Drugs for Peptic Ulcers & Gastric Acidity

Ach --> gastric acid secretion through PLC-IP3 --> Ca from ER --> Ca binds site and activat H/K ATPase --> secretion of H into gastric lumen in exchange for K.

Ca in H secretion: important in mild alkali syndrome (rare) and acid rebound that occurs w/ Ca carbonate.

Histamine --> gastric acid secretion through cAMP --> binds to regulator sites --> activated proton pump.

PGE1/2, PGI2 protect gastric lining --> inhibit acid secretion.

H2 Antagonists

Potency varies, all achieve same therapeutic endpoint.

Dec secretion of pepsinogen --> Digested proteins could be impaired.

Tolerance to H2 antagonists develop w/in 3 days.

Change in gastric acidity --> alter absorption of other rxs.

SE: Headache, Diarrhea, Constipation, drowsiness

ALL cross placenta --> Pregnancy category B/C --> Weight benefits vs. risk

All secreted in breast milk --> but are safe when breast feed.

Uses: Duodenal & gastric ulcers, GERD, Upper GI Bleed (cimetidine), prevent upper GI bleed (expect nizatidine), Heartburn (cimetidine &famotidine), ZES (except nizatidine), Erosive esophagitis (ranitidine), Prevent gastric damage by NSAIDs

Cimetidine, Ranitidine, Famotidine, Nizatidine

Group: H2 Antagonists, IV & IM use. 

Treat Zollinger-Ellison syndrome --> tumor of pancreatic islet cells release massive gastrin --> stimulate secretion of gastric acid.

MOA: Bind to heme iron --> inhibit CYP1A2, 2C9, 2D6 --> dec Rx metabolism --> inc risk of rx interactions

Inhibit hydroxylation of E2 --> E3. High doses --> accumulate E2 --> female effects in men (gynecomastia) --> galactorrhea in female.

Inhibit bind of DHT (needed by testes) --> impotence and dec libido --> NOT seen in H2 antagonists.

CNS --> confuse, agitation, psychosis, anxiety

High doses --> easily done with IV use!

Group: H2 Antagonists

Oral, IV, IM

SE: rare

Group: H2 Antagonists

Oral, IV

Pepcid acid controller = OTC.

Worst Side Effect --> Headache

Group: H2 Antagonists

Oral

SE: Worst --> hepatocellular injury. Most common --> sedation.

Weak bases --> all enteric coated or delayed release dosage forms --> more effective than H2 antagonists.

MOA: protonated form is active --> covalently bind to SH group on proton pump --> irr inactivating enzyme. Takes 2 weeks to restore normal acid secretion as discontinue.

Advantage of PPI over H2 Antagonists:

No effect on pepsinogen, No serious SE w/ high doses, No significant inhibition of CP450 --> dec Rx interactions.

Cautions: Chronic daily use (3mo - 1yr) --> hypomagnesemia

Inc C. difficile infections --> higher PPI > H2 blocker

Dec gastric acid --> inc risk of upper resp tract infection

Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole,Rabeproazole

Group: PPI

racemic mixture.

High doses --> antimicrobial activity vs. H.pylori by inhibiting urease (hydrolyzes urea inco CO2 and NH3).

NH3 helps neutralize acidic microenvironment surrounding H. pylori --> weaken H. Pylori --> more susceptible to antibiotics.

DDI: Inhibits CYP2CP --> inc levels of mang drugs (anticonvulsant, antiarrhythmic phenytoin). Prevents activation of anticoagulant clopidogrel.

Induces CYP1A2 --> dec other drugs.

Group: PPI

S isomer. Longer T1/2 > Omeprazole

Lansoprazole

Dexlansoprazole

Pantoprazole

Oral/IV

R enantiomer of Lansoprazole

Oral/IV

Rabeprazole

Group: PPI

Use: Antimicrobial activity H. Pylori.

High H. pylori eradication rate than other PPI --> to non-enzymatic drug elimination mechanisms.

Inhibit muscarinic receptors on smooth muscl and secretory glands

Teritary Amines --> irritable bowel syndrome & spastic colon (Dicyclomine)

4 Amine --> for peptic ulcers (Propantheline)

Sucralfate

Misoprostol

Miscell

Sulfated polysaccharide complex w/ polyaluminum hydroxide.

Not absorbed systemically --> acts locally w/in gastric lumen

MOA: At pH < 4, sucralfate polymerize --> sticky viscous gel.

Aluminum release & (-) chaged SO4 binds to (+) charged denatured proteins on epithelial cells in crater wall of ulcers.

Viscous gel --> resists removal by food --> provides physical barrier against gastric acid & pepsin-mediated protein hydrolysis --> major factor in erosion of mucosa, and inward diffusion of H.

Does not neutralize acid.

Worst SE: constipation (common to aluminum containing compounds - antacids).

Uses: Gastric/Duodenal ulcers, GERD, NSAID induced ulcers, stress ulcers, GI bleed

Caution: Impaired renal function --> Alumi toxic --> by aluminum osteodystrophy, osteomalacia & encephalopathy.

DDI: Sticky viscous gel traps other Rxs --> dec absorption

Antacid inc  pH --> prevent polymerization of sucralfate

PGE1 analog, orally active &resist metabolism.

MOA: PGE1 inhibit acid secretion & stimulates secretion of protective mucous lining and HCO3.

Use: Cytoprotectant to dec incidence of gastric ulcers in patients on NSAIDs.

Worst SE: Diarrhea & abdominal cramps

Also contract uterus --> Abortifacient --> pregnancy category X

Rx Interactions: Changing gastric & urinary pH

Alter motility (Mg, Al) through effects on GI smooth muscle

Al salts --> Absorb drugs forming complexes w/ tetracycline and fluoroquinolones

Effective (4-8wk) as H2 antagonists in healing duodenal ulcers & are cheap --> not as effective for gastric ulcers.

Problems w/ Antacids: Frequent dose, bad taste, drug interactions --> noncompliance.

Group: Antacids

Worse SE: Constipation --> avoid in old people --> straining valsalva maneuver --> increase intrathoracix pressure --> dec venous return to heart and impede AV nodal.

Also dec PO4 absorptiong w/ chronic renal failure.

Group: Antacids

Worst SE: Diarrhea --> common to Mg.

Some use together with Al --> offset each other effect on intestinal motility.

Group: Antacids
Caution: Hypertensive

Un-neutralized HCO3- can cause metabolic alkalosis.

Group: Antacids

Forms CaCl2 --> liberates Ca.

Inc Ca --> acid rebond by activating Ca dependent proton pump.

Also --> Milk Alkali syndrome (rare) --> hypercalcemia, alkalosis and renal failure.

CaCO3 + milk --> hypercalcemia --> inc reabsorption & dec excretion of HCO --> Alkalosis

Alkalosis --> reab more Ca and cycle repeats --> preciptation of Ca salts in kidney --> renal fail & death unless dialyzed.

Transient hypercalcemia if patient is uremic --> precipitation of Ca urate salt in joints, soft tissue & kidneys --> possible constipation.

Caution: compromised renal fxn --> divalent cations difficult to handle.

Carbonates release Co2 --> Abdominal distention, belching, acid reflux. Simethicone added to dec foaming --> dec surface tension b/w bubbles allow them to coalesce --> gas to pass more easily.

Gram (-) bacillus

Survive in Acidic environment --> Urase (+), Penetrates mucous lining of stomach

Multiple agents are used --> some use omeprazole/rabeprzole + amoxicillin+clarithromycin

As gastric pH inc >4 --> degradation of clarithromycin is dec --> inc activity w/in lumen.

Pylera contains: Bismuth subcitrate K + metronidazole + tetracycline

Bismuth is antibac against H. pylori, inc production of PG

Metronidazole: antibac against H. pylori.

For H. Pylori

Swallow 14C urea

H. pylori breaks into NH3 and 14C-CO2.

14C-CO2 absorbed then expelled and quantited in breath.

Omeprazole & rabeprazole suppress H. pylori --> discontinued several days before test.

Laxative, cathartic, purgative and evacuant --> promote defecation

Cathartic and purgative --> rapid evacuation

Laxative --> less pronounced effect

All drugs --> all evacuants

Constipation is a symptoms --> not a disease --> neuronal, endocrine, stress or diet.

Safest and most physiologic

Fiber --> undigested plant material, cell walls, whole grains, bran, veggies, fruits

MOA: Dietary fiber & bulk forming gels absorb H2O and ions --> Softening stool and inc bulk --> causes intestinal distention --> stimulate peristalsis --> rmr you stretch a muscle and it stimulates contraction.

Onset: 12-24 hour. Maximal effect after 2-3 days --> better for prevention than acute constipation.

Take w/ 8 oz H2O and in divided doses to avoid impaction --> cuase obstruction, choking or asphyxiation.

Don't use if --> Obstructive bowel disease, strictures or Crohn's disease --> perforation.

Caution: All these decrease Rx absorption --> adsorption (clumping) or reduce transit time due to inc peristalsis.

Psyllium, Methylcellulose, Polycarbophil

Group: Dietary Fiber & Bulk Forming Laxatives

Seed husk from her plantago --> dec LDL cholesterol by bind bile acids --> elimination.

To make synthesize new bild acids --> liver must obtain fresh supply of cholesterol --> which get from plasma LDL --> plasma LDL can be reduced.

Group: Dietary Fiber & Bulk Forming Laxatives

Semisynthetic Cellulose

Group: Dietary Fiber & Bulk Forming Laxatives

Nonabsorbed polyacrylic resin --> absorb 60-100x its weight in H2O.

It's a Calcium salt -- >Avoid if taking tetracyclin antibiotic w/ which it will chelate --> inactivating the antibiotic.

Saline = Salts

MOA: Create osmotic force --> Traps fliud in intestinal luman (H2O Follows solute) --> fluid softens the stool and distends the intestine thus stimulating peristalsis.

Mg stimulates CCK release --> CCK will inc intestinal secretion and motility

All can cause dehydration --> take w/ plenty of H2O to avoid electrolyte imbalances

Magnesium Hydroxide, Magnesium Citrate, Na Phosphate/Biphosphate

Magnesium Hydrosize (Mg(OH)2)

Magnesium Citrate (Citrate of Magnesia)

Milk of Magnesia

Caution: 20% of Mg from either of these can be absorbed. Chronic use --> Hypermagnesemia --> muscle weakness, respiratory paralysis, EKG changes, sedation, confusion --> due to competition w/ Ca by Mg.

Group: Saline Laxatives

Oral onset --> 4 hours. Rectal --> 5-30min

Hyperphosphatemia can --> hypocalcemia

Lactulose

Glycerin

Polyethylene Glycol-Electrolyte Solution (Go Lytely)

Group: Osmotic Laxatives

Colonic bac --> Metabolized to galactose + fructose --> by colonic bac to lactate, acetate & formate --> contribute to osmotic effect.

These organic acids dec luminal pH --> stimulate GI secretion & motility

Onset --> 1-3 days

Other use --> treat hepatic encephalopahy --> severe liver disease --> accumulation of NH3 produced by bac metabolism of fecal urea

Symptoms --> disturbed consciousness, behavioral changes, tremors

Dec in pH cause by lactulose ionizes NH3 --> NH4 --> trapped in gut instead of reabsorbed --> NH4 then excreted.

MOA: Ion trapping.

SE: Flatulence & cramping. Diarrhea --> cause dehydration --> hypernatremia & hypokalemia b/c dehydration stimulates release of aldosterone. (Aldosterone excrete K, absorb H) - Acidosis. 

[] effect due to plasma H2O loss also contribute to hypernatremia.

Group: Osmotic Laxatives

Suppositories

Contains Na sterate --> local irrtation --> also burn and slight hemorrhaging of rectal mucosa.

Group: Osmotic Laxatives

Poorly absorbed solution --> take before colonscopy to clean out GI tract.

An isotonic solution of NaSO4, NaHCO3, NaCl & KCl in polyethylene glycol (PEG) --> it's PEG creates osmotic effect as electrolyte are isotonic to prevent net shift of ions causing electroylte imbalance.

Drink 4 L over 4 hr before test.

Miralax --> only PEG, use in smaller volumes for difficult case.

MOA: Stimulates mucosa & myenteric neurons --> peristalsis

Inhibits Na/K/ATPase --> salt/H2O accumulate in Lumen

Inc synthesis of PG & cAMP --> inc fluid/electrolyte secretion

Bisacodyl

Group: Stimulant Laxatives (irritants)

OTC laxative, prodrug --> activated to desacetyl metabolite

Onset: 6+ hrs.

Use: Evacuate bowel before tests

SE: Abdominal cramps. Chronic use --> loss normal bowel fxn, electroyte disturbances, malabsorption & weight loss.

Years of misuse --> cathartic colon (atony & dilation), loss of haustra resembling, ulcerative colits

Anionic Soaps --> Soften stool and prevent patients from straining at stool.

MOA: Dec surface tension b/w intestinal H2O & feces --> inc mixing of GI contents.

Stimulate intestinal fluid & electroylte secretion.

They're weak laxatives --> keep things running smoothly > treat acute constipation.

Potentially inc absorption of other rxs --> increase toxicity

Docusate Na, Docusate Ca

Group: Surfactants (stool osfteners)

Avoid Na salt if CHF or hypertension.

Metabolite of PGE1 --> for chronic idiopathic constipation.

Acts locally by activating Cl channel in apical membrane of intestines --> inc secretion and motilty.

Worst SE: Headache & nausea

Antidiarrheals

Opioids

Bismuth Subsalicylate

Diarrhea w/ IBD & AIDs

Miscell

Dirrhea --> fluid & electrolyte loss --> esp infants, children, elderly.

1st determine the cause --> antibiotic, IBD, lactose intolerant.

DOC for diarrhea --> major SE of opioids is constipation

Opioids Dec GI motility & secretion through u, d, k opioid receptors on myenteric & submucosal neurons & on longitudinal & circular smooth muscles.

MOA: 1. Hyperpol myenteric & submuc neurons --> dec ACh release --> dec peristalsis by longitudinal smooth mm. Ca influx in long smo --> also dec.

2. Direct effect on SM --> inc resting tone --> spasms

3. Contraction of circular sm --> inc segmentation --> impede progression of contents

4. Inhibit release of VIP (vasoactive intestinal peptide) --> dec salt & H2O secretion by mucosa.

NET EFFECT: Slows transit --> inc contact time b/w luminal fluid & epithelial cells --> inc fluid reabsorption --> inc viscosity of intestinal content

SE: Constipation, high dose --> CNS effect & anticholinergic effect of atropin

Contraindicated: Severe infectious diarrhea --> can inhibit expulsion of offending microbes. Also in IBD (Ulcerative colitis) --> cause excessive dilation of colon from retention of fecal matter. --> can cause Toxic megacolon --> inc risk of bowel perforation.

Diphenoxylate + Atropine, Difenoxin, Loperamide

Group: Opioids

Prodrug, rapidly de-esterified --> active difenoxin

Poorly penetrates CNS --> in high doses --> euphoria

To discourage abuse --> add atropine --> cause flushing, other antimus effect

Caution: Limit use in children --> inc penetration across immature BBB --> cause CNS depression.

Group: Opioids

Active metabolite of diphenoxylate

Also has atropine.

Group: Opioids

Exhibits poor oral absorption & actively extrude from CNS by P-glycoprotein transportion --> risk of abuse is dec

No Atropine added.

SE: Constipation, high dose --> CNS effect & anticholinergic effect of atropine.

Indicated: Infectious & inflammatory diarrhea

Hydrolyzed in stomach to --> Bismuth Oxychloride (Bactericidal) & Salicylate (antisecretory & anti-inflammatory)

Caution: Bismuth sulfide also formed --> turn tongue & stool black --> Do not mistake for blood in stool.

Avoid use in kids after smallpox or influenza --> association of salicylates w/ Reye's syndrome.

Diarrhea in AIDS patients contribute to malnutrition & weight loss

Sulfasalazine, Mesalamine, Olsalazine, Balsalazide, Octreotide

Group: IBD & AIS

5-aminosalicyclic acid. Linked by azo bond to sulfonamide sulfapyridine

Azo link --> prevent absorption in stomach & small int --> remains in GI tract where azo bond is cleaved by colonic bac to 5-ASA and sulfapyridine

Mesalamine --> inhibit COX lipoxygenase --> inhibition of COX does not contribute to therapeutic effect.

Many NSAIDS exacerbate IBD.

Leukotrienes --> implicated in IBD & associated diarrhea --> inhibition of LOX contribute to antidirrhea.

Mesalamine (through PPARy) --> inhibit genes NF-kb. In ulcerative colitis --> NF-kb inc, inc pro-inflammatory interleukins.

Sulfapyridine --> antibac activity. Don't know if ulcerative colitis/Crohn is bac in nature. So sulfapyridine don't contribute to effects of salfasalazine. it is absorbed sys --> sys SE --> N, fever, arthragias, rahes and agranulocytosis.

Salfasalazine --> dec folate absorption.

Grouop: IBD, AIDs

5-ASA. Don't have sulfapyridine --> no SE.

Enteric coated, release 5-ASA at pH > 7 --> terminal ileum and colon.

Another formula --> disintegrates in stomach into small beads --> beads absorb H2O which dissolves drugs --> drug to diffuse out & disperse throughout entire GI tract, not just in ielum & colon.

Group: IBD, AIDs

Prodrug of mesalamine containing two 5-ASA link by azo bond --> split by colonic bac into 2 5-ASA.

FDA: Inc risk bleed when use with salicylates or LMWH after neuraxial anesthesia.

Inc risk myelosuppression w/ used w/ cancer drug 6-mercaptopurine or thioguanine.

Group: IBD, AIDs

Prodrug w/ mesalamine bound to carrier molecule --> cleaved by colonic bac to liberate 5-ASA.

Group: IBD, AIDs

analog of somatostatin --> AIDs related diarrhea, diarrhea associated IBD & dumping syndrome (follow surgery drainage procedures)

MOA: 1. inhibit secretion of VIP

2. Inhibit contractility of longitudinal smooth muscles

FDA: depot formula treat acromegaly --> inhibit release of GH. --> can inhibit gallbladder contractility & dec bile secretion --> causing sludge (pseudolithiasis) --> see as N, anorexia, epigastric distress and colic.

Alter balance b/w insulin, glucagon & GH --> hyper/hypoglycemia

Suppresses secretion of TSH --> hypothyroidism

Depot form is intended for acromegaly --> could get it w/ other forms if repeated use.

Rifaximin

Clonidine

Calcium Channel Blockers

Group: Miscell

Non-absorbed antibiotic for Traveler's Diarrhea --> E. Coli

Not absorbed sys --> no sys SE

Group: Miscell

Antihypertensive medication whose SE include constipation --> stimulate alpha2A heteroreceptors on myenteric and submucosal cholinergic neurons.

Dec in ACh release --> intestinal sm to relax --> inhibit peristalsis --> inc time for Na and H2O reabsorption

Group: Miscell

Constipation as unwanted SE --> so take advantage to treat D.

Antiemetics

Block stimulation of chemo trigger zone in postrema or Block signals from periphery to vomit center

N/V --> involves 5-HT3, D2, H1 and muscarinic receptor mechanisms

Mod-Severe Chemo/Rad induce emesis:

5-HT3 Antagonists

Mixed D2/5 Antagonists

Mid-Mod Chemo/Rad induce Emesis :

D2 Antagonists

Antihistamine

Anticholinergic Scopolamine

Cannabinoids

Benzodiazepine

Aprepitant

Group: Antiemetics

Superior to other antiemetics.

Work best when used w/ glucocorticoid Dexamethasone.

Alosetron, Dolasetron, Granisetron, Ondansetron, Palonosetron

Group: Antiemetic (5-HT3 Antagonists). Oral

BBW: Serious GI side effects --> ischemic colitis, complications of constipation --> hospital, transfusion, surgery & death.

Use: Women w/ severe diarrhea-predominant IBS --> who haven't responded

Group: Anti-emetics (5-HT3 Antagonists). Prodrug

Activated to hydrodolasetron.

Low IV dose --> post-OR N/V --> not treat chemo induce NV b/c risk of Torsades.

High Oral dose --> chemo induced NA

SE: Prolong QT/ PR interval and QRS complex.

Granisetron

Ondansetron

Palonosetron

Group: Antiemetics (5-HT3 Antagonists)

SE: Headache. Inc risk prolong QT --> torsades

Give IV only --> NV w/ cancer chemo.

Group: Antiemetics

Metoclopramide, Trimethobenzamide

Group: Antiemetics (Mixed D2/5 HT3 Antagonists)

Chemo & radiation induced vomit & Nausea w/ pregnancy

Prokinetic: Inc ACh release --> stimulate GI motility and gastric emptying --> stimulate coordinated GI motility as opposed to uncoordinated contracts by old drugs. Act through specific receptors --> regulate GI motility

DA --> present in significant amt in GI tract and inhibit motility --> dec ACh release from myenteric motor neurons. Block DA D2 receptors, metoclopramide --> Inc ACh release followed by Inc in GI motility.

Upper GI tract --> inc low esophageal sphincter tone --> stimulate antral & small Intestine contractions.

Prokinetic Uses: Esophageal reflux, Inc passage barium contrast media, facilitate GI intubation

FDA: Linke to tardive dyskinesia (Blck DA D2 R in basal ganglia) --> this drug is mot common cause of Rx induced movement disorders

Erythromycin and macrolide antibiotic --> prokinetic activity b/c stimulate motilin R in intestinal SM --> also inc lower eso sphincter tone, ...

Group: Antiemetics (Mixed D2/5 HT3 Antagonists)

USE: Chemo & radiation induced emesis.

D2 Antagonists

Antihistamine

Anticholinergic Scopolamine

Cannabinoids

Benzodiazepine

Aprepitant

Group: Antiemetic (D2 Antagonists)

Phenothiazines: Orthostatic-hypotension (alpha block) & sedation limit use --> some develop tolerance

Chlorpromazine

Perphenazine

Prochlorperazine - high incidence of dystonia

Promethazine - high antihistaminic activity

only 1 Butyrophenone --> treat NV --> it's Droperidol --> NV due to general anesthetic or chemo --> But Torsades.

Group: Antiemetics

use: NV due to Motion Sickness

Dimenhydramine (Benadryl)

Dimenhydrinate (same amt of chlorotheophylline --> antiemetic activity)

Meclizine (Replaced dimenhydrainate w/ meclizine)

Group: Antimetics

Treat: Motion Sickness

Anticholinergic SE: Sedation, dry mouth, blurred vision

Group: Antiemetics (Mild-Mod Chemo or rad Induced emesis)

Dronabinol, Nabilone

Group: Antiemetic (Cannabinoids) - Mild-Mod Chemo Induced Emesis

Synthetic D9-THC

Not the DOC b/c --> Dysphoria, hallucinations, sedation limit its use.

Also dec seizure threshold.

Reserved for refractory cases.

Group: Antiemetics (Cannabinoids) - Mild-mod chemo

Synthetic cannabinoid agonists at CB1 receptor

Long acting --> 2x day --> for NV due to cancer chemo --> did not respond to other therapy.

Group: Anti-emetics (mild - mod chemo)

Dec anxiety, enhance antiemetic effects of other Rxs

Group: Anti-emetics (Mild mod Chemo)

Central acting antagonist of Substance P NK1 receptors --> chemo induced NV in combo w/ other Rxs.

IV form --> prodrug.

Dec plasma level for OC --> becareful if don't want to be pregnant.