Pharm Study Guide for GI and Cardio
GI Pharm I-III
1. Define the neuronal, paracrine, and endocrine regulators of gastric secretions (mucus and acid).
a. Parietal cell is final common pathway for the secretion of acid (HCl) and represents a key site of
pharmacological regulation.
b. Gastrin – Endocrine - regulator both directly and indirectly. Gastrin is secreted into the blood by
endocrine G cells of the stomach. Gastrin can directly stimulate the parietal cells to increase
activity of the H+-K+-ATPase or indirectly by inducing
the release of histamine from ECL cells.
c. Neurocrine regulation of acid secretion by
acetylcholine is mediated by both direct stimulation of
the parietal cell and indirect stimulation of ECL cells
resulting in the release of histamine. Histamine
release from ECL cells onto neighboring parietal cells
(paracrine regulation) stimulates H+-K+-ATPase
activity.
d. Gastric mucosal protection is mediated by several
factors. The paracrine release of prostaglandins
(PGE2) ↓’s or negatively regulates H+-K+-ATPase
activity. Additionally, prostaglandins and acetylcholine
promote the secretion of mucus and bicarbonate from
gastric epithelial cells. Finally, the release of
somatostatin into the blood by gastric D cells ↓’s acid
secretion by inhibiting the release of gastrin from G
cells, inhibiting the release of histamine from ECL
cells, and inhibiting H+-K+-ATPase activity
2. Understand the therapeutic strategies to treat gastric ulcers and H. pylori infections.
a. Treatment of H. pylori positive patients with ulcers utilizes agents to reduce acid production and
eliminate the bacterial infection. Older therapeutic regimes used to eradicate H. pylori
employed three agents, and was coined “triple therapy”. This strategy employed bismuth
subsalicylate, tetracycline, and metronidazole. The modern “triple therapy” strategy utilizes a
PPI, clarithromycin, and amoxicillin or metronidazole. The newer line of defense may be
combined with the bismuth subsalicylate for “quadruple therapy”. (One acid reducer and 2
abxs)
3. Understand the mechanism of action, adverse effects, and therapeutic use of each of the agents
used to treat acid-peptic disease.
Antacids
1
Duration
of Action
Agent
Rate of
reactivity
Sodium
bicarbonate
[NaHC03]
Calcium
carbonate
[CaCO3]
Magnesium
hydroxide
[Mg(OH)2]
Common
adverse effects
Specific
Adverse effects
fast
-metabolic alkalosis*
-excessive NaCl absorption*
-gas/bloating*
moderate
-acid rebound*
-gas/bloating*
-hypercalcemia (large doses)
-hypophosphatemia (rare)
-reduced drug
bioavailability
1- 2 hrs.
slow
-enteric infection
Aluminum
hydroxide
[Al(OH)2]
-osmotic diarrhea*
-hypermagnesemia (large doses
over extend periods of time)
-constipation*
-aluminum toxicity (impaired renal
function)
-hypophosphatemia
-bone resorption
-hypercalcemia
slow
H2-receptor antagonist
Agent
Duration of
action
Common adverse
effects
cimetidine
(Tagemet)
(safe drugs)
headache*
ranitidine
(Zantac)
nizatidine
(Axid)
10 hrs.
or
6 hrs. OTC
diarrhea
fatigue,
constipation,
infection,
drug kinetics,
bradycardia (IV),
hypotension (IV)
famotidine
(Pepcid)
Adverse effects
Cimetidine specific considerations:
-CNS effects (confusion,
hallucinations, agitation)
-endocrine effects (inhibition of
androgen receptors, inhibition of
estradiol metabolism, increase
prolactin levels)
-inhibition hepatic CYP metabolism
Proton Pump Inhibitors (PPIs)
Agent
Duration of
action
Omeprazole
(Prilosec)
Lansoprazole
(Prevacid)
Rabeprazole
(Aciphex)
Esomeprazole
(Nexium)
Pantoprazole
(Protonix)
Common
adverse effects
Adverse effects
-Extremely safe
24 hours
-Decreased drug
bioavailability
Takes 3-4 days
of dosing to
-Diarrhea,
reach max effect headache,
abdominal pain
(1-5%)
-Decreased nutrient absorption
(Vitamin B12, Iron, Calcium,
Zinc)
-enteric & respiratory infection
2
Mucosal Protective Agents
Agent
Duration of
action
Sucralfate
(Carafate)
Misoprostol
(Cytotec)
Bismuth
subsalicylate
(Pepto-Bismol)
6 hours
Common
adverse effects
Adverse effects
Constipation,
impaired drug
absorption
Caution w/ renal
insufficient
patients
Cramping,
diarrhea
abortificient
Blackening of
stool and tongue
High doses
salicylate toxicity
4. Understand key regulatory receptors and their ligands of gastrointestinal motility.
a. Prokinetic agents
Gastrointestinal motility is
dopamine
5-HT
regulated by multiple
D2
D2
5-HT4
5-HT4
5-HT4
neurotransmitters and
ENS
hormones. The receptors
neurons
that these neurotransmitters
D2
D2
and hormones activate are
Ach
Ach
excellent targets for
M3
M3
MR
AchE
pharmacological regulation
GI
smooth
muscle
of gastrointestinal motility.
Serotonin (5-HT) is a
5-HT4 Serotonin receptor-4
AchE Acetylcholinesterase
common neurotransmitter of
D2 Dompamine receptor-2
Muscarinic receptor-3
M3
the enteric nervous system
(ENS) that stimulates
MR Motilin receptor
gastric motility through
inducing the
release of acetylcholine by neurons onto gastrointestinal smooth muscle. Additionally, serotonin
plays a role in relaying sensory information from the gut to the CNS. Targeting serotonin
receptors has had some therapeutic utility however its clinical usefulness and safety is under
constant evaluation. Dopamine activates presynaptic receptors to ↓ the firing of ENS neurons,
which serves to ↓ gastric motility. Antagonizing these receptors will therefore ↑ neuronal firing
and GI motility. The parasympathetic and ENS neurotransmitter, acetylcholine (Ach) activates
muscarinic receptors to induce contraction of gastrointestinal smooth muscle. The inactivation
of acetylcholine is mediated in part through degradation by acetylcholinesterase (AchE).
Therefore agonists to the M3 receptor and inhibitors of AchE will increase motility. Unlike the
neurotransmitters 5-HT, Ach, and dopamine, motilin is a hormone. Motilin promotes gastric
motility through activation of motilin receptors located on gastrointestinal smooth muscle.
.
3
These receptors
are sites of
pharmacological
intervention that
can be regulated
by several
agonists and
antagonists to
promote the
contraction of
gastrointestinal
smooth muscle,
as indicated in
the table.
Agent
Mechanism
of Action
Metoclopramide
(Reglan)
D2 antagonist
Bethanechol
(Urecholine)
Neostigmine
(Prostigmin)
Erythromycin
(Erythrocin)
M3 agonist
AchE inhibitor
Motilin
Receptor
agonist
Use
Adverse effects
- GERD
- Impaired gastric
emptying
- dyspepsia
- antiemetic
- CNS (restlessness,
drowsiness, insomnia,
anxiety)
- altered motor
function (Parkinsonian
symptoms)
- GERD
- gastroparesis
Cholinergic side
effects
Non-obstructive:
-urinary retention
-abdominal
distension
Cholinergic side
effects
- gastroparesis
Erythromycin
mediated side effects
5. Understand the regulatory inputs that mediate an emetic response.
a. An emetic response can be initiated by sensory stimulation, blood-borne emetics,
or gastrointestinal irritants. The emetic response is ultimately mediated through
the emetic center located in the medulla. Regulation of this response at the
receptor level is under control of serotonin, dopamine, muscarinic, histamine, and
neurokinin receptors. Simply antagonizing these receptors can block or blunt an
emetic response.
Pharmacologist's view of
emetic stimuli.
Myriad signaling pathways
lead from the periphery to
the emetic center.
Stimulants of these
pathways are noted in
italics. These pathways
involve specific
neurotransmitters and their
receptors (bold type).
Receptors are shown for
dopamine (D2),
acetylcholine (muscarinic,
M), histamine (H1), and 5hydroxytryptamine (5-HT3).
Some of these receptors
also may mediate signaling
in the emetic center.
Goodman & Gilman's The
Pharmacological Basis of
Therapeutics, 11th Edition
4
b. In addition to antagonizing these receptors, other central nervous system targets
are useful in the suppression of an emetic response. These sites include
GABAergic neurons, cannabinoid receptors throughout the CNS, glucocorticoid
receptors, and opioid receptors at non-emetic center sites. The following agents
are useful in the suppression of an emetic response :
Agent
Ondansetron
(Zofran)
Mechanism
5-HT3
antagonist
Use
Adverse effects
- Chemotherapy
- Postoperative
- Postradiation
- Headache
- Dizziness
- Constipation
- Prolonged QT interval
Scopolamine
(Transderm Scop)
M1
antagonist
- Motion sickness
- Antimuscarinic effects
Metoclopramide
(Octamide)
D2
antagonist
Chemo- & radiationtherapy induced nausea
and vomiting
-Extrapyramidal
(Parkinsonian symptoms)
- Motion sickness
- Drowsiness
- Chemotherapy
- Fatigue
- Dizziness
- Diarrhea
- CYP3A4 Interactions
- Severe nausea & vomiting
- Extrapyramidal
- Drowsiness
- Anticholinergic
- Anxiety/Chemotherapy
- Drowsiness
- Chemotherapy
-Dysphoria
-Sedation
-Increased appetite
-Chemotherapy
-Postoperative
- Weight gain
- water retention
- other corticosteroid effects
Dimenhydrinate
(Dramamine)
Aprepitant
(Emend)
Prochlorperazine
(Compro)
Lorazepam
(Ativan)
Nabilone
(Cesamet)
H1
antagonist
NK1
antagonist
M1 D2 H1
antagonist
GABA
agonist
Cannabinoid
agonist
Dexamethasone
Glucocorticoid
agonist
(increase effectiveness of 5-HT
antagonists)
6. Understand the mechanism of action, adverse effects, and therapeutic use of
agents for the treatment of motility, emetic, and water flux disorders. (See Emetics
suppressants above)
5
Laxatives
Agent
Mechanism of
Action
Bulk-forming
Methylcellulose
(Citrucel)
Fiber
Adds bulk and retains
H20
Surfactant
Glycerin
(Colace)
Coates and penetrates
fecal material
Use
Adverse Effect
- gas/bloating
constipation
minimize straining
- nutrient
malabsorption
prior to surgical and
endoscopic
procedures
- gas
- electrolyte
flux
poor
Osmotic
Lactulose
(Enulose)
Change osmotic
pressure
Stimulant
Senna
(Ex-Lax)
Stimulate ENS
Serotonin Agonist
Tegaserod
(Zelnorm)
Absorp.
5-HT4 agonist
-GI irritation
10%
chronic idiopathic
constipation
- GI
- CV
- note: not available for
general use
Chloride Channel
Activator
Lubiprostone
(Amitiza)
Prostaglandin
Derivative
poor
chronic constipation
- nausea/vomiting
- diarrhea
Antidiarrheals
Agent
Mechanism of
Action
Loperamide
(Imodium)
Diphenoxylate
(Lomotil)
diarrhea (IBS)
Opioid agonist
diarrhea
Bismuth
subsalicylate
(Pepto-Bismol)
-Inhibit PG synthesis
(intestinal)
- Absorb toxins
Kaolin & Pectin
(Kaopectate)
- Add bulk, absorb
toxins
Cholestyramine
(Prevalite)
Use
Bind bile acids and
salts
-non-specific
diarrhea
-travelers diarrhea
diarrhea
Impaired bile-salt
absorption
mediated diarrhea
Octreotide
(Sandostatin)
Somatostatin
receptor agonist
Secretory diarrrhea
Adverse effects
Constipation (very safe)
CNS effects, atropine
effects
Salicylate toxicity
Constipation
-Bloating, flatus,
constipation
-Fecal impaction
-Impaired fat absorption
-Impaired pancreatic
secretion
-Decreased GI motility
(nausea, pain)
-Decreased gall bladder
contraction
- Glucose homeostasis
6
7. Understand the pathophysiological differences between IBS and IBD.
a. Irritable Bowel Syndrome (IBS)
- Irritable bowel syndrome is an idiopathic chronic relapsing disorder characterized by
abdominal discomfort (pain, bloating, distension, or cramps) in association with
alterations in bowel habits (diarrhea, constipation, or both).
- Since the cause of this disease is unknown, current therapeutic strategies are aimed at
relieving symptoms, such as reducing pain and improving bowel function. Common
approaches to treating IBS-associated pain include use of low doses of tricyclic
antidepressants (desipramine and amitriptyline) or antispasmodics/antimuscarinic
agents (dicyclomine and hyoscyamine). The use of tricyclic antidepressants results
in impaired uptake of serotonin and other amines. This results in downregulation of
serotonin receptors in the CNS which results in a blunted pain response from GI
afferent fibers. The antimuscarinic agents block GI smooth muscle contraction and
spastic activity that may contribute to the pain associated with IBS. Antidiarrheal
agents are useful to treat IBS-associated diarrhea and conversely laxatives are used
to treat IBS-associated constipation. More recent therapies have taken advantage of
more direct serotonergic regulation of bowel motility and sensation. Activation of both
5-HT3 and 5-HT4 receptors stimulates motility. 5-HT3 receptors are also important in
relaying sensory information, such as pain, to the CNS. Therefore antagonizing 5-HT3
receptors can be used to relieve pain and diarrhea, while stimulating 5-HT4 receptors
can be used to relieve IBS-associated constipation.
- Serotonin agonists and antagonists currently or recently used in the treatment of IBS
are: Tegaserod (Zelnorm) and Alosetron (Lotrenex)
b. Irritable Bowel Disease (IBD)
- Inflammatory bowel disease (IBD) can be divided into two distinct diseases, ulcerative
colitis and Crohn’s disease. Both diseases are characterized by inflammation of the GI
tract. However the exact pathogenesis of each disease remains to be determined.
Crohn’s disease can affect any part of the GI tract but is generally associated with the
ileum. The site of origin for Crohn’s disease is the intestinal submucosa and
eventually spreads to the mucosa and serosa and is often characterized by its pattern
of skip lesions. Ulcerative colitis affects the large intestine and originates in the crypts
of Lieberkühn.
- The therapeutic strategies for the treatment of IBD are common strategies to suppress
inflammation and include: 5-aminosalicyclic acid therapy, glucocorticoids,
immunosuppressive agents, anti-TNF therapy.
- The aminosalicylates work “topically” at the mucosal surface of the gastrointestinal
tract. Absorption of the agents prior to delivery of drug to the inflamed tissue renders
them ineffective. Therefore the agents have either been chemically modified or
packaged to prevent absorption by the gut so as to more effectively reach the target
tissue. The precise mechanism of action of these agents is not clearly defined.
Possible mechanisms of action may include the inhibition of the inflammatory
cytokines IL-1 and TNF-, scavenging of free radicals, inhibition of the transcription
factor NF-B, and possibly the inhibition of COX. Key 5-ASA compounds and their
targets are summarized below.
7
Aminosalicylates: 5-aminosalicylic acid (5-ASA)
Agent
Administration
Target
Modification
colon
Azo bond linked
(N N)
MesalaminePentasa
Throughout the
intestine
Time release
microgranules
MesalamineAsacol
ileum/proximal
colon
pH sensitive resin
Rectum/sigmoid
colon
High
concentrations
Sulfasalazine
Balsalazide
Olsalazine
MesalamineRowasa & Canasa
oral
Enema or
suppository
8. Understand how serotonin regulates motility and the sensation of pain in the gastrointestinal
tract.
a. Serotonin (5-HT) is a common neurotransmitter of the enteric nervous system (ENS) that
stimulates gastric motility through inducing the release of acetylcholine by neurons onto
gastrointestinal smooth muscle. Additionally, serotonin plays a role in relaying sensory
information from the gut to the CNS. Targeting serotonin receptors has had some therapeutic
utility however its clinical usefulness and safety is under constant evaluation.
9. Understand the therapeutic strategies for the treatment of both diarrhea- and constipationpredominant IBS.
a. targeting serotonin receptors to modulate GI function holds significant theoretical promise.
Tegaserod is a 5HT4 receptor agonist that was first approved for the treatment of irritable bowel
syndrome (IBS)-constipation predominant and chronic idiopathic constipation
b. The antimuscarinic agents block GI smooth muscle contraction and spastic activity that may
contribute to the pain associated with IBS. Antidiarrheal agents are useful to treat IBSassociated diarrhea and conversely laxatives are used to treat IBS-associated constipation.
More recent therapies have taken advantage of more direct serotonergic regulation of bowel
motility and sensation. Activation of both 5-HT3 and 5-HT4 receptors stimulates motility. 5-HT3
receptors are also important in relaying sensory information, such as pain, to the CNS.
Therefore antagonizing 5-HT3 receptors can be used to relieve pain and diarrhea, while
stimulating 5-HT4 receptors can be used to relieve IBS-associated constipation.
- Serotonin agonists and antagonists currently or recently used in the treatment of IBS
are: Tegaserod (Zelnorm) and Alosetron (Lotrenex)
8
10. Understand the 5 key therapeutic strategies in the treatment of IBD.
11. Understand the mechanism of action, adverse effects, and therapeutic use of the agents used
for the treatment of IBS and IBD.
Glucocorticoids
Agent
Administration
Prednisone
1.
Prednisolone
Hydrocortisone
Mechanism
IV, oral ,
suppository
2.
3.
4.
Suppression of inflammatory cytokines
(TNF, IL-1)
Suppression of chemokines (IL-8)
Suppression of adhesion molecules
Suppression of signal transduction
molecules that mediate cytokine and
chemokine activities (NOS, PLA2,
COX2, NF-B)
Budesonide
9
Antimetabolites (CA chemotherapeutic agents)
Agent
Administration
6-mercaptopurine
azathioprine
IM, SC, and
orally
methotrexate
Mechanism
Inhibition of purine synthesis resulting
in decreased DNA synthesis and
repair leading to decreased cell
proliferation
Inhibits DHFR resulting in impaired
cellular proliferation.
Antibiotics – metronidazole, cirprofloxin, and clarithromycin
Probiotics
Important agents in treating IBD
Agent
Use
Sulfasalazine
(Azulfidine )
Ulcerative colitis
Adverse effects
Nausea, GI upset, headacehe,
arthralgia, myalgia, bone marrow
suppression, malaise (40%)
Very safe
Mesalamine
Ulcerative colitis
(Pentasa)
Prednisone
(Predone)
*
Moderate to severe
active IBD
Glucocorticoid adverse effects
Azathioprine
(Azasan)
Maintenance of remission Nausea, vomiting, bone marrow
of IBD (onset 17 weeks) suppression.
Methotrexate
(Rheumatrex)
Maintenance of remission Low dose side effects uncommon,
of Crohn’s
but include bone marrow
depression
(onset 8-12weeks)
Infliximab
(Remicade)
Moderate to severe
IBD
infection
Inflixamab is a mouse/human chimeric immunoglobulin that binds and sequesters TNF. The TNFantibody complex cannot bind to the TNF receptor and stimulate the production of inflammatory
cytokines thus inhibiting an inflammatory response.
12. Review and understand attached case studies.
10