Lower GI drugs Flashcards
Important regulators of motility and water absorption
- -Acetylcholine
- -Serotonin
- -Dopamine
- -Enkephalins
Where is 5HT released from?
Enterochromaffin Cells (function as sensory receptors)
What drugs work at the level of the sensory neurons?
SSRI’s, bulk-forming laxatives, contact cathartics, 5HT3 antagonists, 5HT4 agonists
Afferent neuron NTs
cGRP, glutamate, substance P
5HT
Major player in lower GI pathology, especially IBS
SSRI drug names
Fluoxetine, paroxetine, sertraline
What are SSRI’s most beneficial in treating (related to GI)?
–Constipation predominant IBS
Mechanism of SSRIs in GI system
Decrease reuptake of 5HT into EC cells –> increase 5HT in synapse–> increase afferent activity –> increase peristalsis
Bulk laxative names
Dietary fiber, methylcellulose, polycarbophil, psyllium
Bulk laxative MOA
- -Drugs that attract H2O and increase stool mass
- -Act as “stool stabilizers”
- -Increase lumen distention
How do bulk laxatives act on diarrhea?
Decrease bowel movements, make stool more solid and decrease pain
How do bulk laxatives act on constipation?
Increase bowel movements, makes stool more loose, decrease pain
What factors limit the use of bulk laxatives?
- Neurons generating peristaltic reflex must be functional (enteric system must be working)
- Cause of constipation must be known
Side effects of bulk laxatives
Allergies, increased flatulence, increased obstruction
Contact cathartic names
Anthraquinone derivatives, bisacodyl, castor oil
Anthraquinone derivative names
Casacara sagrada, danthron, senna
Bisacodyl
- -Prodrug
- -Almost 6 hr latency to effect
- -Acts on large intestine
- -Less potent than castor oil
Anthraquinones
- -Act on large intestine
- -Less potent than castor oil
Castor oil
- -Acts on both small and large intestine
- -Short latency
- -Extremely potent effects
- -More significant side effects
- -Activate ricinoteric acid
Contact cathartic MOA?
Thought to be irritation of mucosa
Not sure if dependent on enteric nervous system
Side effects of contact cathartics
- -Dependency (can’t have BM until take the drug)
- -Destroy myenteric plexus long term
- -Pigmentation of the mucosa (“melonosis coli”)
Additional side effects of castor oil
Dehydration, electrolyte imbalance, uterine contractions
5HT3 receptor antagonist
Alosetron
Alosetron MOA
- -Decrease afferent stimulation–> decreases peristalsis
- -Longer duration of action than antiemetic
Alosetron therapeutic uses
Diarrhea predominant IBS
- -Only used when everything else has failed
- -Restricted use (compassionate use only)
Alosetron side effects
- -Constipation (30% of patients, 10% must stop drug, 0.1% require hospitalization)
- -0.3% develop ischemic colitis–> can be fatal, increased with inhibitors and substrates of Cyp1A2
5HT4 receptor agonists
Cisapride (also a 5HT3 antagonist) and tegaserod (more selective)
5HT4 receptor agonists MOA
Receptors located on presynaptic terminals–> increase release of NT from afferent neurons–> increase peristalisis
5HT4 receptor agonists therapeutic use
- -Used when no other options available, restricted availability
- -Tegaserod: constipation predominant IBS
5HT4 receptor agonist side effects
- -CV toxicity (esp. arrhythmias–long QT)
- -85% w/long QT had pre-existing conditions and/or admin of Cyp3A4 inhibitors
Opiates (that work in GI system) drug names
- -Loperamide
- -Diphenoxylate
Opiate action in GI system
Decrease both GI motility and water excretion and are the most effective antidiarrheal drugs
Can loperamide or diphenoxylate cross the BBB?
Loperamide cannot, but diphenoxylate can sort of cross the BBB (so given via prescription)
What can be used to offset the constipation caused by opiate analgesics?
Alvimopan and methylnaltroxone
What are the Mu receptor antagonists?
Alvimopan and methylnaltroxone
Opiate MOA
- -Inhibition of motility and secretion
- –Generally don’t cross the BBB very well
Why is diphenoxylate usually given with atropine?
Atropine blocks muscarinic receptors–> decreases contraction and also has unpleasant side effects making it less likely to be abused
Therapeutic uses of opiates in GI system?
–Most effective antidiarrheals and good against most forms of diarrhea
Side effects of opiates
- -Abdominal cramps
- -TOXIC MEGACOLON if pt has ulcerative colitis
- -HIGH doses of diphenoxylate–> euphoria –> can lead to physical dependence
Mu receptor antagonists MOA
- -Don’t cross BBB
- -Selective antagonists
Therapeutic uses of Mu receptor antagnoists
- -Constipation caused by opiate therapy
- -Alvimopan: short-term use in hospitalized patients
- -Methylnaloxone: long-term palliative care
Alvimopan side effects
Increased risk of MI
D2 receptor antagonist drug names
Domperidone (doesn’t cross BBB)
Metoclopramide (most widely available in the US)
D2 receptor antagonist MOA
–Cholinomimetics (increased actions of Ach in gut –> inhibition of DA inhibition–> increases motility in entire gut–> prokinetic
Domperidone therapeutic uses
–Compassionate use only in US. Impaired motility, esp. decreased gastric emptying (e.g . from vagotomy, diabetic gastroparesis)
Metoclopramide use
Antiemetic
D2 receptor antagonist side effects
–Somnolence, nervousness, agitation, anxiety, dystonia, tardive dyskinesia (irreversible), parkinsonism, increased prolactin release (menstrual disorders, impotence, galactorrhea)
TCA’s MOA
- -Decrease reuptake of postganglionic sympathetic neurons –> increase activation of alpha2 on presynaptic terminals of Ach postganglionic parasympathetic nerves–> decrease Ach release–> decrease motility.
- -Decrease reuptake of DA–> increases activation of D2 receptors
TCA drug names
Amitriptyline and desipramine
What drugs stimulate motilin?
Macrolide antibiotics (eg erythromycin)
What drugs influence chloride secretion?
Lubiprostone, linaclotide, crofelemer, octreotide, bismuth subsalicylate, opiates.
How do osmotic cathartics and bile acid binding resins work?
Increasing or reducing the osmotic load in the colon
MOA of lubiprostone
- -Activates ClC-2–> increases Cl- secretion
- -Poorly absorbed–> almost no systemic effects
Lubiprostone therapeutic uses
Chronic constipation and constipation-predominant IBS
Lubiprostone side effects
- -Diarrhea
- -Nausea/HA
- -Increased fetal loss–NOT for use during pregnancy
Linaclotide MOA
- -Activates guanylyl cyclase C (cGMP)–> activates CFTR–> increases Cl- secretion–> increases H2O lumen
- -Very little systemic absorption
Linaclotide therapeutic uses
Chronic constipation and constipation-predominant IBS
Linaclotide side effects
Diarrhea
Increased maternal death
Increased mortality of juvenile mice (contraindicated in peds)
Crofelemer MOA
- -Voltage dependent inhibition of CFTR (and another Cl- channel)–> decreases Cl- secretion–> decreases Na+/H2O excretion–> firmer stool
- -Little systemic absorption
Crofelemer therapeutic uses
Diarrhea from anti-HIV drug treatment
Somatostatin analogue drug name
Octreotide
Octreotide MOA
Synthetic: longer T1/2 than somatostatin. Decreases fluid secretion. Low doses increase motility, high doses decrease motility
Octreotide therapeutic uses
Off label: SEVERE diarrhea from dumping syndrome, short bowel syndrome, vagotomy, AIDS
Octreotide side effects
- -Impaired pancreatic secretion–> decreased fat absorption (can cause fat soluble vitamin deficiency)
- -decreased GI motility (dose dependent)–> nausea, abdominal pain, flatulence
- -decreased gallbladder contractility–> gallstones (50%), acute cholecystitis (rare)
- -Insulin/glucagon imbalance
- -Hypothyroidism and bradycardia
Bismuth subsalicylate MOA
Salicylate decreases PG and Cl- secretion in LARGE INTESTINE, antimicrobial, bind enterotoxins
Bismuth subsalicylate therapeutic uses
PREVENTION and tx of traveller’s diarrhea
Bismuth subsalicylate side effects
- -Blackening of stool and tongue
- -High doses: salicylate toxicity: tinnitus, acid-base disturbances etc.
Osmotic cathartic drug names
Lactulose, magnesium hydroxide, sodium phosphate, polyethylene glycol electrolyte solution
Osmotic cathartic MOA
Not absorbed–> increased H2O in lumen by osmosis
Osmotic cathartic therapeutic uses
–Constipation: especially when enteric nervous system disrupted
Lactulose therapeutic uses
Decreases [ammonia]–> treats portal systemic encephalopathy
What can occur if osmotic laxatives are absorbed systemically?
Intravascular volume depletion and electrolyte imbalances (hyperphosphatemia, hypocalcemia, hypernatremia, hypokalemia).
Who should osmotic cathartics be used with caution in?
Elderly, frail, have renal insufficiency or have significant cardiac disease
What can Mg(OH)2 cause in patients with kidney failure?
Hypermagnesemia
Lactulose side effects
Metabolized by gut bacteria–> SEVERE cramps, flatulence, discomfort
Bile acid binding resin drug names
Cholestyramine, colestipol
Bile acid binding resin MOA
- -Decreased reabsorption of bile salts–> secretory diarrhea (Crohn’s disease or resection of terminal ileum)
- -Bind unabsorbed bile acids–> decreases H2O secretion
Bile acid binding resin side effects
- -Bloating, flatulence, constipation, fecal impaction
- -Impairing absorption of other drugs and fat soluble vitamins
Stool softener names
Docusate, mineral oil
Docusate MOA
Surfactant
Mineral oil MOA
Lubricates
Stool softener therapeutic uses
Widespread clinically. Questionable effectiveness in all scenarios
When should stool softeners not be used?
Cases of undiagnosed abdominal pain or unknown intestinal pathology
Side effects of Mineral Oil
Lipid pneumonitis (if aspirated) Can cause decreased absorption of fat soluble vitamins
Prokinetics
Decrease motility throughout entire GI tract (not just the colon)
Types of prokinetics
- D2 receptor antagonists (metoclopramide)
- Macrolides (erythromycin)
- 5HT4 agonists (Cisapride–restricted use)
Prokinetic uses
Impaired gastric emptying and constipation (decreased motility in entire GI tract)
Where are antidiarrheals NOT recommended?
Bloody diarrhea, high fever, systemic toxicity
What should prescription of laxatives be secondary to?
Dietary modifications, increasing fluid uptake, and physical activity
What has a mild effect and long latency?
Laxatives
–Softening of feces (1-3 days)
What has an intermediate effect and latency?
Contact cathartics
–Semi-solid, soft stool (6-8 hrs)
What has a strong effect and short latency?
Osmotic cathartics and castor oil
–Watery evacuation (1-3 hrs)
Constipation predominant IBS treatment
Laxatives and cathartics. Tegaserod can be used (restricted availability)
Diarrhea predominant IBS treatment
Opiates. Alosetran can be used (restricted availability)
