13-1: 1/27 - Gi Pharmacology I

Front 1

Myenteric vs Meissner's Plexuses:
AKA
Location

Back 1

Myenteric (Auerbach's):
Between outer longitudinal and middle circular muscle layers

Meissner's (Submucosal):
Luminal side of circular muscle

Note: plexuses are interconnected and receive info from psymp and symp ns

Front 2

Example of endocrine secretion in GI tract.

Back 2

Gastrin

Front 3

Example of paracrine secretion in GI tract.

Back 3

Histamine

Front 4

Ulcer disease:
General pathophys

Back 4

Imbalance between aggressive factor (gastric acid and pepsin secretion, H pylori infection) and defensive or cytoprotective factors (bicarb and mucous secretion, PG synthesis)

Front 5

Describe the pumps utilized by parietal cells.

Back 5

Parietal cells contain H+, K+ ATPase proton pump.

Activation of proton pump increases permeability of apical membrane to K+ (in) and Cl- (out)

Front 6

Parietal cells:
Describe activation by:
Endocrine stimulation
Paracrine stimulation
Neural stimulation

Include differences in pumps activated.

Back 6

Endocrine: gastrin release from G cells; works 2 ways:
1) Stimulates release of histamine from ECL cells
2) Stimulates CCK2 receptors on parietal cells to activate Ca2+ dependent proton pump

Paracrine: histamine released from ECL cells:
Acts at H2 receptors on parietal cells stimulating cAMP-dep activation of proton pump


Neural stimulation via vagus (ACh)-->2 ways:

1) Stimulates release of histamine from ECL cells
2) ACh (from enteric neurons) act directly on parietal cells stimulating M2/M3 receptors and activating Ca2+ dep activation of proton pump.

Front 7

Prostaglandin effects on gastrin secretion.

Back 7

1) binds PGE receptors on parietal cells-->inhibits cAMP-dep PW

2) Stimulates secretion of mucus and bicarb from epithelial cells

Front 8

H2 Antagonists:
MOA
Metabolism
Clearance
Indications

Back 8

inhibit action of histamine at H2 receptor, thus:
-inhibit gastric acid secretion by histamine, gastrin, and Ach

-inhibits both basal (fasting) acid secretion and acid secretion stimulated by food

-Reduces output of pepsin by chief cells

Metab: hepatic
Clearance: renal for basic drugs

indications:
Duodenal, gastric ulcers
ZE syndrome
GERD

Front 9

Cimetidine:
Drug class
AEs

Back 9

H2 antag

AEs:
inhibits renal elimination of other basic drugs (procainamide)

inhibits cyp450, reducing metabolism of many drugs (phenytoin, theophylline, phenobarb, warfarin, TCA, CCBs)

GYNECOMASTIA, impotence, lactation (enhances secretion of PL)

note: cyp450 inhibition AND PL secretion (also binds androgen receptors) are unique to cimetidine and does not apply to other H2 antags

Front 10

Ranitidine:
Suffix
Drug Class

Back 10

-tidine: cimetidine, ranitidine, famotidine, nizatidine

H2 receptor antags

Front 11

Which H2 antagonists are most potent?

Back 11

Famotidine
Ranitidine = Nizatidine
Cimetidine least potent

Front 12

Proton Pump Inhibitors:
MOA
AEs
Indications

Back 12

Inactive agents diffuse from blood into acid canaliculi of parietal cells
Then become protonated and converted to active agent (sulfenamide)

Sulfenamide binds proton pump and irreversibly inactivates it.

AEs:
Nausea, diarrhea;
less common: HAs, dizziness, skin rashes

Long-term use may increase c. diff infection and hip fractures

Indications:
Duodenal and gastric ulcer
ZE syndrome (DRUG OF CHOICE)
GERD

Front 13

Zollinger Ellison Syndrome:
What is it?
Drug of choice?

Back 13

Tumor of pancreas which causes hypersecretion of gastrin

Drug of choice: Proton Pump inhibitors

Front 14

What drug is contraindicated with clopidogrel?

Why?

Back 14

Omeprazole:
inhibits cyp450 enzyme that activates clopidogrel, thus reducing clopidogrel's inhibitory effect on platelet aggregation.

Front 15

Omeprazole:
Drug Class

Back 15

Proton Pump Inhibitor
RACEMIC MIXTRUE of R and S isomers (S = esomeprazole)

Front 16

Omeprazole vs Esomeprazole

Back 16

Omeprazole (R isomer) har large variability in response between patients

Esomeptrazole metabolized more slowly by CYP2C19 and provides higher plasma levels of active drug, less interpatient variability.

Front 17

Rabeprazole:
Suffix
Drug Class

Back 17

-prazole: omeprazole, lansoprazole, pantoprazole, esomeprazole

Proton pump inhibitors

Front 18

What pH cutoffs are relevant to healing stomach ulcers?

Back 18

pH >2 alleviates pain
pH>4 deactivates pepsin

Front 19

Beyond increasing stomach pH, what are other effects of antacids?

Back 19

Note: Inc stomach pH by neutralizing HCl

Also stimulate mucus and bicarb secretion, enhance PG synthesis

Reduce H pylori colonization

Front 20

Al(OH)3 vs Mg(OH)2:
Drug Class
AE's
Speed

Back 20

Both are antacids

Mg(OH)2:
Diarrhea
Hypermagnesemia (sedation, confsion, skeletal muscle weakness, hypotn)
Reacts rapidly to neutralize acid

Al(OH)3:
Constipation, reacts slowly

Front 21

CaCO3:
Drug Class
Effects
AE
Speed

Back 21

Antacid (Tums)

Activates Ca2+-dependent secretory processes, increasing secretion of gastrin and HCl

Hypercalcemia = AE (impaired renal fn, weakness)

Rapidly acting

Front 22

Why isn't NaCO3 used as an antacid?

Back 22

Increases gastric emptying and presents sodium load (volume expansion, HTN, cardiac failure) and alkali load (SYSTEMIC ALKALOSIS--urinary pH increase)

Front 23

Tums:
Antacid Type

Back 23

CaCO3

Front 24

Milk of Magnesia:
Antacid Type

Back 24

Mg(OH)2 only

Front 25

Maalox:
Antacid Type

Back 25

Mixture of Mg(OH)2 and Al(OH)3

Front 26

Mylanta:
Antacid Type

Back 26

Mixture of Mg(OH)2 and Al(OH)3

Front 27

These antacids cause belching.

Why?

Back 27

Sodium salts and CaCO3--bc of rapid release of CO2

Front 28

This antacid exhibits acid rebound.

Back 28

CaCO3

Front 29

This antacid is contraindicated with tetracycline.

Back 29

Al(OH)3; inhibits tetracycline's absorption

Front 30

Bismuth:
Drug Class
MOA
Effects

Back 30

Bismuth = Pepto-Bismol
Cytoprotective Agent

MOA:
Bismuth chelates with proteins at acid pH and forms a protective barrier against acid diffusion and peptic digestion

Effects:antibacterial and cytoprotective effects such as inc'd secretion of bicarb and mucus; inhibition of pepsin

Front 31

Sucralfate:
Drug Class
MOA
AEs

Back 31

Sucralfate = Al(OH)3 + sulfated sucrose
Cytoprotective Agent

MOA: binds protein components of ulcer to form protective coating; this prevents degradative activity of pepsin and acid.

May also stimulate mucus and bicarb secretion, and may increase PG synthesis.

AE:
Constipation (contains Al(OH)3)

Dec'd bioavail of teatracycline, phenytoin, digoxin, cimetidine

Front 32

Misoprostol:
Drug Class
MOA
Indications
AEs

Back 32

Misoprostol = PGE2 analog

Cytoprotective agent

Acts as PGE2 analog and inhibits acid secretion; stimulates bicarb and mucus secretion

Indicated in pts who require NSAID tx

AEs:
Cramping and diarrhea due to inc'd GI secretion and motility

Contraction of uterine SM-->abortion

Front 33

This drug is contraindicated in pregnancy. Why?

Back 33

Misoprostol

PGE2 analog-->contraction of uterine smooth muscle-->abortion

Front 34

H. pylori:
Direct vs Indirect Damage

Back 34

Direct: due to bacterial enzymes (proteases, lipases, urease which produces ammonia)

Indirect: induction of chronic-active inflammn (IL-1, IL-5, IL-8, TNFalpha release)

Front 35

H. pylori:
Effect on stomach cells

Back 35

G cells: increases plasma gastring levels

D Cells: inhibits somatosatin release
ECL: dec'd histamine produciton/release

Parietal cells; effect varies

Front 36

H. pylori:
Treatment

Back 36

Triple tx x 14d:
PPI + Clarithromycin + metronidazole or amoxicillin
(tetracycline can be subst'd for amox or metronidazole) qd

Front 37

GERD:
Treatment goals

Back 37

enhance esophageal clearance
decrease frequency of tLESR
acid suppression

Front 38

What are the effects of prokinetic agents?

Back 38

Increase LES pressure, enhance esophageal peristalsis

Front 39

Metoclopromide:
Drug Class
MOA

Back 39

Prokinetic AND ANTIEMETIC

Enhanced release of ACh from nerves innervating GI tract smooth muscle

Also: 5HT4/ agonist (release ACh to enhance more ACh release), 5HT3 antag (suppress NANC), D2 antag--provides antiemetic effect (blocks D2 receptors in chemoreceptor trigger zone, solitary tract nucleus)

Front 40

Cisapride:
Drug Class
MOA
AEs

Back 40

Enhances release of ACh from nerves innervating SmoothM of GI tract

Also 5HT4 agonist, 5HT3 antag

FATAL ARRHYTHMIAS due to prolongation of QT interval.

Front 41

Effects of prokinetic agents in GERD.

Back 41

Mild syx relief but no endoscopic or histological healing of esophagitis.

Front 42

This agent results in prolongation of the QT interval.

Back 42

Cisapride (FATAL AE!)--no longer available in the US

Front 43

Lesogaberan:
Drug Class
MOA
Effect

Back 43

Motility altering agent

GABA-B agonist that inhibits signaling from vagal afferents in stomach and esophagus to reduce mechanosensitivity

Also inhibits vagal efferents

Effect: dec'd postprandial, tLESR, inc'd basal LES pressure

STILL IN CLINICAL TRIALS

Front 44

GERD:
Tx of Stage I vs Stage II vs Stage III

Back 44

Stage I: uncomplicated; tx: lifestyle mod, including diet, posnl changes, weight loss; antacids or H2 receptor antag PRN

Stage II: frequent syx w/ or w/o esophagitis (2-3+ events qweek): proton pump inhibitors

Stage III: chronic, unrelenting syx, esophageal complications: Proton pump inhibitor qd-bid

Front 45

Emetic reflex:
Describe (begin with emetic center in brain)

Back 45

Emetic center in brain-->vagal and phrenic efferents + spinal innvervation of abdominal mm

Results in reduced gastric tone and peristalsis
inc'd duodenal and jejunal tone and reflux

Upper stomach relaxes
pylorus constricts
diaphragm and abdominal mm contract to empty gastric contents

Front 46

Ondansetron:
Suffix
Drug Class
MOA
Indications

Back 46

-setron: ondansetron, granisetron

Antiemetic Agent

MOA:
5-HT 3 antag in chemoreceptor trigger zone, solitary tract nuc, stomach, small bowel

Indications: management of chemotx (radiotherapy included); use in combn w/corticosteroids (provide synergistic effect)

Front 47

Chlorpromazine:
Drug Class
MOA
AEs

Back 47

Antiemetic

Muscarinic and histaminergic antagonist

ALSO ACTS AS NEUROLEPTIC

AEs: hypotn, sedation, tardive dyskinesia!

Front 48

Haloperidol:
Drug Class
AEs

Back 48

Antiemetic and neuroleptic

Sedation (less so than chlorpromazine); hypotn (less so than chlorpromazine)

Front 49

This drug class is used in combination with antiemetics.

Examples?

Back 49

Corticosteroids

Dexamethasone

Methylprednisone

Front 50

Meclizine:
Drug Class
Indications

Back 50

Antihistamines only for motion sickness, not chemoreceptor mediated emesis.

Front 51

Scopolamine:
Drug Class
Indications
AEs

Back 51

Antimuscarinic

Motion sickness (not for emesis due to chemotx)

AE: dry mouth, sedation

Note: delivered transdermally

Front 52

Dronabinol:
Drug Class
MOA
AE's

Back 52

Antiemetic

Stimulation of cannabinoid receptors (CB1) near vomiting center

AE: abstinence syndrome w/abrupt withdrawal (irritability, insomnia, restlessness)

Front 53

Dimenhydrinate:
Drug Class
Indications

Back 53

Antihistamines only for motion sickness, not chemoreceptor mediated emesis.