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Lectures > GI Pharm > Flashcards

GI Pharm Flashcards

1
Q

Physiology of acid secretion

A
  1. Neural stimulation via the vagus nerve
  2. Endocrine stimulation via gastrine
  3. Paracrine stimulation by histamine release from enterochromaffine like (ECL) cells
  4. Acid production by proton pumps on the apical membrane of parietal cells
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2
Q

Summary of acid reducer pharmacology

A
  1. Antacids –> chemically inactivate H+
  2. H2 receptor antagonists –> prevent histamine induced activation of H+ release
  3. PPIs –> directly block parietal H+-K+ ATPase to decrease H+ secretion into the lumen
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3
Q

Summary of drugs

A

Antacids

  • CaCO3
  • Mg and Al hydroxides
  • NaHCO3

H2 Antagonists

  • ranitidine
  • cimetidine
  • famotidine
  • nizatidine

PPIs

  • omeprazonle
  • esomeprazole
  • lansoprazole
  • dexlansoprazole
  • pantoprazole
  • rabeprazole
  • omeprazole
  • NaHCO3
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4
Q

Antacids –> Mechanism

A

Chemical reaction to inactivated salt

Al(OH)3 + 3 HCl –> AlCl3 + 3 H2O (slow)

Mg(OH)2 + 2 HCl –> MgCl2 + 2 H2O (slow/mod)

CaCO3 + 2 HCl –> CaCl2 + H2O + CO2 (fast)

NaHCO3 + HCl –> NaCl + H2O + CO2 (fast)

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5
Q

Antacids –> Clinical use

A
  • great for occasional GERD or dyspepsia
  • can be useful when trying to determine if chest pain is from acid reflux
  • previously used for ulcer rx but replaced by H2 blockers and PPIs
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6
Q

Antacids –> adverse reactions

A

NaHCO3

  • systemic alkalosis (especially in renal insufficiency)
  • fluid retention (Na)

Mg(OH)2

  • diarrhea
  • hypermagnesemia (if renal insufficiency)

Al(OH)3

  • constipation
  • hypophosphatemia
  • drug adsorption (decreased bioavailability)

CaCO3

  • hypercalcemia
  • kidney stones
  • acid rebound
  • constipation
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7
Q

H2 receptor antagonists –> characteristics

A
  • chemical similarity to histamine
  • competitive inhibition of the H2 receptor = G protein coupled receptor –> results in decreased intracellular cAMP and decreased production of proton pumps
  • low toxicity
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8
Q

H2 receptor antagonists

A
  • cimetidine
  • ranitidine
  • famotidine
  • nizatidine
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9
Q

Betazole

A

Histamine H2 agonist

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10
Q

Clinical use of H2 receptor antagonists

A
  1. Heartburn and dyspepsia (GERD)
    - once or twice daily, or PRN
    - can be added to PPI for nocturnal breakthrough
    - can suffer from tachyphylaxis
  2. Peptic ulcer disease –> helps healing
    - PPIs are better
  3. Stress ulcer prophylaxes in high risk individuals
  4. Zollinger Ellison syndrome –> gastrin secreting tumor leading to hypersecretion of acid
    - PPIs are better
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11
Q

Toxicity and drug interactions with H2 receptor antagonists

A

Virtually none –> except cimetidine at former rx doses, others in over dose

Cimetidine

  • inhibits cytochrome P450 interfering with other drugs (especially neuroactive, anticoagulant)
  • antiandrogenic –> gynecomastia and galactorrhea
  • cardiovascular problems
  • confusion in elderly
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12
Q

Proton pump inhibitors

A

Block proton pumps (H+K+ATPase) in apical membrane of parietal cells

  • all require conversion to a sulfenamide intermediate which forms a complex with H+K+ATPase
  • irreversible –> requires de novo synthesis of enzyme
  • omeprazonle
  • esomeprazole
  • lansoprazole
  • dexlansoprazole
  • pantoprazole
  • rabeprazole
  • omeprazole
  • NaHCO3
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13
Q

Pharmacokinetics of PPIs

A
  • native drugs are destroyed by GI acid
  • gels/coatings/delayed release forms reduce variability by avoiding acid degradation
  • take 30 min before meals
  • long lasting effect (up to 24-48 hours)
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14
Q

Adverse effects of PPIs

A

Generally well-tolerated

Most commonly reported side effects:

  • headache
  • abdominal pain
  • nausea, diarrhea and flatulance

Metabolized by hepatic P450 system so can have drug interactions:

  • Neuroactive drugs (BZDs)
  • antiepileptics
  • antipsychotics
  • anticoagulants
  • rifampin

Increased risk of gastrointestinal infections:

  • Bacterial (e.g. Salmonella)
  • Traveler’s diarrhea
  • C. difficile infection

Increased risk of bone fractures

Increased risk of aspiration pneumonia for inpatients

Risk of hypomagnesemia

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15
Q

Clinical use of PPIs

A

Primary Rx

  • peptic ulcer disease
  • GERD
  • reflux esophagitis
  • Zollinger Ellison syndrome

More effective than H2 blockers
- if one is ineffective, switch to another

IV formulations have been shown in UGIB to

  • decrease the need for endoscopic intervention
  • decrease the risk of recurrent UGIB in patients s/p endoscopic intervention
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16
Q

Mucosal protectants

  • mechanisms
  • adverse effects
A
  1. Bismuth salts –> “coats” ulcers and inflamed areas; multiple mechanisms of action are poorly understood
    - black tongue and feces
    - interact with anticoagulants
  2. Sucralfate –> forms a gel like material on ulcers and protects them from actions of acid and digestive enzymes
    - take ante cebum (before meal)
  3. Misoprostol –> PGE1 analog, stimulates mucopolysaccharide production, decreases acid secretion
    - caution –> induces labor
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17
Q

Clinical use of mucosal protectants

A
  1. Bismuth salts
    - gastroenteritis –> helps symptoms of nausea, dyspepsia and diarrhea
    - traveler’s diarrhea prophylaxis
  2. Sucrulfate
    - stress ulcer prophylaxes
    - bile reflux gastritis and esophageal ulcers (e.g. post variceal banding ulcers)
  3. Misoprostol
    - combined with NSAIDS to reduce risk of NSAID induced ulcers
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18
Q

Drugs affecting GI motility

A

Antibiotics –> erythromycin

Cholinomimetic

  • bethanecol
  • neostigmine

Dopamine receptor antagonists

  • metoclopramide
  • domperidone

Serotonin –> metoclopramide

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19
Q

Prokinetic drugs

A

Macrolide antibiotics
Cholinomimetics
Dopamine receptor antagonists

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20
Q

Prokinetic drugs –> Macrolide antibiotics

A

Macrolide antibiotics

  • activate motilin receptors on smooth muscle of the antrum and small intestine
  • used sparingly due to tachyphylaxis and QT prolongation
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21
Q

Prokinetic drugs –> Cholinomimetics

A

Activate ACh receptors

  • potently increase GI motility
  • multiple cholinergic and cardiac side effects limit use
  • IV neostigmine shown highly effective in acute colonic pseudoobstruction (Oglivie’s syndrome)
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22
Q

Prokinetic drugs –> Dopamine receptor antagonists

A

Metoclopramide + domperidone

  • pre and post synaptic dopamine receptor antagonism promotes gastric/intestinal motility through release of ACh
  • increased gastric tone/pressure
  • improved antroduodenal coordination
  • accelerated gastric emptying
23
Q

Metoclopramide

A

1 drug related cause of malpractice suits from gastroenterologists –> multiple side effects

Common and reversible

  • somnolence
  • feeling jittery
  • headache
  • insomnia
  • diarrhea

Serious nervous system disorders

  • Tardive dyskinesia –> involuntary repetitive movements, may be irreversible
  • dystonia
  • neuroleptic malignant syndrome

Recommend…

  • confirming diagnosis before using
  • documenting a detailed discussion of risks and benefits
24
Q

Laxatives

A

Bulk forming

  • psyllium
  • CMC
  • polycarbophil

Osmotic agents

  • lactulose
  • Mg slats
  • NaPO4
  • PEG

Stimulants

  • bisacodyl
  • senna
  • cascara
  • castor oil

Stool softeners

  • docusate
  • glycerin
  • mineral oil

Cl channel secretion
- lubiprostone

25
Q

Laxatives

  • fiber
  • osmotic
A

Fiber = carboxymethylcellulose, psyllium, polycarbophil
- bulk laxatives –> form gels in the colon causing water retention and distension = increased peristalsis

Osmotic = milk of magnesia, na phosphate, polyethylene glycol, Mg salts, lactulose
- draws H2O into the intestinal lumen via osmosis resulting in softer/liquid stools and distension induced peristalsis

26
Q

Laxatives

  • stimulants
  • stool softeners
  • Cl channel secretion
A

Stimulant/irritant = bisacodyl, senna
- stimulates colonic smooth muscle and causes H2O accumulation in lumen –> exact mechanism unclear

Stool softeners

  • surfactant = docusate –> causes fat/H2O to mix
  • lubricant = mineral oil –> softens stools, prevents H2O absorption, can inhibit absorption of fat soluble vitamins
  • glycerin –> enhances H2O retention

Cl channel secretion = lubiprostone
- activates ClC2 chloride channels causing chloride secretion –> sodium follows to maintain isoelectric equilibrium –> water follows sodium

27
Q

General ideas about treatment of diarrhea

A
  • investigate the underlying cause
  • eliminate infection
  • remove triggers
  • replace fluids and electrolytes
  • treat symptoms
28
Q

Antidiarrheal agents

A

Antimotility - opiates

  • loperamide
  • diphenoxylate-atropine
  • tincture of opium

Adsorbents

  • bismuth subsalicylate
  • fiber
  • cholestyramine
  • colestipol

Antisecretory

  • octreotide
  • somatostatin
29
Q

Antimotility - opiates

A

Opioid receptor
- loperamide, diphenoxylate/atropine, ticture of opium

Acts directly on circular and longitudinal intestinal muscles

  • inhibits peristalsis and prolongs transit time
  • increases viscosity
  • diminishes fluid and electrolyte loss

Increases anal sphincter tone

30
Q

Adsorbents

A

Bismuth subsalicylate (peptobismol)

  • antisecretory
  • antimicrobial
  • anti-inflammatory

Fiber = bulking agent

  • most people are familiar with fibers use in constipation –> better to think of it as a stool regulator
  • in diarrhea, it acts as a bulking agent by absorbing intraluminal water from stool and therefore improving the consistency

Cholesteryamine + colestipol = bile acid binding resin

  • stimulate colonic secretion, causing a secretory diarrhea
  • bile acids are normally absorbed in the terminal ileum before reaching the colon
  • when the terminal ileum is diseased or resected, bile acids can be malabsorbed and subsequently enter the colon
  • cholestyramine forms a nonabsorbable complex with bile acids in the intestines, preventing them from stimulating colonic mucosa to secrete electrolytes and fluid
31
Q

Antisecretory agents

A

Octreotide/somatostatin

  • reduces fluid and electrolyte secretion by stomach and pancreas
  • mild antimotility effect
  • promotes intestinal electrolyte absorption
  • suppresses neuroendocrine tumor release of peptides that cause intestinal hypersecretion of electrolytes and water
32
Q

Antidiarrheals - warnings and precautions

A

Do not give antidiarrheals in the setting of bacterial infection or inflammation

Use caution when combining loperamide and tincture of opium with other CNS depressants –> side effects can be additive, including sedation and respiratory depression

Remember the “salicylate” in bismuth subsalicylate –> use with caution in patients on aspirin or anticoagulation; reye syndrome

Separate cholestyramine from other medications by at least 2 hours –> just as it binds bile acids, it can also bind other meds, decreasing their absorption and therefore their efficacy

33
Q

Pathogenesis of nausea and emesis

A

Emetic stimuli act at several sites

  • Emesis provoked by unpleasant thoughts or smells originates in the cerebral cortex, whereas cranial nerves mediate vomiting after gag reflex activation.
  • Motion sickness and inner ear disorders act on the labyrinthine apparatus.
  • The area postrema, a medullary nucleus, responds to bloodborne emetic stimuli, and is also known as the chemoreceptor trigger zone.
  • Many emetogenic drugs act on the area postrema, as do bacterial toxins and metabolic factors produced during uremia, hypoxia, and acidosis.
  • Gastric irritants stimulate gastroduodenal vagal afferent nerves, which activate the area postrema.

These emetic stimuli result in release of neurotransmitters such as histamine and acetylcholine from the vestibular system and 5-HT3 and DA from visceral stimuli and the area postrema, which then activate the nucleus tractus solitarius to coordinate the initiation of emesis involving neuromuscular responses in the gut, pharynx and thoracic and abdominal wall.

34
Q

Nausea and emesis agents

A

Anticholinergic –> scopolamine

Antihistamine –> meclizine + dimenhydrinate

DA-antagonist –> prochlorperazine + promethazine

5HT3 antagonist –> ondanestron, dolasetron, granisetron

Cannabinoid –> dronabinol

Neurokinin antagonist –> aprepitant

35
Q

Anti-emetics - anti-cholinergic

A

Blocks action of Ach at M1

  • scopolamine is effective in preventing motion sickness, but not significantly in treating it
  • can also be effective in preventing chemo induced nausea
  • transdermal patch applied every 72 hours

Side effects

  • dry mouth
  • sedation
  • blurred vision
  • confusion and urinary retention in the elderly
36
Q

Antiemetics - antihistamine

A

Anti-histaminic (H1) and anticholinergic

  • Meclizine, dimenhydrinate (dramamine)
  • effective in treatment of motion sickness
  • tablet, oral suspension, IM dimenhydrinate
  • anticholinergic side effects
  • meclizine may be less sedating than dimenhydrinate
37
Q

Antiemetics - DA antagonist

A

D2 receptor blockers, some anticholinergic effect

  • promethazine + prochlorperazine
  • effective antiemetic in multiple settings –> motion sickness, toxic and metabolic induced nausea, and is often used for preoperative prophylaxis
  • available formulations include oral tablet or suspension, rectal suppository, IM and IV

Adverse effects

  • sedation
  • extrapyramidal symptoms –> pseudoparkinsonism, acute dystonic reactions, and tardive dyskinesia
  • QT prolongation
  • anticholinergic side effects
38
Q

Antiemetics - 5HT3 antagonist

A

Selective 5HT3 receptor antagonist, vagal nerve terminals, and chemoreceptor trigger zone

  • ondansetron, dolasetron, granisetron
  • effective anti-emetic in multiple settings, including chemotherapy induced nausea and vomiting

Adverse effects
- QT prolongation

39
Q

Antiemetics - cannabinoid

A

CNS cannabinoid (CB1) receptor agonist, likely interacts with multiple neurotransmitters

  • delta-9-tetrahydrocannabinol (THC)
  • oral tablet
  • approved for chemotherapy induced nausea/vomiting, and as an appetite stimulant in HIV/AIDS

Adverse effects

  • euphoria
  • paranoia
  • CNS depression
  • abuse potential
40
Q

Antiemetics - NK antagonist

A

Substance P/neurokinin-1 receptor antagonist

  • aprepitant + fosaprepitant
  • effective in prevention of acute and delayed chemotherapy induced and postoperative nausea/vomiting, especially as adjunctive therapy
  • oral capsule or IV before chemo chemo or anesthesia

Adverse effects

  • hiccups
  • fatigue
  • increased risk of severe infection
41
Q

Selection of anti-emetics by clinical situation

A

Migraine related nausea –> DA antagonists, 5HT3 antagonists

Motion sickness –> anticholinergics, antihistamine

Chemo induced nausea/vomiting –> 5HT3 antagonists, corticosteroids, NK antagonists
- others = cannabinoids, benzodiazepines

Postoperative nausea/vomiting –> DA antagonist, 5HT3 antagonists, NK antagonists

Hyperemesis gravidarum –> ginger, B6, antihistamines, DA antagonists, 5HT3 antagonists

42
Q

Anti-inflammatories

A

In the GI world, these medications are most often used to treat inflammatory bowel disease. In general, inflammatory bowel disease or IBD is comprised of 2 major disorders– Crohn’s disease and ulcerative colitis. They are chronic autoimmune inflammatory conditions that affect the GI tract. The goals of therapy in IBD are both managing symptoms as well as preventing complications of disease.

Drugs

  • aminosalicylates
  • glucocorticoids –> predinsone, methylpredisolone, budesonide
  • immunomodulators –> 6mercaptopurine, azathioprine, methotrexate
  • bioogics –> infliximab, adalimumab, certolizumab pegol, natalizumab
43
Q

Aminosalicylates

A

Topical anti-inflammatory effect via multiple mechanisms

  • Sulfasalazine: prodrug reduced in the colon
  • 5-aminosalicylate: mesalamine, balsalazide, olsalazine
  • -> Effective in ulcerative colitis (UC) and Crohn’s disease (CD) of the colon

5-ASA is the active component in all of these agents. However, >75% of unconjugated 5-ASA is absorbed in the jejunum, leaving little to act in the colon.
Sulfasalazine is a prodrug of 5-ASA linked to sulfapyridine by an azo bond; in the colon, bacteria produce azoreductase which breaks the bond and releases 5-ASA.

Different mechanisms to allow delivery of 5-ASA to the colon have been developed. There are delayed and controlled-release formulations of mesalamine that consist of 5-ASA molecules within an enteric coating or a semipermeable membrane that resists breakdown in the stomach.

44
Q

Aminosalicylates - warnings/precautions

A

Sulfasalazine

  • Frequent GI, CNS, and hematologic side effects
  • Agranulocytosis is a rare side effect.
  • Decreases folic acid absorption– supplement with folic acid 1mg daily

5-aminosalicylates

  • mild GI side effects
  • hypersensitivity reactions = pancreatitis, pneumonitis
  • paradoxical worsening of disease
  • chronic interstitial nephritis
45
Q

Glucocorticoids

A

Conventional –> predisone + methylpredinsolone

  • Effective in inducing remission in both UC and CD, generally reserved for moderate to severe disease
  • Should be used as a short-term induction therapy, not a chronic maintenance agent
  • Cannot be abruptly stopped, requires taper to avoid secondary adrenal insufficiency

Non-systemic –> budesonide

  • controlled ileal release vs. extended colonic release
  • high first pass hepatic metabolism**
  • induction agent in CD, not effective for long term maintenance
  • lower incidence of adrenal suppression, but still requires taper
46
Q

Glucocorticoid side effects

A
  • eurphoria
  • buffalo hump
  • hypertension
  • thinning of skin
  • muscle wasting
  • poor wound healing
  • easy bruising
  • increased abdominal fat
  • moon face with red cheeks
  • cataracts
47
Q

Immunomodulators - 6 mercaptopurine + azathioprine

A
  • Azathioprine is a purine antimetabolite
  • 6-mercaptopurine is the active metabolite of azathioprine
  • 6-MP is metabolized by thiopurine methyltransferase, or TPMT, into 6-MMP; and by hypoxanthine phosphoribosyl transferase (HPRT) into the precursor of 6-TGN which is the active metabolite.
  • 6-TGN inhibits nucleotide synthesis, which results in decreased numbers of circulating B and T lymphocytes as well as decreased proinflammatory cytokine production.

A very small proportion of the general population can have low or no TPMT enzyme activity, which would cause 6-MP to preferentially be shunted towards the active metabolite 6-TGN.

48
Q

Immunomodulators - 6 mercaptopurine + azathioprine

- mechanism and adverse effects

A

Maintenance of remission in CD and UC

  • These mechanisms suppress autoimmune-medicated inflammation in the GI tract in both Crohn’s disease and ulcerative colitis
  • However, it is effective as only maintenance, does not induce remission.
  • As a result, we use it in combination with an induction agent such as a glucocorticoid
  • It typically takes about 3 months to achieve therapeutic levels

Adverse effects

  • leukopenia and thrompocytopenia** (6-TGN)
  • hepatotoxicity (6-MMP)
  • infection
  • increased risk of malignancy
  • avoid use with allopurinol**
49
Q

Immunomodulators - methotrexate

A

Folate antimetabolite, competitively inhibits the binding of dihydrofolic acid to dihydrofolate reductase.
- It is thought to induce apoptosis of peripheral T cells, thereby suppressing autoimmune-mediated inflammation in the GI tract.

Effective in maintenance of remission in CD
- oral or IM

Adverse effects

  • hepatotoxic –> avoid alcohol
  • myelosuppression
  • interstitial lung disease
  • give folic acid 1mg daily to all patients
  • teratogenic –> contraindicated in pregnancy
50
Q

Biologics - TNFalpha

A

Monoclonal antibodies against TNF alpha = inflammatory cytokine that plays a significant role in IBD
- effective for induction and maintenance of remission in CD and UC

Adverse effects

  • infection –> screen for latent TB and hepB before initiation
  • myelosuppression
  • increased risk of malignancy
  • psoriasis, drug induced lupus, demyelination

Drugs

  • infliximab
  • adalimumab
  • certolizumab
  • golimumab
51
Q

Structure, route, timing, and effectiveness in CD and UC of anti-TNFs

A

Infliximab

  • chimeric AB –> Human constant region and mouse variable region
  • IV
  • every 8 weeks
  • CD and UC

Adalimumab

  • humanized AB –> Human constant and variable regions
  • SC
  • every 2 weeks
  • CD and UC

Certolizumab pegol
- PEG Fab –> Fab’ fragment bonded to polyethylene glycol, increases its half-life

  • SC
  • every 4 weeks
  • CD only

Golimumab

  • humanized AB –> Human constant and variable regions
  • SC
  • every 4 weeks
  • UC only
52
Q

Biologics - anti integrins

A

Natalizumab –> blocks leukocyte migration from blood vessels to sites of inflammation
- increased risk of progressive multifocal leukoencephalopathy (PML) –> JC-virus reactivation resulting in severe demyelination, progressive neurologic dysfunction. It is associated with a 20 percent mortality rate and a high degree of disability among survivors.

53
Q

Anti-inflammatories - induction vs. maintenance

A

Induction

  • 5-ASA
  • glucocorticoids
  • biologics

Maintenance

  • 5-ASA
  • 6MP/AZA
  • MTX
  • biologics

Lectures (46 decks)

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