GI pharmacology Flashcards
Targets of Antacids/treatment of ulcers
Regulation of acid secretion (H+) by parietal cells is controlled by the proton pump.
Muscarinic receptor (M), histamine receptor (H) and gastrin (G) receptor pathways all stimulate acid secretion.
Prostaglandin receptor (PG) pathways inhibit acid secretion.
M, H and G all work by G-protein coupled receptors. Coupled to adenylate cyclase–>increase cAMP–>stimulate proton pump to secrete acid.
PGs help protect gut by increasing blood flow, increasing mucus secretion, which also helps with bicarb buffering capacity.
nb: aside from targeting these receptor pathways, proton pump itself can be a target for drug action
Causes of ulcers
Drugs: NSAIDs, steroids- interfere with production of endogenous PGs- also, tend to use these types of drugs chronically
Shock, hypotension, trauma
bile reflux
metabolic diseases
Antacids
Aluminum salts (AlOH, carbonate, silicate) and Magensium salts (hydroxide, oxide, trisilicate)
These antacids are essentially alkaline chemicals that neutralize acids in stomach.
uses: adjuncts to H2 antagonists and proton pump inhibitors; non-specific therapy.
Mechanism and side effects of antacids
Mechanism: chemically neutralize gastric HCl; inhibit pepsin secretion (benefit: pepsin production is a stimulus for acid secretion); not absorbed systeimcally. H2O and neutral salt are passed out of GI tract
side effects:
rebound acid secretion: stomach neutralized, may start to produce more acid– this side effect is more common with magensium salts; wears off with use
constipation
impair absorption of other drugs- can interfere with function and absorption of other, more specific therapies.
Histamine receptor antagonists
e. g. cimetidine (tagamet) and ranitidine (zantac)
uses: gastritis, gastric ulcers, oesophagitis
Mechanism of action: competitive antagonism of H2 receptors in parietal cells
Pharmacokinetics: oral administration–>direct to action
widely distributed and well-absorbed; hepatic metabolism and renal excretion.
Not a huge number of side effects: H2 receptors are basically only in the stomach. NB: not licensed for use in animals, but widely used.
NB: cimetidine is able to induce synthesis of microsomal enzymes–> can impact use of other drugs.
Sucralfate
sucrose sulfate-aluminum hydroixde complex
Mechanism: polymerizes to viscous gel at pH < 4. forms long chains under acidic conditions–> polymerizes to gel–> exposed sulfate groups bind to protein in ulcerated tissue–>creates a bandage over the area.
Uses: tx of gastric and duodenal ulcers
Side effects: constipation- not absorbed from GI therefore low risk of systemic side effects. Give at least an hour apart from H2 antagonist.
Proton pump inhibitor
e. g. omeprazole (prilosec)
uses: gastritis, gastric ulcers, oesophagitis, prevention and treatment of ulcers caused by NSAIDs
Mechanism: inhibits H+/K+ ATPase pump on luminal membrane of parietal cells.
Binding is irreversible. Body has to synthesize new enzyme to create pump again–> long action, can give SID
NB: can also affect microsomal enzymes
oral administration
accumulates in parietal cells due to chemical make-up. the charged form of the molecuule is active–has selective action in parietal cells. Other ATPase that exists in body is largely unaffected, as charged forms can’t get through membranes.
Hepatic metabolism/renal excretion
PGE 2 analogues
e.g. misoprostol- methyl ester of PG–> very stable and long lasting
Can’t use PG itself because it’s not long-lasting/stable enough
PG analogue will decrease acid secretion, increase blood flow and increase mucus production.
Uses: prevention and treatment of ulcers caused by NSAIDS- working on same pathway can reduce detrimental effect. Commonly used in cats and dogs
Stable analogue of PGE2, agonist at PG receptor
Side effects: diarrhea
PG has critical role in repro cycle-> not good in pregnant animals or in animals who will be/might be pregnant in the future.
Control of vomiting
Stimuli from pharynx/stomach–> visceral afferents: 5HT3
visceral afferents–> Nucleus of solitary tract: H1, mACH
sensory afferents e.g. pain,sight, smells–> Higher centres
Motion–> Vestibular nuclei (H1, mACh)
visc. afferents and vestib inputs–>Chemoreceptor trigger zone (D2, 5HT3)
CTZ, Nucleus of solitary tract and higher centres–> Vomiting centre (mACh, NK-1)–> emesis
H1= histamine
D2=dopamine
5HT3= serotonin
mACh=muscarinic acetylcholine
NK-1= neurokinin 1
further control of vomiting
NK-1: neurokinin– substance P acts on NK-1 receptor (final gate in control of vomiting)
Vomiting centre has NK and mACh receptors. Dogs have H1 receptors in vomiting centre, but cats don’t.
Vomiting reflex well developed in carnivores and pigs; no vomiting reflex in equids, ruminants, rats or rabbits
Induction of vomiting- emetics
Emesis contraindicated if: unconscious, suscpetible to seizures, ingested corrosive, caustic or viscous material
nb: rat poisons work so effectively in rats because they can’t vomit
3% hydrogen peroxide- emetic
if higher than 3%, corrosive
Mechanism: stimulates visceral afferents; mild gastric irritant
Pharmacokinetics: oral admin
Uses: emetic in cats and dogs
no real side effects
5mg/kg
physical agitiation of walking helps mix around in stomach and stimulate afferents. 15-20 minutes time to action.
Ipecac/huana
mechanism: local irritation (similar to hydrogen peroxide); direct central activation of the receptors in the CTZ
Pharmacokinetics: oral admin, but we don’t really know the action of how it works. onset of action is relatively short
Uses: emetic
Side effects: uncommon but OD can lead to cardiotoxicity
Xylazine
mechanism: alpha 2 adrenoceptor agonist (sedative also)
direct central activation of receptors in CTZ–> in most species, CTZ has alpha 2 adrenoceptors
IV or IM admin
emetic in cats because they have a high number of alpha2’s in CTZ
sedative, analgesic
Side effects: sedation, CV side effects
Apomorphine
mechanism: dopamine agonist (doesn’t activate opioid receptors)
- receptors in CTZ
Oral absorption is slow, parenteral admin (IV/IM) preferred.
drug of choice for emesis in dogs
Side effects: protracted vomiting; excitement, restlessness; CNS effects due to stimulation of dopamine receptors in CNS.
Treatment of vomiting- antiemetics
Dopamine antagonists (antidopaminergics)
histamine antagonists (antihistamines)
muscarinic antagonists (anticholinergic)
Neurokinin antagonists
Serotonin antagonists
Phenothiazines
primarily sedatives- i.e. acepormazine is a phenothiazine
Mechanism: block dopamine receptors in CTZ; weak anticholinergic and antihistamine
Oral admin- can give IM too
well absorbed and distributed- significant 1st pass metabolism
excreted by kidneys
Broad spectrum antiemetic
side effects: hypotension, bracycardia d/t anticholinergic action; sedation
Metoclopramide
Mechanism: dopamine antagonist- also some antimuscarinic effects
Prokinetic reaction: stimulate peristalsis through muscarinic action; increase smooth muscle sensitivity through ACh
Oral, SC, IM or slow IV admin
50% first pass metabolism
excreted by kidneys
Uses: antiemetic, treatment for oesphagitis, gastric motility disorders
Side effects: movement disorders, fatigue
Diphenhydramine
mechanism: antihistamine, antimuscarinic
particularly effective for motion pathway
Oral admin
uses: antiemetic for motion sickness
side effects: mild sedation d/t antihistamine effects
Neurokinin antagonists
e. g. maropitant (cerenia)
mechanism: NK-1 receptor antagonist–> shuts down emetic pathway
NK is final gate-keeper in emetic pathway
Oral, SC admin
Hepatic metabolism: high reliane on this- contraindicated with hepatic dysfunction
uses: broad spectrum antiemetic
side effects: hypersalivation, diarrhea
Relatively good safety profile due to specific nature
Serotonin antagonists
e.g. odansetron
Mechanism: blockade of serotonin receptors in CTZ
uses: if metaclopramide is ineffective- not widely used, very expensive. used to treat vomiting associated with cancer chemo
Treatment of diarrhea
diagnose/treat primary cause
dietary modification: acute vs. chronic diarrhea
Anti-diarrheal agents: adsorbents, opioids, anticholinergic, aminosalicylates
Adsorbents
e.g. kaolin (Al3+ salt) suspension
Mechanism: absorb toxins; provide protective coating on inflamed mucosa
Uses: symptomatic therpay of acute diarrhea- primary thing it does is change consistency of the feces
Opioids
e.g. codeine, diphenoxylate, loperamide (immodium)
diphenoxylate and loperamide don’t cross BBB when taken orally–> no CNS effects that we’d normally expect with opoids.
Mechanism: inhibits ACh release in myenteric plexus–> slows gut down; gives chance to reabsorb water
Uses: symptomatic therapy of acute diarrhea
Given PRN
Can exacerbate absorption of microbial toxins from decreased gut activity/slower transit
Constipation is major side effect of opioids (analgesics)
Anticholinergics
e.g. hyoscine (buscopan), atropine
Mechanism: muscarinic antagonist
Uses: antispasmodic–> symptomatic relief of pain (such as in IBD or colic)
Can help to improve rectal compliance
Aminosalicylates
e.g. sulfasalazine, osalazine
Mechanism: cleaved by bacteria in bowel to sulfapyridine and 5-aminosalicylic acid (related to aspirin)
salicylates have an anti-inflammatory effect–> inhibit PG synthesis?
Minimal absorption: dose reaches colon; minimal absorption in rest of GIT, very few side effects
Useful in chronic IBD/colitis
Laxative/cathartics
Lubricate, add bulk, osmotic, stimulant
Lubricant
mineral oil, liquid paraffin
lubricate tract and soften feces
limited absorption
minor words of caution: lubrication of GIT can interefe with absorption of certain things in GIT like fat-soluble vitamins over a long period of time.
Bulk
adding dietary fiber to absorb H2O
e.g. methylcellulose, agar, wheat bran
Hydrophilic colloids absorb water and increase bulk
stimulates peristalsis
slow to take effect- something for animal prone to constipation- build-in as regular feature of diet
Osmotic
e.g. magnesium sulphate, polyethylene glycol, lactulose
non-absorbale salts/polymers
retain water in intestinal lumen- decrease consistenct, soften stools
cathartic of choice for elimination of poisons
Stimulant
e. g. bisacodyl, phenophthalein
v. effective- can be so potent that you get excess fluid loss
stimulate intestinal motility via an irritant effect- promote organized peristalic action
avoid in severe constipation.
