Nausea, Vomiting and Pain (DONE)

Question 1

5-HT distribution

Answer 1

~89% of the total body content of 5-HT is found in entero-chromaffin cells in the intestine, some is also found in the nerve cells of the myenteric plexus
About 10% is found in platelets which take 5-HT up from the plasma
About 1% of the 5-HT is in the CNS where it has a very important role despite the relatively small amounts found there

Question 2

Physiological actions of 5-HT in the GI tract

Answer 2

Main effect is to increase motility and contractility
Direct contractile effect on smooth muscle cells
Indirect effect on enteric nerves leading to the release of ACh and contraction
Indirect effect on enteric nerves leading to relaxation

Question 3

Physiological actions of 5-HT in the nervous system

Answer 3

Peripheral nervous system- involved in the sensation of pain by sensory nerve endings

Question 4

Cardiovascular effects of 5-HT

Answer 4

Receptors on sensory vagal nerves produce reflex bradycardia and hypotension
In the heart causes tachycardia
Many complex cardiovascular CNS effects leading to increased or decreased BP and HR

Question 5

Platelet aggregation effects of 5-HT

Answer 5

Causes platelets to aggregate and adhere to the vessel wall
Platelets release more 5-HT causing further aggregation
Released 5-HT also causes vasodilatation in intact endothelium by stimulating the production of NO, causing vasoconstriction if endothelium damaged
Effects of 5-HT on platelet aggregation most important in vascular disease when the endothelium is damaged

Question 6

Blood vessel effects of 5-HT

Answer 6

Direct vasoconstriction of smooth muscle in arteries and veins, leading to increased BP, vasoconstriction in cranial vessels
Indirect vasodilator action (fall in BP) either by stimulating nitric oxide production from endothelial cells or by inhibiting noradrenaline release from sympathetic nerves
Direct vasodilator effect on smooth muscle, usually only seen when vasoconstrictor responses blocked, more marked in vessels in skeletal muscle and the heart

Question 7

Microcirculation 5-HT effects

Answer 7

In the microcirculation, 5-HT produces vasodilatation in arterioles and vasoconstriction in venules, increasing capillary pressure so fluid escapes from the capillaries
5-HT also increases microvascular permeability, increasing tissue volume

Question 8

Nausea and vomiting

Answer 8

Different types of stimuli can induce nausea and vomiting (emesis):
Gastric irritation and peritonitis- gets rid of the irritant
Inner ear dysfunction
Pregnancy
Drugs- digitalis, cancer chemotherapeutics, general anaesthetics, radiotherapy

Question 9

Brain regions and receptors involved in nausea and vomiting

Answer 9

Different areas of the brain involved: cerebellum- motion sickness, solitary tract nucleus- irritants, CTZ- drugs or chemicals in the blood, higher centres (cortex, hypothalamus)- psychological influences
Vomiting centre in the medulla controls the series of events which precede vomiting
Different receptors- muscarinic, dopamine, histamine, serotonin, neurokinin, cannabinoid, opioid

Question 10

Motion or travel sickness

Answer 10

Inner ear dysfunction
Conflict of messages to the brain
Involves dopamine D2 receptors in the vestibular nucleus
Pharmacological and non-pharmacological treatments e.g. antihistamines, antimuscarinics

Question 11

Nausea and vomiting in pregnancy

Answer 11

Morning sickness but can occur at any time of the day
Causes unknown but thought to be due to hormonal changes
Symptoms often disappear by the end of the third month, 1 in 10 women still feel sick after week 20
About 50% of pregnant women vomit, more than 80% fell nauseous
Generally not treated with drugs

Question 12

Hyperemesis gravidarum

Answer 12

Prolonged, severe vomiting, affects about 1 in 100 women
Associated with dehydration, ketosis, weight loss and postural hypotension
May need hospitalisation for IV fluids and drugs
Treated with anti-emetics, steroids, vitamins B6 and B12

Question 13

Anti-emetics in pregnancy

Answer 13

Anti-histamines (H1 receptors)- cyclizine, promethazine
D2 receptor antagonist- prochlorperazine
D2 receptor antagonist/5-HT receptor antagonist- metoclopramide
D2/D3 receptor antagonist- Domperidone
5-HT3 receptor antagonist- ondansetron
Steroid- prednisolone

Question 14

D2 receptor antagonist prochlorperazine

Answer 14

Severe nausea and vomiting (treatment and prevention)
Caution in various patient groups including cardiovascular disease and elderly
Many side effects including dystonia, esp in children
Oral, IM, buccal tablets e.g. Buccastem
Can be used in combination with dexamethasone, although the mechanism for its anti-emetic action is unknown

Question 15

D2 receptor antagonist/5-HT3 receptor antagonist metoclopramide

Answer 15

Migraine, chemotherapy, radiotherapy and general anaesthetics
Caution in elderly and 15-19 year olds
Many side effects including adverse neurological effects
Restrictions on indications, dose and duraction
Oral, IM, IV
Also used with dexamethasone

Question 16

D2/D3 receptor antagonist domperidone

Answer 16

Periphery only, blocks D2 receptors in the CTZ, less central side effects
Nausea and vomiting
Caution in children and those over 60
Many side effects including serious cardiac effects
Restrictions on indication, dose and duration
Oral

Question 17

Nausea and vomiting with chemotherapy, radiotherapy and general anaesthetics

Answer 17

N+V produced by drugs such as cisplatin, drugs affect all dividing cells including hair follicles, bone marrow and the GI epithelium
Enterochromaffin cells in the gut release 5-HT
3 types of N+V: acute (within 24 hours of treatment), delayed (more than 24 hours after treatment), anticipatory (before the next dose)
General anaesthetics depends on anaesthetic, type and duration of surgery
Range of risk factors: female, non-smoker, history of N+V, motion sickness, opioid use

Question 18

5-HT3 receptor antagonists for treatment of acute symptoms

Answer 18

Ondansetron, granisetron, palonosetron
Oral, IV, IM, rectal, transdermal
Side effects: headache, dizziness, diarrhoea, constipation, insomnia
Receptors found on nerves in the GI tract, CTZ and vomiting centre but it is not known which receptors need to be blocked
Often used in combination with dexamthasone

Question 19

5-HT3 receptor antagonists for treatment of acute and delayed symptoms

Answer 19

Metoclopramide
Neurokinin 1 receptor antagonist, can use with dexamethasone
Given orally, aprepitant, or by IV infusion, fosaprepitant
Many side effects limit use

Question 20

Droperidol

Answer 20

D2 receptor antagonist
Post-operative nausea and vomiting/acute symptoms
Caution in various patient groups including cardiovasulcar disease and elderly
Many side effects including adverse neurological effects e.g. anti-pyramidal
In injection

Question 21

Perphenazine, trifluouoperazine

Answer 21

D2 receptor antgonists
Severe nausea and vomiting unresponsive to other anti-emetics
Caution in various patient groups including cardiovascular disease, elderly
Many side effects including adverse neurological effects e.g. anti-pyramidal
Oral

Question 22

Nabilone

Answer 22

Cannabinoid
Only for nausea and vomiting caused by cytotoxic drugs unresponsive to other anti-emetics
Many CNS side effects including drowsiness and dizziness
Oral, used under hospital supervision

Question 23

Migraine

Answer 23

About 25% of sufferers get an aura that an attack is going to happen- visual field disturbance, numbness, blind spots, weakness on one side of the body or slurred speech
Symptoms: throbbing headache starts 30-60 minutes after the aura, unilateral in ~60%, often associated with photophobia and n+v
Attacks can last from several hours to three days
Usually occasional, sometimes 1-2 a week, never daily
Evidence for a genetic link involving various ion channels
75% of sufferers are female

Question 24

How is a migraine caused?

Answer 24

Spreading cortical depression due to a wave of decreased neuronal activity spreading across the brain probably accounts for the aura, could be related to stress
Increased neuronal activity from the brainstem activates the trigeminal nerve innervating the face and forehead
Terminals of the trigeminal nerve in the meninges release calcitonin gene related peptide
Extra-cerebral vasodilation of cranial arteries and arterio-venous anastsosomes causes the pain
The nerve becomes inflamed releasing more peptides and the vasodilation continues

Question 25

Involvement of 5-HT in migraines

Answer 25

5-HIAA levels are increased during an attack
Platelet 5-HT concentrations fall during the onset of an attack
Intravenous injection of 5-HT aborts headaches induced by reserpine and spontaneous headache
5-HT receptor antagonists are the best drugs for treating migraine

Question 26

5-HT 1B receptors

Answer 26

Receptors are found on blood vessels in the meninges and large cranial arteries
Receptors on smooth muscle cells of large intracranial arteries cause vasoconstriction and reduce nerve activation and CGRP release
Receptors on peripheral trigeminal nerve terminals switch off CGRP release reducing vasodilation
Receptors may inhibit central trigeminal nerve firing in areas of the brainstem which trigger attacks

Question 27

Treatment of migraine

Answer 27

Analgesics: paracetamol, ibuprofen, aspirin, NSAIDs- reduce eicosanoid formation and inflammation
Triptams: sumatriptan, rizatriptan, zolmitriptan- cause vasoconstriction and reduced inflammation
Ergotamine tartrate- vasoconstriction, many side effects including dependence
Anti-emetics: prochlorperazine, metoclopramide

Question 28

Migraine therapy with 5-HT 1B receptor antagonists

Answer 28

Triptans are the best treatment identified to date
Reduce or abolish pain in 75% of cases, not to be used for prophylaxis
Take at onset of migraine, second dose if necessary at least two hours after first dose
Sumatriptan has no effect on the aura as it does not cross the BBB, supporting spreading depression therapy
Side effects: dizziness, weakness, fatigue, drowsiness, nausea, vomiting, tingling, nasal discomfort, pressure/tightness in the chest
CI in patients with cardiovascular and arterial diseases

Question 29

Prophylaxis of migraine

Answer 29

Two or more attacks per month
Increasing frequency
Cannot use acute treatments, problems even with suitable treatments
Risk of medicines overuse headache
Main goals of prophylaxis: reduce attack frequency, severity and duration, improve responsiveness to treatment of acute attack, improve function and reduce disability

Question 30

Drugs used for migraine prophylaxis in the UK

Answer 30

Beta blockers: propranolol
Tricyclic antidepressants: amitriptyline
Anti-convulsants: topiramate
Botox
5-HT2 receptor antagonists: pizotifen
Clonidine

Question 31

Irritable bowel syndrome

Answer 31

Disease associated with recurrent abdominal pain and abnormal bowel activity, may involve hypersensitivity to normal stimuli
Mediated by 5-HT through 5-HT3 and 5-HT4 receptors
Receptor stimulation increases peristalsis and gut transit, increase fluid secretion and bowel movements- diarrhoea
5-HT3 receptor antagonists increase water and Na reabsorption leading to constipation

Question 32

UK treatments for IBS

Answer 32

Anti-spasmodics: anti-muscarinic agents e.g. dicycloverine, hyoscine
Other anti-spasmodics: mebeverine, peppermint oil
Anti-motility drugs for diarrhoea e.g. Loperamide
Osmotic laxative for constipation e.g. soluble fibre
Anti-depressants: central and peripheral effects

Question 33

5-HT3 and 5-HT4 receptors and IBS treatment

Answer 33

5-HT3: receptor antagonist alosteron used in diarrhoea prominent IBS in USA, only useful in women, side effects led to withdrawal, now available with very limited use in the USA
5-HT4 receptor antagonist prucalopride used in constipation dominant IBS, only effective in women, licensed in the UK for women with chronic constipation resistant to other laxatives