Gi Drugs Lin 2-6-2012

Front 1

Ach regulation path for gastric acid secretion

Back 1

M3 receptor - PLC - Ca2+ influx - PKC

Front 2

Gastrin Regulation of gastric acid secretion

Back 2

G cells  gastrin receptor  PLC  Ca2+  PKC

Front 3

Histamin Regulation of gastric acid secretion

Back 3

ECL cells  H2 receptor  adenylate cyclase  cAMP  PKA

Front 4

Histamin comes from what cell?

Back 4

ECL - activated at night - not post prandial

Front 5

Na bicarbonate, Ca carbonate,
Mg hydroxide, Al hydroxide

Back 5

antacids

Front 6

Cimetidine, ranitidine, famotidine, nizatidine

Back 6

H2 antagonists

Front 7

Omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole

Back 7

proton pump inhibitors

Front 8

Sucralfate Misoprostol (Prostaglandin Analogs) Bismuth subsalicylate

Back 8

Mucosal Protective Agents

Front 9

Antacids MOA, Clinical Uses

Back 9

dec intragastric acidity by reacting with gastric HCl to form a salt and water -
Dyspepsia, acid-peptic disorders

Front 10

Antacids Side effects

Back 10

Belching & metabolic alkalosis (CO2)
Diarrhea (Mg) or constipation (Al)
Fluid retention (Na bicarbonate produces NaCl)
Hypercalcemia (milk-alkali syndrome)
dec absorption of other medicines

Front 11

H2-Recptor Antagonists MOA, clinical uses

Back 11

Competitive inhibition at the parietal cell H2 receptor
Effective at inhibiting nocturnal acid secretion (stimu. by histamine), but have a modest impact on meal-stimulated acid secretion (stimu. by gastrin, Ach, and histamine)


GERD (longer duration than antacids), peptic ulcer disease (replaced by PPI), prevention of bleeding from stress-related gastritis

Front 12

H-2 Receptor Antagonist Side Effects and Drug Interactions

Back 12

Safe (<3%: diarrhea, headache, fatigue, constipation) Cross placenta and secret in breast milk
Block cardiac H2 receptor (rapid IV- radycardia/hypotension)
CNS (confusion, hallucination, agitation)

Cimetidine- only
Gynecomastia, impotence, galactorrhea

Drug interactions
Cimetidine & ranitidine inhibit p450 drug metabolism
Inhibit gastric first-pass metabolism of alcohol, esp in
women (except for famotidine)

Front 13

Most potent H-2 R antagonist

Back 13

Femotidine = 20-50x compared to cimetidine

Front 14

PPI MOA

Back 14

Administered as inactive prodrugs Enteric-coated for delayed release (acid-labile)
MOA: Prodrugs are protonated & concentrated in parietal
cell canaliculus; converted to the active thiophilic sulfonamide cations, which inactivate H+/K+ ATPase irreversibly Inhibit both fasting and meal-stimulated acid secretion

Front 15

Clinical Uses for PPI

Back 15

GERD (most effective) Peptic ulcer disease H. pylori: ‘triple therapy’ (w/ larithromycin & amoxicillin or metronidazole) Prevention of stress-related mucosal bleeding Gastrinoma & other hypersecretory cond’ns

Front 16

PPI Side Effects and interactions

Back 16

Safe (1-5% diarrhea, headache, abdominal pain)
dec oral Vit B12 absorption Respiratory and enteric infections (gastric acid prevents colonization and infection of the GI)
Increases serum gastrin (feedback mechanism)
Drug interactions:
All PPI are metabolized by hepatic p450 cytochromes
Altered intragastric acidity affect other drug bioavailability

Front 17

Sucralfate MOA, Clinical Use, SE

Back 17

(negatively charged)
A salt of sucrose complexed with sulfated Al hydroxide

MOA: Forms a viscous paste that selectively binds to
ulcers or erosions

Clinical uses
dec GI bleeding

Side effects
No systemic adverse effect (not absorbed) Constipation (<2%; due to aluminum salt)
May bind to other medications

Front 18

Misoprostol MOA, Clinical Use, SE

Back 18

(PGE1 analog) Short half-life (tid or qd)

MOA
Noncompetitive inhibition of histamine- mediated cAMP production in parietal cells

Clinical uses
NSAID-induced peptic ulcer

Side effects
Diarrhea, cramping abdominal pain (10-20%)

Stimulate uterine contractions (abortifacient)

Front 19

Bismuth subsalicylate

Back 19

OTC (Pepto-Bismol)

MOA
Bismuth coats ulcer and erosions
Salicylate inhibits intestinal prostaglandin & Cl secretion

Clinical uses
Dyspepsia, acute diarrhea

Side effects
Safe
Black stool (bismuth), dark tongue (liq. formulations)

Salicylate toxicity: nausea, vomiting, sweating, rapid breathing, ringing in the ears, and fever

Front 20

Bethanechol MOA

Back 20

Increase GI Motility

Stimulate M3 receptors on muscle cells & myenteric plexus synapses Long duration (resistant to cetylcholinesterase)

Front 21

Neostigmine MOA, Clinical, SE

Back 21

Increase GI Motility

Acetylcholinesterase inhibitor
Enhances gastric, intestinal & colonic emptying
Useful in acute colonic pseudo-obstruction (aka Ogilvie syndrome)

Side effects: cholinergic effects (salivation, nausea,vomiting, diarrhea, bradycardia) = give with atropine

Front 22

Metoclopramide & Domperidone MOA

Back 22

Stimulate GI Motility

Block the activation of dopamine receptor (activation of dopamine receptors in GI inhibits cholinergic smooth muscle stimulation) Anti-nausea/anti-emetic (act on D2 receptors in medulla)

Front 23

Metoclopramide & Domperidone Clinical uses and SE

Back 23

Clinical uses

GERD, impaired gastric emptying, nonulcer dyspepsia, prevention of vomiting,

Side effects Galactorrhea, gynecomastia, impotence (increases prolactin)

Metoclopramide:CNS syndromes (restlessness, drowsiness, insomnia, anxiety, agitation) Extrapyramidal effects (dystonia, parkinsonian) AVOID LT Use

**Domperidone does not cross BBB**

Front 24

Erythromycin MOA, Clinical use

Back 24

Stimulates GI Motility

Stimulate motilin receptors on GI smooth muscle Used in p’ts with acute upper GI hemorrhage to promote gastric emptying of blood prior to endoscopy

Front 25

Lubiprostone MOA, Clinical use, SE

Back 25

(PGE1 derivative)
increase secretion of chloride-rich fluid which promotes bowel movement

Treat idiopathic chronic constipation

Side effects: nausea (30%), diarrhea, headache

Front 26

Psyllium, methylcellulose MOA, Clinical Use, SE

Back 26

Bulk-forming laxatives
Natural Plant Products

Indigestible, hydrophilic colloid that absorb water,forming a bulky gel that promotes peristalsis

Side effects: bloating, flatus

Front 27

Polycarbophil

Back 27

Bulk-forming laxatives
Synthetic Product

Indigestible, hydrophilic colloid that absorb water,forming a bulky gel that promotes peristalsis

Side effects: bloating, flatus

Front 28

Docusate, Glycerin suppository, Mineral oil - Use, MOA

Back 28

Stool surfactant agents (softeners)
Soften fecal material, permitting water/lipids to penetrate

Front 29

MgO, sorbitol, lactulose, Mg-Citrate, Na phosphate - MOA, Use, SE

Back 29

Osmotic Laxatives
Nonabsorbable Sugars or Salts
Increase Stool Liquidity
Used for the treatment of acute constipation or the prevention of chronic constipation
Side effects
MgO: hypermagnesemia
Electrolyte fluctuation (avoid use in p’ts with renal failure or cardiac diseases)
Sorbitol, lactulose: bloating, flatus

Front 30

Balanced Polyethylene Glycol

Back 30

Osmotic Laxatives
Increase Stool Liquidity

Contain an inert, nonabsorbable, osmotically active sugar (PEG), with Na2SO4, NaCl, NaHCO3, and KCl Used for complete colonic cleansing prior to GI endoscopy (no electrolyte fluctuation, no bloating)

Front 31

Aloe, senna, cascara: drug class, clinical use, SE

Back 31

Anthraquinone derivatives
Stimulant Laxatives (Cathartics)

MOA
Induce bowel movement Stimulate enteric nervous system & colonic electrolyte & fluid secretion

Poorly absorbed; hydrolyzed in colon, producing bowel movement Chronic use leads to a characteristic brown pigmentation of the colon (melanosis coli)

Front 32

Castor oil drug class, clinical use, SE

Back 32

Stimulant Laxatives (Cathartics)
MOA
Induce bowel movement Stimulate enteric nervous system & colonic electrolyte & fluid secretion
A potent stimulant laxative (acts in 2-6 hrs) Hydrolyzed in the upper intestine to ricinoleic acid, a local irritant that stimulate intestinal motility

Front 33

Tegaserod

Back 33

partial serotonin 5-HT4 receptor agonist = promotes the parastaltic reflex

Low bioavailability (taken before meals) Avoid in p’ts with severe hepatic or renal impairment Used in chronic constipation
Does not cross BBB (no effect on central serotonin R)
Safe (9% diarrhea)

Front 34

Loperamide

Back 34

Antidiarrheal
Opioid receptor agonists
MOA
Inc colonic phasic segmenting activity through inhibition of presynaptic cholinergic
nerves in the submucosal and myenteric plexuses and lead to increased colonic transit
time and fecal water absorption dec mass colonic movements and the gastrocolic reflex

does not cross BBB; no analgesic/addiction

Front 35

Diphenoxylate

Back 35

Antidiarrheal
Opioid receptor agonists
MOA
Inc colonic phasic segmenting activity through inhibition of presynaptic cholinergic
nerves in the submucosal and myenteric plexuses and lead to increased colonic transit
time and fecal water absorption dec mass colonic movements and the gastrocolic reflex

dependence (high doses & long term use) Atropine is usually added to discourage overdosage

Front 36

Kaolin & Pectin

Back 36

Antidiarrheal Agents

Kaolin: a naturally occurring hydrated Mg Al silicate
Pectin: an indigestible carbohydrate from apples
MOA: Absorbents of bacteria, toxins and fluid
Used in acute diarrhea
Not absorbed (no significant side effect except constipation)
May bind other drugs

Front 37

Cholestyramine, colestipol

Back 37

Antidiarrheal Agents
Bile salt-binding resins

Used to treat diarrhea caused by excess fecal bile acid
Side effects: bloating, flatulence, constipation
May bind other drugs

Front 38

Octreotide MOA, Clinical use

Back 38

Antidiarrheal Agents
analog of somatostatin

Inhibits the secretion of hormones and transmitters
decreases intestinal fluid secretion Slows GI motility and inhibits gallbladder contraction
Clinical uses (poor GI absorption-SC administered)
Inhibition of endocrine tumor effects
Other causes of diarrhea (e.g., vagotomy, dumping syndrome)

Front 39

Octreotide Side Effects

Back 39

Antidiarrheal Agents
analog of somatostatin

Side effects
fat-soluble Vit deficiency (impaired pancreatic secretion)
gallstones hyperglycemia or hypoglycemia hypothyroidism
bradycardia

Somatostatin is an inhibitory hormone released from GI tract, pancreatic D cells, hypothalamus, and enteric nerves

Front 40

Dicyclomine, hyoscyamine

Back 40

Tx IBS
Inhibit muscarinic cholinergic receptors (MR) in the
enteric plexus and on smooth muscle

Side effects: Anti-cholinergic effects (high doses)

Front 41

Alosetron

Back 41

Serotonin 5-HT3-Receptor Antagonists
Tx IBS
Inhibition of afferent GI 5-HT3-receptor (hence inhibits
nausea, bloating, and pain)
Blockade on the terminals of enteric cholinergic neurons
inhibits colonic motility

Long duration
Used for women with diarrhea-predominant IBS’

Side effects:
GI toxicity Constipation, ischemic colitis)

Front 42

Drug induced emesis effects this area of the brain

Back 42

Chemoreceptor Trigger Zone using NK1 - signals the vomiting center in the lower medula

Front 43

Motion sickness induced emesis effects this area of the brain

Back 43

Vestibular apparatus

Front 44

Ondansetron, granisetron, dolasetron, palonosetron

Back 44

Serotonin 5-HT3 receptor antagonists
Antiemetics

Palonosetron has a long half-life (40 hrs)
No effect on dopamine or muscarinic receptors
No effect on esophageal or gastric motility

Clinical uses:
Chemotherapy-induced nausea/vomiting Postoperative and postradiation nausea/vomiting

Side effects: Well-tolerated
Headache, dizziness, and constipation Prolongation of QT interval (esp dolasetron)

Front 45

Aprepitant

Back 45

Neurokinin Receptor Antagonists
substance P antagonist
Antiemetic Agent

Mediated through central blockade in the area postrema

Highly selective NK1 receptor antagonist that cross BBB
and occupies brain NK1 receptor

Used in combination with 5-HT3 receptor antagonists and dexamethasone for the prevention of acute and delayed nausea/vomiting from chemotherapeutic regimens

Side effects: fatigue, dizziness, diarrhea

Metabolized by CYP3A4 and may inhibit other drug metabolism by the CYP3A4 pathway

Front 46

Prochlorperazine, promethazine, thiethylperazine

Back 46

Antipsychotic agents (antiemetic/sedative)

Inhibit dopamine & muscarinic receptors (antiemetic)
Antihistamine activity (sedative)
Side effects:
Extrapyramidal effects & hypotension

Front 47

Droperidol

Back 47

Antipsychotic agents (antiemetic/sedative)
Central dopaminergic blockade (antiemetic/sedative)

Side effects:
Extrapyramidal effects & hypotension
Droperidol may prolong QT interval

Front 48

Metoclopramide

Back 48

Dopamine Receptor antagonists

MOA: dopamine-receptor blockade
Metoclopramide is used as an antiemetic & prokinetic
Side effects: extrapyramidal effects

Front 49

diphenhydramine, dimenhydrinate, meclizine

Back 49

Histamine H1 antagonists
Useful for the prevention/treatment of motion sickness

Side effects: dizziness, sedation, confusion, dry mouth, cycloplegia, urinary retention
Meclizine has less anticholinergic side effect than dimenhydrinate or diphenhydramine

Front 50

hyoscine

Back 50

Anticholinergics
Muscarinic receptor antagonist

Prevention of motion sickness
Side effects: high anticholinergic effects (transdermal patches are better tolerated)

Front 51

Lorazepam, diazepam

Back 51

Benzodiazepines
(anti-anxiety)
Antiemetic Agents
Bind to GABA receptor

Used prior to chemotherapy to dec anxiety-induced vomiting

Front 52

Dronabinol, nabilone

Back 52

Cannabinoids
Antiemetics

The major psychoactive chemical (THC) in marijuana

Used as an appetite stimulant and as an antiemetic (MOA?)

Side effects: euphoria, dysphoria, sedation, hallucination, dry mouth, increased appetite, autonomic effects tachycardia, orthostatic hypotension

Front 53

Sulfasalazine, balsalazine, olsalazine

Back 53

Aminosalicylates (5-ASA)
Azo compounds
Used to Tx IBD (UC/Crohn's)

Modulate inflammatory mediators derived from both COX and LOX pathways
Act ‘topically’ on diseased GI mucosa

Azo structures dec absorption of the parental drugs from the small intestine

Front 54

Mesalamine,
pentasa (time-release),
rowasa (enema),
canasa (suppository)

Back 54

Aminosalicylates (5-ASA)
Mesalamine compounds
Used to Tx IBD (UC/Crohn's)
Modulate inflammatory mediators derived from both COX and LOX pathways
Act ‘topically’ on diseased GI mucosa

Front 55

Sulfasalazine Side Effects

Back 55

Azole - Tx IBD (UC/Crohn's)

Dose-related nausea, GI upset, headaches, arthralgias,
myalgias, bone marrow suppression, malaise

hypersensitivity to sulfapyridine (fever, hepatitis, hemolytic anemia)
Impaired folate absorption/processing
Take Folate!

Front 56

Prednisone, prednisolone, hydrocortisone, budesonide

Back 56

Glucocorticoids Tx IBD (UC/Crohn's)

Treat moderate to severe active IBD

Front 57

Azathioprine, 6-mercaptopurine

Back 57

Purine Analogs
Immunosuppressive activities
Tx IBD (UC/Crohn's)

Clinical uses: induction/maintenance of remission of ulcerative colitis and Crohn’s disease

Side effects: nausea/vomiting, bone marrow depression, & hepatic toxicity (monitor blood count/liver function)

Low TPMT inc. production of active metabolites and
Inc. risk of bone marrow suppression

Front 58

Methotrexate

Back 58

Inhibits DHFR (high doses inhibit cell proliferation)
Treat Crohn’s disease
Side effects: rarely bone marrow suppression (high doses) Take Folate!

Front 59

Infliximab

Back 59

Anti-TNF Therapy
Used to treat moderate to severe Crohn’s disease & ulcerative colitis

Side effects: infection (immunosuppression),
reactivation of TB, hepatic failure (monitor liver enzymes)

Front 60

Pancreatin, Pancrelipase

Back 60

Pancreatic Enzyme Supplements
Treat exocrine pancreatic insufficiency (fat/protein maldigestion)

Pancreatin: extract of hog pancreas (low enzyme activities)

Pancrelipase: Mixtures of amylase, peptidase, lipase (rapidly inactivated by gastric acid: enteric coating or taken with PPI)

Front 61

Ursodiol

Back 61

Bile Acid Therapy For Gallstones
only FDA approved drug to treat primary biliary cirrhosis Dissolve gallstones
works only when stones are made of cholesterol and the opening of the gallbladder is not blocked