Lectures 22-23: GI Drugs

Antacids

bind directly to acidic hydrogen ion and neutralize it to salt and water

Sodium bicarbonate

Acts very quickly to decrease acid

Belch due to CO2 production

If absorbed, possible metabolic alkalosis

Sodium, caution in heart failure patients

Not useful for ulcer

Calcium carbonate

CO2 may cause belching

“Milk alkali” syndrome if too much Ca is eaten

Ca++ enhances acid production, so this can actually make some people worse, especially if they have an ulcer

Often used as a calcium source

Calcium can bind to some drugs and reduce their effectiveness

Magnesium hydroxide

Poorly absorbed

Diarrhea

Mg may accumulate if renal function poor

Drug interactions- decreases absorption

Aluminum hydroxide

Aluminum alone causes constipation

Combined with magnesium, diarrhea/constipation cancel each other out

Decreased renal function a problem, may accumulate

Drug interactions due to chelation

Uses of Antacids

Relief of heartburn, gastritis

Temporary fix

Adjunct to other drugs

Systemic effects rare (watch Na)

drug interactions

Antacids drug interactions

Iron, theophylline, ketoconazole, quinolone

antibiotics, tetracycline, isoniazid

Digitalis, phenytoin, propranolol

Sulfonamides, valproic acid, l-dopa

Elimination of phenobarbital, salicylates increased

H2 Antagonists

H2 receptors on parietal cells- GPCR inc cAMP

Decrease GI acid formation through H2 receptor blockade

NOCTURNAL acid reduced best

Cimetidine

Famotidine

H2 Antagonists Side Effects

Headache, dizziness, nausea

Rash, itch

Cimetidine:

anti-testosterone effect

gynecomastia, loss of libido, impotence with chronic, high dose use

Cimetidine Inhibits metabolism of

Warfarin, phenytoin

Theophylline, propranolol

Benzodiazepines, tricyclics

Nifedipine, digoxin, quinidine

H2 Blockers Uses

NOCTURNAL acid reduced best

Ulcers

Adjunct for GERD, Short bowel syndrome, Zollinger-Ellison syndrome

Pre-anesthesia

SEVERE allergic reaction along with H1 blocker (vasodilation involves both H1 and H2)

Proton Pump Inhibitors

Administered as pro-drugs

Activated in the parietal cell to sulfenamide, which then binds covalently to pump

Irreversible block of acid formation

2-5 days of treatment will block majority of acid production

Can be given once a day

Best to take on empty stomach, eat 30 mins later

Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole

Proton Pump Inhibitors Side Effects

Nausea, diarrhea, colic, weight gain

Osteoporosis- decrease Ca absorption

Hypomagnesia- add Mg if muscle spasms occur

Decreased Vitamin B12

Increased risk of pneumonia, C. difficile

Headache, dizziness, sleepiness

Kidney damage in some long-term

Skin rash, bacterial overgrowth

Omeprazole may inhibit P-450s

PPI Uses

Heal duodenal ulcer ~ 4 wks

Gastric ulcer ~ 8 wks

Ulcers that haven’t responded to H2 antagonists

GERD: acute and maintenance

Zollinger-Ellison syndrome

Misoprostol

Cytoprotective agents

prostaglandin E1 analogue

Prevent or reduce NSAID- induced damage

Diarrhea, nausea, headache, dizziness

Rarely used since H2 blockers and PPIs available

Not in pregnancy, can induce abortion!

Bismuth subsalicylate

H. pylori and Ulcer

Metoclopramide

Prokinetic Agent

D2 antagonist: increases ACh release

Antiemetic

Used to increase GI activity after surgery, esp elderly, hospitalized patients

GI cramping, diarrhea common

High doses: Parkinson’s-like symptoms, especially in elderly patients!

Bethanechol

Prokinetic Agent

muscarinic agonist

Erythromycin

Prokinetic Agent

motilin receptors, sometimes used in diabetic gastroparesis

Irritable Bowel Syndrome

Glycopyrrolate, dicyclomine, Amitriptyline

Muscarinic antagonists, antispasmodic

Amitriptyline good for chronic pain, decreases pain transmission in spinal cord, blocks muscarinic receptors

Ondansetron, Granisetron, Dolasetron, Palonosetron

5-HT3 antagonists

Very effective for chemo, anesthesia, infection-induced nausea and vomiting

Not good for motion sickness

Headache, constipation, dizziness

Prochlorperazine, Promethazine

Block dopamine D2, muscarinic, and histamine receptors in CNS

Post-op, gastroenteritis, chemo

Will work for motion sickness but rarely used this way

Highly sedating

dronabinol

Cannabinoids

Chemo-induced nausea/vomiting

Stimulates appetite

Aprepitant

Neurokinin antagonists

block NK1 receptors, added to 5-HT3 antagonists for severe chemo-induced nausea/vomiting

Bulk-forming laxatives

Fiber

Dietary

Methylcellulose

Psyllium

High-fiber diet best

Bloating and flatulence common

Take with plenty of water

Some may alter absorption of drugs

Osmotic laxatives

Magnesium hydroxide and sulfate stimulates GI tract

Sodium phosphate and biphosphate: overuse can be a problem

Lactulose

cirrhosis and liver disease to decrease blood ammonia levels

conversion to lactic acid decreases pH in gut lumen

causes flatulence and diarrhea

Polyethylene glycol

Insoluble, holds water in intestine

prep for colonoscopy

nausea, bloating, abdominal pain

occasional constipation-use for up to 7 days

Mucosal Agents

stimulate peristalsis by irritating bowel wall or nerves

enhance secretion/ inhibit absorption H2O

mild: Senna

Lubricants/Softeners

Increase bulk

Soften and lubricate stool

Docusate- Emulsifies, softens

Not recommended:

Mineral oil- fat soluble vitamins, inhalation, leaking

Glycerin

Uses of Laxatives

Reduce straining

Maintain soft stools

Empty bowel for diagnostic or surgery

Decreased bowel tone

Geriatrics, pregnancy

Get rid of pathogens/toxins

Constipation

Laxatives Contraindications

Nausea and vomiting

Abdominal cramps

Undiagnosed abdominal pain

Appendicitis

Intestinal obstruction

Laxative overuse

Dependence on laxative

Fluid/electrolyte imbalance

Spastic colitis

Ulcerative colitis

Sodium-containing ones

Lubiprostone

Prostaglandin E1 analogue

Activates Cl - channels in luminal cells to increase fluid secretion

Softer stool, better motility

Fewer symptoms of constipation

No effect on electrolytes

No laxative dependence

Nausea

Headaches and diarrhea

Linaclotide

Activates guanylate cyclase C in lumen

Increase in cGMP activates cystic fibrosis transmembrane conductor (CFTR)

This increases secretion of Cl- and fluid into the lumen

Used in IBS with constipation

May cause diarrhea

Avoid in children and teens < 18 due to risk of dehydration

Nalexogol

Opioid antagonist

Act peripherally to block opioid receptors in the GI tract

no CNS penetration so allow pain control while decreasing effect on GI

constipation in patients taking opioids

long-term for non-cancer pain

Chronic use can result in GI perforation

Abdominal pain and possible symptoms of withdrawal

Loperamide

Opioid

does not enter CNS, low abuse potential

abdominal pain, constipation

Abuse (high doses) can cause serious heart issues

Diphenoxylate/atropine

opioid with atropine, reduces abuse potential, increases effectiveness

Anticholinergic side effects

Overdose will produce symptoms of atropine poisoning

Contraindications to Diphenoxylate and Loperamide

Infections: decrease expulsion of pathogens

ulcerative colitis: toxic megacolon

recovering drug addicts: some abuse potential, especially diphenoxylate, but also loperamide

Bismuth subsalicylate

Absorb water

Absorb pathogens

“Traveller’s diarrhea”

Salicylate: anti-inflammatory

Black tongue, mouth and stool

Contraindications:

patients allergic to aspirin

children (Reyes)

caution in asthmatics (may be aspirin sensitive)