Medical Pharmacology Topics
| Preliminary Outline |
| Proton Pump Inhibitors |
Gastric acid secretion
is stimulated by several mechanisms: muscarnic stimulation (M3), endocrine gastrin,
and histmine actrion at H2 receptors. All of these pathways eventually lead
to stimulation of a H
/K
ATPase in parietal cells that exchanges extracellular K
for intracellular H.
The muscarinic and gastrin pathways are Ca
-
dependent. The histamine pathway is cAMP-dependent.
Prostaglandings inhibit gastric acid secretion by activation of a receptor in parietal cells that inhibit the proton pumps by a cAMP-dependent pathway.
Agents that suppress gastric acid secretion include proton pump inhibitors, H2 receptor antagonists and prostaglandins. Antiacids are used to neutralize acid after it is secreted.
Gastric Acid Inhibitors
The proton pump inhibitors include omeprazole, lansoprazole, rabeprazole and penaprazole. These are prodrugs that accumulate in parietal cells (ion trapping?) an are activated in acid environments. The active metabolites are thiophiulic slfenic acid derivatives that bind irrevesibly to -SH groups (cystines) in the pumps inhibiting upt to 95% of acid secretion.
The proton pump inhibitors are subjected to oxidative metabolism by cytochrome P450. Although their elimination half-life is 1-2 houors, their duration of action lasts 24-48 hours (why? because enteric coated, extended release formulations?). Oral dosage forms are delayed release formulations. Adverse effects of proton pump inhibitors include hypergastremia, decreased absorption of vitamin B12 and inhibition of P450 enzymes.
The H2 blockers include cimetidine, ranitidine, famotidine and nizatidine. They inhibit acid secretion by competitive binding to H2 receptors on the basolaterla membrane of parietal cells. They are especially effective at suppressig nocturnal acid secretion. TheH2 blockers are used to promoe healing of gastric and duodenal ulcers, for the treatment of uncomplicated gastroesophageal reflux (GER) and to prevent stress-induced ulcers.
These agents are excreted non-renally (~25%), bt also by filtration and by tubular secretion. For cimetidine,tublular secetion sfourtims the amountexcreted by glomerular filtration. The H2 antagonits have a low incidence of minor side effect. Drug interactions occur mainly with cimetidine because it causes a greater inhibition of P450 enzymes.
Misoprostol is a synthetic analog of prostaglanding E1 (PGE1) that binds to the EPS receptor on parietal cells and inhibits acid secreton, stimulates mucus and bicarbonate secretion, ad increases mucosa blood flow (cytoprotective effect). This agent is mostly used to prevent mucosal injury bu NSAIDS.
Misoprostol agent undergoes extensive first-pass metabolism to the main active metabolite, misoprostol acid. This agent has a half-life of 20-40 minutes, and elimination is mostly renal. Food and antiacids delay misoprostol absorption. Adverse effects include diarrhea (30%), worsening of inflammatory vowel disease and miscarriage.
Antiacids
Antiacids can raise gastric pH from 1 to 3.5. Their duration of action is determined by their acid-combining ability and the length of stay in the stomach. The efficacy of an antiacid usually depends on the formulatin. Particle size determines efficacy: tablets are usually less effective than liquid suspensions.
The ideal antiacid would have a long duration of action (hours), woul not altere systemic acid-base balance nor interfere with digestion or absorption, and should not cause constipation or have a laxative effect.
The most commonly used antiacids are sodium bicarbonate, calcium carbonate, magneium dihydroxide and aluminum dihydroxide.
Sodium hydroxide is highly effective and very inexpensive. Dissadvantages of sodium hydroxyde include its short duration of action, alkalosis with excessive use (accumulation in plasma) and gas production (CO2). Sodium bicarbonate should not be used by patients on a low sodium diet as it will deliver 12 mEq/g.
Calcium carbonate has a rapid onset of action and long term duration. It provides calcium, an essential nutrient. But it may cause local effects like constipation and acid rebound, and systemic effects like alkalosis and hypercalcemia.
Aluminum dihydroxide can be used as an antiacid, but it may cause constipation. With chronic use, it may cause neurotoxicity, myopathy and a lower plasma phosphate concentration, which promotes mobilization of calcium from bone.
Magnesium dihydroxide is use as an antiacid and a laxative, thus t may cause diarrhea. In patients wit impaired renal function, plasma magnesium will increase and can lead to CNS toxicity.
Antiacids can enhance absorption of weak bses and enteric coatings in the stomach. They can decrease absortion of some drugs like penicillins and tetracyclin, and alter urinary excretion of others by changing urine pH.
Other Agents
Helicobacter pilori, a gram negative rod, is involved in most cases of gstric and duodenal ulcers. Erradication of H. pilori eliminates the risk of developing ulcers, except when using NSAIDs. Therapy is complicated by development of drug resistance y the bacteria. A combination regimen is preferred, using gastric acid inhibitors and antibiotics. Two examples are:
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