Week 1/2 - E - Pharmacology 1-3- Nausea/vomiting (5H.T, M1, D2, H1, N.K1 receptor antagonists), Gastric secretions, acid-inhibitors

Question 1

What is nausea? What is vomiting (emesis)?

Answer 1

Nausea is the subective, highly unpleasant, sensation normally felt in the throat and stomach - often relieved by vomiting Emesis is the forceful expulsion of contents of stomach and duodenum through the mouth

Question 2

What symptoms is nausea usually accompanied by? Is it always followed by vomiting?

Answer 2

Nausea is usually accompanied by pallor, sweating, excessive salivation and relaxation of stomach/oesophagus and sphincters

Question 3

What is the centre known as that co-ordinates vomiting? Where is it found?

Answer 3

The vomiting centre co-ordinates vomiting and it is found in the medulla of the brainstem

Question 4

There are various sources of input to the vomiting centre What is the main source of input to the vomiting centre? What can stimulate this area?

Answer 4

The main source of input is the chemoreceptor trigger zone (CTZ) located in the brainstem Can be stimulated by: -> neurotransmitters -> vesitbular system (labyrinths) - motion sickness - signals CTZ via vestibular nculei -> Vagal afferents sensing mechanical stimuli eg gag reflex or GI tract pathology

Question 5

Toxic materials and systemic toxins can trigger the mucosa in the stomach to release different mediators which can trigger action potentials to the vomiting centre What are the main neurotransmitter systems involved in vomiting? What area of the brainstem do they act on?

Answer 5

The main neurotransmitters involved in vomiting are 5-HT, dopamine and acetylcholine (histamine, opioid receptors and substance P also are involved) They act on the chemoreceptor trigger zone of the brain (CTZ)- stimulation of which trigger the vomiting centre

Question 6

After the vomiting centre in the medulla is triggered by action potentials from different neurotransmitters, what are the events that take place in vomiting? Which muscles cause the gastric emptying?

Answer 6

Vomiting commences with forecful inspiration, reflex closure of the glottis and elevation of the soft palate to close off the airways and nasal passages Releaxation of pyloric sphincter / lower oeseophgeal sphincter take place Contraction of diaphragm and abdominal muscles compresses somtach Ejection of gastric contents through open upper oseophgeal sphincter

Question 7

What are some of the consequences of severe vomiting?

Answer 7

Dehydration Loss of gastric protons and chloride - causing a metabolic alakosis Hypokalaemia - acid loss is accompanied by potassium excretion Rarely oeseophageal damage - Mallory Weiss tear

Question 8

What are the major classes of anti-emetic drugs? (basically antagonise the receptors of the neurotransmitters that are involved in vomiting)

Answer 8

* 5-HT3 serotonin receptor antagonists * M1 Muscarinc acetycholine receptor antagonists * D2-dopamine receptor antagonsits * Histamine H1 receptor atangonists * NK-1 (neurokinin 1) receptor antagonsits

Question 9

5HT3 receptor antagonists What does 5HT stand for and what is it also known as? Where do the 5HT3 receptor antagonsits primarily act?

Answer 9

5HT receptors stands for 5 hydroxytryptamine receptors aka serotonin receptors 5HT3 receptors used as anti-emetics primaruly block the 5HT3 receptors in the chemoreceptor trigger zone of the medulla and the 5HT3 receptors in the GI tract

Question 10

What cells release 5HT3 in the gastric mucosa in response to eg toxins? Give an example of a 5HT3 receptor antagonist?

Answer 10

Enterocrhomaffin cells release 5HT3 in response to eg toxins in the stomach 5HT3 receptor antagonits - are the setrons aka ondansetron, palonosetron

Question 11

When are 5HT3-receptor antagonists used for anti-emesis? What are the side effects?

Answer 11

5HT3-receptor antagonists usually used to suppres chemotherapy and radiotherapy induced emesis and post op nausea/vomitng Side ffects incluce constipation, diarrhoea and headache

Question 12

Antimsucarinic M1 acetylcholine receptors Where do antimuscarincs (muscarinic acetylcholine receptor antagonists) work in the body? What are they indicated for?

Answer 12

Antimuscarins act primarily as antagonists at muscarinic acetylcholine M1 receptors in the brain They are indicated for motion sickness

Question 13

What are side effects of the antimuscarincs? Give an example of the drug

Answer 13

Side effects usually occur due to the anticholinergic effects * ABCDs * Agitation * Blurred vision * Constipation/confusion * Dry mouth * Stasis of urine / sweating Example - antimuscarinic anti-emetic - scopolamine (hyoscine) hydrobromide

Question 14

Histamine H1 receptor antagonists Where do the histamine H1 receptor antagonists work for anti-emesis? What are they used for? Give examples?

Answer 14

Histamine H1 receptor antagonists work primarily as antagonists at H1 receptors in the brain and in vestibular nuclei Indicated for proprhylaxis and treatment of motion sickness and acute labrynthitis and nausea/vomiting due to GI irritants Examples - cyclizine, promethazine

Question 15

What are the side effects of the histamin H1 receptor antagonists?

Answer 15

Because they act at H1 receptors in the brain, they can generally cause CNS depression leading to sedation and drowsiness

Question 16

Dopamine D2 receptor antagonists Where do the D2 dopamine receptor antagonists exert there effect? Give examples of the drug? Which does not cross the blood brain barrier?

Answer 16

D2 dopamine receptor antagonists act primarily at D2 receptors in the chemoreceptor trigger zone in the medulla and also the D2 receptors in the GI tract (oeseophagus, stomach, intestine) Examples include metoclopramide, chlorpromazine, domperidone Only domperiodone does not cross the blood brain barrier

Question 17

When are the D2 receptor antagonists used? What are the side effects of the D2 receptor antagonists?

Answer 17

Used for drug induced vomiting eg cancer therapy Used for treatment of Parkinson’s prevents breakdown of dopamine and therefoe increases levels Used for vomiting in GI disorders Side effects include diarrhoea and extrapyrmidal side effects (except domperidone as it does not cross BBB)

Question 18

As said the main neurotransmitters involved in vomiting are * 5HT - acts on chemoreceptor trigger zone & GI tract * Acetylcholine - acts on M1 muscarinc receptors in the brain * H1 histamine - acts on H1 receptors in brain and vestibular nuclei * D2 dopamine - acts on chemoreceptors in chemoreceptor trigger zone and Gi tract Which drug class is thought to block the effects of substance P (which evokes vomiting)? Where does it act?

Answer 18

Neurokini 1-receptor antagonists Bloc the NK1 receptors in the GI tract and chemoreceptor trigger zone - blocking the effects of substance P

Question 19

Give examples of neurokinin-1 receptor antagonists? When is it used?

Answer 19

Neurokinin-1 receptor antagonists eg fosaprepitant and aprepitant Used in highly emotgenic chemotherapy

Question 20

Which anti-emetics are choices for nausea/vomiting induced by * chemotherapy? * motion sickness? * vesitublar causes? * GI causes?

Answer 20

chemotherapy - * 5HT3 receptor antagonists eg ondansetron * D2 receptor antagonists eg metoclopramide or domperidone * NK1 receptor antagonists eg aprepitant motion sickness * H1 receptor antagonists - eg cyclizine * Antimuscarinic M1 receptor antagonist - Hyoscine vesitublar causes - H1 receptor antagonists - eg cyclizine GI causes - D2 receptors and H1 receptor antagonists

Question 21

GASTRIC SECRETIONS The gastric mucosa has a simple columnar epithelium surface lining with pits existing in the surface of the mucosa. At the base of these pits are gastric glands which are responsible for several secretions What are the two different gland areas of the stomach?

Answer 21

Oxyntic gland area (proximal stomach including the fundus and body) pyloric gland area - distal stomach

Question 22

There are different cells in both gland areas which secrete different hormones What hormones are produced in the oxynitic area of the stomach? What hormones are produced in the pyloric area of the stomach? * State the cells which release these hormones for both

Answer 22

Mucous is secreted by goblet cells in the glands * Oxyntic area * Parietal cells - * Hydrocholric acid (HCl) * Intrinsic factor * Gastroferrin Chief cells - pepsinogen Enterochromaffin like cells - histamine Pyloric area * G cells - gastrin * D cells - somatostain

Question 23

State the function of the different secretions from the parietal cells

Answer 23

Parietal cells * HCl * Activates pepsinogen to pesin, denatures proteins, kills most microorgansims Intrinsic factor * Binds to vitB12 to facilitate future absorption in the terminal ileum Gastroferrin * Binds to ferrous iron Fe2+ to facilitate future absorption in duodenum/jejunum

Question 24

What are the three main transporters involved in the secretion of HCl from the gastric parietal cells?

Answer 24

Carbonic-bicarbonate exchanger allows entry of chloride into the gastric cell at basolateral membrane H+/K+ ATPase (proton pump) allows exchange of these ions at apical membrane Chloride potassium sympoter allows transport of both ions into the gastric lumen at apical membrane

Question 25

What is the function of the chief cells and enterochromaffin like cell secretions?

Answer 25

Chief cells * Secrete pepsinogen which is converted to pepsin by HCl (pepsin is autocatalytic and then stimulates conversion of pepsinogen to pepsin) * Pepsin breaks down proteins Enterochromaffin like cells * Secretes histamine - stimulates HCl secretion from gastric parietal cells

Question 26

Histamine is secreted by the enterochromaffin-like cells in the gastric glands in response to stimulation by acetylcholine What receptors does it bind to on the gastric parietal cells? How does this increase gastric acid secretion?

Answer 26

Histamine binds to H2 receptors on the gastric parietal cells This causes subsequent activation of adenylyl cyclase which increases cAMP (cyclic adenosine monophosphate) which increases the number of H+/K+ proton pumps

Question 27

The three important secretagogues involved in gastric acids secretion are * Histamine - from enterochromaffin like cells acting on H2 receptors * Acetylcholine * Gastrin What is acetylcholine released by? How does it increase gastric acid secretion?

Answer 27

Acetycholine is released from parasymapthetic cholinergic neurons (vagus nerve activity) It binds to Muscarinic (M3) receptors on gastric parietal cells activating PLC complex This increases intracellular calcium which invokes pathways to increase the number of proton pumps

Question 28

State the function of the different secretions from the pyloric gland area (dont need to mention mucous)

Answer 28

G cells * Gastrin - stimulates HCl secretion from gastric parietal cells and gastric motility D cells * Somatostatin - inhibits HCl secretion and gastric motility

Question 29

What does gastrin bind to on the gastric parietal cells? How does this increase gastric acid secretion?

Answer 29

Gastrin binds to CCK2 receptors (cholecystokinin B receptors) with subsequent activation of PLC (phosopholipase C) This increases intracellular calcium which invokes pathways to increase the number of proton pumps

Question 30

Somatostatin essentially inhibits the pathways of histamine What does somatostatin bind to on the gastric parietal cells? How does this inhibit gastric acid secretion?

Answer 30

Somatostatin binds to SST2R (somatostatin 2 receptors) on gastric parietal cells inhibiting adenylyl cyclase which decreases c-AMP which decreases the number of proton pumps inhibting gastric acid secretion Somatostatin also binds to SST2R on enterchromaffin like cells reducing histamine release

Question 31

Antacids, PPIs and Histamine H2-receptor antagonists When excessive amounts of acids are produced in the stomach the natural mucous barrier that protects the lining of the stomach can damage the esophagus in people with acid reflux. How do antacids work?

Answer 31

Antacids contain alkaline ions that chemically neutralize stomach gastric acid, reducing damage and relieving pain

Question 32

How do NSAIDs increase the secretion of HCl from gastric parietal cells and therefore gastroprotection is often given?

Answer 32

NSAIDs disrupt the production of prostoglandins by inhibiting COX-1 The reduced availability of prostaglandins results in histamine secretion from enterochromaffin-like cells, promoting HCl secretion from parietal cells

Question 33

How do proton pump inhibitors work? Give examples of the drug

Answer 33

Proton umpu inhibitors work by irreversibly inhibiting the H+/K+ ATPase proton pump - this reduces HCl secretion Examples - lansoprazole, omeprazole

Question 34

When are PPIs indicated? What are side effects?

Answer 34

Indicated for benign gastric acid ulceration and NSAID-associated gastric ulceration, gastro-oesophageal reflux disease and Zollinger–Ellison syndrome Side effects- increased stomach pH reduce defences against infection via the GI tract , rare but cause hyponatraemia

Question 35

How do histamine H2 receptor antagonists inhibit gastric acid secretion from parietal cells? Give examples When are they indicated?

Answer 35

Histamine H2 receptor antagonists blocking the H2 receptor on the gastric parietal cells therefore preventing the effect of histamine from increasing HCl secretion Examples- ranitidine, cimetidine Indicated for benign gastric acid ulceration and NSAID associated gastric ulceration