Flashcards in Pharmacology Of GIT Drugs Reading Deck (70):
What are the three stages of vomition?
Nausea, retching and vomiting
What happens in nausea? 4
Gastric tone reduced, duodenal and proximal jejunal tone is increased, duodenal contents reflux into stomach, depression hyper salivation and repeated swallowing
Differentiate humoral and neural initiation of vomiting
Humoral involves stimulation of crtz by blood borne substances whilst neural pathway is through activation of vomiting centre within reticular formation of medulla oblongata.
Can rodents and rabbits vomit?
No but they do have a vomiting centre made of the brain stem nuclei and motor systems necessary for emesis but lack the complex synaptic interaction.
Which receptors are important in the vomiting centre?
5-HT1a, alpha2 adrenergic and NK1 which are receptors for substance P.
Are opioid receptors involved in vomiting?
Their role is confusing. Opioids have emetic action in dogs and cats but acts through s receptors in dogs and u- receptors in cats. Of opioid penetrates the vomiting centre it may cause strong blockade of vomiting. But if it penetrates CRTZ first it will initially cause vomiting before blocking the vomiting centre. Morphine has this dual effect although it may also cause vomiting associated with histamine release.
Are d2-dopamine receptor antagonists such as metro loperamide better anti emetics in dogs or cats?
What is xylazine?
An emetic because it is an alpha2-adrenergic agonist.
What is cytotoxic drug induced emesis mediated by?
5HT3 receptors. In CRTZ of cats but in dog visceral. And Vargas after end 5HT3 receptors are activated.
Inappropriate uses of anti-emetics 5
What is maropitant used for?
Prevention and treatment of general emesis in dogs and prevention of motion sickness in dogs. Significantly more effective in dogs with acute vomiting than metoclopramide
Action of maropitant
Selective antagonist of substance p at the NK1 receptor. Inhibits final common pathway so effective against emesis induced by both peripheral and central stimuli.
Adverse effects of maropitant
Post dosing emesis in 8% cases at motion sickness dose.
Significant drug interactions are unlikely to occur due to wide safety margin and well characterised pharmacokinetics.
Indications for metoclopramide control of vomiting 4
Central or peripheral activation of vomiting
Deceased gastric emptying (inflammation, ulcers, neoplasia, autonomic neuropathy, pyloric stenosis, postop GDV, hypokalaemia, abnormal gastric motility)
Mechanism of action of metoclopramide
Dopaminergic and 5-HT3 antagonist in CRTZ and peripheral receptors.. Also promotes release of and increases sensitivity of visceral smooth muscle to achetylcholine. Ultimately causes increased gastric emptying and increased small intestinal activity. Doesn't alter fluid secretion or absorption anywhere.
Contraindications of metoclopramide 3
Gastric outlet obstructions, gastric perforations, epileptic patients as may increase frequency of seizures.
Side effects of metoclopramide 4
Infrequently may cause mental changes
shouldn't be given with phenothiazines or narcotic analgesics
Anticholinergic drugs will block effects of metoclopramide on GIT motility
Rarely may cause gastric spasm and actually increase vomiting
Examples of antihistamines 3
Diphenhydramine, promethazine, dimenhydrinate
Mechanism of action of antihistamines
Acts directly or neural pathways arising in vestibular nucleus so effective against motion sickness and middle ear infections induced emesis but not vomiting induced by other stimuli.
2 side effects of using antihistamines as antiemetics
Drowsiness and xerostomia (dry mouth)
Example of a phenothiazine used as an antiemetic
Mechanism of action of phenothiazines as antiemetics
Block CRTZ at low doses (antidopaminergic) and vomiting centre at higher doses (anticholinergic). Also block peripheral dopamine receptors in stomach. Cannot block visceral afferent (vagal) impulses associated with severe pain and contractions.
Side effect of phenothiazines
Arteriolar vasodilation due to alpha adrenergic receptor blocking action.
Mechanism of action of 5-HT3 antagonists
Antagonism of peripheral 5-HT3 serotonergic receptors in the gut is principal mechanism.
Examples of anticholinergics
Atropine, hyposcine, propanthaline and isopropamide
When are anticholinergic antiemetics effective?
When vomiting is due to smooth muscle spasm which is very uncommon.
What should you be aware of when using anticholinergics as antiemetics?
They reduce GIT motility which can act as a stimulus for further vomiting. Overuse can cause gastric atony and intestinal ileus. Don't use in dogs with parvovirus infection as the potential for endotoxaemia is increased
What makes up the gastric protective barrier? 5
high epithelial turnover
surface active phospholipids
rich vascular supply prostaglandins
Causes of gastric ulcers 8
drugs (aspirin, PBZ, corticosteroids)
increased HCL production
spinal cord disease
Outline conseqeuences of damage to mucosal barrier
back-diffusion of gastric acid into submucosa --> MC degranulation --> histamine release --> stimulation of acid production by gastric parietal cells --> enhanced oedema and inflammation in submucosa.
Examples of anti-ulcer drugs - 5
Histamine receptor antagonists
Which gastric ulcers are H-R antagonists effective against?
NSAID and uraemia induced. not effective in preventing NSAID-induced ulcers
Side effects of histamine-receptor antagonists
-hypoacidity and bacterial overgrowth (chronic use)
-drug eruption (cimetidine in cats)
-decrease hepatic metabolism of some drugs
-may reduce absorption of some drugs that require acid for dissolution and absorption
Can you use histamine-receptor antagonists with impaired renal function?
Yes but reduce dose by 50%
Is sucralfate effective treatment for oral and oesophageal ulcers?
What is sucralfate structurally similar to? 2
HEPARIN - but doesn't poses any anticoagulant activity
SURCROSE - but not used as a sugar by the body
What does sucralfate protect the ulcer against?
hydrogen ion back-diffusion, pepsin and bile and so promotes ulcer healing.
Why does sucralfate preferentially adhere to ulcerated tissues?
because of electrostatic charges.
What are the major drug actions of sucralfate?
stimulates mucosal defence and reparative mechanisms (also inactivates pepsin, absorbs bile acids, and is believed to be cytoprotective by stimulating PG synthesis. doesn't significantly affect gastric acid output and may decrease the rate of gastric emptuing)
Does sucralfate interact with any drugs?
It may do but none that are clinically important.
What is misoprostol? Main use?
a synthetic PGE1. most useful in prevention of NSAID-induced ulceration
How does misoprostol work?
inhibits gastrin secretion
increases gastric mucous formation
increased mucosal BF --> increases epithelialisation
Side effects - misoprostol
-parturition inducer or abortion
-frequently causes diarrhoea, abdominal pain, flatulence and vomiting
When should you use omeprazole in practice? 2
refractory ulcers or ulcers associated with gastrinomas or mastocytosis
How does omeprazole work?
it is a proton pump inhibitor that blocks H/K ATPase, thereby blocking gastric acid secretion (in contrast to H2 receptor antagonists, it inhibits gastric acid secretion by any secretagogue).
Side effects of omeprazole = ?
well tolerated in cats and dogs. Long term therapy may cause reversible gastric hypertrophy in dogs due to the trophic effects of gastrin.
Drug interactions of omeprazole
inhibition of p450 hepatic enzymes may decrease hepatic clearance of some drugs
reduced absorption of drugs requiring low pH
may exacerbate bone marrow suppression
Give some example of non-systemic antacids
oral preparations containing aluminium hydroxide, calcium carbonate and magnesium compounds.
When are non-systemic antacids most commonly used?
in management of uraemia as aluminium hydroxide binds phosphate thus reduces hyperphosphataemia as well as having an antacid effect
Explain how non-systemic antacids are administered.
must be given orally --> poor owner compliance, must be given at least every 4 hours for 4-6 weeks
How do non-systemic antacids work?
neutralise HCl, bind bile acids, decrease pepsin activity, may stimulate local PGE1.
Magnesium increased bowel motility, aluminium decreases bowel motility so the two are usually combined.
Side effects of non-systemic antacids = ?
- calcium-containing antacids tend to promote constipation
- magnesium promotes looser faeces
- aluminium reduces gastric motility and delays gastric emptying
- if given infrequently, they may increase gastric acid production
- may predispose to renal calculi (calcium-containing types)
- hypophosphataemia and aluminium accumulation (aluminium-containing types)
List some examples of motility modifying drugs 4
absorbents and protectants
How are peristalsis and segmental contractions controlled?
PERISTALSIS - influenced by the cholinergic system and gut hormones such as motilin
SEGMENTAL - cholingeric dependent
Is reducing peristalsis a good thing Why?
No this is usually of little clinical benefit and is generally contraindicated so focus on increasing segmental contractions. This is because, in most cases of diarrhoea, the gut is hypomotile not hypermotile and peristalsis and segmental contractions are already reduced.
What two groups of agents may modify GIT motility?
NARCOTIC ANALGESICS - increase segmental contractions
ANTICHOLINERGIC DRUGS - decrease both segmental contractions and peristalsis.
When are opioid analgesics used in veterinary?
limited use in practice. acute diarrhoea is usually self-limiting with appropriate symptomatic treatment and chronic diarrhoea doesn't usually respond to symptomatic therapy.occasionally useful in chronic colitis that can't be controlled by other means.
What are the risks of opioid analgesics? 2
- diarhoea may be beneficial to removing toxins
- reduced motility may allow enterotoxin-producing organimss to remain in SI thus increasing fluid-loss
- may facilitate greater time of organism in lumen
Mechanism of action of opioid analgesics
Opioids increase the amplitude of rhythmic contraction and decrease propulsive contractions. They directly affect intestinal smooth muscle producing both tonic and phasic contractions of the circular muscle. They also act centrally and on synapses to augment segmentation. Opioids either have no effect on longitudinal muscle or they relax it. The net effect of these actions is to inhibit the flow of intestinal contents, delay gastric emptying and increase the tone of the ileocolic valve and anal sphincter.
Drug interactions with opioid analgesics = ? 1
other CNS depressants
Risk of using anti-cholinergic drugs to modify GIT motility?
may produce adynamic ileus especially if electrolyte imbalances such as hypokalaemia are also present.
When are anti-cholinergics indicated to modify GIT motility?
They may be justified in the short
term symptomatic relief of pain and tenesmus associated with large bowel inflammatory
disease. They also may be indicated in stress‐induced colitis where cholinergic mechanisms
might be involved.
What are kaolin and pectin, acitvated charcoal and bismuth salicyate examples of?
absorbents and protectants
What do kaolin and pectin do?
soothe irritated GIT mucosa and bind toxins and pathogenic bacteria. Clinical efficacy is unproven.
What is activated charcoal used for?
treatement of toxicosis - thought to absorb toxic substances and bind bacterial toxins. no controlled studies to evaluate efficacy
What is bismuth salicylate used for?
treatment and prevention of enterotoxigenic diarrhoea.
Clinical indications for sulphasalazine
idiopathic ulcerative colitis in dogs and cats. probably only best to use if there is biopsy confirmation of ulcerative colitis and that there has been no response to dietary or other therapy.
a solution/remedy for all difficulties/diseases
Mechanism of action of sulphasalazine
Sulphasalazine is a combination of sulpha‐pyridine and 5‐aminosalicylic acid (5‐ASA) which
is cleaved by colonic bacteria resulting in the sulpha component being absorbed and ASA
excreted in faeces. 5‐ASA is probably the active ingredient due to antiprostaglandin and
antileukotriene activity. In addition, it is thought to have oxygen‐free radical scavenging
action, to interfere with phagocytic chemotaxis and function, and to inhibit cytokine and