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65 terms

P'cology test 4 GI

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GI drugs
Drugs Used in Acid Peptic Diseases
Drugs Stimulating Gastrointestinal Motility
Laxatives
Antidiarrheal Agents
Drugs Used for the Treatment of Irritable Bowel Syndrome
Antiemetic agents
Drugs Used to Treat Inflammatory Bowel Disease
Drugs Used in Acid Peptic Diseases
pic
Enteric nerous system : surrounds GI tract. Has many neurons as the SC. (controls secretion of peptides, etc). Has a positive effect. Increases H rlease. Increases proton pump to increase stomach acid.
Drugs Used in Acid Peptic Diseases
pic
**cells involved in the production of acid in stomach. All except the antacids work somewhere in here. When antrum fills with food it stimulates these cells - gastrin containing cells - to produce and secrete gastrin. (antrum is lower part and fundus is the upper part). These are hormone peptides, they are CCK-B. Gastrin stimulates the acid in the stomach. There are diff. ways it does this. 2 diff cells involved here. 1. parietal cells (they have the proton pumps that are responsible for producing the stomach acid). 2. ECL cells - enterochromosome cells. Gastrin binds on to both of these cells and has a positive effect on stomach acid production. When it binds to the receptors of the parietal cells, it causes Ca+ influx. This activates the proton pump. ATpase. It uses ATP to pump protons out of the cell into lumen of stomach where it combines with chloride to make Hydrochloric acid. And its exchanged for potassium.
Gastrin increases the pump activity.
ECL cells: gastrin also has a positive effect here. It causes the release of histamines. H then goes to the parietal cells and binds to Histamine (H2) receptors and when this happens it activates the enzyme cAMP (2nd messenger) and activate protein kinase to activate the pump. So this is a more indirect pathway of activating the proton pump to make stomach acid.

Gastrin has 2 ways to increase Acid:
Direct way by causing Ca+ influx in the parietal cells
2. Indirect way by causing H release in the ECL cells and increase Acid by binding onto the receptors.

Other influences in increasing stomach acid: 1. Major one is the enteric nervous system. Major part of the autonomic nervous system, it surrounds all the GI tract and has as many neurons as found in the spinal chord. Peristalsis, secretion, etc.
It has a positive effect due to the cholinergic effect from enteric nevous system this impends on the M1 receptor in the ECL cells and increase H release and impenges on the M3 muscarinic receptors of parietal cells. This is another way to increase stomach acid.

There are inhibitor effects:
Somatostatin peptide has inh. Effect of release H from ECL cells. Increased with stomach acid

Major drugs work thru this way except antacids. Via the PPI and H2RA.!!!!




There are inh. effect. Somatostatin decreases stomach acid.
Antacids
Used for centuries to treat patients with dyspepsia and acid-peptic disorders

Weak bases that interact with gastric hydrochloric acid to form salt and water

~45 meq/h of hydrochloric acid is generated after a meal a single dose of 156 meq of antacid given 1 hour after a meal neutralizes gastric acid for up to 2 hours
Antacids
All are weak bases. Dicretly neutralize the acid. The ave. size adult makes 45 meq/h. Direct way to knock out stomach acid. Not as good as ______

All antacids are weak bases.

Not as good as PPI and H2RA.

Short acting but effective
Antacids
Sodium Bicarbonate: (Alka Seltzer, baking soda) reacts rapidly with HCL to produce CO2 and NaCl
adverse side effects are gastric distention and belching

Calcium Carbonate: (e.g.,Tums) reacts with HCL to form CaCl2 adverse side effects are gastric distention and belching

Magnesium hydroxide and aluminum hydroxide: (e.g., Maalox, Mylanta) reacts slowly with HCl
no gas is generated so no abdominal distention or
belching occurs
1. Na bicarbonate
2. ca+ carbonate
3. mg+ hydroxide
3 major types of antacids.

1. CO2 increases acid thus belching
2. Active ingred in Tums.
3. Do no gen. gas. But don't neutralize gas as quickly as the other two.
H2 -Receptor Antagonists
1970s-1990s the H2-blockers were the most commonly prescribed drugs in the world

Advent of use of antibiotics to treat ulcers and proton pump inhibitors has led to declining usage
H2 Receptor Antagonists
H2RA but largly replaced by PPI b/c they are more effective
Now most ulcers caused by H. pylori (bacteria) thus treated with PPI along with ANTBX.

Most ulcers caused by bacterial infection thus use PPI to treat it best! With ATbx too.
Drugs Used in Acid Peptic Diseases
These are the antag. That bind to parietal cells to block the activity. Prevent H from binding to R and block activity.
Block the H.
Not as effective as the PPI.

Blocks Histamine. No any effect of gas here. No direct effect on acid prodction
H2 -Receptor Antagonists
Four H2 antagonists remain in use
1. Cimetidine (generic, Tagamet), rapidly absorbed, first pass ~ 50%

2. Ranitidine (Zantac), rapidly absorbed, first pass ~ 50%

3. Famotidine (generic, Pepcid), rapidly absorbed, first pass ~ 50%

4. Nizatidine (Axid), rapidly absorbed, little first pass ~100%'

Serum half-lives of 1-4 hours. Cleared by hepatic metabolism, glomerular filtration, renal tubular secretion
H2 Receptor Antagonists
Nizatidine most abs and not broken down rapidly.
H2 -Receptor Antagonists


Pharmacodynamics: act at the parietal cell H2 receptors suppress basal and meal-stimulated acid secretion
Relative Potency
Cimetidine 1

Ranitidine 4-10X

Nizatidine 4-10X

Famotidine 20-50X

Dosages depend on illnesses treated
Clincially used for: stomach acid inhibition, acute duodenal or gastric ulcer, gastroesphageal reflux


The acid go back to esophagus causing damage and pain

Diff. potencies.
H2 -Receptor Antagonists
Adverse Effects: there are few, these are very safe drugs
<3% of patients have side-effects which include
diarrhea, headache, fatigue, myalgias, and constipation

Drug Interactions: Cimetidine interferes with several
hepatic p450s and can slow metabolism of many drugs.
Examples include warfarin, tricyclic antidepressants,
calcium channel blockers, ethanol and benzodiazepines
H2 Receptor Antagonists
DI: interfere with metabolism of drugs and pot. The drugs that are met in the liver.

Fairly safe.
Proton Pump Inhibitors
Now among the most widely selling drugs

Esomeprazole (Nexium)

Omeprazole (Prilosec)

Lansoprazole (Prevacid)

Pantoprazole (Protonix)

Rabeprazole (Aciphex)

All have a short serum half-life and long-duration of action
PPI
Largely replace the H2AR.
Block p+ pumps for a long time. Far superior to antacids.
Proton Pump Inhibitors
Administered as inactive prodrugs with acid-resistant coats

After passing through the stomach into the alkaline intestinal lumen the coating dissolves and the prodrug is absorbed and is concentrated in parietal cells where it is converted to the active form
PPI
Do not bind directly to proton pumps. They pass thru stomach to intestine with the alkaline coat it dissolves. Conc. In the parietal cells it concentrates and block the p+ pump.
Drugs Used in Acid Peptic Diseases
PPI block the all production of HCl acid. Very effective.
Blocks all pos. effects. Block the effects of the enteric nervous system.

Blocks all prodxn of all HCL acid.
Very effective class of drugs. Blocks all pos effects. Blocks everything!
Proton Pump Inhibitors
Clinical Uses

Gastroesophageal Reflux: once daily dosages
give relief and tissue healing in 85-90% of patients

Peptic Ulcers: All pump inhibitors heal >90% of duodenal and gastric ulcers within 4-6 weeks

H pylori-associated ulcers-antibiotics + Proton pump inhibitor

NSAID (e.g., aspirin) -associated ulcers-either H2 or Proton Pump inhibitors
PPI
Ulcers caused by NSAIDS damage lining of stomach n ot cuased by H. pylori.so no need for Atbx.
Proton Pump Inhibitors SE
These are extremely safe drugs with minor diarrhea, headache and abdominal pain in 1-5% of patients.
Some possibility of vitamin B12 deficiency with prolonged usage

Drug Interactions: Decreased gastric acidity may alter absorption of drugs with bioavailabilities that are affected by acidity (ketoconozole and digoxin)
diagram pic of ranitidine , omeprazole etc
What happens to stomach acid. H2 vs. PPI.
Red line is the normal acid pathway. Increase HCl by the p+ pumps. Goes up during eating.
H2 greatly reduces during meals. But the PPI completely block the acids. Way more potent.

PPI replaced H2RA and Antacids.
Mucosal Protective Agents
Gastroduodenal mucosa protects stomach from acid by producing a layer of mucous

Sucralfate (generic, Carafate)-salt + sucrose complexed to sulfated aluminum hydroxide. It binds to ulcers or erosions selectively providing a protective coating.

No side effects but not heavily used because the proton pump inhibitors are more effective.
Mucosal protective agents
There are mucosal protection. Tx try to protect lining from acid attack.
Mucosal Protective Agents
Mucosal Protective Agents

The gastrointestinal mucosa synthesizes prostaglandins that are involved in stimulating mucus and bicarbonate secretion

Misoprostol (Cytotec)-methyl analog of PGE1
acid inhibitory effects, mucosal protective effects, stimulates bicarbonate secretion

Used to treat ulcers in patients on long-term NSAID therapy

Adverse effects: minor diarrhea and abdominal cramps
Drug Interactions: None Known
Mucosal Protective Agents
Colloidal Bismuth- bismuth subsalicylate (Pepto-Bismol and others)

Nonprescription compound that coats ulcers and erosions providing a protective layer against acid and pepsin

Clinical Use: widely used for dyspepsia and acute diarrhea

Adverse Effects: very few, blackening of stool
Drugs Stimulating Gastrointestinal Motility
These work on the ENS. It is the largest in the autonomic system.
Shows cross sxn of intestin.
Several layers of muscle. The coordinated axn of the muscles drives the food thru it.
Myenteric plexus - biggest.
Deep musc. Plexus - minor.

ENS largest of autonomic nervous system.

Longtitudinal and circular muscles resp. for peristalsis for driving fluid through it.
Enteric Nervous System
Enteric Nervous System

Myenteric neurons are very diverse:
1. calcitonin gene related peptide (CGRP)-releasing
ones: peristaltic reflex, promote release of
excitatory or inhibitory mediators depending on
region of gut
2. Acetylcholine, serotonin, substance p-releasing
ones cause contraction of muscle.
3. Vasoactive intestinal peptide, nitric oxide, ATP-
releasing ones relax muscle
ENS
Many diff. neurotransmitters. Same # of NTs in brain and in the ENS.
Drugs Stimulating Gastrointestinal Motility Cholinomimetic Agents
(e.g., neostigmine) enhance gastiric, small intestine, and colonic emptying

Metoclopramide (generic, Reglan)
Cisapride (Propulsid)
Domperidone
All three have effects on cholinergic stimulation
Drugs Stimulating Gastrointestinal Motility
Clinical Uses:
Gastroesophageal reflux disease-Metaclopramide (only one available one in US)-increases lower esophageal pressure

Impaired Gastric Emptying-caused by some surgeries. All three of the drugs on the last slide can effectively treat this condition.

Other uses include prevention of vomiting.

Adverse Effects: CNS-Restlessness, drowsiness
Laxatives
Extensively self-prescribed but seldom needed

Bulk-Forming Laxatives-indigestible colloids that absorb water and distend the colon to promotes peristalsis
Psyllium (generic, Metamucil, others)
Methylcellulose
lax
Ex. Psyllium ingred. In metamucil
Both absorb water in colon and produce peristalsis
Laxatives : stool softeners
Surfactant agents that soften
stool allowing water and lipids to penetrate.
Docusate (generic, Colace, others)-oral or enema
Glycerin Suppository
Mineral oil

Osmotic: treatment of acute constipation
Magnesium Hydroxide (Milk of Magnesia, Epsom Salt, generic)
Sorbital-nonabsorbable sugar
Lactulose-nonabsorbable sugar
Magnesium Citrate
Sodium Phosphate
Polyethylene glycol (CoLyte; GoLYTELY)-for GI
endoscopy
Laxatives
SS: mineral oil used as a laxative

Osmotic: work by they can't be3 abosorbed. They keep the stool watery thus are laxatives.
Stimulant Laxatives (Cathartics)
Induce bowel movement by stimulating enteric nervous system

Anthraquinone Derivatives-
aloe, senna (Ex-Lax), cascara

Castor Oil-potent, now seldom used
Stimulant Laxatives (Cathartics)
Cause peristalsis.

Castor oil: historically used but not no more
Antidiarrheal Agents
Opioid Agonists increase constipation by inhibition of presynaptic cholinergic nerves in the enteric system-leads to increased transit time and water absorption
Loperamide (generic, Imodium)-doesn't cross blood brain/barrier
Diphenoxylate (genric, Lomotil)-high doses can have CNS effects

Colloidal Bismuth Compounds (Pepto-Bismol) can have antidiarrheal effects
Antidiarrheal Agents
The opp of laxatives.
More water abs. in colon and the stool stay there longer.

Diphenoxylate has some CNS effects.
Antidiarrheal Agents Kaolin and Pectin
Kaolin is a naturally occurring clay compound composed of hydrated magnesium aluminum silicate. Pectin is an indigestible carbohydrate from apples

Kaolin/pectin (generic, Kaopectate) Both act to absorb bacteria, toxins, and water.

Octreotide (synthetic analogue of somatostatin):
Inhibits secretion of numerous hormones, reduces
intestinal fluid secretion, slows GI motility
Irritable Bowel Syndrome
IBS: a chronic disorder characterized by abdominal pain, bloating, cramps, and diarrhea or constipation

Anticholinergics

Serotonin 5-HT3 Receptor Antagonists

Serotonin 5-HT4 Receptor Agonists
Serotonin 5-HT4 Receptor Agonists
Anticholinergics (infrequently used):
Dicyclomine (generic, Bentyl)
Hyoscyamine (Levsin)
Both inhibit muscarinic cholinergic receptors in the
enteric plexus and smooth muscles

Have been used but not no mo.
Irritable Bowel Syndrome
5-HT3 Antagonists
Modulate visceral afferent pain sensation and intestinal motility through effects on the enteric nervous system.
Alosterin (Lotronex): potent and specific antagonist approved for treatment of women with severe irritable bowel syndrome in which diarrhea is the predominant symptom.
Adverse side effects: constipation and, rarely, gastrointestinal toxicity
Irritable Bowel Syndrome
5-HT3 Antagonists
Modulate pain sensation and intestinal motility.
Irritable Bowel Syndrome

5-HT4 Receptor Agonists:
Tegaserod (Zelnorm)-partial agonist selective for 5-HT4 receptor resembling serotonin
Stimulates receptors on mucosal afferent nerve fibers causing release of transmitters from the submucosal and myenteric plexus-stimulates gastric emptying
Approved for use in IBS patients in which constipation is a predominant symptom
Adverse effects: very safe, diarrhea rare, no known drug interactions
Antiemetic Agents
Treatment for nausea and vomiting: controlled by brain stem vomiting center which has high concentrations of muscarinic, histamine H1, and serotonin 5-HT3 receptors-afferent input important

5-HT3 antagonists: potent antiemetic agents primarily affecting intestinal vagal afferents to vomiting center
Antiemetic Agents
NV controlled by vomit system. Determines if NV occurs.

These can carry from stomach to brain stem
pic
All diff. inputs. Mostly thru vagus nerve. Input from higher cortex. Meninges can trigger vomiting.
Many diff types of chemicals to induce nv.

Act at this level to block nv.
Antiemetic Agents
5-HT3 antagonists
Ondansetron (Zofran)
Granisetron (Kytril)
Dolasetron (Anzemet


Clinical uses:
Primary agents for treatment of chemotherapy-induced nausea. Usually given by injection before chemotherapy. Also given for postoperative nausea and vomiting.

Adverse effects: very safe, occasional headache, dizziness, and constipation, no drug interactions
Antiemetic Agents
Substituted Benzamides:
Metoclopramide (generic, Reglan)
Trimethobenzamide
-both thought to prevent nausea and vomiting by dopamine receptor blockade'

H1 Antihistamines & Anticholinergics: mostly used for prevention of motion sickness
Diphenhydramine
Dimendhydrinate (Dramamine)


Anticholinergics: Hyoscine (Scopolamine)-muscarinic antagonist excellent for prevention of motion sickness but has many anticholinergic side-effects
antiemetic
Antichol good at preventing pmoiton sickness
Antiemetic Agents
Antiemetic Agents


Benzodiazepine anti-anxiety agents (e.g., lorazepam, diazepam): used prior to initiation of chemotherapy to reduce anxiety-induced vomiting

Cannabinoids (Dronabinal): the major psychoactive chemical in marijuana. useful for treatment of chemotherapy-induced nausea. The means by which cannabinoids reduce nausea is unknown.
Adverse effects include euphoria, sedation, and dry mouth.

Corticosteroids:The means by which corticosteroids reduce nausea is unknown.
Benzodiazepine anti-anxiety agents (e.g., lorazepam, diazepam): used prior to initiation of chemotherapy to reduce anxiety-induced vomiting

Cannabinoids (Dronabinal): the major psychoactive chemical in marijuana. useful for treatment of chemotherapy-induced nausea. The means by which cannabinoids reduce nausea is unknown.
Adverse effects include euphoria, sedation, and dry mouth.

Corticosteroids:The means by which corticosteroids reduce nausea is unknown.
Prior to chemotherapy these ppl get anxiety that induces vomiting. Thus anti-anxiety agent is given.
Inflammatory Bowel Disease
Ulcerative Colitis and Crohn's Disease: unknown cause

Anti-inflammatory drugs:
Aminosalicylates
Glucocorticoids
Purine analogues
Methotrexate
Anti-TNF alpha therapy.
Inflammatory Bowel Disease
Aminosalicylates:

Sulfasalazine (generic, Azulfidine, others) Balsalazide ( Colazal)
Olsalazine (Dipentum)
Mesalamine (5-ASA)
IBD
Clincial Use: Remission in ulcerative colitis, efficacy in Crohn's Disease not well established

Adverse Effects: Sulfasalazine-nausea, headaches, myalgias,bone marrow suppression common Others are well tolerated
Inflammatory Bowel Disease
Glucocorticoids:
Orally administered-prednisone and prednisolone
Rectally administered (enemas, foams, suppositories)-Hydrocortisone

Cinical Use: patients with moderate to severe disease
Inflammatory Bowel Disease
Purine Analogs:
Azathioprine (generic, Imuran)
6-Mercaptopurine
-both treat illness by immunosuppression through an unknown mechanism

Clinical Use: Important agents for induction and maintenance of remission of ulcerative colitis and Crohn's disease
-50-60% of patients undergo remission after 3-6 months of treatment

Adverse Effects: nausea, vomiting, bone marrow depression
Inflammatory Bowel Disease
Methotrexate: widely used in chronic inflammatory diseases and as cancer chemotherapy
-administered orally or by injection
-inhibits dihydrofolate reductase which is important in thymidine and purine producition

Clinical Use: To induce and maintain remission in Crohn's disease

Adverse Effects: bone marrow depression, anemia
-folate supplements given
IBD
Potent anti-inflamm. Good for rheumatoid arthritis.

Often by injeciton b/c hard to tolerate in GI tract.

Depletes folate in body so give supplements.
Inflammatory Bowel Disease
Anti-TNF-Alpha Therapy
TH1 T cell response is dysregulated in these diseases
Infliximab (Remicade)-monoclonal antibody to TNF-α, a chief proinflammatory cytokine in the TH1 response-given by infusion
prevents TNF-α from binding to its receptor

Clinical Use: symptomatic improvement in 2/3 of Crohn's patients

Adverse Effects: infection because of suppression of TH1 inflammatory response
IBD
Used to treat inflammation. Grab onto TNF-a thus antiinflammatory and block from bindding to the receptor.

Very much expensive compared to the other tx.