15. pharmacotherapy gi disorders

Clinical Use of Drugs :Pharmacotherapy GI Disorders

Upper GI Disorders

GI Anatomic region

Gastric Acid Secretion⇨ Neuronal

– sight, smell, taste → cholinergic pathway⇨ Physical

– strecth → ↑acetylcholine & ↑gastrin⇨ Hormonal

● Stimulate parietal cells to secrete gas-tric acid

⇨ Gastrin⇨ Acetylcholine⇨ Histamine

Proton pump (H+/K+- ATPase)

Acid Secretion

Physiological & Pharmacological Gastric Acid Secretion

Pharmacotherapy of Acid – Related Disorders

Acid-suppressing drugsProton-pump Inhibitors (PPIs)Proton-pump Inhibitors (PPIs)⇨ Five PPIs available in clinical use : Omeprazole,

Esomeprazole, Lansoprazole, Rabeprazole, & Pantoprazole

– Similar in their pharmacological properties⇨ All PPIs have equivalent efficacy at comparable

doses⇨ PPIs diminish daily production of acid by 80 –

95% → most potent gastric suppressorsmost potent gastric suppressors

⇨ PPIs → prodrugsprodrugs, require activation in acid envi-ronment → tetracyclic sulfenamide → unable to diffuse back to canalicular membrane

⇨ Activated form of PPIs covalently bound to H+/K+-ATPase → Acid secretion resume after newly formed H+/K+-ATPase molecules → Pro-long acid suppression (24 – 48 hours)

⇨ PPIs block final steps of acid secretionPPIs block final steps of acid secretion ⇨ Effective in acid suppression regardless of other stimulat-

ing factors⇨ Dosage form : Enteric – coated drugs, enteric – coated gran-

ules, enteric – coated tablets, powdered in combination with bicarbonate → to prevent degradation by acid in the stomach

Pharmacokinetics :⇨ Rapidly absorbed, highly protein – bound, ex-

tensively metabolized by hepatic CYPs● CYP2C19 & CYP3A4

– CYP2C19 genotype● Asian vs Caucasian or African American (23% vs (23% vs

3%)3%)⇨ Chronic renal failure does not lead to accumula-

tion of PPIs with once-a-day dosing⇨ Hepatic impairment substantially reduce

clearence of esomeprazole and lansoprazole

⇨ Most common : nausea, abdominal pain, flatu-lence, & diarrhea

● Subacute myopathy, arthralgia, headache, & rash

⇨ Inhibition of CYP2C19, slower the clearence of phenytoin, disulfiram, & other drugs metabolized the same enzymes)

⇨ Increase expression of CYP1A2 (increase clearence of imipramine, antipsychotic drugs, tacrin, & theophylline)

⇨ Loss of gastric acidity → affect bioavailability of ketoconazole, ampicillin esters, & iron salts

⇨ Chronic use ≈ hip fracture, possibly decreasing Ca2+ absorption

Adverse Effects & Drug Interactions

Therapeutic Use⇨ Promote healing of gastric & duodenal ul-

cers⇨ Gastroesophageal reflux disease (GERD)⇨ Hypersecretory conditions : Zolinger-Elli-

son syndrome⇨ Prevention of recurrence of NSAID – asso-

ciated gastric ulcers

H2 Receptor Antagonists

⇨ H2RAs → competitive inhibitors of H2 recep-tor on basolateral membrane of parietal cells

⇨ Available drugs : Cimetidine, Ranitidine, Famotidine, Nizatidine

● Differ in pharmacokinetics & propensity to cause drug interations

⇨ H2RAs predominantly inhibit basal acid secre-tion → suppressing nocturnal acid secretion

⇨

Pharmacokinetics

⇨ Rapidly absorbed, peak serum concentration achieved within 1 – 3 hours

⇨ Small percentage of H2RAs are protein-bound⇨ Liver disease per se is not indication for dose

adjustment⇨ Excreted by kidneys through filtration & tubular

secretion → reduce dose on patients with re-duced creatinine clearence

Adverse Effects & Interactions⇨ H2RAs generally well-tolerated

⇨ Low incidence of AEs : diarrhea, headache, fatigue, muscular pain, & constipation

⇨ Neurologic : headache, dizziness, drowsiness, lethargy, hallu-cination, psychosis)

⇨ Long-term use :– Cimetidine at high doses → inhibit testosterone binding to

androgen receptors & inhibition of CYP reduce hydroxyla-tion of estradiol

– Galactorrhea in women, and gynecomastia, reduced Galactorrhea in women, and gynecomastia, reduced sperm counts & impotence in mensperm counts & impotence in men

⇨ Blood dyscrasia including thrombocytopenia have been reported

⇨ H2RAs cross the placenta & excreted in breast milk

Therapeutic Uses⇨ Promote healing of gastric & duodenal ulcers⇨ Treat uncomplicated GERD⇨ Prevent occurrence of stress ulcers

Agents that Enhance Mucosal Defences

Prostaglandin Analog : Misoprostol⇨ Synthetic analog of PGE1⇨ Gastric acid secretion inhibition – Dose related

⇨ 100 – 200 ug significantly inhibit basal secretion ( up to 95%) or food – stimulated secretion ( 85% inhibition)

⇨ Cytoprotective role of prostaglandin toward gastric acidity⇨ Stimulate Gi pathway → decreasing cAMP & gastric acid se-

cretion⇨ Stimulate mucin & bicarbonate secretion⇨ Increase blood flow

⇨ Recommended dose for ulcer prophylaxis : 200 ug four times a day

● Frequent dosing limited its use → inconvenience⇨

⇨ Misoprostol can cause exacerbation of inflamma-tory bowel disease

⇨ Contraindicated in pregnancy → increase uterine contractility

Therapeutic Use⇨ To prevent NSAID-induced mucosal injury

Sucralfate⇨ Sulfated polysaccaride → Octasulfate of sucrose

⇨ Inhibit pepsin-mediated hydrolisis of mucosal proteins con-tributes to mucosal erosion & ulceration

⇨In acid environment (pH<4), sucralfate → cross-linking → viscous & sticky polymer that adhere to epithelial cells & ul-cer crater up to 6 hours after single dose

⇨Stimulating secretion of PGs & growth factors

Therapeutic Use⇨ In critically patients, sucralfate may offer advantage

over PPIs & H2RAs in preventing stress ulcers⇨ Condition associated with mucosal inflammation / ul-

ceration which is not responsive to acid suppression such as oral mucositis (radiation & aphtous ulcer), bile reflux gastropathy

Bismuth Salts⇨ Binding to and protecting mucosal lesion⇨ Enhancing cellular protective mechanims⇨ Antimicrobial effects, primarily againts H.py-

lori⇨ Frequently use in combination with other an-

tibiotics to eradicate H.pylori

Prokinetic agentsProkinetic agentsMetoclopramide & Betanechol⇨ Stimulate motility of upper GI & increase LES

(lower esophageal sphincter)⇨ Patients with delayed gastric emptying or refractory to

other available treatment options

General Guidelines of medical management of Gastroesophageal Reflux Disease (GERD)

Meta-analysis of H2-receptor antagonists Meta-analysis of H2-receptor antagonists on Functional (Non-Ulcer) Dyspepsiaon Functional (Non-Ulcer) Dyspepsia

Comparison of Prokinetic, Acid Suppression, and Comparison of Prokinetic, Acid Suppression, and Antianxiety Therapies in Functional DyspepsiaAntianxiety Therapies in Functional Dyspepsia

Both Mosapride and Famotidine significantly improved the symptoms of Functional Dyspepsia within 2 weeks and the improvement was maintained for 8 weeks after the beginning of the study (p < 0.001)

Meta-analysis : Helicobacter pylori eradication improve symptoms in non-ulcer dyspepsia ?

PPIs vs AH2 : Effect on persistent or rebleeding of peptic ulcer

In patients with peptic ulcer and H. pylori infection, prolonging In patients with peptic ulcer and H. pylori infection, prolonging therapy with proton pump inhibitor after a triple therapy for 7 therapy with proton pump inhibitor after a triple therapy for 7 days with a proton pump inhibitor and two antibiotics is not days with a proton pump inhibitor and two antibiotics is not necessary to induce ulcer healingnecessary to induce ulcer healing

Step-Up vs Step-Down Therapy in New-Onset Dyspepsia

⇨ Double-blind, randomized controlled trial● Step-up therapy : started with antacids, switched to

H2-receptor antagonists, and then ended with proton pump inhibitors (PPIs)

● Step-Down therapy : reversed order

– Step-Up therapy somewhat more Step-Up therapy somewhat more cost effectivecost effective than a than a step-down approach, but effectiveness of treatment step-down approach, but effectiveness of treatment and adverse events are similar.and adverse events are similar.

Nausea & VomitingPatophysiology of Emesis⇨ Nausea, the imminent need to vomit

● Associated with gastric stasis⇨ Retching,

⇨ Labored movement of thoracic & abdominal muscles before vomiting

⇨ Vomit● Forceful of GI contents caused by GI retroperistalsis

⇨ Act of vomiting require coordinated contraction of abdominal muscles, pylorus, antrum, raised gastric cardia, diminished lower esophageal sphincter, & esophageal dilatation

⇨ Chemoreceptor trigger zone (CTZ)⇨ Neurotransmitter receptor : cholinergic, histaminic, serotoner-

gic, dopaminergic, opiate, neurokinin, & benzodiazepin recep-tors

Specific etiologies of Nausea & Vomiting

Emetogenicity of Chemoterapeutic Agents

Presentation of Nausea & Vomiting

TreatmentNon pharmacologic⇨ Dietary restriction if appropiate⇨ Stable physical position⇨ Psychological & behavioral intervention

● Relaxation● Bio-feedback● Self-hypnosis● Cognitive distraction● Guided imagery● Systematic desentization

⇨ Etc

Pharmacological intervention

Pharmacological Intervention

Factors that enable clinician to discriminate the choices of antiemetic must be recognized, :⇨ The suspected etiology of symptoms⇨ Frequency, duration, & severity of the episodes⇨ The ability of patients to use oral, rectal, in-

jectable or transdermal medication⇨ The success of previous antiemetic medication

Mechanism of Action and Indications

⇨ Anticholinergic agents (ACh blockers)⇨ Bind to and block acetylcholine (ACh) receptors in the inner ear

labyrinth⇨ Block transmission of nauseating stimuli to CTZ ⇨ Also block transmission of nauseating stimuli from the reticular for-

mation to the VC⇨ Scopolamine ⇨ Also used for motion sickness

Mechanism of Action⇨ Antihistamine agents (H1 receptor blockers)

⇨ Inhibit ACh by binding to H1 receptors

⇨ Prevent cholinergic stimulation in vestibular and retic-ular areas, thus preventing N&V

⇨ Diphenhydramine (Benadryl), meclizine (Antivert), promethazine (Phenergan)

⇨ Also used for nonproductive cough, allergy symptoms, sedation

Mechanism of Action (cont'd)

⇨ Neuroleptic agents⇨ Block dopamine receptors on the CTZ⇨ chlorpromazine (Thorazine), prochlorperazine (Com-

pazine)⇨ Also used for psychotic disorders, intractable hiccups

Mechanism of Action (cont'd)⇨ Prokinetic agents

⇨ Block dopamine in the CTZ⇨ Cause CTZ to be desensitized to impulses it receives

from the GI tract⇨ Also stimulate peristalsis in GI tract, enhancing empty-

ing of stomach contents⇨ Metoclopramide (Reglan)⇨ Also used for GERD, delayed gastric emptying


⇨ Serotonin blockers⇨ Block serotonin receptors in the GI tract, CTZ, and VC⇨ Dolasetron (Anzemet), granisetron (Kytril), on-

dansetron (Zofran)⇨ Used for N&V for patients receiving chemotherapy

and postoperative nausea and vomiting


⇨ Tetrahydrocannabinoids (THC)⇨ Major psychoactive substance in marijuana⇨ Inhibitory effects on reticular formation, thalamus,

cerebral cortex⇨ Alter mood and body’s perception of its surroundings


⇨ Tetrahydrocannabinoids (cont'd)⇨ dronabinol (Marinol)⇨ Used for N &V associated with chemotherapy, and

anorexia associated with weight loss in AIDS patients

Side Effects

⇨ Vary according to agent used⇨ Stem from their nonselective blockade of various

receptors

Management Implications

⇨ Assess complete nausea and vomiting history, in-cluding precipitating factors

⇨ Assess current medications⇨ Assess for contraindications and potential drug

interactions

Laxative, Cathartics, & Therapy of Constipation

⇨ Fluid content is principal determinant of stool con-tent (70 – 85% contain water)

⇨ 8 – 9 L of fluid enter small intestine ⇒ 1 – 1.5 L crossing ileocaecal valve, colon extracts most of remaining fluid ⇒ ∽ 100 ml of fecal water daily

⇨ Secretory changes, bowel movement, transit time, extent of absorption determine the consistency of stool⇨ Neurohormonal mechanisms, pathogens, drugs might alter

processes above⇨ Up to 60% of patients with constipation have normal

colonic transit⇨ Predominant factors underlying constipation often not ob-

vious ⇒ therapy remain empiric & non specific

⇨ Laxation : evacuation of formed fecal material from rectum)

⇨ Catharsis : evacuation of unformed, usually wa-tery fecal material from the entire colon

– The terms frequently used interchangebly⇨ Mode of Action of Laxative :

– Enhancing retention of intraluminal fluid by hy-drophilic or osmotic mechanims

– Decreasing the net absorption of fluid by effects on small- and large-bowel fluid & electrolyte transport

– Altering motility by either inhibiting segmenting (nonpropulsive) contractions or stimulating propul-sive contractions

Diarrhea

⇨ Abnormal frequent passage of loose stool or⇨ Abnormal passage of stools with increased frefre--

quency, fluidityquency, fluidity, and weightweight, or with increased increased stool water excretionstool water excretion

Antidiarrheal agents⇨ Oral rehydration solution is the CORNERSTONE CORNERSTONE

OF THERAPYOF THERAPY for patient with acute illness re-sulting significant diarrhea

⇨ Pharmacotherapy should be reservedshould be reserved for patients with persistence symptoms

⇨

Diarrhea (cont'd)

Acute diarrhea⇨ Sudden onset in a previously healthy person⇨ Lasts from 3 days to 2 weeks⇨ Self-limiting⇨ Resolves without sequelae

Diarrhea (cont'd)

Chronic diarrhea⇨ Lasts for more than 3 weeks⇨ Associated with recurring passage of diarrheal

stools, fever, loss of appetite, nausea, vomiting, weight loss, and chronic weakness

Causes of Diarrhea

Acute Diarrhea

Bacterial

Viral

Drug induced

Nutritional

Protozoal

Chronic Diarrhea

Tumors

Diabetes

Addison’s disease

Hyperthyroidism

Irritable bowel syndrome

Etc.

Antidiarrheals: Mechanism of Action

Adsorbents⇨ Coat the walls of the GI tract⇨ Bind to the causative bacteria or toxin, which is

then eliminated through the stool⇨ Examples: bismuth subsalicylate (Pepto-Bismol),

kaolin-pectin, activated charcoal, attapulgite (Kaopectate)

Antidiarrheals: Mechanism of Action (cont'd)

Anticholinergics⇨ Decrease intestinal muscle tone and peristalsis of

GI tract⇨ Result: slowing the movement of fecal matter

through the GI tract⇨ Examples: belladonna alkaloids (Donnatal), at-

ropine


Intestinal flora modifiers⇨ Bacterial cultures of Lactobacillus organisms work by:

⇨ Supplying missing bacteria to the GI tract⇨ Suppressing the growth of diarrhea-causing bacteria

⇨ Example: L. acidophilus (Lactinex)


Opiates⇨ Decrease bowel motility and relieve rectal

spasms⇨ Decrease transit time through the bowel, allow-

ing more time for water and electrolytes to be ab-sorbed

⇨ Examples: paregoric, opium tincture, codeine, loperamide (Imodium), diphenoxylate (Lomotil)

Antidiarrheal Agents: Side Effects

Adsorbents⇨ Increased bleeding time⇨ Constipation, dark stools⇨ Confusion, twitching⇨ Hearing loss, tinnitus, metallic taste, blue gums

Antidiarrheal Agents: Side Effects (cont'd)

Anticholinergics⇨ Urinary retention, hesitancy, impotence⇨ Headache, dizziness, confusion, anxiety, drowsiness⇨ Dry skin, rash, flushing⇨ Blurred vision, photophobia, increased intraocular pressure⇨ Hypotension, hypertension, bradycardia, tachycardia

Antidiarrheal Agents: Side Effects (cont'd)

Opiates⇨ Drowsiness, sedation, dizziness, lethargy⇨ Nausea, vomiting, anorexia, constipation⇨ Respiratory depression⇨ Bradycardia, palpitations, hypotension⇨ Urinary retention⇨ Flushing, rash, urticaria

Antidiarrheal Agents: Interac-tions

⇨ Adsorbents decrease the absorption of many agents, including digoxin, clindamycin, quini-dine, and hypoglycemic agents

⇨ Adsorbents cause increased bleeding time when given with anticoagulants

⇨ Antacids can decrease effects of anticholinergic antidiarrheal agents

Antidiarrheal Agents: Implications

⇨ Obtain thorough history of bowel patterns, gen-eral state of health, and recent history of illness or dietary changes, and assess for allergies

⇨ DO NOT give bismuth subsalicylate to children younger than age 16 or teenagers with chicken-pox because of the risk of Reye’s syndrome

Antidiarrheal Agents:Implications

⇨ Use adsorbents carefully in geriatric patients or those with decreased bleeding time, clotting disorders, recent bowel surgery, confusion

⇨ Anticholinergics should not be administered to patients with a history of glaucoma, BPH, urinary retention, recent bladder surgery, cardiac problems, myasthenia gravis

Antidiarrheal Agents: Implications

⇨ Teach patients to take medications exactly as prescribed and to be aware of their fluid intake and dietary changes

⇨ Assess fluid volume status, I&O, and mucous membranes before, during, and after initiation of treatment

⇨ Teach patients to notify their physician immedi-ately if symptoms persist

⇨ Monitor for therapeutic effect

Selected Antidiarrheal AgentsSelected Antidiarrheal Agents

15. pharmacotherapy gi disorders

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