and is distributed into all body fluids and tissues, including the CSF. It is inactivated by conjugation with an acetyl group. The half-life is 1h in fast and 4h in slow acetylators.

Isoniazid is generally well tolerated. The most adverse effect is liver damage which may range from moderate elevation of hepatic enzymes to severe hepatitis and death. It is probably caused by a chemically reactive metabolite, e.g. acetylhydrazine. Most cases develop within the first 8 weeks of therapy and liver function tests should be monitored monthly during this period at least.

Being a structural analogue of pyridoxin, isoniazid accelerates its excretion, the principal result of which is peripheral neuropathy with numbness and tingling of the feet. Neuropathy is more frequent in slow acetylators, malnourished people, the elderly and those with liver disease and alcoholism.

Pellagra (diarrhea, dermatitis and dementia) has been associated with the use of isoniazid. In the body, the formation of nicotinic acid from the  amino acid tryptophan requires the action of pyridoxal phosphate as a co-enzyme. By forming complexes with pyridoxal phosphate, isoniazid reduces the availability of pyridoxal phosphate for the formation of nicotinic acid. Isoniazid also interferes with pyridoxine metabolism by increasing its urinary excretion. Isoniazid can cause haemolysis in G6PD deficient patients. Large doses of isoniazid can produce psychosis, confusion, coma and convulsions.

Rifampicin is a semi-synthetic derivative of rifamycin, an antibiotic derived from Streptomyces mediterranei. It is a potent bactericidal drug against mycobacteria tuberculosis.

Rifampicin binds selectively and strongly to mycobacterial DNA-dependent RNA polymerase and this suppresses initiation of chain formation in RNA synthesis. Being lipid soluble, it is well absorbed orally and is well distributed throughout the tissues. In plasma, 80% is bound to plasma proteins.

Rifampicin is well known for its hepatotoxicity. It can lead to hyperbilirubinaemia and transaminasaemia with histological evidence of diffuse liver cell damage. Elderly patients and those with a history of liver disease or alcoholism are more prone to develop this toxic hepatitis. Intermittent dosing promotes certain effects that may have an immunological basis such as an influenza-like syndrome, acute haemolytic anaemias and acute renal failure. Other adverse reactions are flushing, itching with or without a rash, and thrombocytopenia.

(c)

Endogenous prostaglandins contribute to the integrity of the gastrointestinal mucosa by: stimulation of mucus and bicarbonate secretion, maintenance of blood flow, prevention of luminal protons from diffusing into the mucosa and reduction of gastric acid secretion.

Gastric or intestinal mucosal damage is the commonest adverse effect of NSAIDs. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the synthesis of prostaglandins from arachidonic acid. Inhibition of prostaglandin biosynthesis is believed to account for the erosions, ulceration and bleeding caused by NSAIDs.

Discontinuation of NSAID use is the most effective way of managing the gastric ulcer by removing its precipitating cause but should its use be still indicated, antacids, cimetidine, omeprazole or misoprostol should be taken concurrently. Cimetidine, a H₂-receptor antagonist, is used to prevent peptic ulcer induced by NSAIDs. Antacids can provide symptomatic relief and accelerate ulcer healing. Misoprostol may prevent peptic ulceration and used to treat NSAID-induced ulcers.