Lower GI drugs Flashcards
1
Q
Important regulators of motility and water absorption
A
- -Acetylcholine
- -Serotonin
- -Dopamine
- -Enkephalins
2
Q
Where is 5HT released from?
A
Enterochromaffin Cells (function as sensory receptors)
3
Q
What drugs work at the level of the sensory neurons?
A
SSRI’s, bulk-forming laxatives, contact cathartics, 5HT3 antagonists, 5HT4 agonists
4
Q
Afferent neuron NTs
A
cGRP, glutamate, substance P
5
Q
5HT
A
Major player in lower GI pathology, especially IBS
6
Q
SSRI drug names
A
Fluoxetine, paroxetine, sertraline
7
Q
What are SSRI’s most beneficial in treating (related to GI)?
A
–Constipation predominant IBS
8
Q
Mechanism of SSRIs in GI system
A
Decrease reuptake of 5HT into EC cells –> increase 5HT in synapse–> increase afferent activity –> increase peristalsis
9
Q
Bulk laxative names
A
Dietary fiber, methylcellulose, polycarbophil, psyllium
10
Q
Bulk laxative MOA
A
- -Drugs that attract H2O and increase stool mass
- -Act as “stool stabilizers”
- -Increase lumen distention
11
Q
How do bulk laxatives act on diarrhea?
A
Decrease bowel movements, make stool more solid and decrease pain
12
Q
How do bulk laxatives act on constipation?
A
Increase bowel movements, makes stool more loose, decrease pain
13
Q
What factors limit the use of bulk laxatives?
A
- Neurons generating peristaltic reflex must be functional (enteric system must be working)
- Cause of constipation must be known
14
Q
Side effects of bulk laxatives
A
Allergies, increased flatulence, increased obstruction
15
Q
Contact cathartic names
A
Anthraquinone derivatives, bisacodyl, castor oil
16
Q
Anthraquinone derivative names
A
Casacara sagrada, danthron, senna
17
Q
Bisacodyl
A
- -Prodrug
- -Almost 6 hr latency to effect
- -Acts on large intestine
- -Less potent than castor oil
18
Q
Anthraquinones
A
- -Act on large intestine
- -Less potent than castor oil
19
Q
Castor oil
A
- -Acts on both small and large intestine
- -Short latency
- -Extremely potent effects
- -More significant side effects
- -Activate ricinoteric acid
20
Q
Contact cathartic MOA?
A
Thought to be irritation of mucosa
Not sure if dependent on enteric nervous system
21
Q
Side effects of contact cathartics
A
- -Dependency (can’t have BM until take the drug)
- -Destroy myenteric plexus long term
- -Pigmentation of the mucosa (“melonosis coli”)
22
Q
Additional side effects of castor oil
A
Dehydration, electrolyte imbalance, uterine contractions
23
Q
5HT3 receptor antagonist
A
Alosetron
24
Q
Alosetron MOA
A
- -Decrease afferent stimulation–> decreases peristalsis
- -Longer duration of action than antiemetic
25
Alosetron therapeutic uses
Diarrhea predominant IBS
- -Only used when everything else has failed
- -Restricted use (compassionate use only)
26
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
27
5HT4 receptor agonists
Cisapride (also a 5HT3 antagonist) and tegaserod (more selective)
28
5HT4 receptor agonists MOA
Receptors located on presynaptic terminals--> increase release of NT from afferent neurons--> increase peristalisis
29
5HT4 receptor agonists therapeutic use
- -Used when no other options available, restricted availability
- -Tegaserod: constipation predominant IBS
30
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
31
Opiates (that work in GI system) drug names
- -Loperamide
| - -Diphenoxylate
32
Opiate action in GI system
Decrease both GI motility and water excretion and are the most effective antidiarrheal drugs
33
Can loperamide or diphenoxylate cross the BBB?
Loperamide cannot, but diphenoxylate can sort of cross the BBB (so given via prescription)
34
What can be used to offset the constipation caused by opiate analgesics?
Alvimopan and methylnaltroxone
35
What are the Mu receptor antagonists?
Alvimopan and methylnaltroxone
36
Opiate MOA
- -Inhibition of motility and secretion
| - --Generally don't cross the BBB very well
37
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
38
Therapeutic uses of opiates in GI system?
--Most effective antidiarrheals and good against most forms of diarrhea
39
Side effects of opiates
- -Abdominal cramps
- -TOXIC MEGACOLON if pt has ulcerative colitis
- -HIGH doses of diphenoxylate--> euphoria --> can lead to physical dependence
40
Mu receptor antagonists MOA
- -Don't cross BBB
| - -Selective antagonists
41
Therapeutic uses of Mu receptor antagnoists
- -Constipation caused by opiate therapy
- -Alvimopan: short-term use in hospitalized patients
- -Methylnaloxone: long-term palliative care
42
Alvimopan side effects
Increased risk of MI
43
D2 receptor antagonist drug names
Domperidone (doesn't cross BBB)
| Metoclopramide (most widely available in the US)
44
D2 receptor antagonist MOA
--Cholinomimetics (increased actions of Ach in gut --> inhibition of DA inhibition--> increases motility in entire gut--> prokinetic
45
Domperidone therapeutic uses
--Compassionate use only in US. Impaired motility, esp. decreased gastric emptying (e.g . from vagotomy, diabetic gastroparesis)
46
Metoclopramide use
Antiemetic
47
D2 receptor antagonist side effects
--Somnolence, nervousness, agitation, anxiety, dystonia, tardive dyskinesia (irreversible), parkinsonism, increased prolactin release (menstrual disorders, impotence, galactorrhea)
48
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
49
TCA drug names
Amitriptyline and desipramine
50
What drugs stimulate motilin?
Macrolide antibiotics (eg erythromycin)
51
What drugs influence chloride secretion?
Lubiprostone, linaclotide, crofelemer, octreotide, bismuth subsalicylate, opiates.
52
How do osmotic cathartics and bile acid binding resins work?
Increasing or reducing the osmotic load in the colon
53
MOA of lubiprostone
- -Activates ClC-2--> increases Cl- secretion
| - -Poorly absorbed--> almost no systemic effects
54
Lubiprostone therapeutic uses
Chronic constipation and constipation-predominant IBS
55
Lubiprostone side effects
- -Diarrhea
- -Nausea/HA
- -Increased fetal loss--NOT for use during pregnancy
56
Linaclotide MOA
- -Activates guanylyl cyclase C (cGMP)--> activates CFTR--> increases Cl- secretion--> increases H2O lumen
- -Very little systemic absorption
57
Linaclotide therapeutic uses
Chronic constipation and constipation-predominant IBS
58
Linaclotide side effects
Diarrhea
Increased maternal death
Increased mortality of juvenile mice (contraindicated in peds)
59
Crofelemer MOA
- -Voltage dependent inhibition of CFTR (and another Cl- channel)--> decreases Cl- secretion--> decreases Na+/H2O excretion--> firmer stool
- -Little systemic absorption
60
Crofelemer therapeutic uses
Diarrhea from anti-HIV drug treatment
61
Somatostatin analogue drug name
Octreotide
62
Octreotide MOA
Synthetic: longer T1/2 than somatostatin. Decreases fluid secretion. Low doses increase motility, high doses decrease motility
63
Octreotide therapeutic uses
Off label: SEVERE diarrhea from dumping syndrome, short bowel syndrome, vagotomy, AIDS
64
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
65
Bismuth subsalicylate MOA
Salicylate decreases PG and Cl- secretion in LARGE INTESTINE, antimicrobial, bind enterotoxins
66
Bismuth subsalicylate therapeutic uses
PREVENTION and tx of traveller's diarrhea
67
Bismuth subsalicylate side effects
- -Blackening of stool and tongue
| - -High doses: salicylate toxicity: tinnitus, acid-base disturbances etc.
68
Osmotic cathartic drug names
Lactulose, magnesium hydroxide, sodium phosphate, polyethylene glycol electrolyte solution
69
Osmotic cathartic MOA
Not absorbed--> increased H2O in lumen by osmosis
70
Osmotic cathartic therapeutic uses
--Constipation: especially when enteric nervous system disrupted
71
Lactulose therapeutic uses
Decreases [ammonia]--> treats portal systemic encephalopathy
72
What can occur if osmotic laxatives are absorbed systemically?
Intravascular volume depletion and electrolyte imbalances (hyperphosphatemia, hypocalcemia, hypernatremia, hypokalemia).
73
Who should osmotic cathartics be used with caution in?
Elderly, frail, have renal insufficiency or have significant cardiac disease
74
What can Mg(OH)2 cause in patients with kidney failure?
Hypermagnesemia
75
Lactulose side effects
Metabolized by gut bacteria--> SEVERE cramps, flatulence, discomfort
76
Bile acid binding resin drug names
Cholestyramine, colestipol
77
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
78
Bile acid binding resin side effects
- -Bloating, flatulence, constipation, fecal impaction
| - -Impairing absorption of other drugs and fat soluble vitamins
79
Stool softener names
Docusate, mineral oil
80
Docusate MOA
Surfactant
81
Mineral oil MOA
Lubricates
82
Stool softener therapeutic uses
Widespread clinically. Questionable effectiveness in all scenarios
83
When should stool softeners not be used?
Cases of undiagnosed abdominal pain or unknown intestinal pathology
84
Side effects of Mineral Oil
```
Lipid pneumonitis (if aspirated)
Can cause decreased absorption of fat soluble vitamins
```
85
Prokinetics
Decrease motility throughout entire GI tract (not just the colon)
86
Types of prokinetics
1. D2 receptor antagonists (metoclopramide)
2. Macrolides (erythromycin)
3. 5HT4 agonists (Cisapride--restricted use)
87
Prokinetic uses
Impaired gastric emptying and constipation (decreased motility in entire GI tract)
88
Where are antidiarrheals NOT recommended?
Bloody diarrhea, high fever, systemic toxicity
89
What should prescription of laxatives be secondary to?
Dietary modifications, increasing fluid uptake, and physical activity
90
What has a mild effect and long latency?
Laxatives
| --Softening of feces (1-3 days)
91
What has an intermediate effect and latency?
Contact cathartics
| --Semi-solid, soft stool (6-8 hrs)
92
What has a strong effect and short latency?
Osmotic cathartics and castor oil
| --Watery evacuation (1-3 hrs)
93
Constipation predominant IBS treatment
Laxatives and cathartics. Tegaserod can be used (restricted availability)
94
Diarrhea predominant IBS treatment
Opiates. Alosetran can be used (restricted availability)
