Drugs Used in Gastrointestinal Disorders

Gastric A & PFirst, some background physiology….

There are 3 cells of the gastric gland:1. Chief

Secretes pepsinogen à pepsin Breaks down proteins in the diet

2. Mucoid Secretes mucus Provides a protective mucous coat to protect stomach from digestion of itself from

hydrochloric acid (HCl)3. Parietal

Secretes hydrochloric acid Keeps the pH of the stomach between 1 and 4 so as to properly digest food

The wall of the parietal cell has 3 types of receptors: acetylcholine, histamine, and gastrin. When any one of these receptors is occupied, the parietal cell will produce and

secrete HCl The receptors can also be blocked:

Atropine (an anticholinergic) blocks acetylcholine from binding with the acetylcholine receptor

Histamine-2 (H-2) blockers block histamine from the mast cell from binding with the histamine receptor

When any of these receptors are bound, the parietal cell is stimulated. The cell must now produce HCl, but needs hydrogen ions (H+ ions) to do so. These H+ ions are produced by the proton pump (H+/K+ ATPase pump) of the cell. The proton pump needs energy to function.

So: Energy à activates the H+/K+ ATPase system (proton pump) à proton pump produces H+ ions needed for the production of HCl à HCl is secreted into the stomach

Proton pump inhibitors bind to the H+/K+ ATPase pump and irreversibly inhibit this enzyme, resulting in a total inhibition of H+ ion secretion from the parietal cells.

The most common impairment is hyperacidity, or the overproduction of acid.- GERD = gastroesophageal reflux disease

The most harmful is peptic ulcer disease.Theory of how formed: aggressive (acid + pepsin) and protective (mucosal layer)

Anti-peptic agents

Antacids- Cheapest- Mainstay of antiulcer therapy until the 1970s- Neutralize acid, stimulate mucus and bicarbonate secretion, improve blood flow to area à

increase protective layer- Problems

- Mg à diarrhea, Al à constipation- Al, Mg, Ca à renal patients unable to eliminate- Use caution if the antacid is high in sodium content in patients with CHF, HTN, sodium

restrictions, and other cardiac diseases- Best acid neutralizing capacity AND lowest sodium content: Riopan Plus (Al-Mg)

and Maalox TC (Mg, Al, simethicone)- There are many drug interactions with antacids because of the effect on absorption of the

medication that is given concurrently with the antacid…check for interactions before ordering the medication.

- Best not to administer other meds within 1-2 hours after an antacid.- Especially important to separate by 2 hours: dig, iron, INH, quinolones, tetracyclines

- Antacids may result in premature dissolving of the enteric coating of meds, resulting in stomach upset.

- Increasing the pH of the stomach with an antacid will cause drugs that are acid salts (HCl salts) to be more ionized and less absorbed and drugs that are basic salts (sulfate salts) to be less ionized and more readily absorbed into the bloodstream.- The same alteration in absorption in the stomach will affect excretion of basic and acidic

drugs in the urine because the urinary pH will be elevated and acidic drugs will be more ionized, less absorbed, and more excreted.

H2 Blockers/Antagonists- Began being used in the 1970’s- Bind to and block histamine receptors located on parietal cells- This blockade renders the parietal cells less responsive to stimuli and thus acid secretion.- Up to 90% inhibition can be achieved with these agents (dose-related)- Indications

- Ulcer (gastric, duodenal)- GERD- Upper GI bleeding- Hypersecretory conditions (Zollinger-Ellison syndrome = non-insulin-secreting

pancreatic tumor; releases large amount of gastrin)- Examples (and their equipotent dosages)

- Cimetidine (Tagamet) 1600 mg.- Ranitidine (Zantac) 300 mg.- Nizatidine (Axid) 300 mg.- Famotidine (Pepcid) 40 mg.

- All are equally effective in healing ulcers; need to look at pharmacokinetics and adverse effects- Tagamet = shortest ½ life- Pepcid = longest ½ life

- Caution with renal /hepatic dysfunction- Problem with Tagamet: inhibits the hepatic enzyme (cytochrome P-450 system) metabolism

of the following drugs, thereby increasing their levels and effects:- Theophylline- Phenytoin- Oral anticoagulants- Propranolol- Procainamide- Quinidine- Lidocaine- Calcium channel blockers

- Adverse effects of H2 blockers (worse with patients with multiple illnesses, elderly, those with hepatic or renal dysfunction)- CNS effects (headache, lethargy, confusion, depression, hallucinations (<1%)- Endocrine (impotence, increased prolactin, gynecomastia)- GI (diarrhea, abdominal cramps, jaundice, increased LFTs)- GU (increased BUN, creatinine)- Hematopoietic (agranulocytosis, thrombocytopenia, neutropenia, aplastic anemia)- Integumentary (urticaria, rash, alopecia, sweating, flushing exfoliative dermatitis)

Proton Pump Inhibitors- More effective than H2 blockers- More expensive than H2 blockers- Block the final step in the acid production pathway- Blocks all acid secretion - Examples:

- omeprazole (Prilosec) 10, 20 mg (also available OTC and generic)- lansoprazole (Prevacid) 15, 30 mg- rabeprazole (AcipHex) 20 mg- pantoprazole (Protonix) 20, 40 mg- esomeprazole (Nexium) 20, 40 mg

- Adverse effects- CNS (headache, dizziness)- GI (diarrhea, abdominal pain, N, V, anorexia)- GU (proteinuria, hematuria, glycosuria)- Hematopoietic (pancytopenia, thrombocytopenia, neutropenia, leukocytosis, anemia)- Integumentary (rash, dry skin, urticaria, pruritis, alopecia)- Respiratory (URI, cough)- Other (back pain, fever, fatigue)

- Used for treatment of H. pylori - Example: 2 weeks of Prilosec 40 mg once daily plus Biaxin 500 mg 3X/day; follow with

2 week course of Prilosec 20 mg once daily- Example: PrevPac: 1 dose bid X 14 days (1 dose = 1 tab of lansoprazole [Prevacid], 2

tabs amoxiciliin, and 1 tab clarithromycin [Biaxin])

Sucralfate (Carafate)- A cytoprotective agent for stress ulcerations and PUD (peptic ulcer disease)- Binds to exposed proteins of ulcers and thus limits pepsin’s proteolytic action- Made of sucrose, Al, sulfate- Drug effects

- Sulfate anions bind to positively charged tissue proteins that are exposed at the tissue surface of an ulcer or an erosion

- As a weak base, it buffers the acidic pH of the stomach- Binds and concentrates epidermal growth factor (EGF), which accelerates the healing

process- Simulates gastric mucosal prostaglandin E2 synthesis- The aluminum salt stimulates the secretion of mucus and bicarbonate from the cells of the

stomach to counteract the actions of HCl- Side effect: constipation- Renal patients may have problems with Al- Good drug for long-term use- Separate drugs by 2 hours; ciprofloxin should not be used at all

Misoprostol (Cytotec)- A synthetic prostaglandin analog- Inhibits gastric acid secretion, enhances local production of mucus or bicarbonate- Also helps maintain mucosal blood flow- Used in drug induced PUD (from NSAIDs) or for gastric ulcer prophylaxis during NSAID

therapy [Arthrotec = diclofenac + misoprostol]

Upper GI Drug RegimensFor acute ulcer therapy, full dose, and for ulcer prophylaxis, ½ usual dose, given at hs. For example: for active duodenal ulcer, Axid 150 mg bid or 300 mg @ hs. For maintenance therapy, Axid 150 mg @ hs

For drug-induced ulcer prophylaxis, Cytotec, 100-200 mcg qid pc and hs or 200 mcg bid or tid - Maximum plasma concentrations are diminished when taken with food. Because of

GI side effects of abdominal pain and nausea, manufacturer recommends that drug be taken with food.

- Diarrhea is also a common side effect and is dose-related. It is usually self-limiting (often resolving in 8 days). The incidence of diarrhea can be minimized by taking the drug after meals and at bedtime.

NOTE: “Symptomatic response to therapy does not preclude the presence of gastric malignancy.”

Nausea and Vomiting Basics

Vomiting, or emesis, is the forcible emptying or expulsion of gastric and occasionally intestinal contents through the mouth.

Signals from 1) the gastrointestinal tract, 2) the labyrinth, and the 3) cortex go to the 4) chemoreceptor trigger zone (CTZ) which then send the message to the 5) vomiting center in the medulla.

These signals are sent via neurotransmitters:- Dopamine (GI tract and CTZ)- Histamine 1 (vestibular, vomiting center, and labyrinth pathways)- Prostaglandins (GI tract)- Serotonin (5 HT3) (GI tract, CTZ, and vomiting center)- Acetylcholine (ACh) (vestibular, vomiting center, and labyrinth pathways)

The drugs used as antiemetics effect these neurotransmitters:- ACh is blocked by anticholinergic drugs- Histamine 1 is blocked by antihistamines (H1 receptor blockers)- Dopamine is blocked by neuroleptic agents and prokinetic agents- Serotonin is blocked by serotonin blockers (5-HT3 antagonists)

The drugs used as antiemetics work on each of these areas:

Antiemetics

Area Types of Drugs Affecting AreaGastrointestinal Tract - Prokinetic drugs

- Serotonin blockersLabyrinth - Anticholinergics

- Antihistamines- Neuroleptics- Prokinetic drugs

Cortex - THC (tetrahydrocannabinoid) = the major psychoactive substance in marijuana

Chemoreceptor trigger zone - Neuroleptics- Prokinetic drugs- Serotonin blockers

Vomiting center (medulla) - Serotonin blockers

Let’s look at each of the categories of antiemetics:

Category: Anticholinergics Examples ScopolamineMechanism of Action Block ACh receptors in the vestibular

nuclei and reticular formationTherapeutic Effects Motion sickness, secretion reduction before

surgery, nausea and vomitingCommon Drug Interactions With antihistamines and antidepressants,

additive effect à increased anticholinergic effects (drying effects)

Adverse Effects Rash, erythema, difficult urination, dizziness, drowsiness, disorientation, blurred vision, dilated pupils, dry mouth

Category: Antihistamine (H1 receptor blockers)Examples Promethazine (Phenergan), meclizine

(Antivert), diphenhydramine (Dramamine)Mechanism of Action Block histamine 1 receptors, thereby

preventing ACh from binding to receptors in the vestibular nuclei

Therapeutic Effects Motion sickness, nonproductive cough, sedation, rhinitis, allergy symptoms, N & V

Common Drug Interactions With barbiturates, narcotics, hypnotics, tricyclic antidepressants, alcohol, additive effect à increased CNS depression

Adverse Effects Dizziness, drowsiness, confusion, urinary retention, blurred vision, dilated pupils, dry mouth

Category: Neuroleptic agentsExamples Chlorpromazine (Thorazine),

prochlorperazine (Compazine)Mechanism of Action Block dopamine in the CTZ and may also

block ACh (** Not for use with Parkinson’s)

Therapeutic Effects Psychotic disorders (mania, schizophrenia, anxiety), intractable hiccups, N & V

Common Drug Interactions Blocks levodopa, which may cancel the beneficial effects of levodopa in treatment of Parkinson’s disease. With quinidine, additive effect à increased adverse cardiac effects

Adverse Effects Orthostatics hypotension, ECG changes, tachycardia, blurred vision, dry eyes, dry mouth, N & V, anorexia, constipation, urinary retention, extrapyramidal symptoms, pseudoparkinsonism, akathisia, dystonia, tardive dyskinesia, headache

Category: Prokinetic AgentsExamples Metoclopramide (Reglan), cisapride

(Propulsid)**** Problem with Cytochrome P450 (with Biaxin, emycin, -azoles à ventricular arrhythmias)

Mechanism of Action Block dopamine in the CTZ or stimulate ACh receptors

Therapeutic Effects Increases gastric emptying, GERD, N & VCommon Drug Interactions With alcohol, additive effect à CNS

depressionWith anticholinergics and analgesics, block à antagonism of motility effects of metoclopramide

Adverse Effects Sedation, fatigue, restlessness, headache, dystonia, dry mouth, N & V, hypotension, SVT

Category: Serotonin blockersExamples Ondansetron (Zofran), granisetron (Kytril)Mechanism of Action Block serotonin receptors in the GI tract,

CTZ, and vomiting centerTherapeutic Effects N & V associated with cancer

chemotherapy, postop N & VCommon Drug InteractionsAdverse Effects Headache, diarrhea, increased AST and

ALT levels, rash, bronchospasm

Category: TetracannabinoidsExamples Dronabinol (Marinol)Mechanism of Action Has inhibitory effects on the reticular

formation, thalamus, and cerebral cortexTherapeutic Effects N & V associated with cancer

chemotherapyCommon Drug Interactions Additive effect with other CNS depressantsAdverse Effects Drowsiness, dizziness, anxiety, confusion,

dry mouth, visual disturbances

NOTE: Antiemetics in general should be given before any chemotherapy agent is administered, often 1 to 3 hours beforehand.

Problems of Gastrointestinal Motility: Diarrhea and Constipation

Diarrhea:- Leading cause of morbidity and mortality in third world countries- 5-8 million deaths per year in infants and children- Loss of time and productivity at work has an enormous financial impact with an

estimated cost of $23 billion per year or $108 per person per year in the U.S.- Most acute diarrhea is self-limiting, subsiding in 3 days to 2 weeks- Fluid and electrolyte replacement is vital- Causes of acute diarrhea:

o Bacterialo Drug-inducedo Viralo Nutritionalo Protozoalo Other

- Causes of chronic diarrhea:o Tumorso Diabetes mellituso Hyperthyroidismo Addison’s diseaseo Irritable bowel syndromeo Other

Constipation: Causes- Metabolic and endocrine disorders (DM, hypothyroidism, pregnancy, hypercalcemia,

hypokalemia)- Neurogenic disorders (autonomic neuropathy, intestinal pseudo-obstruction, multiple

sclerosis, spinal cord lesions, Parkinson’s disease, CVA)- Adverse drug effects (analgesics, anticholinergics, iron supplements, aluminum

antacids, calcium antacids, opiates, calcium channel blockers, Vinca alkaloids)- Lifestyle

o Poor bowel movement habits (voluntary refusal to defecate resulting in constipation)

o Diet (poor fluid intake and/or low-residue (roughage) diets or excessive consumption of dairy products)

o Physical inactivity (lack of proper exercise, especially in elderly individuals)o Psychologic (anxiety, stress, hypochondria)

Drugs affecting gastrointestinal motility

Dealing with Diarrhea

Drugs therapy for diarrhea includes:- Adsorbents- Anticholinergics- Opiates- Intestinal flora modifiers

Category: AdsorbentsExamples Bismuth subsalicylate (Pepto Bismol),

attapulgite (Kaopectate)Mechanism of Action Coat walls of GI tract, absorbing bacteria

or toxins causing diarrhea, and eliminating them with stool

Adverse Effects With bismuth subsalicylate: increased bleeding time, constipation, dark stools, confusion, twitching, hearing loss, tinnitus, metallic taste, blue gums

Drug Interactions With digoxin, clindamycin, quinidine: decreased absorptionWith oral anticoagulants: increased bleeding time, bruisingWith methotrexate: increased toxicityWith probenecid: decreased probenecid effectsWith hypoglycemia agents: decreased hypoglycemic effects

Category: AnticholinergicsExamples AtropineMechanism of Action Decreased intestinal muscle tone and

peristalsis, thereby slowing the movement of fecal matter through the GI tract. Often combined with other antidiarrheals to increase their effectiveness

Adverse Effects Urinary retention and hesitancy, impotence, headache, dizziness, confusion, anxiety, drowsiness, hypotension, HTN, Bradycardia, tachycardia, dry skin, rash, flushing, blurred vision, photophobia, increased pressure in the eye

Drug Interactions With antacids, decreased anticholinergic effectsWith amantadine, tricyclic antidepressants, MAOIs, antihistamines à increased anticholinergic effects

Category: OpiatesExamples Opium tincture, paregoric, codeine

diphenoxylate (Lomotil), loperamide (Imodium)

Mechanism of Action Cause constipation by lowering the motility of the bowel and relieving rectal spasms. By slowing the time it takes to pass food through the intestines, water and electrolytes have a greater chance of being absorbed, with reduces tool frequency and volume

Adverse Effects Drowsiness, sedation, dizziness, lethargy, N & V, anorexia, constipation, respiratory depression, bradycardia, palpitations, hypotension, urinary retention, flushing, rash, urticaria

Drug Interactions Increased CNS depressant effects with CNS depressants, alcohol, narcotics, sedative hypnotics, antipsychotics, skeletal muscle relaxants

Category: Intestinal Flora ModifiersExamples Lactobacillus acidophilusMechanism of Action Suppress the growth of diarrhea-causing

bacteria and help reestablish the normal intestinal flora that has been depleted by the diarrhea

Adverse Effects N/ADrug Interactions N/A

NOTE: alosetron HCl tablets (Lotronex) – was used for irritable bowel syndrome, diarrhea-dominant Withdrawn from US Market in 2000 due to deaths from bowel obstruction; now available

with "Restricted Access" for diarrhea-predominant IBS.

Dealing with Constipation: Laxatives and Stool Softeners

Drugs for constipation include 5 types:- Bulk-forming- Emollient- Hyperosmotic- Saline- Stimulant/Irritant

Category: Bulk-formingExamples Psyllium, methylcellulose (Metamucil)Mechanism of Action Absorbs water to increase bulk, distending

bowel to initiate reflex bowel activity (onset of action 12 hours to 3 days)

Therapeutic Effects Acute constipation, IBS, diverticulosisAdverse Effects Impaction above strictures, fluid overloadDrug Interactions Increased absorption of antibiotics,

digoxin, nitrofurantoin, salicylates, tetracyclines, oral anticoagulants

Note: Bulk-forming agents: Drug of ChoiceNote: Psyllium contains sugar: give cautiously in DM

Category: Emollient/SurfactantsExamples Docusate salts (Surfak, Colace), mineral oilMechanism of Action Wetting agent used to soften fecal mass

(onset of action 1-3 days)Therapeutic Effects Acute constipation, softens fecal impacts,

facilitates bowel movements in anorectal conditions

Adverse Effects Skin rashes, decreased absorption of vitamins, lipid pneumonia

Drug Interactions With mineral oil, increased effect of oral anticoagulants, decreased absorption of fat-soluble vitamins (A, D, E, K)

Note: Lipid pneumonia – especially in elderly (inhale the mineral oil)Leakage of oil can cause pruritis ani; disturbs normal defecation reflex

Category: HyperosmoticExamples Lactulose, sorbitol, glycerineMechanism of Action Osmotic molecules (like excess sugar)

pulls water into GI tract (onset of action 24-48 hours)

Therapeutic Effects Chronic constipation, diagnostic and surgical preparations

Adverse Effects Caution with diabetics, galactose or lactose intoleranceAbdominal bloating, rectal irritation

Drug Interactions With oral antibiotics, decreased effects of lactulose

Category: SalineExamples Magnesium sulfate, magnesium phosphate,

magnesium citrate, MOMMechanism of Action Increases water content of feces, resulting

in distention, peristalsis, and evacuation (onset of action 1-3 hours)

Therapeutic Effects Constipation, removal of anthelmintics and parasites, diagnostic and surgical preparations

Adverse Effects Magnesium toxicity (with renal insufficiency)

Drug Interactions With barbiturates, general anesthetics, narcotics, and antipsychotics à increased CNS depressionWith neuromuscular blockers, increased effects

Caution: MOM contains high concentration of sodium à Watch renal disease!

Category: Simulant/IrritantExamples Castor oil, bisacodyl (Dulcolax)Mechanism of Action Direct action on intestinal mucosa (onset of

action 6-10 hours)Therapeutic Effects Acute constipation, diagnostic and surgical

bowel preparationsAdverse Effects Nutrient malabsorption, skin rashes, gastric

irritation, rectal stimulationDrug Interactions With antacids and H2 blockers à gastric

irritationWith antibiotics, digoxin, nitrofurantoin, salicylates, tetracyclines, oral anticoagulants à decreased absorption

Stimulant/Irritant Laxatives: Most commonly abused by teens and elderly

NOTE: Long-term use may lead to laxative dependence.

Zelnorm (tegaserod maleate):

New medication (2004) for constipation-dominant IBS A serotonin 5-HT4 receptor partial agonist For short-term treatment of women who have IBS with constipation as their main bowel

problem FDA warning in May 2004: Zelnorm associated with serious consequences of diarrhea

and ischemic colitis; withdrawn from US Market in March 2007    

Amitiza (lubiprostone) For chronic idiopathic constipation (24 mcg bid) and constipation-predominant IBS (8

mcg bid) Activates chloride channels, increasing intestinal fluid secretion and motility Cost:  8 mcg (60 ea) $220; 24 mcg (30 ea) $114

Drugs for chronic inflammatory bowel: Ulcerative colitis

o Sulfasalazene 2 Gm (Azulfidine)

o Steroids useless

Crohn’s o Azothioprine (Imuran)=immunosuppressant [inhibits T-lymphocytes], Cromolyn