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AS 25/26 - GI Pharmacology I/II

Pathophysiology and pharmacology of peptic ulcer disease. Peptic ulcer disease is an imbalance of between acid+pepsin and mucus+bicarbonate to

result in deterioration of the epithelial barrier.o Gastric Acid Secretion: ACh, gastrin, histamine, PgE - stim adenylate cyclaseo Helicobacter pylori is the most common cause of gastric/duodenal ulcers

Basis and application of ‘triple therapy, to include role of antimicrobialagents.

Two anti-biotics(microbial): amoxicillin and clarithromycin One acid suppressant: Proton pump inhibitor (H 2 antagonist) Given for 1-2 weeks, results in 90% eradication, acid suppression continued

Pathophysiology and pharmacology of gastroesophageal reflux disease. Gastric acid comes back up and erodes the oesophagus Lifestyle modification, antacids (symptomatic relief ), H2 (OTC), Proton pump

inhibitors, metoclopramide and Domperidone

Stimulants of upper GIT motility Metoclopramide , Domperidone - Stim. the upper GIT motility and gastric emptying

and increases the LES tone, extrapyramidal side effects ( Meto ), increased prolactinsecretion (Dom)

**Cisapride is also used when nothing else works but has fatal cardiac arrhythmias possible

Pathophysiology and pharmacology of nausea and vomiting (emesis). Nausea frequently precedes the act of vomiting Stimuli for vomiting: GI irritation, motion sickness, intracranial pathology, pain, drug

side effects, metabolic disturbance, hormonal, horrific sight or smell. Involves : the vomiting center (In medulla), chemoreceptive trigger zone (floor of 4th

ventricle outside of blood-brain barrier) Regulating receptors : cholinergic (M), histaminergeric (H 1), dopaminergic (D 2),

serotonergic (5-HT 3), cannabinoid (CB 1)**Preferred treatment of vomiting is removal of the source/drug/stimulus

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Mechanism of action and adverse effects of proton pump inhibitors, histamineH2 antagonists, cytoprotective agents and antacids.

Proton Pump Inhibitors -Omepra zole

o Irreversibly blocks theH +/K + ATPase (proton

pump)o Inactive prodrug

(protonated at acid pH toactive derivative)

o Side effects: Diarrhoea,flatulence, nausea

o Treats: Peptic ulcer,gastroesophageal reflux,

prophylaxis against ulcerdevelopment by NSAIDS(Single daily dose gives long-lasting inhibition)

H 2 Receptor Antagonist - Cime tidine and Rani tidine o Competitively block histamine-induced acid released by parietal cells.o Less acid suppression than PPIo Cimetidine - inhibits cytochrome P450 enzymes

Drug interacts with phenytoin and warfarin (inactivates them) Antiandrogenic - gynaecomastia (swelling of breasts) ↑ Prolactin Confusion, drowsiness, headache, rash, diarrhoae

o Ranitidine - little to no inhibition of cytochrome P450 enzymes andantiadrogenic activity and fewer side effects

Cytoprotective Agents - Misoprostol, Sucralfate, Bismuth o Analogue of PgE1 (cytoprotective PG)o Side effects: Diarrhoea, uterine contraction, contraindicated in pregnancyo Sucralfate - binds to ulcer base (mucosal protecting action, stimulates PG and

bicarbonate production)o Bismuth - binds to ulcer base (inhibits H. pylori), precipitates at acid pH to

protect mucosa and stimulates PG and bicarbonate production.

Antacids - AlOH, MgOH, NaHCO 3 (used in combinations) o Weak bases acting to neutralize gastric acido Symptom relief (not usually used in ulcer healing)o NaHCO 3 - Can cause alkalosis (not intended for long-term use)

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Mechanism of action and adverse effects of muscarinic anticholinergics,histamine H1 antagonists, dopamine D2 antagonists, serotonin 5-HT3antagonists and cannabinoids.

Anticholinergics – Muscarinic Antagonists – Hyoscineo

Motion sickness (Short duration)o Little antiemetic effect in other situationso Side effects: Anticholinergic side effects

Antihistamines – H 1 Antagonists - Cyclizine o Motion sicknesso Little antiemetic effect in other situationso Side effects: Sedation

Dopamine receptor antagonists (D 2) – o Decrease vomiting caused by drugs (Chemotherapy)o Phenothiazines (Ex: prochlorperazine), Butyrophenones (Ex: haloperidol)o Side effects: Extrapyramidal, increased prolactin secretion

Serotonin receptor antagonists (5-HT 3) – Ondan setron o Decrease vomiting caused by drugs (especially chemotherapy)o Side effects: constipation, headache

Cannabinoids – THC analogues acting on CB receptor – Nabilone o Decrease vomiting due to drugs stimulating CTZ (chem-receptive trigger zone)o Side effects: drowsiness, psychological effects (incl. psychosis)o Steroids can be used as a refractory emesis.

Pathophysiology and pharmacology of inflammatory bowel disease. Crohn’s Dise ase

o Transmural inflammation of the lower GIT, panenteric (mouth to anus)o Diarrhoea with bleeding not common and TNF- α (proinflamm cytokine) involved

Ulcerative colitiso Mucosal/Sub-mucosal inflammation of rectum (always), colon (variable)o Diarrhoea with bleeding

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Mechanism of action and adverse effects of aminosalicylates, corticosteroids,immunosuppressive agents, antimicrobials and TNFa inhibitors.

5-Aminosalicylates – Sulfasalazine [Mesalamine]o Inhibit leukotriene/prostaglandin formationo Adverse effects: GIT disturbance, hypersensitivity reactions

Corticosteroids - Hydrocortisone , prednisolone (topical), Budesonide (low bioavail.)o Inhibit of cytokine production to induce remission

Immunosuppressive Agents – Azathioprine [Mercaptopurine] o Purine analogues which inhibit nucleic acid synthesis

Antimicrobials - Metronidazoleo Interrupt bacterial role in inflammatory process

TNF- α inhibitors - Infliximabo Antibodies to inflammatory effects of TNF- α in the gut for refractory Crohns

Pathophysiology and pharmacology of constipation and laxatives. Laxatives – promote defaecation, three main properties are characteristic:

o 1. Retain water and electrolytes in lumen via hydrophilic/osmotic propertieso 2. Decreasing mucosal absorption of water and electrolyteso 3. Increasing intestinal motility

Mechanism of action and adverse effects of dietary fibre/bulk-forminglaxatives, osmotic laxatives and contact/stimulant laxatives.

Dietary Fibre/ Bulk-forming laxativeso Increasing stool mass via component polysaccharides (transit over 1-7 days) o Bran; methylcellylose; ispaghula o Adverse effects: ↓ Drug absorption, intestinal/oesophageal obstruction, +water

Osmotic Laxatives – MgSO 4, MgOH, NaPO 4, Lactulose o Engaged in bowel and hold water in lumen via osmotic propertieso Increased transit over 1-3 hourso Adverse effects: Little absorbed but care in children and w/ renal impairment

Contact/Stimulant Laxatives o Direct stimulation of myenteric plexus/mucosao Decreased permeability of mucosal surfaceo Increased transit over 6-8 hours

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Pathophysiology and pharmacology of diarrhoea and antidiarrhoea agents. Three main approaches

1. Maintain fluid and electrolyte balanceo Oral rehydration, use NaCl+Glucose for infant diarrhoea

2. Use of anti-infective agentso Little role in simple gastroenteritis, antimicrobial very common

3. Use of constipating agentso May be indicative of intestinal pathology (Crohns/ UC)

Mechanism of action and adverse effects of oral rehydration/electrolytebalance, anti-infective agents, absorbent agents and opioid derivatives.

Constipating Agents – Absorbent compoundso Absorb fluids and toxins

Opiateso ↑ Muscle tone and ↓ propulsive movementso ↓ Sensory stimulation for defaecation reflex

Opiate derivatives without CNS effects and dependence of morphineo Diphenoxylate and Loperamide