Discuss the following:

(a)            adverse effects and drug interactions involving antacids.

(b)        the combination of L-DOPA and a decarboxylase inhibitor in the treatment of Parkinsonism.

(c)        the mechanism of action of warfarin.

Suggested Answer:

(a)

Antacids are weak bases which can neutralize gastric acid from pH 1 –2 to pH 4 – 5, relieve gastric pain and promote ulcer healing.

Magnesium hydroxide causes diarrhea whereas aluminium hydroxide and calcium carbonate are associated with constipation. Sufficient aluminium may be absorbed from the intestine to create a risk of encephalopathy in patients with chronic renal failure. Hypophosphataemia may result from binding phosphate so that it is not absorbed from the gut. Sodium bicarbonate is absorbed and causes alkalosis which can be a serious matter in patients with renal insufficiency. Sodium bicarbonate can release carbon dioxide in the stomach to cause discomfort and belching. Calcium containing antacids may cause rebound acid hypersecretion and with prolonged used, hypercalcaemia and alkalosis.

Magnesium trisillicate and aluminium hydroxide strongly bind iron, phenothiazines, tetracyclines, propranolol, phenytoin, isoniazid, ranitidine, indomethacin and sulfadiazine to decrease their bioavailability. Aluminium hydroxide delays gastric emptying and slows the rate of absorption of indomethacin, dicumarol, isoniazid and some benzodiazepines. Increased urinary pH delays the elimination of amines such as quinidine and lignocaine and increases the elimination of salicylates and phenobarbitone.

(b)

L-DOPA is the natural amino acid precursor of dopamine. Parkinson disease is believed to caused by a deficiency of dopamine in the CNS especially the corpus striatum, and L-DOPA is believed to act principally by increasing dopamine concentration in the brain. Dopamine is not able to penetrate the blood-brain barrier. L-DOPA is able to enter the brain where it is decarboxylated to dopamine.

As L-DOPA is extensive decarboxylated in the peripheral tissues, only 5% of an oral dose reaches the brain. Decarboxylase inhibitors such as carbidopa and benserazide do not enter the CNS so that they inhibit only the extra-cerebral metabolism of L-DOPA. They are given in combined formulations with L-DOPA as Sinemet and Madopar which produce the same concentrations in the brain with L-DOPA alone, but only 25% of the original dose is required. As such, incidence of L-DOPA adverse effects is also reduced.

(c)

Warfarin is an indirect-acting oral anticoagulant. During the gamma-carboxylation of factors II, VII, IX and X as well as proteins C and S, active vitamin K is oxidized to an epoxide and must be reduced by the enzyme vitamin K epoxide reductase to become active again. Warfarin is structurally similar to vitamin K and competitively inhibit epoxide reductase, so limiting availability of the active form of the vitamin to form coagulant proteins. The overall result is a shift in haemostatic balance in favor of anticoagulation because of the accumulation of clotting proteins with absent or decreased gamma-carboxylation sites.