GI Drugs Flashcards
Regulation of gastric acid secretion
Histamine (endocrine)
- H2 receptor coupled to Gs - Increased cAMP in parietal cell - Protein kinases upregulate activity of proton pump --> pumps acid into gastric lumen
Ach (neural via vagus nerve)
- M3 coupled to Gq - Increased intracellular Ca2+ - Increased activity of proton pump
Gastrin (paracrine)
- Does not use a gastrin receptor - Uses CCKb receptor, results in increase in intracellular Ca2+
Prostaglandin E2
- Coupled to Gi - Inhibitory activity --> decreased AC and cAMP and downregulates the proton pump - Has a protective activity
Antacids MOA
Weak bases
Act as chemical antagonist –> neutralisation reaction with acid to produce salt and water –> increases gastric pH –> protects esophageal mucosa from reflex corrosion
3 antacids and their AE
Aluminium hydroxide = constipation
Magnesium hydroxide = osmotic diarrhoea
—-> both combined to produce no change in bowel movements
Calcium carbonate = belching –> metabolic acidosis –> milk alkali syndrome –> renal failure
What drugs cannot be given along with antacids?
Alter dissolution of weakly charged acids due to increased pH
Decreased absorption of co-administered tetracyclines, fluorquinolones, itraconazole and iron.
H2 receptor antagonists MOA and drugs
Selective competitive inhibition at parietal cell H2 Gs coupled receptor
Suppress histamine inducing acid secretion –> Upstream blockade. Only partial suppression of acid production as the Ach and Gastrin pathways are still active.
Suppress basal gastric acid secretion but modest effect on meal stimulated secretion
1st gen = cimetidine
2nd gen = ranitidine, famotidine and nizatidine
H2RA AE
Tachyphlaxis develops in 2 to 6 weeks = repeated exposure to drug will cause down regulation of expression of H2 receptors and will lead to non-responsiveness
Cimetidine
- Gynecomastia, galactorrhea and male impotence (Block androgen receptor and stimulates prolactin)
- Crosses BBB: confusion, dizziness and headaches
- B12 deficiency and myelosuppression in long-term use due to increased gastric pH (meat and animal products cannot be digested properly)
- Inhibits CYP450: increased conc of drugs (warfarin, diazepam, phenytoin)
H2RA uses
GERD
PUD
Nonulcer dyspepsia
Prophylaxis against stress-related gastritis (burn and head-trauma patients)
PPIs drugs and MOA
Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole
Irreversibly inhibit H+/K+ ATPase proton pump in parental cells (final common pathway)–> inhibit 90-98% of 24 hours acid secretion
Suppress both basal and meal stimulated gastric acid production
PPIs uses
Patients who fail twice daily H2RA therapy
Severe GERD
PUD (H. pylori, NSAID associated) and prevention of peptic ulcer rebreeding
Nonulcer dyspepsia
Prophylaxis against stress-related gastritis (burn and head-trauma patients
PPIs AE with long term use (4)
Vitamin B12 deficiency due to reduced pepsin function (due to increased pH)
Risk for community acquired pneumonias and C. difficile colitis
Hypomagnesemia
Osteopenia: reduced Ca2+ absorption or osteoclast inhibition –> increased risk of hip, spine, wrist fractures
PPIs drug interactions
Omeprazole = inhibit CYP450 enzymes (increased conc of drugs)
Omeprazole, Esomeprazole, Lansoprazole = inhibit CYP2C19 –> If clopidogrel is given with these drugs, it will not be activated as it is a prodrug
Pantoprazole or rabeprazol is preferred in people on clopidogrel
Why use PPIs for h. pylori eradication
1) direct antimicrobial properties
2) increased ph –> microbe will be actively dividing so antibiotics will be more effective –> lowers MIC of antibiotics needed to clear the organism
Triple therapy for h. pylori eradication
Clarithromycin + amoxicillin + PPI
In penicillin allergic patients:
Clarithromycin + metronidazole + PPI
Quadruple therapy for h. pylori eradication
Bismuth subsalicylate + metronidazole + tetracycline + PPI
Misoprostol MOA
Analog of PGE1
Binds EP3 receptor –> stimulates Gi pathways to decrease gastric acid secretion
Stimulates mucus and bicarb secretion
Enhances mucosal blood flow
Misoprostol uses
Prevention of NSAID-induced ulcers in high risk patients
Misoprostol AE and contraindications
Diarrhea, abdominal pain, cramps
Contraindicated in pregnancy –> causes uterine contractions –> abortion
Sucralfate MOA and use
Forms a viscous paste that binds selectively to ulcers –> neg charged sucrose sulphate binds pos charged proteins forming a physical barriers which stops further damage
Stimulated mucosal prostaglandin and bicarb secretion
Used for initial management of GERD in pregnancy
Bismuth Subsalicylate MOA and uses
Suppresses H. pylori but no neutralisation action of acid
Used in quadruple therapy
Used for dyspepsia and acute diarrhea
Bismuth Subsalicylate AE and contraindications
Bismuth toxicity rare
Metabolite bismuth sulfide causes harmless blackening of the stool
Can cause salicylate toxicity in combination with other salicylate products –> contraindicated in renal failure
Prokinetic agents general MOA and drugs
Should enhance coordinated GI motility
Activating M1 receptors does not enhance coordinated contractions so drugs should act upstream of Ach at receptor sites on enteric neuron itself or higher
Erythromycin
Cisapride
Metoclopramide
How is GI peristalsis regulated
1) Serotonin. Binds first and stimulates enteric neurons via 5-HT4 receptor–> which stimulate Ach via M1 to stimulate muscles –> More coordinated response of muscle contraction
2) Motilin binds directly to receptor on muscularis to stimulate contraction
Erythromycin MOA and use
Macrolide antibiotic
Agonist effects the motion receptor
Rapid down-regulation of motion receptor –> early tolerance so only used for short courses
Used for diabetic gastroparesis
Cisapride MOA and uses
5-HT4 receptor agonist, 5-HT3 antagonist and direct smooth muscle stimulant
No longer used as it is a pro-arrhythmic drug –> serious and fatal cardiac ventricular arrhythmias
Metoclopramide MOA and uses
5-HT4 receptor agonist, vagal and central 5-HT3 antagonist and D2 receptor antagonist
Effects upper GI tract only:
Increased LES tone
Stimulates astral and small intestinal contractions
Uses:
- Gastroparesis
- Anti-emetic
Metoclopramide AE
Extrapyramidal effects - due to dopamine antagonism (effects children and young adults)
Galactorrhea - block inhibitory effect of dopamine on prolactin –> increased prolactin release
Chemotherapy induced N/V phases
Associated with some chemotherapeutic agents like cisplatin
Acute phase = universally experienced (within 24 hours)
Delayed phase = only affects some patients (on day 2-5)
Prevention and treatment of motion sickness
Scopolamine (anticholinergic) as motion sickness is mediated by H1 and M receptors from inner ear to cerebellum
Not first line for CINV
H1 antagonists used for motion sickness and post-operative emesis
Diphenhydramine, meclizine and cyclizine
Act on vestibular afferents and brainstem
Ondansetron and granisetron MOA and uses
5-HT3 antagonists –> present in vagal afferents, the solitary tract nucleus, chemoreceptor trigger zone and area postrema
DOC for proxylaxis against immediate CINV
Also used for hyperemesis gravidarum in pregnancy
NK1 antagonists and uses
Aprepitant - oral
Fosaprepitant - parenteral
Antagonist for NK1 receptor for substance P
Used for prophylaxis against delayed CINV
Aprepitant metabolism
NK1 antagonist
Extensive CYP3A4 metabolism –> may affect metabolism of warfarin and OCP
D2 antagonists drugs, use and AE
Promethazine
Droperidol
Antagonism at chemoreceptor trigger zone
Also has anti-histamine and anti-cholinergic effects = good for treating motion sickness
AE: extrapyramidal effects
Dexamethasone
Methylprednisolone
MOA and uses
Corticosteriods.
Effective in treatment of nausea in patients with metastatic cancer => suppression of peritumoral inflammation and prostaglandin production
Lorazepam
Alprazolam
Diazepam
Use as anti-emetics
MOA and AE
Benzos: No intrinsic anti-emetic effects
Useful adjuncts to do sedative, amnesic and anti-anxiety effects which reduce the anticipatory component of N/V
MOA: facilitate GABAa action in CNS by increasing Cl- channel opening
AE: CNS depression and dependence
Dronabinol MOA and use as anti-emetics
Naturally occurring cannabinoid
Stimulates CB1 receptor in brainstem
Prophylaxis in patients receiving chemotherapy when other anti-emetic medications are not effective
Dronabinol AE
Marijuana-like highs
CNS activity = palpitations, tachycardia, vasodilation, hypotension and bloodshot eyes
Paranoid reactions and thinking
Abrupt withdrawal => abstinence syndrome (irritability, insomnia, restlessness)
Bulk-forming laxatives (3)
MOA
Methylcellulose
Psyllium
Bran
Non-digestable colloids –> absorb water to form bulky, soft jelly that distends the colon to promote peristalsis
Contraindications of bulk-forming laxatives
Immobile patients
Patients on long-term opioid therapy
Can result in intestinal obstruction
Cathartics (stimulant laxatives)
drugs, MOA and contraindications
Directly stimulate enteric nervous system to increase intestinal motility
Caster oil = broken down into ricinoleic acid in SI. Contraindicated in pregnancy as it causes uterine contractions.
Bisacodyl = acts at level of colon. Minimal systemic absorption –> can be used in acute and long-term.
Senna = chronic use can cause melanosis coli –> harmless brown pigmentation of colonic mucosa (unrelated to colon cancer risk)
Stool softeners (2)
Docusate
Glycerin
Surfactants –> allow water to penetrate and soften formed stool in the bowel
Lubricant laxative
Mineral oil = coats decal material and prevents water reabsorption
Cannot be given at the same times as stool softeners
Osmotic laxatives (3)
MOA: non-absorbable sugars or salts –> exert osmotic pull to retain water in intestinal lumen
Lactulose - metabolised by colonic bacteria and can cause severe flatus with cramping
Magnesium salts - should not be used for long time in patients with renal insufficiency as thy can cause hypermagnesemia
Polyethylene glycol
- water soluble
- low toxicity and systemic absorption
- creates very high osmotic pressures in gut lumen
- used for total bowel prep before GI endoscopy
- less AE, better for long term use
Lubiprostone
Stimulates type 2 Cl- channels in SI –> increases Cl- secretion –> increased intestinal motility
Uses:
- chronic constipation
- IBS with predominant constipation
AE: diarrhea
Contraindicated in children
Alvimopan
Methynaltrexone
Selective Mu-Opioid receptor antagonists
Use of opioid analgesics causes constipation due to stimulation of Mu receptors in bowel
Do not cross BBB –> do not negate analgesic effect of opioids
Loperamide
Diphenoxylate
Low potential for addiction
