Immunology Flashcards
Aulus Cornelius Celsus defined the cardinal symptoms of inflammation in his 1st century BCE book De Medicina. What are they (4)?
redness (rubor), swelling (tumor), heat (calor) and pain (dolor).
Give the causes for each of Celsus’ 4 cardinal symptoms of inflammation
- Redness – increase in local blood flow caused by vasodilator action of inflammatory mediators
- Swelling – increase in vascular permeability, proteins and fluid leak from vasculature
- Heat – as for redness
- Pain – direct action on nociceptors (sensory neurones tuned to detect noxious stimuli)
Give 3 causes of inflammation
noxious stimulation
infection
autoimmune reaction
What is the triple response of Lewis
after drawing a pointed object across the skin:
within seconds- flush
30 to 60 secs after - flare
within minutes - wheal
What causes the flush response in Lewis’ triple response to injury
within seconds of injury, a band of redness that matches the size and shape of the stimulus appears due to local release of vasodilator substances, such as histamine, from cells disturbed by the stimulus causing dilation of capillaries
What happens during flare (Triple response of Lewis )
reddening spreads to the surrounding area because of an axon reflex (neurogenic inflammation)
What happens in neurogenic inflammation
stimulated branch of a sensory nerve fibre will send an action potential to the branching point, an action potential travels orthodromically to the spinal cord giving rise to the sensation of pain and antidromically along collateral branches resulting in the release of vasodilatory substances, which causes vasodilatation of the surrounding arterioles
What happens to the inflammatory flare response if you section a central axonal branch from the injured area
sectioning of the central branch will prevent perception of the stimulus, but the flare will continue to occur until the nerve degenerates
What happens during wheal (Triple response of Lewis )
localised swelling occurs within a few minutes of the stimulus due to histamine causing increased vascular permeability
leakage of plasma from the blood to the extracellular space results in swelling due to increased tonicity of plasma compared to normal ECF
Do you have to cut someone to replicate the triple response of Lewis?
no
responses can be largely replicated by injection of histamine (effects are mediated by H1 receptors)
Noxious stimulation of a sensory neuron sends APs to CNS and also to other fibre branches. What do these branches release
what process is this?
calcitonin gene related peptide (CGRP) and substance P (SP), which are able to directly cause vasodilatation and SP is a potent activator of mast cell degranulation
neurogenic inflammation
What does production of SP in neurogenic inflammation result in
give a piece of experimental evidence of this
vasodilation and degranulation of mast cells, which leads to the local production of histamine resulting in both vasodilatation and increased vascular permeability
mast cell deficient mice display no increased vascular permeability after intradermal injection of SP
What is D
dermatographic urticaria
what is the cause
how is it treated
a condition in which the triple response is exaggerated;
largely idiopathic
generally treated with H1-receptor antagonists, but it is also treated with the monoclonal antibody omalizumab, which recognises IgE and acts to decrease mast cell activation
How does bacterial/viral/fungal infection cause inflammation (3)
directly cause inflammation through release of toxins, which cause inflammation or by lysing host cells that liberate inflammatory factors, such as ATP.
also activate the innate and adaptive immune systems
Give an example of a bacteria directly causing inflammation through toxin release
alpha-haemolysin secreted by uropathogenic Escherichia coli induces Ca2+ oscillations in cells that cause synthesis of the proinflammatory cytokines interleukins IL-6 and IL-8
What are the two key components of the host’s immune response to pathogens
1) innate response – first line of defence, non-adaptive, developed early in evolution, present in some form in many multicellular organisms
2) adaptive response – second line of defence, physical basis of immunological “memory”, emerged later in evolution, only present in vertebrates
What are PAMPs
products of bacteria, viruses, fungi etc. that they are unable to readily change to avoid detection.
What are the best studied PRRs
Toll-like receptors (TLRs)
Why are they called Toll Like Receptors
the first toll gene was identified in Drosophila melanogaster as necessary for establishing the dorsal-ventral axis, the underdeveloped ventral portion of fruit fly larvae mutant for toll evoked the exclamation, “das ist ja toll!” (“that’s amazing!”) from Christiane Nüsslein-Volhard
How many TLRs are there
what do they do upon activation
~10
activation recruit various adaptor molecules and trigger signalling cascades that result in increased expression of pro-inflammatory cytokines and interferons
On which part of the cell are TLRs expressed
. Some TLRs are expressed at the plasma membrane like TLR4, which detects lipopolysaccharide, but others are expressed intracellularly in endosomes and generally detect DNA/RNA, e.g. TLR8 detects ssRNA.
Give 3 examples of sentinel cells
macrophages, dendritic cells and mast cells
What happens when TLRs on sentinel cells are activated by PAMPs
initiates production of a variety of proinflammatory mediators, which varies depending upon the cell type activated
Name some proinflammatory mediators released from sentinel cells upon activation of TLRs from PAMPs
prostaglandins (PGE2/PGI2 both cause vasodilatation),
histamine (vasodilatation and vascular permeability)
the cytokines tumour necrosis factor alpha (TNFα) and IL-1, which induce the production of further cytokines, vascular permeability and expression of adhesion molecules on the intimal surface of postcapillary venules.
Generally how do leukocytes leave the blood vessel to reach the site of infection
Leukocytes adhere to endothelial cell adhesion molecules, which enables them to migrate out of the vascular system and attack pathogens, a process aided by pathogen generated chemotaxins and host chemokines whose expression the pathogen has induced.
Components from which 4 systems does inflammatory exudate contain
complement system, coagulation system, fibrinolytic system and kinin system
How is factor XII activated
what is the product and its role?
Factor XII becomes activated upon contacting negatively charged substances such as collagen, producing Factor XIIa, which results in the production of thrombin, plasmin and bradykinin
Give an example of the coagulation, fibrinolytic and complement system interacting
Factor XII becomes activated upon contacting negatively charged substances such as collagen, producing Factor XIIa, which results in the production of thrombin, plasmin and bradykinin. Thrombin and plasmin hydrolyse the complement protein C3 to produce active C3a and C3b
What converts fibrinogen into fibrin
thrombin
What are the roles of C3a and b
C3a stimulates mast cells,
C3b attaches to pathogens aiding their destruction by white blood cells and cleaves C5 into C5a and C5b
Give 3 roles of C5a
activates mast cells, is chemoattractant for white blood cells and also activates them
Describe the roles of C5-9
form a membrane attack complex that can attach to bacterial membranes and induce lysis (one subunit of C5b, C6, C7, C8 and 12-18 C9 subunits)
Which cells are usually first to the site of injury
neutrophils
Give the 5 steps required for neutrophils to exit the vascular system
1) PRRs detect PAMPs causing release of TNFα and IL-1 inducing expression of adhesion molecules (e.g. selectins) on the endothelium
2) Neutrophils initially tether to and are captured by the endothelium via interaction between endothelial P-selectin and neutrophil expressed ligands, such as P-selectin glycoprotein 1 (PSGL1). involves interaction between neutrophil expressed integrins eg LFA1 and ICAM1 expressed by the endothelium.
3) Transmigration across the endothelium and basement membrane takes up to ∼15 minutes and requires both integrins and further adhesion molecules such as platelet/endothelial cell adhesion molecule 1 (PECAM1)
4) Numerous chemotaxins (e.g. C5a and the bacteria derived formyl-Met-Leu-Phe, fMLF) attract the neutrophils to the bacteria invader
5) Neutrophils eliminate pathogens via intracellular and extracellular mechanisms
What are ICAM1 and LFA1
Firm arrest and adhesion involves interaction between neutrophil expressed integrins such as lymphocyte-associated antigen 1 (LFA1) and intercellular adhesion molecule 1 (ICAM1) expressed by the endothelium.
Is it faster for a neutrophil to migrate across the vascular endothelium transcellularly or paracellularly
transmigration can occur either paracellularly (between endothelial cells), or transcellularly (through endothelial cells, which takes longer ∼30 minutes).
Give some strategies used by neutrophils to eliminate pathogens (3)
phagocytosis and killing via reactive oxygen species and antibacterial proteins (e.g. cathepsin, lysozyme and defensins)
degranulation to release antibacterial proteins into the extracellular fluid
neutrophil extracellular traps (NETs), which are composed of a core DNA element alongside enzymes that immobilise pathogens, thus preventing spreading and facilitating phagocytosis, as well as likely also directly killing some pathogens
What predisposes neonates to infection
Neutrophil dysfunction is thought to be important in the development of sepsis in newborns and neonatal neutrophils fail to form NETs, which likely contributes to newborns being predisposed to infection
What TLRs/ receptors do mast cells express
what does activation of these trigger? (5)
receptors for C3a, C5a and IgE,
stimulation of these receptors results in release of histamine, heparin, leukotrienes, nerve growth factor and, unusually, pre-formed packets of cytokines.
What is 2-(1H-imidazol-4-yl)ethanamine
chemical named for what is usually called histamine, a name resulting from it being an amine occurring in tissues (histos = tissue)
Where is histamine made and found?
Histamine is formed from the amino acid histidine by histidine decarboxylase
at the cellular level histamine is found in 4 cell types: mast cells, basophils, enterochromaffin-like cells (ECL) in the gut and histaminergic neurones in the brain. In mast cells and basophils, histamine is packaged in acidic granules with a high molecular weight heparin called macroheparin
Name 3 substances that evoke histamine release from mast cells
C3a/C5a, SP, and IgE
trigger increased [Ca2+]i which leads to degranulation
How do C3a and C5a affect mast cells
C3a and C5a receptors are Gi-coupled; the βγ subunits activate PLCβ and induce intracellular Ca2+ release via IP3
this leads to degranulation and histamine release
How does SP affect mast cells
SP primarily induces mast cell degranulation, not via neurokinin 1 receptors, but rather Mas-related gene X2 (MrgX2) receptors, which in human mast cells appear to be Gq-coupled resulting in PLCβ/IP3 mediated Ca2+ release
How does IgE affect mast cells
Allergen-induced cross linking of IgE with its high affinity receptor FcεRI induces phosphorylation of the adaptor protein linker for activation of T cells (LAT) that causes activation of PLCγ/IP3 mediated Ca2+ release.
True or false
all histamine receptors are GPCRs
true There are four histamine receptors that are GPCRs (H1-4) H1= Gq/11 H2= Gs H3=Gi H4=Gi
What are the effects of H1 receptors
H1 = Gq/11 -> PLCβ -> IP3 + DAG/PKC (important in inflammation)
How do H2 receptors work
what are they important for
Gs coupled so increases AC, increasing cAMP/PKA
important for gastric secretion
How do H3 and H4 receptors work
what are they important for
both decrease AC so decrease cAMP/PKA
H3 is an important inhibitory autoreceptor in the CNS
H4 is important for chemotaxis/cytokine release
Give the 7 key effects histamine has in the body
give the receptor important for each effect
- smooth muscle contraction (H1) in the ileum, bronchioles and uterus
- blood vessel dilation, largely mediated via endothelial release of nitric oxide (H1)
- itching evoked by activation of distinct sensory nerves (pruritoceptors, H1)
- triple response of Lewis (H1)
- increased heart rate (H2)
- gastric acid secretion (H2)
- brain neurotransmission (predominantly H1-3, but also H4)
How is histamine metabolised
2 possible enzymes:
histaminase -oxidatively deaminates histamine to produce imidazole acetaldehyde,
histamine N-methyltransferase -catalyses the transfer of a methyl group on to the nitrogen of the imidazole ring to produce NT-methylhistamine
both products are inactive at histamine receptors.
What are the names of the 2 enzymes that can metabolise histamine
histaminase (also called diamine oxidase)
histamine N-methyltransferase (also called imidazole N-methyltransferase)
Give 3 allergic conditions which involve histamine
allergic rhinitis (hay fever)
urticaria (incl. dermatographism urticaria)
allergies such as nut allergy and penicillin allergy.
What responses are involved in the allergic reactions involving histamine (5)
include swelling, itchiness, nasal congestion, watery eyes and in non-human animals poor coat quality
Give 3 symptoms of severe anaphylaxis
how is it treated
throat swells
heart rate increases
blood pressure drops
rapid adrenaline treatment
What is mastocytosis
a group of conditions where too many mast cells are present leading to excessive allergic-type reactions when an attack is triggered by various factors (heat, cold, stress, infection, exercise, drugs etc.)
What causes mastocytosis in humans
Often results from a gain-of-function mutation in the receptor tyrosine kinase c-Kit/CD117 (D816V) causing enhanced mast cell proliferation and survival
What can cause mastocytosis in non humans
Mastocytosis resulting from mast cell tumours has also been described in dogs and cats, but, non-cancerous mastocytosis has also been described in dogs, but, where tested, there was no c-Kit mutation
What is the driver of symptoms in mastocytosis
histamine
What is the aim of treatment for pathophysiology associated with histamine
inhibition of mast cell degranulation
Name a mast cell stabiliser
Sodium cromoglycate
How does Sodium cromoglycate work
inhibits mast cell degranulation
MOA unclear but decreased Ca2+ influx is seen in mast cell activation in presence of sodium cromoglycate
perhaps Sodium cromoglycate inhibits an inward Cl- channel required to maintain a negative enough membrane potential to enable sustained influxes of extracellular Ca2
What can you use sodium cromoglycate to treat
mastocytosis
available as eye drops for the treatment of hay fever e.g. Opticrom and is occasionally used in the treatment of asthma
True or false
Raising [cAMP] inhibits mast cell degranulation
true
thus β2-adrenoceptor agonists (salbutamol and formoterol) and phosphodiesterase (PDE) inhibitors (theophylline) used in the treatment of asthma are partially efficacious through mast cell inhibition although their main therapeutic action is via bronchodilation
Name a monoclonal antibody used in allergic reactions
how does it work
omalizumab
recognises IgE, decreases mast cell degranulation because allergen bound IgE induces mast cell degranulation when bound to its receptor FcεRI.
Which drugs are classical antihistamines
H1-receptor antagonists
Name 2 β2-adrenoceptor agonists that are used to treat allergic reactions
name another drug which works via a similar mechanism
salbutamol
formoterol
phosphodiesterase (PDE) inhibitors (theophylline)
both types of drug work by increasing [cAMP] in mast cells to inhibit degranulation
name a first generation antihistamine
what was an issue with it
mepyramine
rapidly permeated the blood-brain barrier and caused drowsiness, and so were not suited for systemic use,
true or false
first generation antihistamines eg mepyramine are no longer in use
false
not suited for systemic use, but it is still used in topical creams for treating insect bites.
First generation drugs are also used in some cold/flu medications to aid sleeping
How did second generation antihistamines improve on first generation drugs
not cross the blood-brain barrier (terfenadine was the first)
What was the issue with the first second generation antihistamine to come to market
Terfenadine was a blockbuster drug in the treatment of hay fever ($440 million in 1996, the year before withdrawal), but there were increasing reports of people taking it developing torsade de points syndrome (also known as prolonged QT interval) and also reports of sudden cardiac death
How did terfenadine cause prolonged QT syndrome
inhibits KV11.1/hERG, which is important for repolarisation of the action potential
How is terfenadine metabolised
Terfenadine is a prodrug, metabolised by the 3A4 isoform of cytochrome p450 (CYP450) to fexofenadine, which is the active compound
Who is at enhanced risk of death from terfenadine
what else can make this drug extra dangerous
people with in conditions of diminished p450 3A4 activity (3A4 form of CYP450 metabolises terfenadine to fexofenadine, the active compound)
p450 3A4 is inhibited by many drugs, as well as bergamottin, a component of grapefruit juice
How do 3rd generation antihistamines improve on the previous 2 generations
name 2 3rd gen drugs
non-drowsy and lack cardiac side-effects
fexofenadine and loratadine
name a 1st, 2nd, and 3rd generation antihistamine
1: mepyramine
2: terfenadine
3: fexofenadine (also loratadine)
What are the main uses for fexofenadine and loratadine
treating hay fever, allergy and urticaria
Why do we think that histamine is not involved in the underlying pathology of hypersensitivity reactions in cattle
antihistamines are of little use in treating hypersensitivity reactions in cattle
How is adrenaline administered in anaphylaxis
can you use NA instead?
why might you inject a corticosteroid
administered i.m. to counteract systemic vasodilatation and reduction in tissue perfusion. also reduces bronchospasm
no: noradrenaline is such a potent vasoconstrictor it causes reflex bradycardia and is thus unsuitable
corticosteroid hydrocortisone is often co-administered for its anti-inflammatory effects
What is a potential treatment for mastocytosis in humans (other than of inhibitors of mast cell degranulation and histamine receptor antagonists)?
imatinib
only efficacious in patients not presenting with the common D816V c-Kit mutation.
Which drugs are used to control rare cases of mastocytosis in dogs
A combination of H1R and H2R antagonists
What is atopic dermatitis
how can it be treated
a relatively common allergic condition in dogs (~10%)
although H1-receptor antagonists can be used they are often inefficacious. Oclacitinib is a beneficial treatment, which works by inhibiting Janus kinases (JAK, greatest specificity for JAK1)
A canine monoclonal antibody against IL-31 has also been developed
How is oclacintinib involved in inflammation treatment
inhibits JAK
JAKs are common to many cytokine signalling pathways associated with allergic skin diseases and thus oclactinib lowers pro-inflammatory signalling and can be used as an alternative to corticosteroids and ciclosporin
Which cells are responsible for gastric acid secretion
parietal cells
What do parietal cells do
are responsible for secreting HCl into the stomach to aid digestion and kill pathogens
Where are mucous secreting cells in the stomach and what is their role
in the gastric mucosa
secrete HCO3- ions which are trapped in mucous creating a protective barrier (pH6-7)
What can disturbances in parietal and mucus secreting cells in the stomach lead to
can contribute to the pathogenesis and pain associated with peptic ulcers and gastro-oesophageal reflux disease.
What do G cells do
secrete gastrin on to ECL cells where it binds to CCK2 receptors to produce an increase in ECL [Ca2+], which causes ECL cells to release histamine.
What does histamine secreted from gastric ECL cells do
acts at Gs-coupled H2-receptors on parietal cells causing an increasing in cAMP and PKA activity. PKA phosphorylates proteins involved in trafficking of K+/H+ pumps to the apical membrane resulting in enhanced K+/H+ pump activity and thus increased H+ release
How does somatostatin affect gastric pH
it is a negative regulator of H+ release and has both direct and indirect mechanisms of inhibition
What are somatostatin’s direct and indirect methods of inhibiting H+ release into the stomach
activation of Gi-coupled SST2R on parietal cells counteracts the effects of histamine (direct inhibition),
activation of SST2R on G and ECL cells reduces gastrin and histamine release respectively (indirect inhibition).
Which antagonists are used to decrease histamine release in the stomach
CCK2 receptor antagonist (eg proglumide)
What does proglumide do
CCK2 receptor antagonist (decreases histamine secretion)
however its use in treating peptic ulcers has been surpassed
What type of drug were the first success at treating peptic ulcers
give an example
H2-antagonists
cimetidine (Tagamet)
What is a problem with cimetidine
which drug was soon competing with it
inhibit CYP450
soon had competition from ranitidine
What was the first PPI introduced
omeprazole
Describe the activation and MOA of proton pump inhibitors
what are 3 drawbacks of PPIs
converted to their active form in the acidic environment of the parietal cell and form disulphide bonds with the K+/H+ pump.
However, PPIs are broken down by H+, have a slow onset to maximal effectiveness and predominantly metabolised by CYP2C19
What metabolises PPIs predominantly
what is the issue with this
CYP2C19
exhibits significant genetic polymorphism producing extensive and poor metabolisers, especially in Asians (1-2% in Europeans vs. ~20% in Asians).
name a K+/H+ pump blocker (not omeprazole)
what is the MOA
vonoprazan
a potassium-competitive acid blocker (P-CAB)
Why is vonoprazan an improvement on omeprazole (2)
has greater stability than PPIs in H+ and CYP2C19 is less vital in its metabolism
Give methods for treating peptic ulcers (8)
PPIs/ P-CABs CCK2 inhibitors H2 antagonists antacids cholinergic blockade vagotomy eradication of Helicobacter pylori stopping NSAID use
Name an antacid
how do they help with gastric ulcer
Gaviscon
help neutralise pH in stomach
True or false
cholinergic blockage and vagotomy for peptic ulcer treatment essentially work in the same way
true
acetylcholine stimulation of muscarinic type 3 receptors (M3R) on parietal cells enhances acid release, which is then inhibited by atropine/vagotomy
both virtually obsolete
which antibiotic do you use to treat H pylori infection
clarithromycin
Does H pylori cause gastric ulcers in dogs
Helicobacter are not generally thought to be the cause although they are often present, e.g. H. heilmannii
Why do NSAIDS cause peptic ulcers
NSAIDs inhibit prostaglandin (PG) synthesis and PGE2 acts on ECL cell EP2/3R to inhibit gastric acid secretion, as well as enhancing mucin (EP4R) and bicarbonate secretion (EP1/2R).
when would you prescribe NSAIDs in combination with eg omeprazole
what can they be given instead of omeprazole
In patients at risk of developing peptic ulcers (e.g. the elderly) or those with gastric complications
misoprostol - a synthetic prostaglandin E 1 (PGE1) analogue
What is Arthrotec
a combination of the NSAID diclofenac and misoprostol that can be used in the chronic treatment of rheumatoid arthritis with misoprostol acting as a prophylactic against NSAID-induced ulceration
If you are giving a dog NSAIDs when ulcers have been induced through prior NSAID administration, which other drug should you give it
misoprostol
Etymology of bradykinin
originally identified as a slow (brady) contractor (kinin) of guinea pig ileum smooth muscle (slow being relative to tachykinins like SP)
How is bradykinin formed generally
by the action of kallikrein upon kininogens, which exist as high- and low-molecular weight forms
describe the steps involved in forming bradykinin
Hageman factor/Factor XII to become activated by contacting negatively charged surfaces, such as lipopolysaccharide, collagen or basement membrane.
Activated Hageman factor is a protease that converts plasma prekallikrein to kallikrein, which clips HMW-kininogen to bradykinin and LMW-kininogen in tissues to kallidin
How do you activate factor XII
by contacting a -ve surface
Hageman factor only contacts negatively charged surfaces, such as lipopolysaccharide, collagen or basement membrane when leaking out of leaky blood vessels during inflammation
How is bradykinin inactivated
clipped kininase II
What is kininase I activity mediated by
what does it form
via several peptidases, including serum carboxypeptidase,
results in the removal of the C-terminal arginine to form des-Arg-bradykinin, which is an agonist for bradykinin B1 receptors
Describe kininase II
a peptidyl dipeptidase that inactivates kinins by removing the two C-terminal amino acids, this enzyme is angiotensin converting enzyme (ACE)
What type of receptor are bradykinin receptors
bradykinin B1 and B2 receptors and are both Gq-coupled GPCRs
When/ where are bradykinin B1 and B2 receptors expressed and activated
B1 receptors are upregulated during inflammation through the action of cytokines, such as IL-1, and respond primarily to des-Arg-bradykinin (bradykinin itself is a very poor B1 agonist),
B2 receptors are constitutively expressed and potently activated by bradykinin and kallidin (des-Arg-bradykinin has virtually no efficacy)
What does the activation of bradykinin B1 and 2 receptors on vascular endothelium result in
causes an increase in [Ca2+], which activates cytosolic phospholipase A2 (cPLA2) resulting in prostacyclin (PGI2) production and endothelial nitric oxide synthase (eNOS) resulting in NO production
PGI2 and NO diffuse to the vascular smooth muscle cell layer and through increasing cAMP and cGMP levels respectively, mediate vasodilatation
Do ACE inhibitors only decrease vasoconstriction via ACE inhibition
no - not only reduce angiotensin II levels, thus reducing vasoconstriction, but they also cause an increase in bradykinin levels and thus enhance vasodilatation
How is bradykinin involved in pain (2)
Activation of bradykinin receptors causes activation of nociceptors and drives pain (due to increased [Ca2+]i).
Bradykinin also induces nociceptor sensitisation because activation of Gq GPCRs results in activation of PKC, which phosphorylates numerous ion channels involved in the sensation of pain.
What inhibits kallikrein
C1-esterase inhibitor (C1-INH).
What is HAE
what is the prevalence
hereditary angioedema
HAE, prevalence ~0.01%
What is the mutation in HAE
mutation in the gene encoding C1-INH causes excessive levels of bradykinin resulting in sufferers experiencing periods of severe and painful swelling
how does the cause of type I HAE differ from type II
Type I HAE results from mutations that compromise C1-INH synthesis/secretion,
whereas Type II HAE results from mutations that produce inactive C1-INH
How common is ACE inhibitor associated angioedema
what predisposes to it
0.1% but is higher (~0.5%) in African American
it is currently poorly understood what makes people susceptible to this, but there are indications that it may be linked to genetic variation in genes that regulate the immune system
How can you treat HAE
can anything else be treated in the same way
recombinant C1-INH, kallikrein inhibitors and the B2 antagonist icatibant can be used
anecdotal evidence for efficacy in treating ACE inhibitor associated angioedema.
Which drug is used to treat HAE
icatibant (B2 antagonist)
Can you exploit B1 receptors to treat pain
Plenty of research to develop B1 antagonists for inflammatory pain, but none clinically available
What are cytokines generally
a very broad group of proteins that are largely, but not exclusively, synthesised and released by cells of the immune system and generally help to coordinate the immune response
Why are mast cells unusual in terms of cytokines
why is this important pharmacologically
they contain granules containing pre-formed cytokines.
Thus, because most cells have to synthesise cytokines, drugs that inhibit cytokine transcription (e.g. corticosteroids, see later) have a major impact on immune responses
How many cytokines are there
are they all pro-inflammatory
over 100 cytokines, some of which are pro-inflammatory and some of which are anti-inflammatory.
What are the 4 main groups of cytokines
interleukins
chemokines
interferons
colony stimulating factors
What are the key pro inflammatory interleukins
what are they released from
are IL-1 (actually three cytokines: the agonists IL-1α and IL-1β and an endogenous receptor antagonist, IL-1ra) and TNFα
predominantly released from macrophages
What do IL-1 and TNFα do once released from macrophages
promote proliferation and maturation of other immune cells, as well as causing fever (IL-1).
are there any anti inflammatory interleukins
yes
which inhibit cytokine production and inhibit some T-cell responses (e.g. IL-10 and IL-1ra).
Why are ILs called interleukins
originally observed to communicate between leukocytes
Why is the name chemokines misleading
non-cytokines also act as chemoattractants and chemokines have other roles, e.g. CCL3 induces mast cell degranulation by acting at CCR1 receptors.
What does the nomenclature of chemokines relate to
the cysteine residues in the N-terminus of the peptide chain,
CXC chemokines have a single amino acid separating the two cysteines, CC chemokines have two adjacent chemokines, C chemokines only have one N-terminus cysteine and lastly, CX3C chemokines have three amino acids separating the two cysteines
these classes are also sometimes termed α, β, γ and δ.
What kind of receptor are chemokine receptors
GPCRs
What are the 3 classes of interferon and what is the role of each class
(IFN) α, β and γ, the former two have anti-viral activity and the latter has a role in induction of Th1 responses
What is the role of colony stimulating factors
stimulate the formation of maturing colonies of leukocytes and are primarily used to overcome deficits in a person’s white-blood cell count, e.g. following chemotherapy
What is NGF
Nerve growth factor
released from both macrophages and mast cells and is a potent sensitising agent, i.e. it does not excite nociceptors directly, but rather activates signalling pathways that result in a lesser stimulus causing pain
Give an example of the sensitising effect of NGF
following NGF injection, there is a >5°C lowering of the temperature required to generate pain in humans
What are the effects of NGF mediated through
mediated by the high affinity NGF receptor tropomyosin-related kinase A (TrkA).
How is NGF related to treatment of pain
in the treatment of inflammatory pain, blocking the actions of NGF is desirable and anti-NGF monoclonal antibodies such as tanezumab have been developed, but are still in clinical trials
name a monoclonal antibody against NGF
what is it hoped to treat
tanezumab
inflammatory pain
What is Annexin A1
a protein produced by many cells, which downregulates both inflammatory cell activation and mediator release, actions that are brought about by binding to the GPCR formylpeptide receptor 2 (FPR2)
What is FPR2 a receptor for
lipoxin
what are the 3 lipid mediators of inflammation
What is the main precursor for them? What is an exception to this?
leukotrienes,
platelet-activating factor
prostanoids
arachidonic acid (exception = PAF)
How are lipid mediators produced
on demand from membrane phospholipids by the action of phospholipases.
What is PAF
Platelet activating factor
Describe arachidonic acid
a 20-carbon unsaturated fatty acid containing four double bonds
AKA 5,8,11,14-eicosatetraenoic acid
eicosa refers to the 20 carbon atoms and tetraenoic to the 4 double bonds and thus lipid mediators are often referred to as eicosanoids
what is the rate limiting step for eicosanoid synthesis
liberation of arachidonic acid from membrane phospholipids and the usual one-step process involves PLA2.
What is the most important isoform of PLA2
cPLA2
which is activated by a combination of phosphorylation and Ca2+
cytosolic PLA2 (cPLA2) is activated by a combination of phosphorylation and Ca2+. Therefore, what else can stimulate it ?
can be stimulated by a plethora of substances, e.g.
bradykinin acting at B2 receptors raises [Ca2+]i
TNFα acts at TNFR1 to promote MAPK phosphorylation of cPLA2 at serine 505 and serine 727, as well raising [Ca2+]i via TNFR2.
What does the action of PLA2 result in
production of arachidonic acid (prostanoid and leukotriene precursor) and lysoglyceryl-phosphorylcholine (PAF precursor called lyso-PAF)
Which type of enzymes synthesise leukotrienes
synthesised by lipoxygenase enzymes from arachidonic acid
describe lipoxygenases
cytosolic enzymes, expressed primarily in the lungs and leukocytes
Describe how 2 lipoxygenases act of arachidonic acid
Arachidonic acid is converted by 12-lipoxygenase to produce 12-HETE (hydroxyeicosatetraenoic acid), which is a chemotaxin and 5-lipoxygenase to produce leukotriene A4 (LTA4).
Arachidonic acid is converted by 5-lipoxygenase to produce leukotriene A4 (LTA4). What further reactions occur to LTA4
converted in cells expressing the cytosolic enzyme LTA4 hydrolase to LTB4, whereas in cells expressing the membrane bound LTC4 synthase (also called glutathione S-transferase) LTA4 is converted into LTC4, which in turn is cleaved by peptidases to produce LTD4 and LTE4.
What are LTC4-LTE4 known as
the cysteinyl leukotrienes (CysLT)
What are the cysteinyl leukotrienes (CysLT)
LTC4-LTE4
What do different leukotrienes act on
what kind of receptor is each
LTB4 acts at BLT1 and BLT2 receptors,
the CysLTs act at CysLT1 and CysLT2 receptors;
BLT receptors can be either Gq- or Gi-coupled, whereas CysLT receptors are Gq-coupled.
all act on GPCRs
Different CysLTs have different efficacy at different receptors and thus CysLT metabolism has biological implications. What does this mean?
CysLT1: LTD4»_space; LTC4 > LTE4
CysLT2: LTC4 = LTD4 > LTE4.
Give some of the roles of LTB4 (3)
potent chemoattractant and activator of neutrophils and macrophages,
it upregulates neutrophil adhesion molecule expression
promotes macrophage cytokine release
Name a leukotriene found in inflammatory exudate
what does this mean
LTB4
makes LTA4 hydrolase a therapeutic target
Why was a drug targeting LTA4 hydrolase withdrawn
caused dermatitis
What 3 things do all CysLTs do
cause bronchoconstriction,
increase vascular permeability
mucous secretion
What are CysLTs released from
why is this unsurprising?
from both mast cells and eosinophils
characteristic leukocytes in airways of asthmatics and all CysLTs cause bronchoconstriction
CysLTs are released from mast cells and eosinophils to cause bronchoconstriction. How has this knowledge been used pharmacologically?
montelukast (CysLT1 receptor antagonist) is used in maintenance treatment of asthma
What are the 2 main ways to synthesise lipoxins
either 12-lipoxygenase conversion of LTA4 to LXA4
or
15-lipoxygenase conversion of arachidonic acid to 15S-HETE, which is then converted by 5-lipoxgenase to LXA4
What does LXA4 bind to
what kind of receptor is this?
what is the effect?
binds to the FPR2,
Gi-coupled
reduces neutrophil chemotaxis and degranulation, as well as acting as an antagonist of CysLT1 receptors
How is PAF formed briefly
through the action of acetyltransferase on lyso-PAF
Why is PAF misleadingly named
it has effects upon a variety of cell types and acts through GPCRs that are variously coupled
What are the effects of PAF generally (4)
increases thromboxane (TXA2) production in platelets
can be spasmogenic;
chemotactic for neutrophils
activates PLA2
Where does the name ‘prostaglandin’ originate
experiments in the 1930s showed that semen contained a lipid that could evoke uterine smooth muscle, named prostaglandin (PG) because of originating from the prostate gland
How are prostaglandins formed
Arachidonic acid is metabolised to prostaglandins by cyclooxygenases (COX)
Following the production of PGH2, it is the cell specific enzymes that are responsible for the downstream production of a particular PG or thromboxane
How does COX convert arachidonic acid to PGH2
COX catalyses two reactions:
arachidonic acid is first cyclised and oxygenated forming the endoperoxide PGG2;
the hydroperoxyl in PGG2 is then reduced to form PGH2.
Where are COX 1 and 2 found
COX-1 is constitutively expressed in many cell types, whereas COX-2 expression is induced in inflammation, although some constitutive expression does occur.
What does prostanoid refer to
PGs and TX
What does the 2 in PGH2 refer to
the number of carbon-carbon double bonds in the final structure
What happens if an acid with a different amount of C=C double bonds is used to form PGs instead of eicosatetraenoic acid (four carbon-carbon double bonds) ?
if eicosatrienoic acid (three C=C double bonds) is used in place of eicosatetraenoic acid as a substrate then the resulting PGs have one fewer double bond and are named, for example, PGE1, and if eicosapentaenoic acid (five C=C double bonds) is used as a substrate then PGs have one more double bond and are named, for example, PGE3
What are the sources of prostanoids in inflammation?
varies
, PGE2 and PGI2 tend to be produced locally by tissues and blood vessels,
PGD2 is predominantly released by mast cells and in chronic inflammation macrophages release PGE2 and TXA2
True or false
Prostanoids act at RTK
false
Prostanoids act at GPCRs and some PGs can activate multiple receptors, e.g. PGD2 can activate TP and DP receptors
Describe the coupling of different prostanoid GPCRs
- DP1, EP2, EP4 and IP receptors are Gs-coupled causing increased cAMP production
- EP1, FP and TP receptors are Gq-coupled causing an increase in [Ca2+]i
- DP2 and EP3 receptors are Gi-coupled causing decreased cAMP production
What are the predominant effects of the following prostanoids in terms of inflammation: PGD2 PGE2 PGI2 TXA2 PGF2α
- PGD2 = vasodilatation, inhibition of platelet aggregation and relaxation of GI (GI)/uterine muscle via DP1 receptors; bronchoconstriction via TP receptors
- PGE2 = bronchial/GI smooth muscle contraction (EP1), bronchodilation, vasodilatation and relaxation of GI smooth muscle (EP2), contraction of GI/uterine smooth muscle and fever (EP3), and sensitisation of nociceptors (EP4)
- PGI2 = vasodilatation and inhibition of platelet aggregation
- TXA2 = vasoconstriction, bronchoconstriction and platelet aggregation
- PGF2α = uterine contraction in humans, bronchoconstriction in cats/dogs
what is the balance in healthy blood vessels what is the balance that has to be struck with regards to platelet aggregation
how does this change if the endothelium is damaged
balance between the pro-aggregation effects of TXA2 (produced by platelets) and the anti-aggregation effects of PGI2 (produced by endothelial cells)
the balance shifts towards TXA2, platelets aggregate and the damage is sealed.
if the vascular endothelium is damaged then the balance shifts towards TXA2, platelets aggregate and the damage is sealed. How is this related to certain thromboembolic strokes
atherosclerotic plaque rupture damages the endothelium and the platelets adhere forming a clot;
part of the clot can break off and block a cerebral artery
Why do people with oily fish in their diet tend to have lower incidence of heart attacks
fish oil is high in eicosapentaenoic acids resulting in the production of PGI3 and TXA3, TXA2 is far more potent than TXA3, but PGI3 is more potent than PGI2
thus there is an overall tip in the balance towards anti-aggregation and less vasoconstriction
How do most NSAIDs work
Is it reversible?
inhibit COX by entering a hydrophobic channel on the enzyme and forming hydrogen bonds with an Arg120,
this prevents the entrance of fatty acids, like arachidonic acid, into the catalytic domain and thus PG production is stopped.
This inhibition is reversible
Why were selective COX inhibitors thought to be better than non-selective NSAIDs
COX-1 is constitutive and expressed in many tissues, whereas COX-2 is induced during inflammation.
It was thus hypothesised that drugs that only inhibited COX-2 would result in all of the benefits of COX inhibition (analgesia, decreased swelling and antipyresis etc.) without any of the side effects such as gastric bleeding
How can you make a COX inhibitor COX-2 selective
NSAIDs have to enter the hydrophobic tunnel of COX to reach Arg120 and whereas COX-1 has a narrow tunnel, COX-2 has a wider tunnel.
Consequently, drugs have been developed that have bulky sulphur-containing side groups and selectively act upon COX-2, but not COX-1 because they cannot enter the narrow, hydrophobic tunnel
Are non-selective NSAIDs common
yes
Most NSAIDs, such as ibuprofen, are non-selective because they are small and enter the hydrophobic tunnels of both COX-1 and COX-2
How can you recognise the name of a COX2 selective NSAID
generally name ends in -coxib
eg etoricoxib
Name a non selective and a COX2 selective NSAID
non-selective: ibuprofen
COX2 selective: etoricoxib
What is the most common side effect of non selective NSAIDs
Is this a trivial side effect
GI bleeding
no - accounts for approximately 5000 deaths in the UK each year
Name 3 groups NICE have identified to be at high risk of gastric bleeding
can you give these people NSAIDs
adults aged 65+, people with a history of gastric ulceration and those taking NSAIDs chronically
yes but must be co-administered with PPIs or with the PGE1 analogue misoprostol.
Why are COX2 selective NSAIDs not as safe as originally thoughout
although COX-2 is upregulated in inflammation, it is also constitutively expressed in some endothelial and vascular smooth muscle cells (e.g. in the kidney) and thus its inhibition results in decreased PGI2 production – PGI2 is vasodilatory and decreases platelet aggregation
also inhibiting COX-2 raises levels of endogenous inhibitors of eNOS, which would lead to decreased NO production. Consequently, some, but not all, COX-2 inhibitors have been associated with increased myocardial risk
Why did Merck withdraw rofecoxib
it was associated with increased myocardial risk (rofecoxib is a selective COX2 inhibitor)
Are COX2 inhibitors still in use?
Current guidance suggests that COX-2 inhibitors should be reserved for people suffering from chronic inflammation, e.g. osteoarthritis/rheumatoid arthritis, who are not thought to have a substantial cardiovascular risk and when conventional NSAIDs are thought to pose a high GI risk
NB GI problems can still occur with COX-2 inhibitors
Why might COX2 inhibitors still cause gastric ulcers
perhaps because they interfere with the healing of pre-existing ulcers
Do all NSAIDs pose a CV risk?
yes
True or false
naproxen carries a lower cardiovascular risk than other NSAIDs
false
although it was thought that the non-selective NSAID naproxen carried a lower risk, results from a recent large trial comparing naproxen, ibuprofen and a COX-2 inhibitor did not support this hypothesis (the COX-2 inhibitor did however show significantly lowered GI side effects)
How does aspirin differ from other NSAIDs
Rather than forming a hydrogen bond with Arg120, it acetylates Ser530 and irreversibly inactivates COX, an action that explains aspirin’s long-lasting actions
What type of molecule is aspirin
acetylsalicylate
Why is aspirin considered an acetylsalicylate
by donating an acetyl group to COX, salicylate is formed
What can salicylate do
reversibly inhibit COX (like most NSAIDs)
but the concentrations produced are unlikely to have a significant therapeutic effect
Explain how aspirin’s its irreversible action means that it is used at low doses for reducing the risk of platelet aggregation
platelets express COX-1 and TX synthase and are a major source of TXA2 (induces platelet aggregation and vasoconstriction), whereas endothelial cells predominantly produce PGI2 (inhibits platelet aggregation and vasodilatation);
acetylated COX-1 can be replaced by newly synthesised protein in endothelial cells, but TXA2 production by platelets is switched off for their lifetime (~10 days). Therefore, overall switch to beneficial, anti-thrombotic effects, with a lower risk of stomach ulcers (but PPIs are often co-prescribed to limit the risk.)
Is aspirin COX selective
Although weakly COX-1 selective, aspirin also acetylates COX-2
What does aspirins acetylation of COX2 result in
COX-2 no longer producing intermediates for PG and TXA2 synthesis, but instead 15R-HETE, which is the stereoisomer of 15S-HETE (product of 15-LO conversion of arachidonic acid, which is used to synthesise LXA4
5-LO then converts 15R-HETE to aspirin-triggered lipoxin – ATL, also known as 15R-epi-lipoxin A4, which has similar functions to LXA4.
What is ATL
aspirin triggered lipoxin
has similar functions to LXA2 so its production contributes to the anti-inflammatory action of aspirin
Give 4 predominant side effects of NSAIDs
Give the mechanism behind each side effect
GI bleeding (PGs inhibit gastric acid secretion and increase the release of protective mucin),
renal insufficiency and nephropathy (PGE2/PGI2 involved in maintenance of renal blood flow),
stroke/myocardial infarction (constitutive expression of COX-2 in endothelial/vascular smooth muscle cells, inhibition of which results in decreased PGI2 production, PGI2 is vasodilatory and decreases platelet aggregation),
bronchospasm (COX inhibition implicated, mechanism unclear).
What are the 2 specific side effects of aspirin
Reye’s Syndrome
Salicylism
Who gets Reye’s Syndrome
what is it characterised by
occurs almost exclusively in children (hence not recommended for use in children under the age of 16)
characterised by hepatic encephalopathy, often occurs when aspirin is taken for treating viral symptoms
Have health warnings about aspirin had any effect
yes
health warnings in the late 1980s have reduced the cases from 41/year in the 1980s to only 1 case of Reye’s Syndrome in 2002 and 3 further suspected cases up to 2009
When is salicylism seen
– essentially the result of an overdose of aspirin, often seen in children or in suicide attempts
What is the pathophysiology of salicylism
a progressive condition resulting from Kreb’s cycle inhibition and uncoupling of oxidative phosphorylation, primarily in skeletal muscle, which causes increased O2 consumption and thus increased CO2 production. CO2 stimulates peripheral and central chemoreceptors resulting in increased ventilatory rate causing respiratory alkalosis, which can be compensated for by increased renal bicarbonate excretion. However, larger doses depress the respiratory centres and CO2 accumulates, which is superimposed upon the reduced plasma bicarbonate to cause respiratory acidosis, which can combine with metabolic acidosis resulting from accumulated acidic metabolites due to disrupted carbohydrate metabolism. Fever and repeated vomiting occur, followed by dehydration, respiratory depression, coma and death
How do you treat salicylism (3)
fluids are administered, as is bicarbonate to enhance aspirin elimination,
activated charcoal adsorbs aspirin in the GI tract
in severe cases haemodialysis may be required.
What is paracetamol also known as
known as acetaminophen in the Canada, U.S., Iran and Japan
Where do the names paracetamol and acetaminophen come from
Both names are derived from a chemical name of the drug: N-acetyl-para-aminophenol and N-acetyl-para-aminophenol respectively
Why is paracetamol not really an NSAID
it is a v poor anti-inflammatory (but does have good anti-pyretic and analgesic effects)
Which enzymes does paracetamol inhibit
COX1 and 2 (but not through binding to arginine 120 or acetylation)
How does paracetamol inhibit COX enzymes
through reduction of the active site in COX enzymes required for the production of PGH2 from PGG2
How does paracetamol affect dogs
paracetamol inhibits the COX-1 splice variant COX-3 with greatest potency, and COX-3 might be preferentially expressed in the brain, however, COX-3 is likely non-functional in humans due to a shift in the reading frame producing a truncated COX protein.
How does paracetamol give analgesia
some paracetamol metabolites have also been demonstrated to have actions that contribute to analgesia
How is paracetamol eliminated usually
coagulation using hepatic enzymes
when these are saturated, oxidases act to metabolise paracetamol to NAPQI, which is usually conjugated to glutathione
What happens during paracetamol overdose
there is insufficient glutathione to eliminate paracetamol and NAPQI can oxidise the thiol groups of cellular proteins resulting in major hepato- and renal toxicity
how is NAPQI formed
when paracetamol dosage is high enough to saturate hepatic coagulation enzymes needed to eliminate the drug, oxidases (CYP2E1) metabolise paracetamol to NAPQI
NAPQI is also formed at therapeutic doses suggesting that other pathways for its formation exist
How does a paracetamol overdose present clinically
. Symptoms often do not occur until 24-48 hours post-ingestion and begin with nausea and vomiting and lead to liver failure induced death
can you reverse a paracetamol overdose
If the patient is seen soon after ingestion then prevention of liver damage can be attempted by administering substances that increase hepatic glutathione production, e.g. acetylcysteine
Name a drug given to treat paracetamol overdose
acetylcysteine
increases hepatic glutathione production
What is required to overdose on paracetamol
how has legislation tried to tackle this problem? has this been effective?
Toxicity occurs from as little as 150 mg/kg, for a 65 kg adult = 9.75 g, paracetamol often comes in packs of 16 x 500 mg = 8 g, e.g. not difficult to buy enough to overdose.
However, pre-1998, pack sizes were often 100 x 500 mg, legislation in England and Wales restricted over the counter packs in non-pharmacy premises to 16 x 500 mg,
studies show that this caused a significant reduction in paracetamol-related deaths
What increases the risk of toxicity from paracetamol
Alcohol can increase risk of toxicity because it upregulates CYP2E1, which converts paracetamol to NAPQI, fasting is also a risk, perhaps because of decreased hepatic glutathione levels.
Which enzymes converts paracetamol to NAPQI
CYP2E1
Can you give aspirin and paracetamol to cats and dogs
aspirin is not suitable for use in cats because they lack the ability to conjugate salicylate with glycine.
Paracetamol should also be avoided in dogs and especially in cats because they lack enzymes that in humans enable efficient excretion
What is ‘bute’
Phenylbutazone
NSAID used for treating horses but causes a plethora of side effects in humans (it is also abused in racehorses, which are regularly tested for bute use).
What is robenacoxib
an NSAID licensed for use in cats and dogs
What is firocoxib (species differences)
NSAID used for dogs and horses
Where does the name ‘serotonin’ come from
because it was detected in serum following clotting of the blood and caused vasoconstriction
When are high 5-HT serum levels seen
after coagulation because platelets contain 5-HT, which is released during platelet activation and aggregation and induces further platelet aggregation, as well as causing vasoconstriction in damaged blood vessels
true or false
serotonin is a vasoconstrictor
true but can also dilate
5-HT can cause both vasodilatation and vasoconstriction depending upon receptor expression
Which gut cells express high levels of 5-HT
intestinal enterochromaffin cells and in serotonergic neurones of the enteric (and central) nervous system.
How is 5-HT formed
from tryptophan through the actions of tryptophan hydroxylase (Tph) and L-aromatic acid decarboxylase (= dopa decarboxylase)
Where is 5-HT formed
from tryptophan in both serotonergic neurones and enterochromaffin cells.
What is the rate limiting step in 5-HT formation
Tph conversion of tryptophan to 5-hydroxytryptophan
What are the 2 Tph isoforms
Tph1 is primarily expressed in enterochromaffin cells and Tph2 is predominantly expressed in neurones
True or false
Platelets produce serotonin
false
platelets expresses SERT which take up 5-HT from intestinal circulation
how do platelets take up 5-HT
Platelets express a serotonin transporter (SERT) enabling platelets to become loaded with 5-HT when they pass through the intestinal circulation (platelets are not thought to synthesis their own 5-HT), which has a high 5-HT concentration
Describe the degradation of serotonin
how is it excreted and why is this useful clinically
2 steps:
1) oxidative deamination via monoamine oxidase
2) through oxidation to produce 5-hydroxyindoleacetic acid (5-HIAA)
5-HIAA is excreted in the urine and levels of urine 5-HIAA are a measure of systemic 5-HT synthesis.
What type of receptors are each of the different 5-HT receptors (7)
- 5-HT1A, B, D – F are Gi-coupled GPCRs (note that there is no 5-HT1C)
- 5-HT2A – C are Gq-coupled GPCRs
- 5-HT3 is an ionotropic receptor/ligand gated ion channel
- 5-HT4 is a Gs-coupled GPCR
- 5-HT5A is a Gi-coupled GPCR
- 5-HT6 is a Gs-coupled GPCR
- 5-HT7 is a Gs-coupled GPCR
(2A – C are Gq-coupled GPCRs; 3 is ionotropic; 1 and 5A are Gi GPCR; all the rest are Gs GPCR)
Give 2 reasons for emesis
chemicals in the intestine or blood or disturbance of the labyrinth in the ear
name 2 key components governing emesis
the vomiting centre and the chemoreceptor trigger zone (CTZ), both of which are located in the medulla
how do the vomiting centre and CTZ work together
circulating chemicals can activate the CTZ, which sends signals to the vomiting centre to produce emesis
Name a receptor important in vomiting
how is this exploited pharmacologically
Both visceral afferents that project to the CTZ and the CTZ itself express 5-HT3 receptors
inhibition of these receptors, eg by ondansetron is an effective preventative and treatment of vomiting
