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GI/Pulmonary EXAM 3 - Sandoval
GI/Pulmonary EXAM 3 - Sandoval GI

Additional Pharmacology Flashcards





the stomach is divided into 3 sections: the fundus, body, and anstrum

the lower esophageal sphincter is located between the esophagus and the stomach and keeps acid out of the esophagus

the pyloric sphincter is between the stomach and the small intestine

the stomach has openings known as pits that empty MOST of their secretory products into the gastric lumen (gastrin is the exception and is secreted into the blood stream)

these pits are lined with epithelial cells

depending on the location of the stomach, there are different glands composed of different cell types that secrete different substances

oxyntic glands are contained in the body of the stomach

oxyntic glands are composed of parietal cells (which secrete acid and intrinstic factor), mucus cells (which secret mucus), and chief cells (which secrete pepsinogen)

the pyloric glands are located in the antrum of the stomach

the pyloric glands have deeper pits than the oxyntic glands

the pyloric glands contain 2 cell types: mucus cells and G cells
the mucus cells secrete mucus into the lumen, HOWEVER, the G cells secrete gastrin NOT into the gastric lumen, but into the circulation
anatomy of the stomach
the major cell types in the gastric mucosa are the parietal cells, chief cells, G cells, and mucus cells

parietal cells:
responsible for secretion of HCl and intrinsic factor
intrinsic factor is needed for vitamin B12 absorption

chief cells:
secrete pepsinogen (a zymogen, meaning that it is an inactive precursor) at low pH it is converted to its active form pepsin, which is responsible for protein digestion

G cells:
secrete gastrin
stimulated by products of protein digestion, vagal stimulation, and distension of the stomach
gastrin has 2 functions: stimulate parietal cell HCl secretion and the growth of gastric mucosa
G cells release gastrin INTO THE CIRCULATION thus, gastrin acts as a hormone
the actions of gastrin are terminated by decreased pH

mucus cells:
secrete mucus, bicarbonate, pepsinogen
mucus and bicarbonate have a protective effect on gastric mucosa
gastric juice and the cell types of the gastric mucosa
facilitates digestion of protein and absorption of several key nutrients

prevents bacterial overgrowth

pH is key for keeping several mediators involved in regulating acid secretion in check (somatostatin, gastrin)
physiological importance of acid secretion in the stomach
acid secretion can be activated by neural, hormonal, and paracrine pathways.

parietal cells are the cell type involved in acid secretion

vagal nerve stimulation, which is the neural component, stimulates release of ACh
ACh then acts on M3 receptors on the parietal cells
M3 receptors are coupled to Gq -> activation leads to increased IP3 and intracellular Ca -> activation of H/K/ATPase
ATP is used to pump H+ into the lumen in exchange for K+, resulting in acid secretion by the parietal cell

hormonal stimulation is mediated through gastrin
gastrin is released from G cells into circulation and is circulated BACK to the stomach where it acts on the CCKB receptors on the parietal cells
similar to M3 receptors, CCKB is coupled with Gq
Activation of CCKB, results in increased IP3 and Ca2+ which then leads to activation of the H+/K+ ATPase pump, leading to increased HCl secretion by the parietal cell

histamine acts in a paracrine manner
histamine is released from the ECL cells and diffuses to the body of the stomach and binds to H2 receptors on the parietal cell
the H2 receptor is coupled with Gs
activation of H2 leads to increased cAMP and activation of H/K/ATPase and increased HCl secretion by the parietal cell
3 cell types involved in acid secretion

there are interactions between all 3 pathways, which can result in potentiation, meaning 2 or more stimuli produce a response that is greater than the sum of their individual responses. The reason why potentiation occurs is due to the fact that:

1) each agent acts on a different receptor which ultimately leads to insertion and activation of H/K/ATPase to produce acid
2) vagal stimulation also results in vagal nerve endings releasing gastrin releasing peptide (GRP), which stimulates gastrin secretion from G cells. Thus, vagal stimulation cause the release of ACh (which can act on M3 receptors leading to acid secretion) and can also cause for gastrin secretion, which after circulating can bind to CCKB receptors leading to acid secretion
3) ACh and gastrin also stimulate histamine release from ECL cells. the potentiation of acid secretion is therapeutically significant as use of the H2 receptor antagonist, cimetidine, can block the effect of histamine on the H2 receptor, but can also block the potentiating effects of gastrin and ACh on histamine induced acid secretion
regulation of gastric acid secretion

unstimulated parietal cells have vesicles and intracellular canaliculi that contain short microvilli along the apical surface
the H/K/ATPase are expressed in the vesicles and are not active as they are impermeable to K+
when acid secretion is stimulated, the parietal cell undergoes a morphologic transformation and the H/K/ATPase enzyme is transported and fuses with the secretory canaliculus, resulting in acid secretion in response to ATP
H/K/ATPase induced acid secretion

acid is produced at the apical membrane (luminal side)

one H+ ion is secreted in the lumen of the stomach in exchange for K+ and ATP via the H/K/ATPase (an active transport system against a concentration gradient)

carbonic anhydrase is the source of H+ ions
carbonic anhydrase catalyzes the formation of H2CO3 from carbon dioxide and water
H2CO3 dissociates into H+ and HCO3-
H+ is exchanged with K+ and ATP
H+ is secreted with Cl- into the lumen of the stomach

HCO3- is absorbed into the blood at the basolateral membrane via a Cl-/HCO3- exchanges
the absorption of HCO3- is responsible for the "alkaline tide" (high pH) that can be observed after a meal
acid production by the parietal cell

acid secretion occurs under basal and stimulated conditions

the highest levels of basal acid production are at night; the lowest are during the early morning hours

basal acid secretion is driven by cholinergic imput from the VAGUS NERVE as well as by paracrine HISTAMINE release

mechanism of basal acid secretion

smell, sight, and taste of food stimulates gastric acid secretion

the vagus nerve releases ACh -> binds to M3 receptors -> acid secretion by parietal cells

stimulation of the vagus nerve also stimulates GRP stimulating gastrin secretion by G cells -> binds to CCKB receptors -> acid production


activated when food enters the stomach

distention causes direct vagal stimulation of parietal cells (release ACh -> acid production) and indirect stimulation by gastrin release (enhances release of GRP) - this mechanism is shared by the cephalic and gastric phase

additionaly, distension of the antrum leads to gastrin release and acid production

amino acids and small peptides can act on G cells to stimulate gastrin release
mechanism of stimulated acid secretion

the major inhibitory control of HCl secretion is decreased pH

the major inhibitory mechanism for inhibiting parietal cells is somatostatin
in response to low pH, somatostatin is released from anstral D cells (located in the lower part of the stomach)
somatostatin can inhibit HCl via a direct mechanism and an indirect machanism

DIRECT mechanism:
somatostatin binds to somatostatin 2 receptors (SSTR2) on parietal cells
SSTR2 is coupled with Gi and antagonizes the actions of histamine on H2 receptors

INDIRECT mechanism:
somatostatin inhibits release of gastrin from G cells and histamine from ECL cells -> results in decreased acid secretion

prostaglandins also inhibit acid secretion via the EP3 receptor, coupled with Gi resulting in decreased cAMP
inhibitory control of gastric acid secretion
decreased pH, increased somatostatin release
increased pH, decreased somatostatin release


when food is eaten, pH increases and somatostatin is inhibited

once food leaves the stomach, the pH drops and signals the release of somatostatin which decreases acid release
impact of pH on somatostatin secretion
imbalance between protective factors and damaging factors

too many damaging factors or loss of protective factors can lead to an ulcer

damaging factors: acid, pepsin, NSAIDs

protective factors: mucus, bicarbonate, mucosal blood flow, prostaglandins
pathophysiology of acid peptic disease

pre-epithelial mechanism:
mucus forms a gel like protective barrier
gastric epithelial cells secrete bicarbonate that is trapped in the mucus; if acid penetrates the mucus, it is quickly neutralized before reaching the gastric epithelium

epithelial mechanisms:
restitution - gastric epithelial cells can migrate to a site of injury to repair it; requires uninterrupted blood flow and an alkaline pH
epidermal growth factor, transforming growth factor, basic fibroblast growth factor modulate the process of restitution
this process involves cell migration, not cell devision and can only seal minor defects
large defects require regeneration (cell division and actions of prostagladins)

post-epithelial mechanism:
blood mucosal flow - helps to remove acid that diffuses through injured mucosa

if all 3 defense mechanisms are overwhelmed, this results in peptic ulceration where pepsin and acid begin to digest the gastric mucosa
gastric protective mechanisms

PGs regulates the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion and are important in maintaining mucosal blood flow and epithelial cell restitution
NSAIDs decrease tissue inflammation due to inhibition of COX-2 while the toxicity of these drugs (ulceration) is related to inhibition of the COX-1 isoform.
The highly COX-2-selective NSAIDs were developed to avoid the problem of NSAID induced ulcers.
however, if an ulcer is present, COX2 inhibition can delay repair
protective mechanism of prostaglandins
decreasing levels of gastric acidity: H2 receptor antagonists, PPIs, and antacids

enhanceing mucosal protection: sucralfate and misoprostol

eradication of Helicobacter pylori: antibiotics

combination of these drugs
treatment of acid peptic diseases
omeprazole, rabeprazole, pantoprazole, esomeprazole


reduce gastric acidity

acid labile prodrugs: most PPIs are enteric coated to protect them from premature activation and degradation

PPIs are unprotonated in the blood and readily pass through cell membranes (including that of parietal cells)

in the acidic environment of the canaliculi of the parietal cell, the PPIs become protonated (b/c they are basic drugs) which traps the drug from diffusing back into the circulation

the sulfenamide then covalently binds to the sulfhydryl group of cysteine in the H/K/ATPase which irreversibly inhibits the proton pump for the life of the proton pump

PPIs only inhiibt active pumps; inactive pumps are in vesicles in the parietal cell and aren't available for PPIs to bind

for this reason, it is recommended that PPIs be given prior to ingestion of food (0.5-1h) as ingestion of food is a major stimulator of acid
inhibition of basal and stimulated gastric acid production (b/c inhibiting the final step of acid production)


short plasma half life - any pumps that weren't active and inhibited by the PPI can still produce acid

have to activate pumps to be effective

MOA, drawbacks, and examples of proton pump inhibitors

the increased pH removes the negative feedback from gastrin (by somatostatin due to the fact that pH is increased) to where gastrin remains active

gastrin stimulates the growth of gastric mucosa

more prominent with PPIs than others b/c inhibiting final step

higher gastrin also leads to higher amounts of acid after discontinuation of therapy (lasts for 1 month) = rebound acid secretion

hypergastrinemia can induce proliferation of ECL and parietal cells - more acid producing cells after treatment than before

may necessitate chronic use of a PPI

Hypochlorydia: significant reduction in acid secretion

increased gastric pH may alter the availability of other orally administered drugs

acid secretion in the stomach has a protective role against infection; reduced acid secretion -> increased risk of enteric infections such as C. dificile

long term use of PPIs may lead to nutritional deficiencies: gastric acid is important for vitamin B12, iron, and calcium absorption

long term use also associated with gastric atrophy - results in shrinkage in the stomach and reduced secretion of digestive juices
ADRs of PPIs

raises intragastric pH immeidately, leading to faster relief of symtpoms

do not have to stimulate the pumps with food, so there is less of a dosing issue: increased pH produced by sodium bicarbonate stimulates gastrin, leading to activated pumps


same as other PPIs

because it contains Na, it is not to be used in people with heart problems (hypertension, congestive heart failure)
advantages and disadvantages of immediate release PPIs (omeprazole with sodium bicarbonate)
delayed release PPI

irreversibly inhibits H/K/ATPase, but longer duration of action due to its dual release tchnology

like other PPIs, the 1st phase of release is in the duodenum where the intestinal pH is ~6

when it reaches the jejunum and ileum (pH = 7-8) a 2nd phase of release occurs

prolonged acid suppression

can be taken without food

ADRs similar to other PPIs
MOA of dexlansoprazole
histamine H2 receptor antagonists

competitive H2 receptor antagonists

act on gastric parietal cells to predominantly inhibit BASAL acid secretion

H2 receptor blockers competitively antagonize the effects of histamine on the H2 receptors present on the basolateral membrane of the parietal cell

additionally, H2 receptor blockers antagonize the actions of gastrin and ACh on increasing gastric acidity by histamine as the H2 receptor is blocked
tolerance can develop within 3 days of starting treatment and may be resistant to increased doses

tolerance develops due to increased levels of gastrin due to the increased pH of the gastric lumen

b/c there is increased pH, there is no negative feedback on the production of gastrin (by somatostatin) leading to increased acid secretion

increased gastrin may also increased histamine release, which may also reduce the efficacy of H2RAs
mechanism of tolerance to H2RAs
rebound increases gastric acidity and may occur with discontinuation

occurs b/c changes in function: increased gastrin levels leading to increased parietal cell mass and acid secretion (due to trying to overcome the decreased acid production)

once H2RAs are discontinued, there is an increased production of acid = acid rebound
mechanism of acid rebound with H2RAs
aluminum hydroxide
calcium carbonate
magnesium trisilicate
sodium bicarbonate

chemically neutralizes stomach acid
raise gastrointestinal pH to relieve the pain of dyspepsia and acid indigestion


antacids can increase pH which can affect drug BA (azole antifungals)

some antacids can chelate other drugs present in the GI tract

aluminum antacids: constipation

magnesium antacids: diarrhea

aluminum and magnesium are often combined together to combat these effects

calcium antacids: activate Ca dependent processes that can increase acid production leading to acid rebound
gastric antacids

examples, MOA, ADRs
a sulfated polysaccharide

undergoes extensive cross-linking to produce a viscous, sticky, polymer which adheres to epithelial cells and ulcer craters for up to 6 hours

inhibits hydrolysis of mucosal proteins by pepsin

may stimulate the production of prostaglandins and epidermal growth factor in mucosal cells; this contributes to the formation of a protective barrier to acid and pepsin and thereby facilitate the healing of ulcers

cytoprotective drug

misoprostol is a prostaglandin E1 analogue used to PREVENT ulcers in those taking NSAIDs

misoprostol exerts a cytoprotective effect by:

1) inhibiting gastric acid secretion; PGs act via the EP3 receptor to decrease acid secretion; EP3 receptors are coupled to Gi

2) promoting the secretion of mucus and bicarbonate, which is protective against damaging factors
MOA of misoprostol
gram negative rod

associated with the development of:

gastric and duodenal ulcers
gastric adenocarcinoma as well as gastric B cell lymphoma

H. pylori elaborates urease

urease is an enzyme that catalyzes the breakdown of urea to ammonia and CO2

H. pylori protects itself from acid injury by surrounding itself by the alkaline ammonia

it then burrows through the gastric mucus layer, attaching to the gastric epithelial cells by using its flagella

it then releases cytotoxins that break down the mucosal barrier and underlying cells
how does Helicobacter pylori cause ulcers?
single antibiotic drug therapy is rarely effective in eradicating H. pylori

PPIs or H2RAs significantly enhance the effectiveness of antibiotics

antibiotics: clarithromycin, amoxicillin, metronidazole, tetracycline

bismuth subsalicylate can also be used
drugs to treat H. pylori infection

bismuth subsalicylate reacts with HCl to form bismuth oxychloride and salicylic acid

salicylate is absorbed in stomach and small intestine

produces multiple effects:

antimicrobial: against H. pylori

anti-inflammatory: due to salicylic acid which inhibits COX

anti-secretory: reduces water secretion, helping with diarrhea

cytoprotective: may increase PGs and mucus


dark stools and black staining of the tongue (a reaction between the drug and bacterial sulfides in the GI tract)
MOA and ADRs of bismuth subsalicylate
prokinetic drugs are used in the management of a number of disorders characterized by gastrointestinal HYPOMOTILITY:

achalasia of the esophagus (impaired relaxation of the lower esophageal sphincter resulting in difficulty swallowing and regurgitation)


chronic intestinal dysmotility


gastroesophageal reflux disease

goals of therapy:

stimulate gastric emptying and accelerate small and large intestinal transit
use of prokinetic drugs
the GI tract is in a continuous contractile, absorptive, and secretory state

the enteric nervous system is responsible for regulating GI function (ENS can be modulated by the parasympathetic and sympathetic activity)

the enteric nervous system is organized into 2 networks of neurons:

1) myenteric (Auerbach's) plexus: found between the circular and longitudinal muscle layers; collection of nerves regulates gastric motility

2) submucosal (Meissner's) plexus: regulates fluid transport, secretion, and vascular flow; group of neurons is found between the circular muscle and submucosa
neuronal control of the GI tractui
motility is accomplished by contractions of circular and longitudinal muscles:

contraction of circular muscle decreases the diameter and is involved in peristaltic contraction which propels the food forward along the GI tract

most drugs have action on the contraction of the circular muscle

the longitudinal muscle decreases the length of a segment (helps mix the chyme and exposes it to enzymes and secretions)

longitudinal muscle contraction does not produce any forward movement

migrating myoelectric complex:
mediated by motilin
during fasting, there are periodic strong peristaltic contractions every 90 minutes
serve to clear the stomach and small intestine of residual food or chyme
mechanism of gastric motility
contraction of GI smooth muscle is preceded by electrical activity

slow waves are unique to GI smooth muslce

slow waves are not action potentials, but are oscillating depolarizations (opening of Ca channels; inward flux of Ca) and repolarizations (opening of K channels; outward flux of K)

if the outer membrane reaches threshold, action potentials can occur resulting in phasic contractions

the greater the number of action potentials, the stronger the contraction

important note: slow waves are NOT action potentions (APs only occur if the membrane reaches threshold)

the frequency of the slow waves is controlled by the interstitial cells of Cajal (pacemaker of the GI found in the myenteric plexus)

the frequency of the slow waves varies along the GI tract

NEURONAL AND HORMONAL INPUT DO NOT INFLUENCE THE FREQUENCY OF THE SLOW WAVES, but influence the frequency of action potentials which in turn influences the force of contraction

increase in frequency of action potentials: parasympathetic stimulation and motilin (both act on GPCRs to increase intracellular Ca)

decrease frequency of action potentials: sympathetic stimulation (NE or EPI); act on GPCR to increase cAMP
electrical activity and neuronal control of GI contraction
intracellular Ca mediates smooth muscle contractility

Ca combines with calmodulin to form a complex that converts MLCK to its active form -> activated MLCK phosphorylates MLC thereby initiating the interaction of myosin with actin -> smooth muscle contraction

2 types of excitation contraction coupling:

1) ionotropic
mediated by changes in membrane potential leading to the activation of voltage gated Ca channels -> increased intracellular Ca -> muscle contraction

2) metabotropic
activated by various signal transduction pathways (Gq) -> increased intracellular Ca -> muscle contraction
smooth muscle excitation contraction coupling
parasympathtic nerve activity stimulates intestinal motility by inducing the release of ACh

sympathetic nerve activity inhibits activity by blocking the release of ACh
autonomic nervous system influence of GI motility
peristalsis is a series of reflex responses to a bolus in the lumen of the intestine

the peristaltic reflex is an integrated neuronal response composed of:
the ascending excitatory reflex - results in contraction of the CIRCULAR muscle on the oral side of the bolus
the descending inhibitory relex - results in relaxation

the net pressure gradient moves the food bolus

enterochromaffin cells line the mucosa of the gut and release serotonin in response to chemical and mechanical stimulation

serotonin binds to its receptors on the primary afferent neuron exciting the primary afferent neuron of the myenteric plexus

the primary afferent then communicates with interneurons (through the release of neurotransmitter) which connects the primary afferent neuron (sensory input) to the motor neuron (motor output)

the motor neuron is part of the efferent component of the peristaltic response and translates sensory information into mechanical force

2 types of motor neurons: excitatory and inhibitory

the transmitter released from each type of motor neuron differs

excitatory motor neurons release ACh to produce contraction of the circular muscle on the oral side

inhibitory neurons release nitric oxide to produce relaxation of the circular muscle on the anal side

end result is movement of the food bolus
neural network and the peristaltic response
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