GI and Endocrine Drugs Flashcards
What area within the brain regulates emesis?
the nucleus tractus solitarius in the medulla
The nucleus tractus solitarius regulates emesis and receives input from what three major sites?
- the stomach via vagal afferents
- the semicircular canals via CN VIII
- the area postrema located nearby in the 4th ventricle, outside the BBB
Describe how GI irritation modulates the emetic response.
- GI irritation in the form of distention, infection, or chemotherapy leads to mucosal release of serotonin
- this serotonin binds 5-HT3 receptors on vagal afferents
- vagal afferents project to the nucleus tractus solitarius and promote emesis
Ondansetron
- a 5-HT3 antagonist used to prevent emesis
- it blocks binding of serotonin from the gastric mucosa to 5-HT3 receptors on vagal afferents projecting to the nucleus tractus solitarius
- side effects include constipation, headache, dizziness, serotonin syndrome, and QT prolongation
How do the semicircular canals mediate emesis? What receptors are involved?
- they mediate the emesis associated with vertigo and motion sickness
- the vestibular system contains H1 receptors, coupled to a Gq cascade, as well as M1 receptors
- activation of these receptors leads to emesis
How does the area postrema mediate emesis? What receptors are involved?
- the area postrema is located in the fourth ventricle outside the BBB
- it senses and responds to emetogenic substances in the blood or CSF
- D2 receptors and NK1 receptors (for substance P) are critical for this mechanism
List five receptor types involve in the emetic response and where they can be found.
- 5-HT3 on vagal afferents in the GI tract
- H1 in the semicircular canals
- M1 in the semicircular canals
- D2 in the area postrema
- NK1 (for substance P) in the area postrema
What role do antihistamines play as anti-emetics? What is the primary side effect?
first generation H1 antagonists, like diphenhydramine and meclizine, are capable of crossing the BBB and can be used to treat motion sickness, but they often cause sedation
Describe scopolamine as an anti-emetic.
- it is an M1 antagonist
- functions in the vestibular system for the treatment of sea sickness and motion sickness
Motion sick (i.e. vestibular nausea) is best treated with what two agents?
- first generation antihistamines like diphenhydramine or meclizine
- an M1 antagonist like scopolamine
Aprepitant
- an NK1 receptor antagonist (blocks substance P binding)
- functions in the area postrema to inhibit chemotherapy-induced vomiting with very few side effects
Metoclopramide
- a D2 receptor antagonist that acts in the area postrema to inhibit emesis
- side effect profile includes a pro kinetic effect in the upper GI system, which can be useful in treating ileus, but is contraindicated in those with GI obstruction
- may cause diarrhea, extra-pyramidal side effects and eventual tardive dyskinesia, sedation, depression, neuroleptic malignant syndrome, and hyperprolactinemia
Describe how gastric acid secretion is regulated.
- parietal cells in the gastric mucosa of the body and fundus secrete acid via an H/K-ATPase
- these cells express M3 receptors, which can be activated by vagal efferents
- alternatively gastrin can stimulate enterochromaffin-like cells to release histamine, which activates Gs-coupled H2 receptors expressed by parietal cells
- gastrin is secreted by G cells in the antrum in response to luminal proteins and when stimulated by GRP from vagal efferents
H2-Blockers
- these drugs, ending in the suffix “-tidine”, block H2 receptors on parietal cells to prevent their activation
- they are really only effective at reducing nocturnal acid secretion, not post-prandial secretions, thus they are only second line therapy for GERD
- they have limited side effects except for cimetidine, which inhibits CYP450, can contribute to hyperprolactinemia with galactorrhea, and anti-andronergic effects leading to impotence
PPIs
- a group of drugs ending in the suffix “-prazole”
- they form disulfide bonds with and irreversibly inhibit the H/K-ATPase on gastric parietal cells
- considered first-line therapy for acid-related conditions
- can impair absorption of dication metals such as Ca2+, Mg2+, and Fe2+, leading to osteoporosis and hip fractures, iron deficiency anemia, or hypomagnesia
- also increase the risk for respiratory infections and C. diff
What role does octreotide play in the treatment of acid-related conditions?
- somatostatin is capable of inhibiting gastrin and ECL cells, reducing gastric acid secretion
- some gastrinomas even express somatostatin receptors, and in these cases, the somatostatin analog, octreotide, can be used to treat peptic ulcer disease
What is the difference between a laxative and a pro kinetic agent?
pro kinetics stimulate GI motility but laxatives work on the contents of the GI tract
Osmotic Laxatives
- a group of non-absorbable substances that draw water into the intestinal lumen, leading to distention, which stimulates peristalsis
- includes magnesium compounds, milk of magnesia, PEG, and lactulose
- may cause diarrhea and dehydration
Which laxative is also a suitable treatment for hepatic encephalopathy and how does this work?
- hepatic encephalopathy is a complication of cirrhosis mediated by a buildup of ammonia (NH3)
- lactulose is a non-absorbable sugar and osmotic laxative, which is metabolized by intestinal flora into acidic metabolites
- these acidic metabolites cause ammonia to turn to ammonium (NH4+), which is trapped in the intestinal lumen and excreted rather than absorbed
Psyllium
- a bulk-forming laxative
- functions as a hydrophilic colloid that absorbs water and distends the colon, inducing peristalsis
Docusate
- a surfactant laxative
- facilities penetration of stool by water and lipids, serving as a stool softener to increase passage of stool
Senna
- a stimulant laxative, also known as a cathartic
- it stimulates the enteric nervous system and cause colonic secretions
- chronic use causes melanosis coli, a brown pigmentation of the colon
Loperamide
- a u-opioid receptor agonist that induces colonic phasic segmenting, an activity that increases colonic transit time
- used to treat diarrhea because it doesn’t cross the BBB and thus poses no risk for addiction or dependence
Diphenoxylate
- a u-opioid receptor agonist that induces colonic phasic segmenting, an activity that increases colonic transit time
- used to treat diarrhea
- but does cross the BBB, so it is combined with atropine to prevent abuse
Anti-diarrheal agents are contraindicated in patients with what sorts of diarrhea?
bloody diarrhea or diarrhea with fever
What role does octreotide play in the treatment of diarrhea?
it is a somatostatin analog used to treat the diarrhea caused by VIPomas and carcinoid tumors
Beta-islet cells are primarily stimulated by what two things?
high serum glucose and activation of B2 receptors
Describe the mechanism whereby beta-islet cells release insulin in response to high serum glucose.
- glucose enters beta-islet cells through GLUT-2
- glucose is utilized to produce ATP, and the growing ATP/ADP ratio closes potassium channels, preventing further efflux and depolarizing the cell
- depolarization activates voltage-gated calcium channels
- the resulting calcium influx leads to release of insulin
Describe the effects of insulin in the periphery and what receptor/mechanism mediates these effects.
- insulin binds a TK receptor
- binding stimulates anabolic processes like glyconeogenesis, protein synthesis, and fat storage
- it also stimulates expression of GLUT4 receptors to promote glucose uptake by insulin-dependent tissues
Short-Acting Insulin
- includes glulisine, aspart, and lispro
- rapid acting because they don’t form dimers or hexamers
- useful for controlling post-prandial glucose levels
Regular Insulin
- the only insulin available IV
- IV administration has a rapid onset and is the preferred treatment for DKA, but be careful and watch K+ levels
- IV administration can also be useful in the treatment of hyperkalemia, driving potassium into cells, but should be co-administered with glucose to prevent hypoglycemia
What is the preferred treatment for DKA?
IV regular insulin
Which are the two long-acting insulins?
detemir and glargine
List two treatments for hypoglycemia.
with IM glucagon or IV glucose
Sulfonylureas
- function by inhibiting potassium channel opening on beta-islet cells, stimulating release of endogenous insulin
- includes first generation agents like tolbutamide and chlorpropamide, ending in the “-mide” suffix, and second generation agents like glipizide, glyburide, and glimepiride with the “-ride” suffix
- side effects include weight gain, a risk for hypoglycemia, and possible sulfa-drug reaction
- first generation also have a disulfiram-like effect and should not be used with alcohol
Glinides
- type II DM drugs ending in the suffix “-glinide”
- function by inhibiting potassium channel opening on beta-islet cells, stimulating release of endogenous insulin
- carry a risk for weight gain and hypoglycemia but are not sulfa-drugs
GLP-1 Agonists
- type II DM drugs ending in the suffix “-tide” (e.g. exenatide or liraglutide)
- function by activating GLP-1 receptors, which delay gastric emptying (reducing post-prandial glucose peak), promoting satiety, inhibiting glucagon release, and stimulating endogenous insulin release
- euglycemic so they don’t carry a risk for hypoglycemia or weight gain but may stimulate pancreatitis
Gliptins
- function by inhibiting DDP-4 and the breakdown of endogenous GLP-1; thereby, delaying gastric emptying, promoting satiety, inhibiting glucagon release, and promoting insulin release
- euglycemic so they don’t carry a risk for hypoglycemia or weight gain but increase the risk for URTI
Metformin
- functions to increase insulin sensitivity and reduce hepatic gluconeogenesis by activating AMPK
- may also promote weight stabilization or reduction
- most common side effects are related to GI distress, including n/v, diarrhea, and anorexia
- should not be used in those with renal failure as it increases the risk for lactic acidosis
Glitazones
- rosiglitazone and pioglitazone, type II DM medications
- function by activating the intranuclear PPARy receptor, which then serves as a transcription factor for adiponectin
- PPARy activation increases insulin sensitivity and storage of triglycerides
- known to cause fluid retention with edema and exacerbation of heart failure, bone reabsorption with atypical fractures, and weight gain
Pramlintide
- an amylin analog used to treat type I and type II DM
- functions like endogenous amylin, secreted in the same granules as insulin, to inhibit appetite, glucagon secretion, and gastric emptying
- may cause GI upset or hypoglycemia
Acarbose
- inhibits alpha-glucosidases in the brush border
- thus preventing digestion of disaccharides to monosaccharides, inhibiting absorption, and reducing post-prandial glucose spikes in type I DM
- cause severe GI distress
Miglitol
- inhibits alpha-glucosidases in the brush border
- thus preventing digestion of disaccharides to monosaccharides, inhibiting absorption, and reducing post-prandial glucose spikes in type I DM
- cause severe GI distress
Flozins
- a group of type II DM medications that inhibit SGLT-2, thereby preventing reabsorption of glucose from the PCT
- may cause UTI or hypotension due to osmotic diuresis and should not be used in those with renal dysfunction
Mecasermin
an IGF-1 analog, which may cause hypoglycemia
Desmopressin
- an ADH agonist
- activates V2 receptors in the collecting tubules and induces release of VIII and vWF from endothelial cells
- useful in the treatment of central diabetes insipidous, vWF deficiency, FVIII deficiency, and bed wetting
- may cause a dilutional hyponatremia
Vaptans
- a group of V2-receptor antagonists
- first line therapy for those with SIADH
- may cause a hypernatremia or central pontine myelinolysis
PTU
- inhibits thyroperoxidase and 5’-deiodinase
- useful in treating hyperthyroidism as well as thyroid storm
- may cause an agranulocytosis, hepatotoxicity, drug-induced lupus, ANCA-associated vasculitis
- not teratogenic, however, so the preferred agent for pregnancy
Methiomazole
- inhibits thyroperoxidase
- not useful in the treatment of thryoid storm but is the preferred drug for hyperthyroidism
- may cause a lupus-like syndrome or agranulocytosis
- contraindicated in pregnancy due to teratogenic effects
