GI drugs 1 Flashcards
Anti-emetic drugs use
- used to non-specifically manage vomiting induced by:
- drugs and other foreign chemicals
- radiation therapy sickness or motion sickness (prophylaxis, therapy)
- organ dysfunction
how are antiemetics classified
by the receptor they exert their dominant effects on
> however considerable overlap exists
where is the emetic center in the brain
medulla
what general categories of locations in the body do antiemetics work on
- labrynths
- higher centers
- chemoreceptor trigger zone
- peripheral organs
- emetic center (medulla)
important anti-emetic categories for our use
- anti-histamines
- dopamine antagonists
- serotonin
- neurokinin -1 antagonists
- other agents
anti-histamines that are used as antiemetics
- diphenhydramine (Benadryl®)
- meclizine (Bonamine®)
what kind of emesis do anti-hostamines work to stop? what is a common side effect? what other properties do these drugs have?
- can be used to control motion sickness
- sedation can be common side-effect with the H1 blockers; paradoxical excitement in cats possible
- many have anticholinergic properties as well
types of dopamine antagonists that are used as anti-emetics
- phenothiazines
> prochlorperazine (Stemetil®), acepromazine (Ace®) - metoclopramide (Maxeran®)
how do phenothiazines work as anti-emetics? mechanism of action?
- these are broad-spectrum anti-emetics as they are capable of blocking several neurotransmitters
- principal mechanism of actions is blockade of dopamine receptors in the CTZ
phenothiazines adverse effects
- sedation
- hypotension from α-adrenergic blockade
- can lower seizure threshold in epileptics
how does metoclopramide work as an anti-emetic? what type of emesis is it useful for?
- effectively blocks emesis mediated at the CTZ
> antagonizes dopamine (low doses)
> antagonizes serotonin (5-HT3) (higher doses) - also has peripheral antiemetic effects thru prokinetic effects promoting upper GI motility
> contraindicated in GI obstruction or perforation - useful for emesis induced by GI disease and possibly chemotherapy
adverse effect of metoclopramide
CNS stimulation is possible adverse effect
types of serotonin antagonists used as anti-emetics
- Ondansetron (Zofran®)
- Granisetron (Kytril®)
- Mirtazapine (Remeron®)
how do Serotonin (5-HT3) antagonists work as anti-emetics? what kind of vomitng are they useful for? are they well tolerated?
- block central (CTZ) and peripheral 5-HT3 receptors
- useful for refractory vomiting
v chemotherapy
v parvovirus infection
v post-operative vomiting
v pancreatitis - generally very well tolerated
how does Mirtazapine work as an antiemetic? when can it be useful?
- Antidepressant in humans
- Antiemetic effects in cats; also appetite stimulation
> Maybe useful in vomiting with chronic kidney disease
> Attributed to 5-HT3 receptor antagonism
Neurokinin -1 antagonist used as an anti-emetic
Maropitant
how do neurokinin -1 antagonists work as anti-emetics? when are they useful?
- block effects of substance P in the emetic center
- licensed for use in dogs and cats
> acute vomiting from parvovirus, gastroenteritis and pancreatitis
> prevention of chemotherapy-induced vomiting
> motion sickness
what form are neurkinin -1 antagonists available in
available in injectable (SC or IV) and tablets
Neurokinin -1 antagonists adverse effects
- swelling/pain at injection site possible
- some vomiting and hypersalivation possible with tabs
Maropitant may be useful for what conditions, other than as an antiemetic
interest with maropitant for analgesia and pain
glucocorticoid used as an anti-emetic
Dexamethasone
glucocorticoids use as anti-emetic - when is it used? how does it work? is it indicated?
- Veterinary approved injectable; but not indicated for tx of vomiting
- May work to reduce vomiting by inhibiting prostaglandin production
- Can be added to other antiemetics for refractory vomiting
Cannabinoids use as anti-emetic? can veterinarians dispense it?
Cannabidiol (CBD)
- Potential for antiemetic effects based on human experience with
antineoplastic drugs; works by activating CB1 receptors in the CNS
- Cannabis Act does not include veterinary patients
> Currently, no legal way for veterinarians to prescribe, dispense or recommend medical marijuana or CBD to veterinary patients in Canada
why induce emesis?
Emesis is induced pharmacologically to empty anterior part of the GI tract
- prior to general anesthesia
- following ingestion of non-corrosive intoxicants
types of emetics
- Peripherally acting (reflex) emetics
- Centrally acting emetics
types of Peripherally acting (reflex) emetics
- “household remedies”
> table salt with/without warm water
> hydrogen peroxide (3%) - Ipecac syrup—contains alkaloid “emetine”
hydrogen peroxide emesis adverse consequence
aspiration of foam possible
ipecac syrup contains what? adverse effect and how to deal with it? 2nd mechanism of action aside from reflex emesis?
- contains alkaloid “emetine”
- cardiotoxicity possible with repeat doses
> gastric lavage to remove if no vomiting - can also activate CTZ centrally
Centrally acting emetics
- Apomorphine
- α2-agonists eg Xylazine,
dexmedetomidine
when can apomorphine be used for emesis? when shouldn’t it be? how does it work?
Apomorphine—derivative of morphine
- used in dogs successfully
- use in cats controversial; less successful
- stimulates CTZ via dopaminergic receptors
forms that apomorphine comes in? how fast it works?
- tablets or injectable (SC or conjunctival)
- emesis usually in 2-10 minutes
is repeat dosing of apomorphine effective? why? adverse effects?
- repeat dosing less effective; direct depression the vomiting center
- respiratory depression possible with excess dosing; protracted vomiting also possible
α2-agonists - when are they used as emetics? mechnaism of action?
- more reliable in cats
- activates CTZ
requisite for GI ulceration
Acid injury of the gastroduodenal mucosa
Defense mechanisms that oppose gastric acid injury
v mucus (alkaline) production
v bicarbonate secretion into lumen
v mucosal re-epithelialization and repair of gastric barrier
v mucosal blood flow
v local PGE2 production—cytoprotection
Factors predisposing ulcer formation include:
v Diet; composition and feeding practices
v NSAIDs and corticosteroids
v Stress; transport
v Exercise intensity (horses)
v Disruption of mucosal blood supply
gastric acid secreted by what? 3 sources of input required to yield HCl production?
secreted by parietal cells of the fundic region of the glandular stomach
3 sources of input:
v ACh (vagus and enteric cholinergic ganglion cells)
v Histamine (enterochromaffin-like cells)
v Gastrin (circulating hormone from gastric G-cells)
targets of pharmalogical intervention to reduce or inhibit HCl production, as anti-ulcer agents
- binding of histamine to H2 receptors on perietal cells
- ATPase
- parietal cell apical surface
- acid secretion
- PGE2 binding to parietal cells
ANTI-ULCER AGENTS broad categories based on functionality
-Gastric Antisecretory Drugs
-Mucosal Protectants
types of gastric antisecretory drugs
- H2 Blockers
- Proton Pump Inhibitors
types of H2 blockers
- Cimetidine (Tagamet®)…used less now !
- Ranitidine (Zantac®)
- Famotidine (Pepcid®)
mechanism of action of H2 blockers
Histamine binds to H2 receptors on parietal cells to cAMP and proton pump activity
- histamine is the common mediator of HCl secretion
- H2 blockers competitively inhibit histamine binding
- H2 blockers reduce HCl acid production including gastric juice and pepsin
content of secretions
Drug interactions of H2 blockers
altered gastric pH—affect absorption of other drugs requiring an acid environment
Indications for H2 blockers? is there good evidence?
evidence lacking !!
v Gastric and duodenal erosions and ulcers
v Uremic and stress-related gastritis
v Hypersecretory conditions (gastrinoma)
v Duodenal gastric reflux and esophageal reflux
v NSAID-induced ulcers
Cimetidine - how it works and what is its use? adverse effects?
H2 blocker
v Potent inhibitor of P450 metabolizing enzymes and drug interactions possible !!
v Ability to raise stomach pH in dogs questionable; efficacy in horses ?
v Rebound hypersecretion possible upon stopping drug; consider tapering off
drug
Rantidine - how it works and how it compares to cimetidine?
H2 blovker
v More potent (4-10X) than cimetidine
v Rebound hypersecretion possible
v Minimal inhibition of P450 enzymes
Famotidine - how it works and how it compares to ranitidine and cimetidine?
H2 blocker
v More potent (9X) than ranitidine and cimetidine (~30X) v Longest duration of action
v Less rebound hypersecretion
v Does not inhibit P450 enzymes
Proton Pump Inhibitor we use
Omeprazole
how do proton pump inhibitors work? are they good at what they do?
v Works by irreversibly binding the parietal cell H+/K+-ATPase (proton pump) which is the final step in gastric acid secretion
v Proton pump inhibitors are the most potent gastric antisecretory drugs available
Omeprazole available in what form? when indicated? how long does it take to work?
- Available as oral paste for horses (Gastrogard®)
- Indicated for the treatment and prevention of ulcers in horses and
foals - Also available in human approved tablets and capsules used in dogs and cats (Losec®)
- May take 2-4 days to accumulate in parietal cells and produce a clinical effect
-Mucosal Protectants, what types do we use
- Sucralfate
- Antacids
- Misoprostol
what is sucralfate and how does it work? when to use and what does it require to work? other useful properties?
- Mucosal protectant
- An orally administered disaccharide (sucrose) aluminum hydroxide product
v Binds to and protects the ulcerated area (crater) from further damage by acid.
> beneficial for tx of uclers, but not prevention
v Requires an acid environment for activation
v Tablets must be disintegrated for effects; crush or give as a liquid v Will also bind bile and pepsin reducing their harmful effects
v May also increase local blood flow and beneficial
prostaglandin production
how do antacids work? possible adverse effects? formulations? possible other effects?
- Antacids chemically neutralize HCl present in the gastric lumen thereby increasing gastric pH
> Drug interactions possible from altered pH in the stomach, and also
direct binding of other drugs eg fluorquinolones - Formulated as hydroxide bases of aluminum, magnesium and calcium
> Aluminum containing agents may also stimulate prostaglandin production
what is Misoprostol? how does it work? when is it used?
- is a PGE analog
- It is a mucosal protectant
> Increases mucus production
> Increases bicarbonate
> Enhances re-epithelialization of mucosa
> Increases local blood flow - It also has gastric antisecretory properties by reducing HCl production from parietal cells
- Used for the prevention of gastric ulcers, especially involving NSAIDs; effectiveness in treating ulcers is less beneficial
contraindication for misprostol and why
Contraindicated during pregnancy due to its promotion of uterine contractions
how are GI motility disorders usually treated?
GI motility disorders are complex and poorly understood—treatment is often empiric
what do prokinetics do? general mechanisms?
“Prokinetics” enhance the coordinated net
movement of ingesta thru the GI tract
v generally raise lower esophageal tone
v accelerate gastric emptying
v shorten intestinal transit time
Indications for prokinetics:
v post-operative ileus
v delayed gastric emptying
v delayed intestinal transit
v megaesophagus, megacolon
Prokinetics contraindicated:
v GI hemorrhage
v Obstruction
v Perforation
regulation of GI motility can be divided into what?
Extrinsic
- vagus / pelvic nerves
> efferent activity to the GI tract
> acetylcholine released by these nerves act on receptors of intrinsic nerves, to stimulate motility and secretion
- sympathetic
> inhibitory for motility, but increase tone in GI tract sphincter
enteric / intrinsic
- ganglia and receptors on smooth muscle of GI tract
> control contractions mediated by acetylcholine, and relaxations mediated by NO2 or vasoactive intestinal peptide
Drugs that promote the release of acetylcholine from terminals on the presynaptic neuron
??
