GI Pharm Flashcards
Physiology of acid secretion
- Neural stimulation via the vagus nerve
- Endocrine stimulation via gastrine
- Paracrine stimulation by histamine release from enterochromaffine like (ECL) cells
- Acid production by proton pumps on the apical membrane of parietal cells
Summary of acid reducer pharmacology
- Antacids –> chemically inactivate H+
- H2 receptor antagonists –> prevent histamine induced activation of H+ release
- PPIs –> directly block parietal H+-K+ ATPase to decrease H+ secretion into the lumen
Summary of drugs
Antacids
- CaCO3
- Mg and Al hydroxides
- NaHCO3
H2 Antagonists
- ranitidine
- cimetidine
- famotidine
- nizatidine
PPIs
- omeprazonle
- esomeprazole
- lansoprazole
- dexlansoprazole
- pantoprazole
- rabeprazole
- omeprazole
- NaHCO3
Antacids –> Mechanism
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)
Antacids –> Clinical use
- 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
Antacids –> adverse reactions
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
H2 receptor antagonists –> characteristics
- 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
H2 receptor antagonists
- cimetidine
- ranitidine
- famotidine
- nizatidine
Betazole
Histamine H2 agonist
Clinical use of H2 receptor antagonists
- Heartburn and dyspepsia (GERD)
- once or twice daily, or PRN
- can be added to PPI for nocturnal breakthrough
- can suffer from tachyphylaxis - Peptic ulcer disease –> helps healing
- PPIs are better - Stress ulcer prophylaxes in high risk individuals
- Zollinger Ellison syndrome –> gastrin secreting tumor leading to hypersecretion of acid
- PPIs are better
Toxicity and drug interactions with H2 receptor antagonists
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
Proton pump inhibitors
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
Pharmacokinetics of PPIs
- 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)
Adverse effects of PPIs
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
Clinical use of PPIs
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
Mucosal protectants
- mechanisms
- adverse effects
- Bismuth salts –> “coats” ulcers and inflamed areas; multiple mechanisms of action are poorly understood
- black tongue and feces
- interact with anticoagulants - Sucralfate –> forms a gel like material on ulcers and protects them from actions of acid and digestive enzymes
- take ante cebum (before meal) - Misoprostol –> PGE1 analog, stimulates mucopolysaccharide production, decreases acid secretion
- caution –> induces labor
Clinical use of mucosal protectants
- Bismuth salts
- gastroenteritis –> helps symptoms of nausea, dyspepsia and diarrhea
- traveler’s diarrhea prophylaxis - Sucrulfate
- stress ulcer prophylaxes
- bile reflux gastritis and esophageal ulcers (e.g. post variceal banding ulcers) - Misoprostol
- combined with NSAIDS to reduce risk of NSAID induced ulcers
Drugs affecting GI motility
Antibiotics –> erythromycin
Cholinomimetic
- bethanecol
- neostigmine
Dopamine receptor antagonists
- metoclopramide
- domperidone
Serotonin –> metoclopramide
Prokinetic drugs
Macrolide antibiotics
Cholinomimetics
Dopamine receptor antagonists
Prokinetic drugs –> Macrolide antibiotics
Macrolide antibiotics
- activate motilin receptors on smooth muscle of the antrum and small intestine
- used sparingly due to tachyphylaxis and QT prolongation
Prokinetic drugs –> Cholinomimetics
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)
Prokinetic drugs –> Dopamine receptor antagonists
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
Metoclopramide
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
Laxatives
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
Laxatives
- fiber
- osmotic
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
Laxatives
- stimulants
- stool softeners
- Cl channel secretion
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
General ideas about treatment of diarrhea
- investigate the underlying cause
- eliminate infection
- remove triggers
- replace fluids and electrolytes
- treat symptoms
Antidiarrheal agents
Antimotility - opiates
- loperamide
- diphenoxylate-atropine
- tincture of opium
Adsorbents
- bismuth subsalicylate
- fiber
- cholestyramine
- colestipol
Antisecretory
- octreotide
- somatostatin
Antimotility - opiates
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
Adsorbents
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
Antisecretory agents
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
Antidiarrheals - warnings and precautions
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
Pathogenesis of nausea and emesis
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.
Nausea and emesis agents
Anticholinergic –> scopolamine
Antihistamine –> meclizine + dimenhydrinate
DA-antagonist –> prochlorperazine + promethazine
5HT3 antagonist –> ondanestron, dolasetron, granisetron
Cannabinoid –> dronabinol
Neurokinin antagonist –> aprepitant
Anti-emetics - anti-cholinergic
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
Antiemetics - antihistamine
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
Antiemetics - DA antagonist
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
Antiemetics - 5HT3 antagonist
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
Antiemetics - cannabinoid
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
Antiemetics - NK antagonist
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
Selection of anti-emetics by clinical situation
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
Anti-inflammatories
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
Aminosalicylates
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.
Aminosalicylates - warnings/precautions
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
Glucocorticoids
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
Glucocorticoid side effects
- eurphoria
- buffalo hump
- hypertension
- thinning of skin
- muscle wasting
- poor wound healing
- easy bruising
- increased abdominal fat
- moon face with red cheeks
- cataracts
Immunomodulators - 6 mercaptopurine + azathioprine
- 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.
Immunomodulators - 6 mercaptopurine + azathioprine
- mechanism and adverse effects
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**
Immunomodulators - methotrexate
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
Biologics - TNFalpha
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
Structure, route, timing, and effectiveness in CD and UC of anti-TNFs
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
Biologics - anti integrins
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.
Anti-inflammatories - induction vs. maintenance
Induction
- 5-ASA
- glucocorticoids
- biologics
Maintenance
- 5-ASA
- 6MP/AZA
- MTX
- biologics
