Case 1: Therapeutics Flashcards
(42 cards)
1
Q
What is a neuronal agent that stimulates acid release ?
A
Acetylcholine
2
Q
What is a paracrine agent that stimulates acid release ?
A
Histamine
3
Q
What is an endocrine agent that stimulates acid release ?
A
Gastrin
4
Q
Where is histamine released from ?
A
Enterochromaffin like cells (ELC)
5
Q
Where is gastrin released from ?
A
G cells
6
Q
What receptor does Ach bind to in the stomach?
A
M3
7
Q
What G protein are M3 receptors coupled to ?
A
Gq
8
Q
What receptor does histamine bind to ?
A
H2 type histamine receptor
9
Q
What G protein are H2 receptors coupled to ?
A
Gs
10
Q
What receptor does gastrin bind to ?
A
Cholecystokinin (CCK) receptors
11
Q
What G protein are CCK receptors coupled to ?
A
Gq
12
Q
What does COX-1 do ?
A
Converts arachadonic acid into prostaglandins
13
Q
Explain how a neuronal agent increases acid release
A
- Parasympathetic nerves release Acetylcholine which synapses onto the parietal cell.
- Ach binds to the M3 Ach receptor which is a GPCR that is coupled to a Gq protein.
- The activation of this receptor stimulates HCl release.
14
Q
Explain how a paracrine agent can increase acid release
A
- Histamine is released from Enterochromaffin like cells (ELC) which are found in gastric pits.
- Histamine is released into the local area and diffuses and binds to H2 type Histamine receptors (GPCR) on the parietal cell.
- The H2 receptors are Gs coupled, so activation increases acid production.
15
Q
Explain how an endocrine agent can increase acid production
A
- G-cells at a distant site release Gastrin into the blood stream.
- The blood stream carries Gastrin to parietal cells.
- Gastrin bind to CCK receptors on the parietal which are also GPCR and coupled to a Gq protein.
16
Q
How does activation of these receptors lead to stimulation of the proton pumps ?
A
- Activation of the G proteins leads to activation of PKA and PKC.
- This causes the tubulovesicle to translocate to the parietal cell membrane and fuse with the membrane.
- This introduces more proton pumps that are active into the membrane, increasing HCl production.
17
Q
How else can Histamine release be stimulated?
A
Ach and Gastrin also have receptors on ECL cells. When they bind to these receptors, it stimulates release of Histamine. This causes indirect HCl release.
18
Q
How does mucus protect the stomach from acid damage ?
A
Mucous neck cells secrete thick, sticky mucus which forms a physical barrier between the stomach lining and gastric acid
19
Q
How do bicarbonate ions protect the stomach from acid ?
A
They are secreted into the mucus layer.
They neutralise the H+ ions from gastric acid that diffuses into the mucus, making it less acidic and likely to cause damage.
20
Q
How do prostaglandins protect the stomach from acid damage ?
A
- Cox1 enzyme converts arachadonic acids into prostaglandins: PGI2 and PGE2.
- They bind to GPCR receptors on the parietal cell, activating the Gi protein pathway. This causes the conc of cAMP to be decreased, which reduces proton pump activity, so less HCl is secreted.
- They stimulate mucus and bicarbonate secretion.
- They cause vasodilation, which increases mucosal blood flow. This supplies the mucosa with oxygen and bicarbonate ions, which removes H+ and toxic agents diffusing from the lumen into the mucosa.
- They also play a role in feeling that there is pain and inflammation present.
21
Q
What is an ulcer ?
A
A hole or sore in the lining of an organ
22
Q
What are the symptoms of a gastric ulcer ?
A
- A pain like indigestion in the upper abdomen or lower chest
- Difficulty swallowing food
- Regurgitating food
- Feeling sick after eating
- Loss of appetite
- Weight loss
23
Q
What is H.pylori ?
A
A spiral shaped Gram-negative bacteria.
It causes >90% of duodenal ulcers and up to 80% of gastric ulcers.
24
Q
How does H.pylori colonise the human stomach ?
A
- It colonises the Antrum (bottom) of the stomach, where little acid is produced. The antrum has a thick mucus layer for the bacteria to hide in and grow.
- H.pylori produces large amounts of the enzyme Urease which converts urea into ammonia. Ammonia reacts with protons in the stomach to form ammonium ions. This neutralises the gastric acid, which provides a PH neutral environment in which to reside.
25
How does H.pylori directly damage host cells ?
-Urease produces ammonia which Is toxic to gastric epithelial cells.
- Inhibits the process of gastric mucosal healing - cytotoxin associated gene A (CAG A) disrupts signalling pathways, which interupts cell division
- Stimulates cell proliferation and increases DNA mutation rate leading to gastric carcinoma. - CAG A increases the MAPK/ERK pathway which promotes cell proliferation
26
How does H.pylori indirectly damage host cells ?
• The body's immune response eg. neutrophis, macrophages and T cells, cannot reach the bacterium in the mucus lining of the stomach - gastric mucus is thick and acts as a barrier.
• The WBCs release Reactive oxygen species such as superoxide which damage the stomach lining.
• All of these cause inflammation
27
Describe the direct evidence that can diagnose a gastric ulcer
1. Endoscopy
• A long, thin flexible tube that has a light and camera on the end.
• It is inserted into the mouth and then passed down the oesophagus to the stomach and duodenum.
• There is a side channel through which instruments can be passed.
2. Stool antigen test
• Stool sample collected trom patient, diluted and added to antibody-coated micro wells.
• Sample washed to remove unbound proteins.
• H. pylori - specitic antibodies (lined to a peroxidase enzyme) are added to the microwell.
• Sample washed and peroxidase substrate added. It H. pylori antigens are present, a measurable colour change occurs.
28
Describe the indirect evidence that can diagnose a gastric ulcer
1. 13C urea breath test
• Patient is given a drink containing the naturally occuring substance urea.
• The urea has a form ot carbon in it (13c) which is naturally found in food and the body.
• It H. pylori is present, it breaks down the urea leading to an increase in 13C in the CO2 you breathe out. This is then measured.
2. Lab - based serology
• Blood tests to detect H. pylori antibodies
• High inflammatory marters
• Increased WBC count to fight infection
29
Define NICE
National institute for health and care excellence
30
What are the roles of NICE ?
1. Develops guidance based on the best scientific research
2. Helps healthcare professionals make informed decisions about patient care
3. Accesses the cost-effectiveness of treatments
4. Supports equitable access to healthcare serves across the UK
31
How is chronic use of NSAIDS damaging to the GI tract ?
NSAIDS inhibit COX-1, which decreases production of prostaglandins causing many effects:
- Increased gastric acid secretion as Gastrin and Histamine are released
- Decreased mucus and bicarbonate ion production which reduces protection of the stomach lining
- Decreased blood flow, which also reduces protection
NSAIDS also increase the expression of intercellular adhesion molecules in the vascular endothelium. This increases neutrophil adherence to vascular endothelial cells. This causes mucosal damage due to neutrophil-derived free radicals and proteases.
32
What is misoprostol ?
It is a PGE1 analogue that is a synthetic form of the prostaglandins normally made in the body.
It is used to prevent the damage that NSAIDS cause over a long period of time.
It does this by restoring all the protective effects in the stomach: mucus, vasodilation and decreased acid production.
33
What is Bismuth chelate ?
Used as part of quadruple therapy if triple therapy isn’t effective
34
Describe the bacteriacidal effect of bismuth chelate
- Inhibits bacterial enzymes eg. Urease and catalase which H.pylori use to survive
- Inhibits adhesion of the bacteria to the gastric mucosa
- Inhibits ATP synthesis
- Disrupts the cell wall of the bacteria
35
Describe the mucosal protective actions of bismuth chelate
- Increases secretion of mucus, bicarbonate ions and prostaglandins
- Chelates at acidic PH to form a coat over the base of the ulcer, which protects it from acid
36
What is a pro drug ?
A drug that is pharmacologically inactive when ingested, then is converted in the body into its active form
Eg. Omeprazole
37
Describe the MOA of omeprazole
Distribution:
• After oral administration, Omeprazole diffuses from the stomach into the parietal cell cytoplasm. The cytoplasm is PH = 7.1, so the drug is inactive at this PH.
• It then diffuses into the acidic canaliculus where the PH<2.
The increased conc of H+ ions bind to Omeprazole and convert it into active Sulfenamide.
Effects:
• Active Sulfenamide binds to the external side of the proton pump and forms a covalent disulphide bond with the cysteine residue on the proton pump. It is an Irreversible bond.
• This inhibits the proton pump, stopping H+ Ions being pumped into the gastric pit, so reduces acid production.
38
If Omeprazole binds irreversibly to proton pumps, why does acid production resume over time ?
The inhibitory effect eventually wears off due to the fact that proton pumps are continuously synthesised and inserted into the cell membrane
39
What is Amoxicillin?
A beta-lactam antibiotic that directly targets the H.pylori infection.
It has a bactericidal MOA
40
Describe the MOA of Amoxicillin
Amoxicillin binds to Penicillin binding proteins (PBP) which inhibits the reaction between two individual monomers to form the peptidoglycan cell wall.
Autolytic enzymes in the cell wall lyse the cell wall, resulting in death of the bacteria.
41
What is clarithromycin ?
A macrolide antibiotic
It has a bacteriostatic MOA at therapeutic concs
42
Describe the MOA of Clarithromycin
1. Macrolides gain entry into the cell by diffusing across the lipid bilayer. They bind to the 23S ribosomal RNA receptor within the exit tunnel of the ribosomal 50S subunit, blocking the tunnel, and disrupting protein formation.
2. They also disrupt protein formation by preventing the ribosome from catalysing peptide bond formation, so no polypeptide chain can be made.
