GIT / peptic ulcer

Question 1

how does NSAIDs cause PUD?

Answer 1

1. inhibits COX, hence decreases production of PGE2, which is cytoprotective (gastric acid secretion dec, inc mucous and bicarb secretion)
2. increase adhesion molecules on gastric vasacular endothelium, increases neutrophil adherance, release of FR and protesases, increased mucosal damage
3. weak acid, un charnged in stomach, enters cell, ionised due to pH diff, damages the cell directly

Question 2

how does H. Pylori cause PUD

Answer 2

1. 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
2. induces urease activity - conversion of urea into nh3 (basic) increasing pH - simua=ltes the G cells .. same
3. colonises, binds to mucousal epithelium, decreases mucous and bicarbonate secretion
4. secretes immunogenic rpoteins- immune cells infiltratino and local inflammatioN

Question 3

what receptors involved in PUD

Answer 3

Proton pump (H+/K+)
M3 - gq
H2 - gs
CK2 (gastrin)

Question 4

what are the drug classes involved in treating PUDs?

Answer 4

1. anti-secretory drugs: M3, H2 and proton pump antagonists (PPI)
2. antacids
3. mucosal protectants

Question 5

M1.3?? antags

Answer 5

M1 antag - pirenzipine
inhibits ACh induced release of histmaine from gastric paracine cells

side effects of many anti cholinerfics

Question 6

H2 antagonists

Answer 6

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)

Question 7

PPI MOA + indicatinos

Answer 7

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

Question 8

M1 antag eg

Answer 8

pirenzipine

Question 9

H2 antag eg

Answer 9

cimetidine

Question 10

PPI eg

Answer 10

omeprazole

Question 11

antacid eg (4)

Answer 11

al(oh)3, mg(oh)2, CaCO3, NaHCO3

Question 12

antacid MOA + indications

Answer 12

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)

Question 13

mucosla protectants eg

Answer 13

sucralfate
colloidal bismuth subcitrate
misoprostol

Question 14

sucralfate MOA

Answer 14

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

Question 15

colloidal bismuth subcitrate MOA

Answer 15

selective binding to ucler necrotic tissue protecting it from pepsin

may also inhibt pepsin activity, stimulating mucousal production

toxic to H pylori

Question 16

misoprostol MOA

Answer 16

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

Question 17

nausea / vomiting drug classes

Answer 17

5-HT3, D2, antihistamine, antimuscarinic, anti-neurokinin-1, others (CBD and BZPs)

Question 18

constipation drug classes

Answer 18

1. bulk forming agents - methylcellulose
2. osmotic laxatives - lactulose
3. faeecal softeners and lubricants - (S) docusate (L) liquid paraffin
4. GIT irritants - senna

Question 19

diarrhoea drug classes

Answer 19

1. antimotility - loperamide
2. locally acting: can be either adsorbants (kaolin-pectin) or antisecretory (bismuth subsalicylate)

Question 20

tell me waht you know abotu the 2 centres involved in nausea and vomiting

Answer 20

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.

Question 21

nausea - ondesetron, doperidone

Answer 21

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.

Question 22

nausea - scopolamine, promethazine

Answer 22

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.

Question 23

nausea - apripetant, dronadiol, diazepam

Answer 23

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.

Question 24

which drug classes target which centre in the brainn (for nausea or vomiting)

Answer 24

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.

Question 25

nausea - key thigns to note about chemotherapeutic drugs and their effects on the brain (why is it an emei=tic)

Answer 25

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.

Question 26

constipation - bulkforming agaents

Answer 26

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,

Question 27

constipation - faecel softeners and lubrcicants

Answer 27

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

Question 28

constipation - osmotic laxative

Answer 28

lactulose

not absorbed in the gut, enters the intestines increase water retention in the intestinal lumen, increassing hte intraluminal pressure, clearing the bowels

Question 29

constipation - GIT irritants

Answer 29

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

Question 30

diarrhoea - antimotility

Answer 30

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.

Question 31

diarrhoea - locally acting drugs

Answer 31

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.