Lower GI pharmacology

Question 1

Drugs that primarily affect motility

Answer 1

1. Enhance/disrupt afferents (5HT)
2. Affect interneurons (DA, enkephalins)
3. Efferent neurons of circular muscle (ACh)
4. Affect muscle cells (motilin)

Question 2

Afferent neurons of peristaltic reflex

Answer 2

• stimulated by 5HT released from enterochromaffin cells which as sensory receptors

Question 3

SSRIs

Answer 3

Fluoxetine, Paroxetine, Sertraline

• most beneficial in constipation IBS
• decrease reuptake of 5HT into EC cells -> increase 5HT in synapse -> increased afferent activity -> increased peristalsis

Question 4

Bulk Laxatives

Answer 4

Fiber, methylcellulose, polycarbophil, psyllium
- attract water and increase mass of stool -> increased distention of lumen -> increase release of 5HT from EC cells -> increased peristalsis
“STOOL STABILIZERS”
- diarrhea = decrease BM, solidify stool, decrease pain
- constipation = increase BM, loosen stool, decrease pain
S.E. = allergies, flatulence, obstruction

Question 5

Limits of bulk laxatives

Answer 5

1. need neurons to be functional

2. cause of constipation must be known

Question 6

Contact cathartics

Answer 6

Anthraquinone (act on large intesine-> less potent), Bisacodyl (prodrug), Castor Oil (acts on both small and large intestine -> potent)
- mechanism is thought to be dependent on enteric nervous system -> possible irritation increases EC cell activity
S.E. = dependency and destroy myenteric plexus
- pigmentation of mucosa
CASTOR OIL -> dehydration and electrolyte imbalances and uterine contractions

Question 7

5HT3 receptor antagonists

Answer 7

Alosetron
- blocks 5HT3 receptor -> decreases afferent tranmission -> decreases peristalsis
- used for diarrhea IBS when nothing else works (restricted availability)
S.E. = constipation (BAD), hospitalization, ischemic colitis
- interaction with CYP1A2

Question 8

5HT4 receptor agonists

Answer 8

Cisapride (prokinetic), Tegaserod (more selective)
- agonist 5HT4 receptor -> increase release of NT from afferent -> increased peristalsis
- used when nothing else works
Tegaserod -> constipation IBS
Cisapride -> diabetic gastroparesis
S.E. = CV toxicity (arrhythmia and long QT)

Question 9

Enkephalins

Answer 9

interneurons -> ENK inhibit both contraction and relaxation -> so these drugs are inhibiting the inhibitors`

Question 10

Opiates

Answer 10

Diphenoxylate (BBB), Loperamide (no BBB) (antidiarrheals)
- inhibit motility and secretion
- combine diphenoxylate with atropine because it blocks muscarinic receptors to decrease contractions
- most effective antidiarrheals
S.E. = ab cramps, toxic megacolon -> UC, euphoria

Question 11

Mu receptor antagonists

Answer 11

Alvimopan (short term hospital), Methylnaloxone (long term palliative)
- don’t cross BBB -> just work in gut, given at time of opiate administration
- used for patients on opiates for pain
S.E. = Alvimopan -> increase risk of MI

Question 12

Dopamine D2 receptor antagonists

Answer 12

Domperidone (no BBB), Metoclopramide
- cholinomemetics -> increase ACh actions -> inhibit DA inhibition ==> increase motility of entire gut (prokinetic)
- D -> compassionate use only -> impaired GI motility
- M -> antimemetic
S.E. = somnolence, nervousness, agitation, anxiety, dystonia, Parkinsonism, tardive dyskinesia, increased prolactin

Question 13

Acetylcholine

Answer 13

RULE -> drugs directly affecting cholinergic nerves are NOT used for diarrhea
EXCEPTION -> TCA and Atropine

Question 14

TCA

Answer 14

Amitriptyline, Desipramine

1. decrease reuptake of NE from postganglionic sympathetics -> increased activation of alpha2 on presynaptic terminals of cholinergic postganglionic parasympathetics -> decrease ACh release -> decreased motility
2. decrease reuptake of DA -> increase activation of D2 receptors -> decrease ACh and decrease motility

Question 15

Atropine

Answer 15

direct anti-muscarinic effects –> decrease peristalsis

Question 16

Motilin

Answer 16

macrolides –> erythromycin

• stimulate motilin receptors on smooth muscle –> initiation of migrating motor complex
• subclinical doses work but increase risk of resistant bugs

Question 17

Newest treatments for diarrhea and constipation?

Answer 17

directed toward transporters responsible for chloride secretion in colon

Question 18

CIC-2 stimulants

Answer 18

Lubiprostone
- activates CIC-2 -> increased Cl secretion
- it’s poorly absorbed which is good -> no systemic effects
- used for chronic constipation and constipation IBS
S.E. = diarrhea, nausea, headache, increased fetal loss (class C drug)

Question 19

GC-C activator

Answer 19

Linaclotide
- activates guanylyl cyclase C -> increase cGMP -> activates CFTR -> increased Cl- secretion -> increased water in lumen
- poorly absorbed -> good
- used for chronic constipation and constipation IBS
S.E. = diarrhea, increased pregnancy maternal death (C), increased mortality in juvenile mice -> no pediatrics

Question 20

CFTR inhibitor

Answer 20

Crofelemer

• voltage independent inhibition of CFTR -> decreased Cl secretion -> decreased water in lumen -> firm stool
• poorly absorbed -> good
• used for diarrhea due to anti-HIV treatment

Question 21

Somatostatin analog

Answer 21

Octreotide

• synthetic analog -> longer t1/2 (6-12 hrs)
• decreases fluid secretion
• increases motility (low dose), decreases motility (high dose)
• used for severe diarrhea (dumping, short-bowel, vagotomy, AIDS)
• S.E. = impaired pancreatic secretions -> fat malabsorption & vitamins, decreased GI motility, decreased gallbladder contractility -> gall stones

Question 22

Bismuth Subsalicylate

Answer 22

direct antimicrobial activity -> binds enterotoxins
- Bismuth = stimlates PG, mucous, HCO3 secretion in stomach
- Subsalicylate - inhibits PG and Cl in colon
- used for diarrhea -> prophylactically
S.E. = blackening of stool (Bismuth), tinnitus (subsalicylate)

Question 23

Osmotic Cathartics

Answer 23

Lactulose, Magnesium Hydroxide, Sodium Phosphate, Polyethylene glycol
- increase water and electrolyte [ ] in colon -> mostly by osmosis
- used for constipation when enteric nervous system is compromised
- Lactulose -> decreases plasma ammonia [ ]
S.E. = if absorbed systemically -> intravascular volume depletion and electrolyte imbalances

Question 24

Bile acid binding resins

Answer 24

Cholestyramine, colestipol
- complex with bile salts -> decreased water secretion
- used for ileum diseases (Crohn’s, surgical resections)
S.E. = bloating, flatulence, constipation, fat malabsorption & vitamins

Question 25

Stool softeners

Answer 25

Docusate -> surfactant -> allows mixing of aqueous and fatty substances Mineral Oil -> lubricates feces -> decreases water absorption - widespread use but only moderate efficacy in constipation S.E. = mineral oil can cause lipid pneumonitis if aspirated

Question 26

Prokinetics

Answer 26

D2 antagonists, macrolides, 5HT4 agonists dramatically increase motility throughout entire GI tract - used for impaired gastric emptying (vagotomy and diabetic gastroparesis)

Question 27

Antidiarrheals

Answer 27

don't use with bloody diarrhea or fever | - Opiates, BABR, octreotide, bismuth, crofelemer, absorbants

Question 28

5HT3 antagonists

Answer 28

anti-emetics --> DolaSETRON, GraniSETRON, OndanSETRON, PalonoSETRON - blockade of peripheral 5HT3 receptors on intestinal vagal afferents - primary agents for preventing/treating chemo induced N/V - most effective when given 30 mins before chemo S.E. = excellent safety except Alosetron, headache, dizziness, constipation

Question 29

Anticholinergics

Answer 29

Scopolamine --> anti-emetic - inhibition of muscarinic receptors in cerebellum --> rapidly and fully distributed to CNS - partially effective for motion sickness -> give as transdermal patch (less S.E.)

Question 30

Neurokinin Receptor 1 Antagonists

Answer 30

Aprepitant (oral), Fosaprepitant (IV) - substance P is preferred ligand for NK, tachykinin receptor (antagonist the NK1 receptor) - used for prevention of acute and delayed chemo-induced N/V - given with 5HT3 antagonist and Dexamethasone - well tolerated, but CYP3A4 --> drug interactions

Question 31

Antihistamines (H1)

Answer 31

Dimenhydrinate, Diphenhydramine, Meclizine - H1 blockers --> cross BBB (sedation) - efficacy is increased with ephedrine or amphetamine S.E. = anticholinergic, teratogenic ?, drug-interactions

Question 32

Dopamine D2 antagonists

Answer 32

Droperidol, Metoclopramide, Prochlorperazine, Promethazine, Thiethylperazine - inhibition of D2 receptors and muscarinic receptors in CTZ --> causes sedation

Question 33

Cannabinoids

Answer 33

Dronabinol, Nabilone - mechanism not well understood --> acts on central cannabinoid receptors S.E. = euphoria, dysphoria, sedation, hallucinations, dry mouth, increased appetite

Question 34

Corticosteroids

Answer 34

Dexamethasone, Methylprednisolone - unknown mech for why they work - combine with 5HT3 receptor antagonists

Question 35

Aminosalicylates

Answer 35

Balsalazide, Mesalamine (5-ASA), Olsalazine, Sulfasalazine - blocks PG synthesis by inhibiting COX pathway --> reduces inflammation - B, O, S -> limited absorption until bacteria break it down - used as first line treatment for mild/moderate UC --> not for Crohn's S.E. = well-tolerated, nausea, headaches, arthralgias, sensitivity

Question 36

Sites of action of Aminosalicylates

Answer 36

``` Jejunum - Rectum = 5-ASA Ileum to Rectum = 5-ASA pH dependent Prox Colon to Rectum = Balsalazine, Sulfasalazine Distal Colon to Rectum = 5-ASA enema Rectum = 5-ASA suppository ```

Question 37

Corticosteroids

Answer 37

Budesonide, Prednisone, Prednisolone - used for treatment of moderate/severe IBD - Budesonide = extensive first pass metabolism --> local rather than systemic effect --> used for Crohn's disease involving ileum and proximal colon

Question 38

Antimetabolites

Answer 38

Azathioprine, 6-Mercaptopurine, MTX | - given in low doses for induction and maintenance of remission of UC and Crohn's

Question 39

Anti-TNF alpha

Answer 39

Infliximab (chimeric) - dysregulation of Th1 response occurs in IBD (TNF alpha is major proinflammatory cytokine) - antibody to bind solute and receptor bound TNF alpha --> no binding to cytokine --> no inflammation - can lead to symptomatic improvement and remission of Crohn's disease S.E. = infection, pruritis, fever, chills, urticaria, lymphoma

Question 40

Monoclonal antibodies

Answer 40

Natalizumab --> targets alpha4 subunit of integrin - prevents integrins from binding selectins on vascular endothelial cells - used for Crohn's when all else has failed - stop tx with anti-TNF's 2 months before starting Natalizumab