Drugs used in gastrointestinal diseases
Drugs used in peptic ulcer include the following1- Antacids: magnesium salts, Aluminum salts, calcium bicarbonate
2- Antihistamine (H2-antagonists) as Cimetidine, Ranitidine, Famotidine
3- Proton pump inhibitors as Omeprazole, Lansoprazole, Pentaprazole
4- Mucosal protective agents as Sucralfate, Bismuth chelate
5- Prostaglandins analogues as Misoprostol
6- Antimuscarinic as Pirenzepine
1-Antacids
Act by raising intra gastric PH and therefor reduce irritation by gastric acid secretion, they are useful in symptomatic treatment and has no effect on ulcer healing; antacids are divided into two groups
A) Systemic antacids as Sodium bicarbonate
B) Non-systemic antacids as magnesium salts, aluminum salts and calcium carbonate
Sodium bicarbonate
Has a rapid onset of action its systemic antacid which can be absorbed systemically can alter the PH of the extracellular fluid and may cause systemic alkalosis especially in patients with renal failure ;it can also increase the absorption of calcium from the GIT leading to hypercalcemia ; the excessive sodium may lead to hypernatremia and edema ;when interact with gastric acid bicarbonate release CO2 which cause abdominal distention
Magnesium salts
As magnesium trisilicate and magnesium hydroxide, both have slow onset of action due to their insolubility, the magnesium salts can cause diarrhea due to osmotic effect, they are not absorbed systemically
Aluminum salts
As aluminum sulphate and aluminum hydroxide, they also not absorbed systemically, but they combined to phosphate in the GIT, so can be used to reduce phosphate absorption in case of hyperphosphatemia of renal failure and in normal individual, they may cause hypophosphatemia
Clinical uses of antacids
1- Symptomatic treatment of peptic ulcer by relief the pain, but they do not promote healing
2- Dyspepsia due to esophageal reflex or other causes
Interactions with antacids
1- Antacids can bind to drugs in the GIT and reduce their absorption such as iron, Tetracycline and Digoxin
2- Systemic antacids may change urine PH and increase excretion of drugs as Salicylate (weak acid)
2- H2-receptor antagonists as Cimetidine, Ranitidine, Famotidine
They act by blocking H2- receptors in the parietal cells of stomach and therefore, inhibit acid secretion, they reduce the volume of acid secretion and also increase the PH of the acid (make the lumen of the stomach more alkaline) ,they relief symptoms and promote healing in peptic ulcerPharmacokinetic
Cimetidine is well absorbed when given orally ,half-life about 2 hours, partly metabolized in the liver ,but mainly excreted unchanged by the kidney ,the half-life increase up to 5 hours in case of renal failure
Clinical uses
1- Peptic ulcer as they promote healing of peptic ulcer and reduce relapse rate
2- Reflux esophagitis
Adverse effects
1- Diarrhea and skin rash
2- Dizziness and mental confusion in the elderly
3- Gynecomastia due to anti-androgen effect
4- Cimetidine is an enzyme inhibitor which inhibit the metabolism of other drugs as Warfarin, phenytoin and theophylline
5- Ranitidine, less enzyme inhibitor than Cimetidine and fewer incidence of adverse effects
6- Famotidine, less adverse effects than Cimetidine, less enzyme inhibition and longer half-life
3- Proton pump inhibitors as Omeprazole, lansoprazole, Pantoprazole, Rabeprazole
Inactivate H/K- ATPase (proton pump) in the parietal cells, they are more potent than all the other antiulcer drugs as they inhibit the final step in acid secretion, they also promote healing of the ulcer
Omeprazole
Is a pro-drug that enter the parietal cell from the blood by non-ionic diffusion, but become ionized inside the cells, it binds to the sulfhydryl (-SH) group in the H/K-ATPase pump, this irreversibly inactivate the pump causing inhibition of acid secretion
Pharmacokinetic
Omeprazole is given orally and because it is degraded by the acid medium in the stomach, it is given in enteric-coated tablet
Clinical uses
1- Peptic ulcer
2- Zollinger- Ellison syndrome (gastrin secretion tumor of the pancreas)
Adverse effects of Omeprazole
1- Nausea, diarrhea, headache and skin rash
2- It inhibits drug metabolism, decreasing the metabolism of Warfarin, Phenytoin, Carbamazepine and Diazepam
3- Chronic use of proton pump inhibitors may change the acid medium of the stomach and shown in experimental animals to cause gastric carcinoma, also the hypochlorhydria enhances the growth of bacteria in the stomach, and these may activate carcinogens
4- Chronic hypochlorhydria, also decrease the absorption of vitamin B12, which lead to megaloblastic aneamia
4- Misoprostol (Prostaglandins analogue)
Is a synthetic analogue of prostaglandin EI, protect against the formation of gastric
and duodenal ulcer in patients taking NSAIDs; Misoprostol also can heal gastric
and duodenal ulcers not related to NSAIDs
Mechanism of action
1- Improve blood supply to the gastric mucosa
2- Enhancing gastric secretion of mucous and bicarbonate
3- Enhances cell replication in gastric mucosa
Clinical uses of Misoprostol
It is usually given in combination with NSAIDs and sometimes in fixed combination to susceptible individuals to prevent gastric damage, especially with non- selective COX- inhibitors as Indomethacin and Diclofenac sodium
Adverse effects:-
1- Diarrhea and abdominal pain
2- Vaginal bleeding and dysmenorrhea (contraindication in pregnancy lead to abortion)
5- Mucosal protective agents
Sucralfate; its complex salts of Sucrose sulphate and aluminum hydroxide ;at low PH of the stomach sucralfate form a polymer that bind to protein molecules transudate from the damage mucosa of the ulcer base ,this result in the formation of viscous paste that adheres to the ulcer base ;Sucralfate can also bind to pepsin and bile salts in the stomach ;it has unequal efficacy to H2 –antagonists
Adverse effects
1- It well tolerated, but may cause constipation
2- Aluminum blood concentration may increase, and toxicity occur specially in patients with renal failure
Interactions
The drug is effective only in acid medium and therefore, should not be given in combination with antacids
Sucralfate can reduce the intestinal absorption of Ciprofloxacin, Theophylline, Digoxin and Phenytoin
Bismuth chelate
Acts by chelating with protein in the ulcer base to form a coating in the ulcer base, which protects the ulcer from acid, pepsin, and bile, in addition, it has a valuable action against Helicobacter pylori, it has similar efficacy to Cimetidine, but in addition, it causes less changes of recurrence due to bacterial eradicationAdverse effects
1- Liquid dosage form, causes dark discoloration of the tongue and mouth, occur less with tablets
2- There is little systemic absorption, but bismuth may accumulate in patients with renal failure
6- Anticholinergic drugs as Pirenzepine, Probantheline
These agents reduce the volume of gastric acid secretion without affecting the PH, they produce symptomatic relief in peptic ulcer, but they do not enhance ulcer healingPirenzepine is water-soluble and does not penetrate the CNS and has no central side effects, it is also selective to muscarinic (M1) receptors in the gastric mucosa.
All the anticholinergics have Atropine like adverse effects
Laxatives and purgatives
Laxatives, purgatives and cathartics are similar; they are drugs used to promote or help defecation by reducing the viscosity of the contents of the lower colon or stimulate colonic contraction
Classification:-
1- Bulk laxatives
2- Osmotic laxatives
3- Fecal softeners
4- Stimulants laxatives
1-Bulk laxatives include (Bran and methylcellulose)
Acts by increasing the volume and reducing the viscosity of the intestinal contents which lead to effective reflex bowel activity
Bran, is the residue left when the flour is made from cereals, it contains fibers which are not digestible, so enter into the colon intact, it has great capacity for holding water, increasing the volume and reducing the viscosity of the colonic contents
2- Osmotic laxatives as Magnesium salts, Lactulose, polyethylene glycol
These are little absorbed and increase the bulk and reduce the viscosity of intestinal contents due to holding water by osmotic effect
Magnesium salts
As magnesium sulphate and magnesium hydroxide, act by retaining water in the intestinal lumen and can withdraw water from the body to the intestine, both salts act in 2-4 hours; magnesium sulphate is more powerful than magnesium hydroxide and can be given by retention enema
Lactulose
Is a synthetic disaccharide can be taken orally as it is not metabolized and acts as osmotic laxative, it is also used in hepatic encephalopathy as it is split into lactic and acetic acids which inhibit the growth of ammonia producing organism and also by lowing intestinal PH can reduce diffusion of ammonia into the colon
Osmotic laxatives can be used to clear the colon in diagnostic procedures as colonoscopy or radiology or in preparation for colonic surgery
Osmotic laxatives can be given orally or as retention enema
3- Fecal softeners
Docusate sodium and liquid paraffin lead to softening of the fecal material, which is useful in condition like hemorrhoids and fissure
Docusate sodium causes softening of the faces by lowering the surface tension of fluids in the bowel, this allows more water to remain in the faces, and it also has a weak bowel stimulate effect, it takes 1-2 days to act
Liquid paraffin
Is an inert mineral oil, which is not digested, it promotes the passage of soft fecal matters, may be aspirated and cause lipoid pneumonia
Stimulant laxatives (Bisacodyl, Glycerol, sodium, Senna and Caster oil)
These drugs increase the intestinal motility by various mechanism, they may cause abdominal cramps
Bisacodyl
Stimulates the sensory nerve endings of the colon by a direct action from the intestinal lumen ,it is effective when given orally and acts in 6-10 hours ; can also be given by suppositories especially in the elderly people ,it acts about one hour, have no, important adverse effects
Glycerol: - Has a mild stimulant effect on the rectum when given as suppositories
Senna
Senna hydrolyzed by the liver into senoside A and B; it enhances the response of the colon to normal stimuli; it is absorbed in the small intestine and secreted in the colon , take about 8 hours to act
Enemas: - Administered rectally, produce defecation by softening the fecal materials and distending the bowel; they used in the preparation of patients for surgery, endoscopy and radiological examination
The clinical uses of laxatives and purgatives
1- Treatment of constipation
2- Painful anal conditions as hemorrhoids and anal fissure to soften the stool
3- Preparation of the colon for surgery, colonoscopy and radiological examination
4- In the post –operative management of colostomy
5- Irritable bowel syndrome
6- Diverticular disease
Antidiarrheal drugs
1- Ant motility drugs as Codeine, Diphenoxylate and Loperamide
2- Drugs increase viscosity of faces as Kaolin
Codeine
Act on the opioid receptors in the smooth muscles of the bowel to reduce peristalsis and increase segmentation contraction
(Segmentation involves contraction of the circular muscles in the digestive tract, while peristalsis involves rhythmic contraction of the longitudinal muscles in the GIT)
Diphenoxylate
Has an effect similar to Codeine, usually given mixed with Atropine (Lomotil), it
causes nausea, vomiting, abdominal pain and CNS depression
Loperamide
It is also opiate act by inhibiting contraction of the smooth muscles of the intestine; it is also cause nausea, abdominal pain and vomiting
All anti-motility drugs should not be given to children with acute diarrhea as they may
cause paralytic ileus and respiratory depression
Antiemetic drugs
Are group of drugs used in vomiting due to different causes
Classification
1- Antimuscarinic drugs as Hyoscine
2- Anti histamines as Cyclizine and Promethazine
3- Dopamine receptors antagonists as Metoclopramide and Domperidone
4- Phenothiazines as Prochlorperazine and Haloperidol
5- 5HT3 receptors antagonists as Ondansetron and Granisetron
6- Others: Cannabinoids, Corticosteroids
7- Neurokinin receptors (NK) antagonists as Aprepitant
Metoclopramide
Acts centrally by blocking dopamine D2 receptors in the chemoreceptors trigger zone (CTZ) and peripherally by enhancing acetylcholine action at muscarinic nerve endings in the GIT; it increases the tone of the lower esophageal sphincter and relaxes the pyloric sphincter and increase peristaltic movement of intestine (half-life is 4 hours)Clinical indications:-
1- Nausea and vomiting associated with GIT diseases
2- Cytotoxic and radiotherapy induced vomiting
3- In migraine to relief nausea and vomiting and increase absorption of analgesic drugs
4- To empty the stomach in emergency anesthesia
Adverse effects:-
1- Extrapyramidal dystonia (torticollis, facial spasm, oculogyric crisis) more common in children and young adults
2- Diarrhea
3- Stimulation of prolactin release with gynecomastia and galactorrhea
Domperidone
Is a selective D2 receptors antagonist, it has no acetylcholine like action; its half-life is about 7hours. It used for treatment of nausea and vomiting associated with GIT disorders and cytotoxic induced vomiting; it may cause gynecomastia and galactorrhea
Ondansetron
Is a selective 5-HT3 receptors antagonist, it is highly effective against nausea and vomiting induced by cytotoxic drugs and radiotherapy, causes constipation, headache and facial flushing
Corticosteroids (as Dexamethasone) are also effective in cytotoxic drugs induced vomiting; probably act by reducing edema in vomiting center or other CNS effect
Nabillone
Is a synthetic Cannabinoid, used mainly to relief nausea and vomiting associated with cytotoxic drugs
Side effects:- dryness of the mouth, decrease appetite, dizziness, postural hypotension, euphoria, dysphoria, confusion and psychosis
Hyoscine (Scopolamine):-
Is structurally related to Atropine, it has a CNS depressant effect, its antiemetic effect is due to the anti-muscarinic action and also due to its central actions, it is especially effective in motion sickness (nausea and vomiting associated with travel);it mainly cause antimuscarinic adverse effectsCyclizine and Promethazine
Are both antihistamine (H1-receptos blockers), effective mainly in motion sickness and middle ear disorders.