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Pharm Block 4 > GI > Flashcards

GI Flashcards

1
Q

Where is enteric plexus located?

A

Enteric neurons are organized in ganglia found within two main plexi:

  • An outer myenteric plexus develops first and occupies a position between the longitudinal and circular muscle layers
  • An inner submucosal plexus forms later in gestation and resides within the submucosa
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2
Q

What is MMC

A

MMC: Migrating motor complex during fasting for sweeping. Propulsive, peristaltic reflex contraction during intermittent feeding for mixing

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3
Q

Which cells release serotonin?

A

Enterochromaffin cells

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4
Q

What are the primary positive physiological stimuli for GI contraction?

A

ACh and substance P

(Released from motor neurons in the myenteric plexus of the ENS. These stimulate contraction of GI smooth muscle by inducing increased intracellular Ca2+)

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5
Q

What are the negative signals and what are they generated by?

A

NO (nitric oxide) and VIP (vasoactive intestinal peptide),

Maintain muscle relaxation downstream of the contractions

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6
Q

What are the common neurotransmitters in GI-related signaling pathways

A

ACh- cholinergic receptors

Dopamine - dopaminergic receptors

Serotonin - serotonergic receptors

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7
Q

What are prokinetic agents?

A

Prokinetic agents promote coordinated gastrointestinal motility and luminal transit of material in the GI tract

Modern prokinetic agents enhance acetylcholine release without interfering with the normal physiological pattern and rhythm of motility

These drugs modulate rather than mediate motility

Prokinetic agents commonly used for gastroparesis (delayed gastric emptying); may also be used for treatment of indigestion/dyspepsia; GERD

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8
Q

What are the classes of prokinetic agents?

A
  • Cholinergic agents
  • Dopamine antagonists
  • Serotonin agonists
  • Macrolides
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9
Q

Neostigmine

A

It is a cholinergic agent, increases the availability of ACh by reversibly inhibiting acetylcholinesterases

(It is stimulatory but not directly)

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10
Q

Domperidone

A

Dopamine receptor (D2) antagonist, thus preventing the inhibition of the nerve fiber releasing ACh

  • Dopamine normally inhibits gastric motility, preventing/reducing the release of ACh
  • Domperidone inhibits the effects of dopamine in the myenteric plexus, but does not penetrate/cross the BBB/CNS
  • Domperidone not approved by the FDA for use in the US, risk of sudden cardiac death
  • Classic dopamine antagonists, such as the phenothiazines, are effective, but produce extrapyramidal side effects
  • Off-label use: use as a “galactagogue” to enhance breast milk production in lactating women
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11
Q

Metoclopramide

A

Causes seretonin receptor modulation (5-HT)
It activates serotonin receptor 5-HT4 and acts as an antagonist against dopamine receptor D2

  • Metoclopramide is the only FDA-approved drug for gastroparesis
  • Primary mechanism for the effects of metoclopramide on motility is stimulation of 5-HT4R on interneurons that facilitate acetylcholine release
  • A secondary effect of metoclopramide on motility: inhibition of D2R

Combined effect of metoclopramide on the GI tract leads to increased gastric emptying and decreased transit time through the small intestine.

*CAN cross the BBB, and thus antagonize D2 receptors in the brain. Has a “Black box warning” for risk of the development of tardive dyskinesia (TD). Highest risk for TD is seen in the elderly, especially older women

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12
Q

Erythromycin

A
  • Motilin-like agent
  • Macrolide class
  • activates motilin receptors (Motilin (22 amino acid peptide) is the main peptide transmitter that regulates the migratory motor complex (MMC))
  • Erythromycin and azithromycin are macrolide antibiotics and motilin agonists that enhances upper GI motility with little or no effect in the colon
    Both can improve gastric emptying and are used (off-label) for gastroparesis
  • Camicinal is a new, non-macrolide small molecule with potential to serve as the next generation motilin agonist
  • ESPECIALLY used in diabetics with gastroparesis or used to clean GI tract prior to emergency surgery or an endoscopy for acute upper GI bleeding
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13
Q

Actions of Grehlin

A

Increased gastric acid secretion & increased gastric movement

Ghrelin itself has too short a half-life and plasma instability for use as a a therpaeutic

(relamorelin (RM-131)
Relamorelin is a pentapeptide derived from the ghrelin sequence. Accelerates gastric emptying of solids in patients with proven gastroparesis, 100 times more potent than ghrelin)

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14
Q

Compare/Contrast Motilin & Grehlin

A
  • Both are released during fasting
  • Both stimulate gastrin gastric motility
  • Motilin and its receptor are mainly restricted to the GI tract whereas Gremlin and its receptor are relatively widespread
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15
Q

Where can anti-emesis/nausea meds target?

A

Antiemetic and antinausea compounds can target central emesis centers and/or the GI smooth muscle

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16
Q

What are central emesis centers regulated by?

A

Central emesis centers are regulated by 5HT3R, D2R, and opioid receptors

  • The Chemoreceptor Trigger Zone (CTZ) lacks a blood brain barrier and can therefore monitor blood and cerebrospinal fluid for toxicants
  • Feedback from gut to CTZ comes from vagal afferents and neurons enriched with receptors for enkephalins, histamine, and acetylcholine
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17
Q

What are the different ways the vomitting response can be brought about?

A
  • psychogenic input from cortex (memory/fear)
  • vagal afferents (food poisoning/chemo)
  • motion input (vestibular apparatus)
  • emetic substances in blood
  • CTZ
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18
Q

Which serotonin receptor is involved in emesis?

releases when GI tract is distended or irritated

A

5-HT3

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19
Q

What are the 2 main stream antiemetic drugs?

A

Ondansetron (5HT-3 receptor antagonist)
Metoclopramide (centrally acting DA receptor antagonist)

*often used in combination to improve efficiency and reduce side effects

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20
Q

Dopamine antagonsist as antiemetics:

A
  • Metoclopramide or domperidone are commonly used for serious vomiting and act by blocking D2R in the CTZ
  • High dose metoclopramide is more effective for use in chemotherapy-induced nausea due to its prokinetic effects (but high doses can result in extrapyramidal SIDE EFFECTS)
  • Dopamine antagonists are NOT useful for motion sickness, unless they also have muscarinic (cholinergic) antagonist activity
  • Phenothiazines (prototypical is chlorpromazine) = useful in acute or emergency situations, but have too many extrapyramidal side effects to warrant chronic use (crosses BBB)
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21
Q

Seretonin receptor antagonists as antiemetics:

A
  • Ondansetron is a 5HT3R antagonist used in the treatment of nausea, especially that which originates in the gut.
  • inhibit emesis mediated through blocking 5-HT3 receptors both in the periphery and central nervous system (area postrema), with primary effects being in the GI tract
  • Binding to 5-HT3Rs located on the vagal neurons in the lining of the GI tract could block the signal to the vomiting center in the brain, thus preventing nausea and vomiting
  • Effective against CHEMOtherapy or irradiation-induced nausea; also in pregnancy (and to a lesser extent, in postoperative nausea)
  • Same efficacy as high dose metoclopramide for chemotherapy-induced emesis, without the extrapyramidal/CNS side effects
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22
Q

Antihistamines & muscarinic (cholinergic) antagonists:
(Diphenhydramine - Antihistamine)
(Scopolamine - Antimuscarinic)

A
  • Most effective for motion sickness
  • Nonsedating antihistamines appear less effective
  • scopolamine (hyoscine) patches, are effective in more severe vestibular disorders and motion sickness
  • Antihistamines and muscarinic antagonists are NOT useful for treating chemotherapy-related nausea
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23
Q

Receptor affinity

A

Ondansetron - high affinity to Serotonin
Domperidone - high affinity to Dopamine
Metoclopramide - high affinity to Dopamine

24
Q

Dronabinol

A
  • Canniboid receptor antagonist used in cases of cytotoxic drug induced emesis
  • pure isomer of THC, (-)-trans-Δ9-tetrahydrocannabinol, the main isomer in cannabis)

*cannabinoid used prophylactically for cancer chemotherapy-related nausea

25
Q

What is the most commonly used agent in combination anti-emetic therap?

A

Dexamethasone (a glucocorticoid steroid) is the most commonly used agent in combination anti-emetic therapy

26
Q

Nature’s antiemetic?

A
  • ginger can prove mildly effective against nausea from motion sickness, morning sickness, and after surgery
  • Antiemetic action attributed to the shogaols and gingerols, thought to stimulate the flow of saliva, bile and gastric secretions
  • Constituents in ginger believed to interact with 5HT-3 receptors, and partially responsible for antiemetic activity
27
Q

What is the principal determinant of stool volume?

A

Water

The treatment approach for diarrhea & constipation remains largely empirical

28
Q

The treatment for constipation:

A

Mild constipation should initially be treated with diet and behavior changes: adopting a fiber rich diet, increase fluid intake, increase physical activity, and develop bowel habits that take advantage of natural physiological rhythms

Slower bulk-forming and surfactant laxatives represent the common first ‘pharmacotherapy’ intervention

When using stimulant laxatives (promote water accumulation of water in the intestines, as well as stimulate intestinal motility), they should be administered at the least-effective dosage for the shortest period of time, to prevent developing a laxative dependence for normal bowel function and to prevent a diarrheal-like response

If conventional laxatives prove ineffective, prokinetic agents may be employed

29
Q

Diarrhea treatment

A

A sudden onset of diarrhea is usually a benign, self-limited, illness requiring no treatment

In severe cases dehydration and electrolyte imbalances are the principal risks, particularly in infants and frail elderly patients

Oral rehydration therapy is a cornerstone treatment of patients with significant diarrhea. Sodium and chloride absorption is linked to glucose uptake by the enterocyte; this is followed by the movement of water in the same direction

FINALLY of those don’t work:

  • Bulk forming agent = Metamucil (psyllium seed husks)
  • Clay = Kaopectate (kaolin), which bind water avidly
  • Bismuth compounds, most commonly Pepto-Bismol (bismuth subsalicylate) Has anti-secretory, anti-inflammatory and antimicrobial effects. Generally safe, but will blacken the stool, and side effects may include tinnitus and constipation
  • Opioids can act as antidiarrheal agents
  • Loperamide (Imodium and Imodium-AD) is 40-50 times more potent than morphine, as an antidiarrheal agent, and has a limited ability to enter the CNS. It is orally active and generally safe, but side effects may include abdominal pain, constipation, dizziness, nausea
30
Q

Gastric Acid regulation

A

Antacids

(Histamine) H2-receptor antagonists
- Cimetidine

Proton pump inhibitors
- Omeprazole

31
Q

What controls gastric acid secretion?

A

Gastric acid secretion is under:

  • neuronal (acetylcholine)
  • paracrine (histamine)
  • endocrine (gastrin) control

*All three impact the activity of the H+, K+-ATPase (proton pump) responsible for gastric acid release

*Gastrin from antral G cells binds to cholecystokinin B receptors (CCKBR or CCK2) in parietal cells and ECL cells (the latter stimulates the release of histamine)
Gastrin’s mechanism is both direct and indirect

32
Q

Where does histamine come from and what does it do?

A

Histamine comes from ECL cells and it binds H2 receptors in parietal cells, stimulating gastric acid secretion of proton pumps

33
Q

Function of antacids:

A
  • Neutralize secreted acid; do not alter acid secretion
  • Most clinically useful preparations are combinations of aluminum or magnesium hydroxide (Liquids are more effective than tablets)
  • Primary mechanism is neutralizing the released acid to raise pH and thereby inactivate pepsin
  • Aluminum hydroxide can cause constipation
  • Magnesium hydroxide has laxative properties
34
Q

Histamine-receptor (H2) blockers

A

“-dine”

  • Pepcid AC® (Famotidine), Pepcid Complete® (Famotidine + CaCO3 + Mg(OH)2), Zantac® (Ranitidine), Tagamet® (Cimetidine)
  • Safe competitive inhibitors of the H2-receptor
  • Available OTC
  • Highly effective in healing duodenal ulcers and treating uncomplicated GERD
  • greatest effect of H2 blockers is on basal acid release; less effective on stimulated release
35
Q

Proton Pump Inhibitors (PPIs)

A
  • Omeprazole is the prototypical PPI; all others are clinically comparable
  • PPIs are prodrugs that are activated to a highly reactive species in an acid environment
  • Inhibition occurs by the covalent and irreversible binding of the reactive PPI metabolite to the pump protein
  • Indicated for short-term treatment and prevention of several acid-related disorders
  • Longer term use, however, has been increasingly associated with adverse outcomes of varying significance
  • interactions w/ Clopidogrel
  • Individuals on PPIs had significantly increased risk of incident dementia compared with those not receiving PPIs (statistical association)
36
Q

Severity of GERD & management:

A

Stage 1 (sporadic symptoms, less than 2-3 per wk) – lifestyle changes, antacid, & maybe H2 antagonist

Anything more than stage 1 = PPI

37
Q

What is Irritable Bowel Syndrome (IBS)?

A

A functional disorder, marked by chronic or recurrent GI symptoms, which are not explained by obvious organic (anatomical or biochemical) abnormalities
IBS-C (constipation)
IBS-D (diarrhea)
IBS-M (mixed constipation & diarrhea)

  • Lower abdominal pain is the central defining feature
38
Q

Serotonin levels and IBS

A

Reduced plasma serotonin levels may be correlated with IBS-Constipation
Increased serotonin release may play a role in IBS-Diarrhea

39
Q

Treating IBS with serotonin receptor modulators:

Alosetron (Lotronex) for IBS-D

A

Alosetron (Lotronex) for IBS-D

  • 5-HT3 receptor antagonist for women with severe diarrhea-predominant IBS (IBS-D) who have failed to respond to conventional treatment for IBS
  • Reduces motility and intestinal sensitivity to distension

*withdrawn from the market in November, 2000, because of serious, life-threatening, gastrointestinal side effects (ischemic colitis).

40
Q

Treating IBS with serotonin receptor modulators:

Tegaserod (Zelnorm) for IBS-C

A

Tegasarod is a 5-HT4 agonist intended for short-term treatment of women with IBS-C, or chronic constipation.

  • Relieves pain, bloating and constipation. Can induce mild to severe diarrhea, which is dose-dependent. There may also be increased risk of ischemic colitis
  • higher chance of heart attack, stroke, and unstable angina (compared to placebo)
41
Q

Adverse effects of the early 5‑HT4 agonists are thought to be related to:

A

Adverse effects of the early 5‑HT4 agonists are thought to be related their relative lack of selectivity and resultant actions on other targets

hERG potassium channels
dopamine receptors
5‑HT1 and 5‑HT2 receptors

42
Q

Lubiprostone (Amitiza) for IBS-C

A

Uses:

  • IBS-C (adult women)
  • Chronic idiopathic constipation (CIC in adults)
  • Opioid-induced constipation (OIC in adults w/chronic non-cancer pain)

Mechanism:
- Activates ClC-2 chloride channel in epithelial cells lining the intestinal tract. [Cl-] in the intestinal lumen increases; as chloride moves into the intestinal lumen, Na+ ions and fluids passively follow

43
Q

Linaclotide (Linzess) for IBS-C

A

Mechanism:

  • Guanylate cyclase-C (GC-C) agonist (First in class)
  • Increases [cGMP]; increases [Cl-] in intestinal lumen; as chloride moves into the intestinal lumen, increase in intestinal fluid and faster transit
  • Metabolized within the GI tract to its principal, active metabolite by loss of the terminal Tyr
44
Q

New drug for IBS-D

Eluxadoline

A
  • A mixed opioid receptor agonist that reduces bowel contractions
  • μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system
45
Q

Inflammatory Bowel Disease (IBD)

A
  • IBD is a spectrum of chronic idiopathic inflammatory intestinal conditions.
  • Etiology is unknown, but genetic, environmental and intestinal microbial factors are reported to play a role
  • Symptoms include diarrhea, abdominal pain, bleeding, anemia, weight loss

IBD conventionally divided into two major subtypes:

  • Ulcerative colitis (UC): lining of the large intestine (colon) and rectum are inflamed
  • Crohn’s disease (CD): can affect the small and large intestine as well as other organs in the digestive tract; commonly involves all layers of the intestinal wall (transmural inflammation of any part of the the GI tract)
46
Q

Medical therapy for IBD problematic

A

no unique abnormality identified, pharmacological therapies seek to to dampen generalized inflammatory response

  • Mild to moderate disease is treated with sulfasalazine/mesalamine and steroids
  • Steroid refractory or intolerant patients are treated with methotrexate or cyclosporine for short-term efficacy and azathiopurine/6-mercaptopurine for long-term therapy
  • Newer therapies (‘biologics’) target immunologic mediators and are changing therapeutic strategies
47
Q

Sulfasalazine

A
  • Used to treat mild to moderately active UC with lower doses useful in remission.
  • Major action is anti-inflammatory
  • More effective in UC than CD
  • Not given to patients with sulfa drug or salicylate allergies.
  • prodrug cleaved by gut bacteria (diazo linkage cleaved… azo linkage in sulfasalazine prevents absorption in the stomach or small intestine)
  • Mesalamine (5-aminosalicylic acid, or 5-ASA) is primary active metabolite in the gut. Sulfapyridine is the more toxic metabolite
  • mesalamine couldn’t be given orally w/o azo linkage, the bulk of it would be absorbed in the upper GI tract. Second generation 5-ASA compounds were designed as prodrugs with an azo linkage, or were coated to control site of absorption
48
Q

Corticosteroid treatments for IBD

A

Budesonide approved for treatment of mild-to-moderately active CD and UC

Prednisone and prednisolone used for moderate-to-severe CD and UC

Steroids are potentially toxic; withdrawal must be tapered

49
Q

Immunomodulator treatments for IBD

A

Azathioprine and 6-mercaptopurine (‘Mercaptopurine’ or 6MP) are the most commonly used immunosuppressive agents to treat moderate to severe IBD and to maintain remission

Azathioprine is the prodrug and can be used interchangeably with its metabolite mercaptopurine, to treat moderate to severe disease and to maintain remission

The major limitation of these drugs is that they take several weeks to produce effects in ulcerative colitis and Crohn’s disease. However, they reduce the requirement for steroids to maintain patients in remission

Major side effects are bone marrow depression, leukopenia, teratogenesis

50
Q

Methotrexate

A

alternative immunosuppressant used for IBD

Effective for CD

Originally used for cancer treatment, through inhibition of dihydrofolate reductase, DNA synthesis blocked, resulting in cell death

Subsequently recognized to have beneficial effect in autoimmune disease (rheumatoid arthritis, psoriasis). Anti-inflammatory mechanism not fully understood

Reserved for patients with CD that is steroid-resistant or steroid-dependent, although treatment has largely been replaced by biological therapies

51
Q

Categories of therapeutic mAbs

A

Murine antibodies

  • short half-life*
  • potential issues concerning the generation of human anti-mouse antibodies leading to allergic-like reactions or immunogenicity

Chimeric antibodies
- fusion of mouse variable with human constant domains
25-33% mouse and 67-75% human amino acid sequences
relatively favorable safety profile and half-life, while retaining the specificity (e.g., high target or antigen affinity) of murine antibodies

Humanized antibodies

  • contain 5−10% mouse and 90−95% human amino acid sequences
  • exhibited a lower challenge to the human immune system
  • CDRs within variable regions of heavy and light chains grafted or interspersed by murine antigen into the human immunoglobulin.

“Fully human” antibodies
100% human amino acid sequence

52
Q

Treating IBD with biologicals

A

Protein-based therapies (e.g. antibodies, receptor antagonists) are becoming the main strategy for treating refractory CD and UC

  • high level of efficacy in patients unresponsive to conventional therapies
  • Potentially dangerous in individuals with chronic infections, cancers, or immune deficiencies
  • Possible induction of neutralizing antibodies (“antidrug antibody” or ADA), with loss of response to drug
53
Q

Targeting tumor necrosis factor-α (TNF-α)

A

TNF-α is a potent proinflammatory cytokine that plays a key role in orchestrating the inflammatory process in multiple autoimmune diseases

IBD is characterized by a dysregulated mucosal immune response toward the commensal enteric flora in genetically susceptible individuals

This immune dysregulation results in an overproduction of TNF-α by monocytes, macrophages, and T cells
mAbs targeting TNF-α (infliximab, adalimumab, and certolizumab) induce the formation of regulatory macrophages with immunosuppressive properties

This population of macrophages inhibits proliferation of activated T cells and produces anti-inflammatory cytokines

54
Q

Infliximab (& adalimumab)

A

bind to TNF and prevent the molecule from interacting with its two receptors, TNFRI and TNFRII, thereby stopping signaling events. These large inhibitor molecules prevent binding of either sTNF or proTNF to their membrane receptor targets

55
Q

TNF-α inhibitors used in Crohn’s Disease

A

Infliximab (Remicade) - mouse/human IgG Ab

Adalimumab - Human IgG Ab
(Humira)

Certolizumab pegol - Humanized Fab fragment linked to 2 PEG molecules
(Cimzia)

56
Q

Targeting integrins

A

Integrins are cell adhesion molecules essential for the regulation of cell growth and function

cell surface receptors, comprising non-covalently linked α- and β-subunits

  • Natalizumab, a humanized mAb specific for α4, found to be effective in the treatment of MS, then for Crohn’s disease
    FDA approved for MS in 2004, then withdrawn when several patients developed fatal viral infection PML
    Targets both α4β1 and α4β7 integrins
    Reintroduced in 2006 with a black-box warning
  • Vedolizumab, humanized mAb specific for α4β7, shown effective in CD
    Modulates gut but not brain lymphocyte trafficking
    Received FDA approval in 2014 for moderate-to-severe UC and CD

Pharm Block 4 (1 decks)

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