Medical Pharmacology Topics
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Proton Pump Inhibitors |
Drugs affecting gastrointestinal function may be classified as:
Agents to suppress acid production include proton pump inhibitiors, H2 receptor antagonists and prostaglanding analogs. The proton pump inhibitors (PPIs) are prodrugs that accumulate in parietal cells (ion-trapping??) and are activated in acid environment. Activation produces a thiophilic sulfenic acid derivative that inhibits Na+/H+ ATPases, binding irreversibly with sulfidril groups (cysteins) on the pump. In this manner they can inhibit up to 95% of acid secretion. Proton pump inhibitors include omeprazole (Prilosec®), lansoprazole (Prevacid®), rabeprazole (Acidiphex®) and pantaoprazole (Protonix®).
The proton pump inhibitors are administered as delayed release forms. Their elimination half-time is 1-2 hrs, but duration of action is 24-48 hrs. The prodrug is sujected to oxidative metabolism (P450) and elimination. Side effects include hypergastrinemia, decreased absorption of vitamin B12 and inhibition of some cytochrome P450 enzymes.
The histamine 2 (H2) receptor antagonists inhibit acid secretion by reversiby competing with histamine for receptors on the basolateral membrane of parietal cells. They are especially effective at suppressing nocturnal acid secretion. Agents include cimetidine (Tagamet®), ranitidine (Zantac®), famotidine (Pepcid®), and nizatidine (Axid®). They are indicated to promote healing of gastric and duodenal ulcers, for treatment of uncomplicated GERD and prophylaxis of stress ulcers.
Misoprostol is an example of a prostaglandin analog, indicated for prevention of mucosal injury induced by NSAIDs. It is a synthetic analog of PGE1 that binds to EP3 receptors on parietal cells and inhibit acid secretion, stimulates secretion of mucin and bicarbonate and increases mucosal blood fow (cytoprotective effect).
Misoprosol undergoes extensive first-pass metabolism to misoprostol acid, the principal and active metabolite. Food and antiacids may delay absorption. Its is eliminated in the urine, with a t1/2 of 20-40 hrs.Adverse effects include diarrhea (30%), exacerbation of inflammatory bowel disease and abortion.
H. pylori, a gram-negative rod bacteria, is involved in a majority of cases of gastrtic and duodenal ulcers. Its erradication all but eliminates the risk of recurrence (except with use of NSAIDs). Treatment is complicated by develoment of drug resistance, therefore a combination regimen is preferred, like:
Prokinetic drugs include cholinergic agents (like bethanechol and neostigmine, their use is obsolete), serotonin receptor agonists (metoclopramide), dopamine receptor antagonists (domperidone) and motilin-mimetics (erythromycin). They enhance coordinated gastrointestinal motility and transit of material in the GI track. Most prokinetic drugs do not stimulate GI muscle diretly (except cholinergics) but influence the activation of innervation to the gut, thereby maintaining coordination of propulsive function.
The seratonin agonist (mostly 5HT4) metoclopramide increases tone of lower esopageal sphincter, stimulates antral and small intestinal contractions, and facilitates gastric emptying. Most adverse effects of metoclopramine occur in the CNS: extrapyramidal symtoms and tardive diskinesia.
The D2 antagonist domperidone inhibits acetylcholinesterase release and emesis via the chemoreceptor trigger zone (CTZ), without extrapyramidal effects. Erythromycin has a motilin-like effect on GI smooth muscle, inproving gastric emptying as in diabetic gastroparesis.
Antiemetic drugs include the H1 antihistamines, phenothiazines, metoclopramine, ondasetrron, marijuana and glucocorticoids. The H1 antihistamines dimenhydrinate (Dramamine®), diphenhydramine (Benadryl®) and mezclizine (Bonine®) depress labyrinth excitability and are good for motion sickness, but have some adverse effects. The phenothiazines and metoclopramine block dopamine receptors in CTZ. Ondansetron blocks serotonin receptors in CTZ. The mechanism of action of marijuana or glucocorticoids is unknown.
Antidiarrheal drugs include the intraluminal agents and the antimotility/antisecretory agents. The intraluminal agents include the bulk-forming/hygroscopic agents like psyllum (Metamucil®) and kaolin/pectin (Kaopectolin®), and bismuth subsalicylate (Pepto-Bismol®). Bismuth is thought to be antisecretory, anti-inflamatory and antibacterial. Opioids like loperamide, diphenoxylate and difenoxin are antimotility/antisecretory agents, preffered over the intraluminal agents. These opioids do not cross the blood-brain barrier.
Agents used to treat irritable bowel disease (IBD) include glucocorticoids, 5-aminosalicilates and infliximab. The 5-aminosalicilates inhibit COX and LOX, reducing production of inflammatory mediators like LTB4 and 5-HETE, among other possible reactions. Sulfasaladine (5-ASA/sulfapyridine conjugate) is not the preferred drug because its metabolite sulfapyridine is cleaved by bacterial azoreductases in the colon to produce side effects. Olsalazine and balsalazine are cleaved by pHdependent baterial azoreduction in the colon. Olsalazine releases two molecules of 5-ASA. Mesalamine suppositories are 5-ASA in wax matrtix for rectal administration.
Infliximab is a monoclonal antibody directed at TNF-alpha. A single infusion may induce remission in refractory moserate to severe Crohn's disease. Follow-up infusions reduce the number of draining fistulas. A single treatmet costs $2,000.
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Omeprazole
D2 Antagonists
Bulk-forming