GIT / peptic ulcer Flashcards
how does NSAIDs cause PUD?
- inhibits COX, hence decreases production of PGE2, which is cytoprotective (gastric acid secretion dec, inc mucous and bicarb secretion)
- increase adhesion molecules on gastric vasacular endothelium, increases neutrophil adherance, release of FR and protesases, increased mucosal damage
- weak acid, un charnged in stomach, enters cell, ionised due to pH diff, damages the cell directly
how does H. Pylori cause PUD
- release of inflammatory mediators - inhibit D cells - relieving disihibition of somatostatin on G cells - secretion of gastrin from G cells - stimulate parietal cell proliferation and gastric acid secretion
- induces urease activity - conversion of urea into nh3 (basic) increasing pH - simua=ltes the G cells .. same
- colonises, binds to mucousal epithelium, decreases mucous and bicarbonate secretion
- secretes immunogenic rpoteins- immune cells infiltratino and local inflammatioN
what receptors involved in PUD
Proton pump (H+/K+)
M3 - gq
H2 - gs
CK2 (gastrin)
what are the drug classes involved in treating PUDs?
- anti-secretory drugs: M3, H2 and proton pump antagonists (PPI)
- antacids
- mucosal protectants
M1.3?? antags
M1 antag - pirenzipine
inhibits ACh induced release of histmaine from gastric paracine cells
side effects of many anti cholinerfics
H2 antagonists
e.g. cimetidine
similar strucutre to histamine, blocking the H2R on gastric parietal cells, inhibting gastric acid secretion
70-80% clears in 4 wekks, but 90% recurrance rate.
ulcer preventing, healing, zollinger-ellison syndrome
metabolised by the liver and excreted in the urine
!! Drug interactions : inhibts CYP450 systems, hence inteferest with teh hepatic metabolism of other drugs, esp if has a narrow therapeutic range (warfarin, lignocaine, phenytoin, theophylline)
PPI MOA + indicatinos
e.g. omeprazole
acid labile drug, hance enteric coating to prevent acidic degradation by the stomach acid, absorped as prodrug in the duodenum and to gastric parietal cells, converted to active metabolite (sulfanemide)
active metabolite forms covalent disufilde link with cys residues on proton pump, irrversible inhibiting it and irrversibily inhibitnig gatric acid secretion.
metabolised in the liver, excreted in the pee.
metabolised by the CYP2C19, and might intefere with other drugs that are acitveted by C19 also (clopidogrel), or affect the pH dependet absorption (ketoconazole)
for NSAID-induced ulcers, zollinger ellison, short term treatment of ulcers
M1 antag eg
pirenzipine
H2 antag eg
cimetidine
PPI eg
omeprazole
antacid eg (4)
al(oh)3, mg(oh)2, CaCO3, NaHCO3
antacid MOA + indications
al(oh)3, mg(oh)2, CaCO3, NaHCO3
chemical antagonists, neutralising stomach acids, weak abses, reacting with acid forming water and salt, diminishing gastric activity
** al and mg binds and neutralises pepsin
pepsin activity diminished at ph > 4, hence also indirecly reducing pepsin activit y
interferes w oral drug drug absorptions, and drug solubility / absorption (e.g. tetracycline, iron)
relieve pain, promote healing, relieves symptoms (e.g. heartburn, indigestion)
mucosla protectants eg
sucralfate
colloidal bismuth subcitrate
misoprostol
sucralfate MOA
what: at pH <4, forms a thick viscous polymer (of sucrose octasulfate and al(oh)3
adheres to the positvie glycoproteins (ulcer exposes it), forming a protective layer against pepsin, acid and bile
may stimulate prostaglandin synthesis , increased mucousal and bicarb,
PK: protective barrier ~6h, and not absorbed by liver, kidnaye (yay)
contraindications:
1. dont adm with other PPI/H2 antag as increasing hte pH means that it cant polymerise, and
2. can bind to other mediators (e.g. digoxin, narrow TI, used in HF)
3. constipation
colloidal bismuth subcitrate MOA
selective binding to ucler necrotic tissue protecting it from pepsin
may also inhibt pepsin activity, stimulating mucousal production
toxic to H pylori
misoprostol MOA
issa prostaglandin analogue
inhibits the suuporting cels frmo secreting gastric acid
stimualte the surface endothelial cells to increase mucous production
for NSAID indudec peptic ulcers, but can cause diarrhea, uterine contraction
nausea / vomiting drug classes
5-HT3, D2, antihistamine, antimuscarinic, anti-neurokinin-1, others (CBD and BZPs)
constipation drug classes
- bulk forming agents - methylcellulose
- osmotic laxatives - lactulose
- faeecal softeners and lubricants - (S) docusate (L) liquid paraffin
- GIT irritants - senna
diarrhoea drug classes
- antimotility - loperamide
- locally acting: can be either adsorbants (kaolin-pectin) or antisecretory (bismuth subsalicylate)
tell me waht you know abotu the 2 centres involved in nausea and vomiting
There are 2 major centres in the brain that trigger vomiting, The chemoreceptor trigger zone (CTZ) and the vomiting centre (VC). The CTZ lies outside the BBB and can respond directly to the mechanical stimuli in the blood or cerebrospinal fluid. Both the centres are related, with the CTZ simulating the VC. The VC is located in the lateral reticular formation of the medulla, and it acts to coordinate the motor mechanisms of vomiting. VC also receives afferents from the vestibular system (implicated in motion sickness), the peripheral organs (pharynx and GIT) as well as higher brainstem / cortical structures. Antiemetic drugs act on the CTZ and VC, inhibiting their stimulation.
nausea - ondesetron, doperidone
ondeseron:
5-HT3 receptor antagonists such as ondansetron block the 5-HT3 receptors in the periphery (visceral afferents in the GIT) and the brain (nucleus of tractus solitarius, NTS and CTZ), preventing peripheral and central stimulation of the VC. Since dopamine receptors are not involved, there are no extrapyramidal side effects.
domperidone:
D2 receptor antagonists such as domperidone inhibits the dopamine receptors in the CTZ, decreasing stimulating of VC. It also decreases afferent impulses from the gut to the NTS. However, it can cause EPS such as parkinsonism and anticholinergic effects.
nausea - scopolamine, promethazine
H1 receptor antagonists such as promethazine inhibits the neural pathway from the vestibular nucleus to CTZ, decreasing stimulation of VC. It has antimuscarinic activity.
mAChR antagonists like scopolamine inhibit mACh receptors in the cerebellum and VC.
nausea - apripetant, dronadiol, diazepam
Neurokinin (NK1) receptor such as aprepitant inhibits the action of substance P on NK1 receptors in the CTZ. It is metabolised by 3A4 in the liver, but also acts as an enzyme inducer of 3A4, which affects other drugs such as warfarin when administered together. Aprepitant is used in the treatment of chemotherapy-induced nausea and vomiting, and is coadministered with dexamethasone + ondansetron, where it can enhance their activity by increasing their plasma concentrations.
Additionally, cannabinoids like dronabinol can also be used in the treatment of chemotherapy induced emesis refractory to conventional antiemetic drugs. Benzodiazepines like diazepam, a sedative-hypnotic agent can be used as treatment of anticipatory nausea and vomiting.
which drug classes target which centre in the brainn (for nausea or vomiting)
CTZ: D2 and 5-HT3 receptors. Targeted by D2 / 5-HT antag (also GIT) + neurokinins + CBDs
VC: M and H receptors. Targeted by antiH and antiM.
nausea - key thigns to note about chemotherapeutic drugs and their effects on the brain (why is it an emei=tic)
Chemotherapeutic agents can act by destroying GI tract cells, causing 5-HT3 to be released from ECL cells, stimulating vagal/splanchnic afferents which sends sensory signals to the medulla which induces an emetic response.
constipation - bulkforming agaents
used in patients who are recovering from acute MI stroks, eye surgery and cerebral aneurysms, or have to avoid the valsalva maneovur.
e.g. methylcellulose is an indigestible hydrophilic icnreases water retention, increasing faecal mass, increased swelling, and mechanical distension of the intestinal wall, increasing peristalsis,
constipation - faecel softeners and lubrcicants
softeners: docustate - decreases surface tension of the shit, better penetration of water and fat, softening hte poop, and easier bowel movements
lubricants: liquid paraffin - lubricates both the faeces and mucosal wall, also decreases water reabsorption, increasing hte faecal mass and inducing peristalsis
constipation - osmotic laxative
lactulose
not absorbed in the gut, enters the intestines increase water retention in the intestinal lumen, increassing hte intraluminal pressure, clearing the bowels
constipation - GIT irritants
senna - irritates the mucosa, increasing fluid secretion and stimulating peristalsis, same as osmotic laxatives, but are preffered
abdominal cramping electrolyte imbalace fluid depletion
6-12h
diarrhoea - antimotility
loperamide
Antimotility drugs are the most efficacious antidiarrheal agents. An example is loperamide, which binds to the 𝝁 opioid receptor in the enteric nervous system, inhibiting ACh release. This results in sustained contraction of the intestinal smooth muscle, disrupting the rhythmic waves of contraction and relaxation needed in normal peristalsis, increasing time of passage of faeces in the intestines, increasing water reabsorption. Loperamide is selective for opioid receptors in the ENS over CNS, leading to less CNS effects.
diarrhoea - locally acting drugs
Adsorbents such as kaolin-pectin are locally acting drugs, acting to absorb water and binding to the irritants, bacteria and toxins on the intestinal mucosa. Pectin also decreases the intestine pH, which soothes the irritated mucosa, and is used in the treatments of mild to moderate diarrhoea.
Bismuth subsalicylate is another locally acting drug that acts as an antisecretory agent, inhibiting intestinal secretions through an unknown mechanism. It is used in the treatment of infectious diarrhoea, which is characterised by high secretory levels.
