💊 Flashcards
(77 cards)
1
Q
How much gastric acid secreted daily?
A
2.5L
2
Q
What do endocrine secretions release?
A
substances into GIT (peptides eg gastrin).
3
Q
Which areas of GIT are of pharmalogical importance + why?
A
- Gastric secretion - vomiting –> damage –> ulcer
- Gut motility - stasis of gut increases likelihood of reflux + reduces ability of clearance of acid from oesophagus, in intestine –> constipation
- Bile formation + excretion - gallstones or malnutrition
4
Q
What are paracrine secretions?
A
regulatory peptides released by cells GIT wall (eg histamine) + function as NT (eg CCK)
5
Q
Describe what happens when parietal cell stimulated
A
- parietal cell stimulated
- H-K pumps H+into lumen of gastric gland in exchange for K+
- K+recycles back into lumen via K+channels
- carbonic anhydrase provides H+ extruded by H-K pump,
- exits via basolateral anion exchanger (AE2)
- Cl−enters basolateral membrane via AE2
- Na/K/Cl cotransporter NKCC1 + electrogenic SLC26A7
- Cl−exits via apical CFTR (+ ClC) channels
6
Q
Stimuli that act on parietal cell?
A
gastrin, ACh, histamine, PGE2 + PGI2
7
Q
How gastrin acts on parietal cell?
A
- peptide hormone secreted by gastric mucosa + duodenum
- stimulates gastric secretion, BF, gastric motility
- parietal cells express gastrin receptors
- release of gastrin controlled by NT, other mediators eg milk + Ca2+ solutions stimulate gastrin release in stomach
- so don’t use Ca2+-containing salts to control acid secretion
PGE2 & PGI2: Inhibit acid secretion
8
Q
How ACh acts on parietal cell?
A
NT stimulates muscarinic ACh receptors on parietal cells + on histamine-containing cells
9
Q
How histamine acts on parietal cell?
A
- local hormone
- acts on H2 receptors on parietal + mast cells
- release increased by gastrin + ACh
10
Q
How PGE2 + PGI2 acts on parietal cell?
A
inhibit acid secretion
11
Q
Role of proglutamide?
A
drug blocks CCK2 receptors
12
Q
Effect of metoclopromide?
A
- Inhibits pre- + post-synaptic dopamine (D2), 5-HT3 receptors (CNS) – inhibiting vomiting
- Stimulates 5-HT receptors (ENS) – prokinetic
- Stimulates inhibitory nitregeric (NO) neurons → coordinated gastric motility
13
Q
Role of dopamine?
A
- Inhibits ACh release from intrinsic myenteric cholinergic neurons by activating prejunctional D2 receptors which leads to indirect inhibition of musculature
- Relaxant effect on gut by activating D2 receptors in LOS, stomach (fundus + antrum)
- Mixed effects on gut – induce contraction in proximal but relaxation in distal small intestine
14
Q
Describe features of all dopamine receptors
A
- 2 D1-like receptor subtypes : D1 + D5 couple to Gs
- activate adenylyl cyclase
- other receptor subtypes belong to D2-like subfamily : D2, D3, D4 + prototypic of G receptors
- inhibit adenylyl cyclase
- activate K+ channels
- genes for D1 + D5 receptors are intronless, but pseudogenes of D5 exist
- D2 + D3 receptors vary in tissues, species due to alternative splicing
- D4 receptor gene exhibits extensive polymorphic variation
- in CNS dopamine receptors expressed since they’re involved in control of locomotion, cognition, emotion + neuroendocrine secretion
- in periphery dopamine receptors in kidney, vasculature, pituitary to affect sodium homeostasis, vascular tone, hormone secretion
15
Q
Antagonistic activity of metoclopramide at dopamine (D2) receptors?
A
↑ACh release :
- (↑ peristalsis of duodenum, jejunum, ileum)
- ↑intragastric pressure (due ↑LOS tone + ↑tone of gastric contractions)
- -> improve antroduodenal coordination which accelerates gastric emptying, relaxes pyloric sphincter
16
Q
Prokinetic effects of metoclopramide?
A
Stimulates presynaptic excitatory 5-HT receptors + inhibitory nitregeric neurons –> coordinated gastric motility
17
Q
Major roles of 5-HT receptors in GIT?
A
- Stimulates 5-HT3 or 5-HT4 receptors on enteric cholinergic neurons to release ACh –> smooth muscle contraction
- Stimulate 5-HT4, 5-HT1A or 5-HT1D receptors on inhibitory enteric or nitrergic neurons to release NO –>smooth muscle relaxation.
18
Q
Role of Prochlorperazine?
A
(a phenothyziane, very potent antipsychotic agent)
D2 receptor antagonist for nausea/vertigo.
19
Q
Feaures of dopamine receptor antagonist metoclopramide?
A
- Increasing LOS pressure + gastric emptying rate
- Treatment of diabetic gastroparesis, severe gastroesophageal reflux, postoperative situations involving visceral atony
- Useful adjunctive drug for intestinal intubation + radiologic examination
- Intravenously controls headache, nausea, vomiting of intensive cancer chemotherapy eg with cisplatin
- Antiemetic due to actions on chemoreceptor trigger zone + intestinal motility
- Not long-term use
- Oral preparations 4-12 weeks of therapy
- Parenteral metoclopramide 1-2 days
- Adverse reactions : restlessness, drowsiness, fatigue, lassitude
- Extrapyramidal symptoms rare + only with high dosage or prolonged use
20
Q
Role of metoclopramide?
A
- For gastrointestinal reflux (but useless in paralytic ileus since causes moderate to diffuse abdominal discomfort eg abdominal distension, nausea/vomiting after meals, lack of bowel movement/flatulence)
- Stimulates gastric motility
- Accelerates gastric emptying
21
Q
Clinical utility of metoclopromide?
A
Symptoms of gastroparesis
Promotes gastric emptying
Anti-emetic effects via central pathways
22
Q
What’s paralytic ileus?
A
= postoperative adynamic ileus
- Ileus/obstruction persisting for > 3 days following surgery
- Obstruction of intestine due to paralysis of intestinal muscles
- Intestinal muscles so inactive preventing passage of food –> functional blockage of intestine
23
Q
Summary of metoclopromide effects :
A
Promotes gut motility by:
- Inhibits presynaptic + postsynaptic D2 receptors
- Stimulates ACh release/SP from enteric neurons
- Mixed 5-HT agonist + antagonist effects :
- stimulates excitatory 5-HT4 receptors (ENS)
- inhibits 5-HT3 receptors (CNS antiemitic)
- Stimulates inhibitory nitregic neurons for NO release
- Increases intragastric pressure -↑LOS + gastric tones
- Motility stimulant - improves antro-duodenal coordination + accelerated gastric emptying
-GORD; nausea due to surgery or cancer; symptoms of gastroparesis
- Increases gastric emptying by enhancing antral contractions + decreasing postprandial fundus relaxation
- Prokinetic effects limited to proximal gut
24
Q
Features of antispasmodic agents + eg?
A
eg propantheline, dicycloverine (dicyclomine), mebeverine
- ↓Spasm in bowel
- Relax smooth muscle in GIT)
- Propantheline = antimuscarinic agent
- Useful in IBS + diverticular disease – congenital lesion, source of bacterial overgrowth
25
Role of muscarinic receptor antagonists + eg?
inhibit parasympathetic activity - reduces spasm in bowel eg Propantheline
26
Role of Dicycloverine?
=dicyclomine
- For intestinal hypermotility + symptoms of IBS (spastic colon)
- Relieves muscle spasms – non-selective smooth muscle relaxant
27
What's kolanticon?
Anti-flatulent simethicone added + antacid
28
Role of Mebeverine?
- Eases bloaty/crampy/colicky-type pain associated with IBS
| - Musculotropic that potently blocks intestinal peristalsis.
29
Goals of pharmacological intervention in gastric ulcer?
- Reduce acid secretion with H2 receptor antagonists
- Neutralise secreted acid with antacids
- Eradicate H. pylori
Drugs can be used to inhibit or neutralise gastric acid secretion for the following conditions:
Peptic ulcer
Reflux oesophagitis: gastric acid secretion can damage oesophagus
Zollinger-Ellison syndrome: gastrin-producing tumour
It is unclear why gastric ulcer develop
But H. pylori infection is a risk factor.
H. pylori: a Gram negative bacillus→ chronic gastritis → duodenal ulcer.
30
Goals of pharmacological intervention in gastric ulcer?
- Reduce acid secretion with H2 receptor antagonists
- Neutralise secreted acid with antacids
- Eradicate H. pylori
31
When to use drugs to inhibit or neutralise gastric acid secretion?
- Peptic ulcer
- Reflux oesophagitis: gastric acid secretion damage oesophagus
- Zollinger-Ellison syndrome: gastrin-producing tumour
32
Why remove H. Pylori to treat gastric ulcer?
- Risk factor.
| - H. pylori: gram negative bacillus→ chronic gastritis → duodenal ulcer
33
Describe action of antacids
- neutralise gastric acid
- ↑pH of gastric acid
- (peptic activity stops at pH 5)
34
Describe action of antacids
- neutralise gastric acid
- ↑pH of gastric acid
- (peptic activity stops at pH 5)
- relieves heartburn
35
Features of sodium alginate or algin?
- Anionic polysaccharide in cell walls of brown algae
- Natural polysaccharide extracted from brown seaweed -Ingredient in gaviscon
- Combines with bicarbonate for reflux as it forms a viscous gum : a component of biofilms produced by pseudomonas aeruginosa (pathogen in CF) so confers high antibacterial resistance + killing by macrophages
36
Effect of bismuth chelate?
- protects gastric mucosa
- forms a base over crater of ulcer
- adsorbs pepsin
- ↑HCO3- + PG secretion
- toxic against H. pylori – part of triple therapy to eradicate it
- Blackens stool + tongue
37
Effect of H2 receptor antagonists?
eg ranitidine, cimetidine, famotidine, nizatidine
- Inhibit histamine-, ACh-, gastrin-stimulated acid secretion
- Reduce gastric acid secretion (also reduces pepsin secretion)
- Decrease basal + food-stimulated acid secretion by 90%
- Promote healing of duodenal ulcers
- Peptic ulcer
- Reflex oesophagitis
In clinical trials: Promote the healing of duodenal ulcers
But if you stop treatment, you get relapse
38
Effect of H2 receptor antagonists + eg?
eg ranitidine, cimetidine, famotidine, nizatidine
- Inhibit histamine-, ACh-, gastrin-stimulated acid secretion
- Reduce gastric acid secretion (also reduces pepsin secretion)
- Decrease basal + food-stimulated acid secretion by 90%
- Promote healing of duodenal ulcers but if stop treatment --> relapse
- Peptic ulcer
- Reflex oesophagitis
39
Diff between Ranitidine vs Cimetidine?
Ranitidine has lower IC 50 so at lower conc produces 50% response so more potent than Cimetidine
40
How do prostaglandins protect stomach mucus against damage?
- Stimulating bicarbonate secretion
- Reducing H+ secretion
- Promoting vasodilation
41
Why do NSAIDS (e.g. aspirin) cause gastric bleeding + alternative?
- Inhibits PG synthesis (less protection) + Thromboxane A2 (involved in healing)
- Use selective COX-2 inhibitors causing less bleeding eg Celecoxib, rofecoxib
42
How does H. Pylori cause mucosal damage?
Causes crater, exposing epithelium to HCl, pepsin +
| cytotoxins
43
Combination therapy for H. Pylori infection?
- Omeprazole, amoxicillin, metronidazole
- Omeprazole, clarythromycin and amoxicillin or tetracycline, metronidazole, bismuth chelates
- Lansoprazole, clarithromycin, tinidazole, bismuth chelates
44
Drugs that protect gastric mucosa?
eg bismuth chelate (colloidal bismuth subcitrate, tripotassium dicitratobismuthate) - cytoprotective effects
45
Describe how drugs protect gastric mucosa (bismuth chelate)
- physical barrier (coat) over surface/base of ulcer
- enhances local synthesis of PGs
- promote bicarbonate secretion
- bismuth chelate has toxic effects on bacillus:
* prevents adherence of H. pylori to mucosa
* or inhibit its proteolytic activity - stimulates bicarbonate secretion to ↑PG synthesis + adsorbs pepsin
46
Unwanted effects of bismuth chelate?
nausea, vomiting, blackening of tongue + faeces
47
Warning of bismuth chelate?
If patient has renal impairment, [bismuth chelate]plasma rises causing encephalopathy
DO NOT EXCEED RECOMMENDED DOSE
48
Effect of diff does of bismuth chelate?
- Minor ingestions: nausea, epigastric discomfort only
- Moderate/substantial ingestions: nausea, vomiting, abdominal pain within hrs, precede features of nephrotoxicity + neurotoxicity delayed for days eg renal glomerular, tubular failure, muscle cramps, weakness, blurred vision, hyperreflexia. Liver transaminase activities increased
- Chronic excess ingestion (excess daily ingestion or exceeding advised duration) : bismuth encephalopathy with insidious onset of incoordination, behavioural changes, memory deterioration, psychiatric symptoms progressing to fulminant encephalopathy with myoclonic jerks, confusion, dysarthria, coma, convulsions
- Chronic bismuth poisoning : erythematous rashes, renal failure, thrombocytopenia, bone demineralisation, spontaneous fractures of thoracic vertebrae, paralytic ileus-like syndrome.
49
Patient advice when taking metronidazole for treatment of H. pylori infection?
- Adhere to treatment
- Resistance to metronidazole
- Disulfiram-like reaction if metronidazole taken with alcohol :
* If severely ill stop taking drug
* Disulfiram inhibits acetaldehyde dehydrogenase, build up of acetaldehyde → unpleasant flushing + nausea
- Don't give in 1st trimester or else --> midline facial defects (cleft lip/palate, holotelencephaly)
Holoprosencephaly (arhinencephaly) = cephalic disorder where prosencephalon (forebrain of embryo) fails to develop into 2 hemispheres
50
Clinical uses of proton pump inhibitors + eg?
eg omeprazole, lanzoprazole, rabeprazole
- Peptic ulcer, reflux oesophagitis, component therapy for H. pylori
- Treatment of Zollinger-Ellison syndrome
- If hyper-secretion occurs eg Zollinger-Ellison syndrome
51
Describe how proton pump inhibitors work
- Weak bases; inactive at neutral pH + irreversibly inhibit H+/K+-ATPase pump
- Decreases basal + food-stimulated gastric acid secretion
52
Role of Omeprazole + Ranitidine?
lower acid production
Omeprazole = proton pump inhibitor
Ranitidine = H2 receptor agonist
53
Constipation :
- Subjective complaint
- Obstruction? → constipation so investigate
- Is freq of bowel movement normal?
* Normal/regular bowel opening = 1-3x daily
* Doesn't have to be regular to be physiologically adequate
* No toxic substances accumulate upon prolonged constipation
54
Consequences of constipation from rectal distension?
```
Headache from low blood sugar
Loss of appetite
Nausea
Abdominal distension and stomach pain
Holding of faecal matter → ↑water loss + dryer faeces (painful + harder to defecate)
```
55
Causes of constipation?
```
Diet
↓ motility of large intestine
Damage to enteric nervous system of the colon?
Disease?
Old age
Drugs?
```
In elderly
Diet
Inactivity
Drugs (polypharmacy)
56
Alarm signs + symptoms of patients with chronic constipation?
Acute onset constipation in older individuals
Weight loss (10lb)
Blood in the stool
Anaemia
Family history of colon cancer or inflammatory bowel disease
57
Factors that can increase colonic motility?
↑Distension of large intestine to improve symptoms :
- ↑Fibre, cellulose, complex polysaccharides
- Bran, fruits + vege with high fibre
- Laxatives, but excessive → ↓responsiveness
- Mineral oil – lubricates faeces
- Castor oil – stimulates motility of colon
58
Management of constipation?
Lifestyle changes
Diet, fluid intake, exercise and their effects on constipation (appealing?)
↑ fibre intake → bloating and flatulence (not appealing)
↑ water intake??
59
Features of bulk-forming + osmotic laxatives?
- Bulk laxatives: methylcellulose,
- Plant gums (eg sterculia, agar, linseed, bran, ispaghula husk- are polysaccharide polymers)
- Retain water in gut lumen → promotion of peristalsis few days to work
- Increase stool’s solid content
- Bloating + flatulence
60
What are purgatives?
laxatives, faecal softeners, stimulant purgatives can modulate/hasten food transit in intestine
61
What are laxatives?
=(purgatives, aperients)
-Loosen stools + increase bowel movements
-Treat + prevent constipation
Psyllium husks = isphaghula
62
What's sterculia?
Natural dietary fibre to treat constipation or to regulate passage of food via digestive system in people with certain long-term bowel disorders
63
Describe effect of osmotic laxatives: lactulose
- ↑+maintain volume of fluid in bowel lumen by osmosis
- ↑ transfer of gut contents into intestine
- ↑ volume of gut content entering colon
- distension + purgation (evacuation of the bowels)in 1hr
- High doses → flatulence, cramps, diarrhoea, vomiting, tolerance
64
Why does lactulose increase growth of colonic bacteria?
carbohydrate source for lactobacilli + bifidobacteria
65
Describe lactulose mode of action
- unchanged lactulose reaches colon
- colonic bacteria breaks it down -> short chain FA (isobutyrate, butyrate, isovalerate, valerate, isocaproate, caproate)
- osmotic p + biomass increases
- softening of faeces
- volume of stool increases
- stimulates peristalsis
- colon transit time decreased
66
Role of antidiarrhoeal agents?
- Maintain body fluids + electrolytes
- Identify causal organism + if possible treat with antibiotics eg. erythromycin for Campylobacter jejuni
- Modify secretion/absorption balance
67
Features of Campylobacter jejuni?
- Gram-negative slender, curved, motile rod
- Microaerophilic organism so needs reduced levels of oxygen
- Fragile, sensitive to environmental stresses (eg 21% oxygen, drying, heating, disinfectants, acidic conditions)
- Cause of gastroenteritis in developed countries
68
Causes of diarrhoea?
Infectious agents
Toxins
Anxiety
Drugs: antidepressants (amitriptyline, doxepin), antihypertensives (clonidine); pain medication (codeine, tramadol, methadone), opioid –containing cough medicines hydrocodone butyrate; aluminium antacids, calcium supplements; antibiotics
69
Acute diarrhoeal diseases:?
- Diarrhoea → ↑motility of GIT, with ↑secretion +↓ absorption of fluid → ↓electrolyte (Na+) +H2O
- Malnutrition
- Cholera toxins → loss of gut contents
70
Therapeutic strategies to diarrhoea treatment?
- Maintain fluid + electrolyte balance: Oral rehydration therapy
- Anti-infectives: Bacterial infections may resolve with time :
* Campylobacter sp: cause of gastroenteritis in UK
* Use erythromycin or ciprofloxacin in severe infections
- If viral no anti-infectives
- Non-microbial anti-diarrhoeal agents
- Anti-motility drugs: adsorbents + agents that modify fluid, electrolyte transport
71
Movement of substances modulated by?
Purgatives: ↑passage of food via intestine
72
Agents that ↑motility without → purgation?
Antidiarrhoeal drugs → ↓movement
| Antispasmodic drugs → ↓movement; relax smooth muscles in GIT
73
Features of traveller’s diarrhoea?
- Gorbach, 1987: Travelling broadens the mind + loosens the bowel
- 3 million people travel abroad/yr + experience it
- But some infections may be self-limiting
74
Effect of Loperamide?
Selective on GIT, decreases passage of faeces;
| Decreases duration of illness
75
Effect of Codeine + loperamide
Anti-secretory action;
↓ intestinal motility
↓ stomach cramps
76
Effect of Bismuth subsalicylate?
Decreases fluid secretion in bowel;
Safe for young children;
May cause tinnitus + blackening of stool
77
Effects of loperamide?
-μ-opioid receptor agonist of the myenteric plexus (controls motility + secretion of GIT) of large intestine
Inhibits gastric emptying
-Increases sphincter tone
-Induces stationary motor patterns
-Blocks peristalsis
-Spasmolytic (antispasmodic) agent which reduces smooth muscle activity in GIT --> reduces passage of faeces
-Reduces force + speed of colonic movement
-Increases haustral mixing of proximal colon
-Inhibits propulsive mass movement of distal colon
-Doesn't cross BBB – no CNS effects
