Drugs used to treat GIT disordes

Anton Kohút

Gastric ulcer

Pathogenesis of UlcersPathogenesis of Ulcers

Aggressive FactorsAggressive Factors Acid, pepsinAcid, pepsin Bile saltsBile salts Drugs (NSAIDs)Drugs (NSAIDs) H. pyloriH. pylori

Defensive FactorsDefensive Factors Mucus, bicarbonate layerMucus, bicarbonate layer Blood flow, cell renewalBlood flow, cell renewal ProstaglandinsProstaglandins PhospholipidPhospholipid Free radical scavengersFree radical scavengers

Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.

Gastric ulcer and NSAIDsGastric ulcer and NSAIDs

H. H. pyloripylori infection infection

Drugs used to treat gastric ulcer

Regulation of gastric acid secretion I. Antisecretory drugs

1. H2 – blockers: cimetidine, ranitidine, famotidine nisatidine

2. M1 – blockers: pirenzepine, dicyclomine, propantheline

3. Antagonist of gastrin

receptors: somastatine 4. Agonists of PG receptors:

misoprostol, entprostyl

II. Antacids

-sodium bicarbonate,

-calcium carbonate,

-aluminium hydroxide,

-magnesium hydroxide

Control of gastric acid secretion

                                                                                                                                                                                                                                                                                                                                                         

                                                                      

Antisecretory agents

1. H2 histamine blockers – cimetidine, ranitidine, famotidine, nisatidine

2. Antimuscarinic agents –pirenzepine, dicyclomine,

3. Agonists of prostaglandine receptors - misoprostol

4. Antagonist of gastrin receptors- somatostatin

5. Inhibitors of proton pump – omeprazole, pantoprazole

H2 receptor antagonists

Therapeutic uses of H2 Therapeutic uses of H2 antagonistsantagonists Acute stress ulcers:Acute stress ulcers: in managing acute stress ulcers associated with major in managing acute stress ulcers associated with major

physical trauma in high-risk patients in intensive care physical trauma in high-risk patients in intensive care units. They are usually injected intravenously.units. They are usually injected intravenously.

Gastroesophageal reflux disease:Gastroesophageal reflux disease: Low doses appear to be effective for prevention and Low doses appear to be effective for prevention and

treatment of heartburn (gastroesophageal reflux).treatment of heartburn (gastroesophageal reflux). However, about 50 percent of patients do not find However, about 50 percent of patients do not find

benefit, and PPIs are now used preferentially in the benefit, and PPIs are now used preferentially in the treatment of this disorder.treatment of this disorder.

they may not relieve symptoms for at least 45 they may not relieve symptoms for at least 45 minutes.minutes.

Antacids more efficiently, but temporarily, neutralize Antacids more efficiently, but temporarily, neutralize secreted acid already in the stomach. secreted acid already in the stomach.

Finally, tolerance to the effects of H2 antagonists can Finally, tolerance to the effects of H2 antagonists can be seen within 2 weeks of therapy.be seen within 2 weeks of therapy.

All H2 antagonists are equally effective in All H2 antagonists are equally effective in promoting healing of duodenal and gastric promoting healing of duodenal and gastric ulcers. However, recurrence is common ulcers. However, recurrence is common after treatment with H2 antagonists is after treatment with H2 antagonists is stopped (60–100 percent per year).stopped (60–100 percent per year).

The use of these agents has decreased The use of these agents has decreased with the advent of the PPIs. with the advent of the PPIs.

Patients with NSAID-induced ulcers should Patients with NSAID-induced ulcers should be treated with PPIs, because these agents be treated with PPIs, because these agents heal and prevent future ulcers better than heal and prevent future ulcers better than H2 antagonists. H2 antagonists.

Antacids

• Calcium containing Calcium carbonate

• Magnesium containing

Magnesium hydroxide• Aluminium containing

Aluminium hydroxide

Antacids may decrease absorption of other drugs

• Cytoprotective agents - misoprostol (PGE1), sucralfate, bismuth subsalicylate

• Antibacterial agents colloidal bismuth ATB: ampicilline

tetracyclines, metronidazole, clarithromycin

Sucralfate:Sucralfate:

- - This complex of This complex of aluminum hydroxidealuminum hydroxide and and sulfated sucrose binds to positively sulfated sucrose binds to positively charged groups in proteins of both normal charged groups in proteins of both normal and necrotic mucosa. and necrotic mucosa.

- By forming complex gels with epithelial - By forming complex gels with epithelial cells, cells, sucralfatesucralfate creates a physical barrier. creates a physical barrier.

- - Effectively heals duodenal ulcers and is Effectively heals duodenal ulcers and is used in long-term maintenance therapy.used in long-term maintenance therapy.

- Because it requires an acidic pH for - Because it requires an acidic pH for activation, activation, sucralfatesucralfate should not be should not be administered with H2 antagonists or administered with H2 antagonists or antacids. antacids.

Bismuth subsalicylate:Bismuth subsalicylate:

Effectively heal peptic ulcers.Effectively heal peptic ulcers.

In addition to their antimicrobial In addition to their antimicrobial actions, actions,

They inhibit the activity of pepsin, They inhibit the activity of pepsin, increase secretion of mucus, and increase secretion of mucus, and interact with glycoproteins in interact with glycoproteins in necrotic mucosal tissue to coat and necrotic mucosal tissue to coat and protect the ulcer crater.protect the ulcer crater.

Antibacterial agentsAntibacterial agents

Currently, either Currently, either triple therapytriple therapy consisting of a PPI consisting of a PPI

with either with either metronidazolemetronidazole or or amoxicillinamoxicillin plus plus clarithromycinclarithromycin, ,

or quadrupleor quadruple therapy of therapy of bismuth bismuth subsalicylatesubsalicylate and and metronidazolemetronidazole plus plus tetracyclinetetracycline plus a PPI, are plus a PPI, are administered for a 2-week administered for a 2-week course. course.

GIT motility disorders

GIT motility disorders

• Constipation means hard stools, difficulty passing stools, or the sense of incomplete emptying after a bowel movement.

• Diarrhoea is a watery stool occurring more than three times in one day. Prolonged diarrhea can be a sign of other problems and it can cause

dehydration.

Constipation

Some drugs causing constipation

• Analgesics (inhibitors of prostaglandin syntesis)• Antacids (containing calcium carbobate or

aluminium hydroxide)• Anticholinergics• Antihistamines (H1 blockers)• Corticosteroids• Clonidine• Ganglionic blocking agents• Laxatives (used chronically)• Myorelaxants• Opioids• Phenothiazines• Tricyclic antidepresants• Verapamil

LaxativesLaxativesI.I. Bulk formingBulk forming l laxativesaxatives:: high fiberhigh fiber, ,

absorbs water to increase bulkabsorbs water to increase bulk, , distends distends bowel to initiate reflex bowel activitybowel to initiate reflex bowel activity – –

- - polysaccharides and cellulosespolysaccharides and celluloses derived derived from grains, psyllium, from grains, psyllium, methylcellulose, and methylcellulose, and carboxy-methylcellulosecarboxy-methylcellulose, synthetic resin , synthetic resin polycarbophilpolycarbophil

II. Emolients- surfactants:II. Emolients- surfactants: stool softeners stool softeners and lubricantsand lubricants, , promote more water and fat promote more water and fat in the stoolsin the stools, , lubricate the fecal material lubricate the fecal material and intestinal wallsand intestinal walls - -stool softeners: stool softeners: docusate saltsdocusate salts, , lubricants: mineral oillubricants: mineral oil

Laxatives (cont.)Laxatives (cont.)

III.III. Saline and osmotic laxatives:Saline and osmotic laxatives: increase osmotic increase osmotic pressure within the intestinal tract, causing more water pressure within the intestinal tract, causing more water to enter the intestinesto enter the intestines. .

RResult: bowel distention, increased peristalsis, and esult: bowel distention, increased peristalsis, and evacuationevacuation

magnesium sulfatemagnesium sulfate, , magnesium hydroxidemagnesium hydroxide, , magnesium magnesium citratecitrate, , sodium phosphatesodium phosphate

the disaccharide lactulose; glycerin; sorbitol and the disaccharide lactulose; glycerin; sorbitol and mannitol; and polyethylene glycol-electrolyte solutions.mannitol; and polyethylene glycol-electrolyte solutions.

IV.IV. Stimulant laxativesStimulant laxatives (contact, iritant) (contact, iritant) – – increases peristalsis via intestinal nerve stimulationincreases peristalsis via intestinal nerve stimulation:: diphenylmethane diphenylmethane phenolphthalein, bisacodyl, phenolphthalein, bisacodyl,

anthraquinone laxatives, anthraquinone laxatives, castor oilcastor oil (ricin, ricinoleic acid) (ricin, ricinoleic acid)

V. V. Prokinetic Prokinetic aagentsgents

Laxatives: Side Effects

Bulk-forming laxatives have few side effects and minimal systemic effects:

 allergic reactions (plant gums)

flatulence

systemic retention of Na+ and H2O (psyllium,

carboxymethylcellulose)

dextrose should be avoided in diabetic patients

cellulose can reduce the absorption of many drugs

(cardiac glycosides, salicylates, nitrofurantoin)

psyllium may bind coumarin derivatives

Saline laxatives

up to 20% of the salt is absorbed

Mg2+ - toxicity in patients with impaired renal function

Na+ salts should not be used in patients with congestive heart failure or renal disease

phosphate laxatives can cause hyperphosphatemia and a reduction of plasma Ca2+

hypertonic salt solutions can produce significant dehydration and must be administered with sufficient water to ensure that no net loss of body water occurs

Hyperosmotic

lactulose: flatulence, cramps, abdominal discomfort

excessive dosage can cause diarrhea, loss of fluid and

K+, hypernatremia, exacerbation of hepatic

encephalopathy

 

Contraindications

 patients requiring a galactose-free diet must not use

lactulose

 patients with diabetes must be cautious in using

lactulose

Stimulantsfluid and electrolyte deficits

(overdosage)they can damage enterocytes

(inflammatory response in the colon)allergic reactions, osteomalaciaprotein- losing gastroenteropathypossible pink coloring of the urine and

feces (phenolphthalein)an excessive laxative effect and

abdominal pain (senna, cascara)

Prokinetic agents

direct M-receptor agonists (bethanechol)

AChE inhibitors (neostigmine)

inhibitory presynaptic D2-receptor blockers

(metoclopramide)

excitatory presynaptic 5-HT4-receptor agonists (cisaprid)

excitatory motilin receptor activators (erythromycin)

prokinetic drugs increase gastric emptying

they increase tone of the lower esophageal sphincter

they exhibit antiemetic activity (metoclopramide)

they improve coordination of gastroduodenal contractions

Side effects

cholinergic agonists have variety of muscarinic

side effects (excess GI secretions, cramps,

salivation, sweating, urination, lacrimation,

defecation)

dopamine-receptor antagonists can induce

dystonia, Parkinson´s disease-like effects

hyperprolactinemia (gynecomastia, galactorhea

Diarrhoea

Diarrhoea

• Traveller’s diarrhoea is one of the most common illnesses for tourists going to tropical climates. As many as 60% of all travellers suffer some form of diarrhoea

Some drugs causing diarrhoea

• Adrenergic neuron blocking agents (reserpine, quanethidine)

• Antimicrobials (e.g. sulfonamides, tetracyclines, most broad spectrum ATB

• Cholinergic agonists and cholinesterase inhibitors

• Procinetic agents (metoclopramide, domperidone, cisapride)

• Prostaglandins• Quinidine

Antidiarrhoeal drugs

I. Opioids: diphenoxylate and loperamide free of opiate – like CNS effect, opium tincture, codeine,

decrease bowel motility, decrease transit time through

the bowel, allowing more time for water and electrolytes

to be absorbed, opioids are effective in the treatment

of moderate-to-severe diarrhea!

III. Octreotide (the synthetic analog of somatostatin) inhibition of gastric acid and pepsinogen secretion, inhibition of endocrine secretions (e.g., gastrin,

cholecystokinin, secretin, VIP, and motilin), inhibition of intestinal fluid and bicarbonate secretion,

and diminution of smooth muscle contractility.

IV. Other Agents a. Adsorbents: kaolin, pectin, bismuth subsalicylate,

activated charcoal coat the walls of the GI tract, bind to the causative

bacteria or toxin, which is then eliminated through the stool

b. Intestinal flora modifiers : lactobacili (supplying missing bacteria to the GI tract, suppressing the growth of diarrhea-causing bacteria),

c. Muscarinic antagonists b. fiber supplements - adsorbents (psyllium,

polycarbophil, carboxymethylcellulose) - increase the viscosity of feces

Antiemetics

Receptors involved in vomiting

Causes of vomiting

I. Drugs• Anticancer drugs,

cardiac glycosides, apomorphine, levodopa, bromocryptine, cholinomimetics, opiates, ergot alkaloids

II. Physiological• Pregnancy, head

motion, weitghlesness

III. Pathophysiological• Uremia,

endocrinopathies, alcoholism, migraine, allergies,

• gastric irritations

IV. Toxic• Food poisons,

industrial poisons, radiations, infections

Recomended antiemetic treatment