Dr Henderson - Inflammation Flashcards

0
Q

What are the two kinds of stimuli that can excite action potentials in primary afferent nerve fibres?

A

External stimuli

Internal stimuli - Released by tissue damage eg ATP and NO

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
1
Q

What causes flare? How is this shown?

A

Neurogenic inflammation

Denervated or anaesthetised tissue does not show flare

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the effect of stimulation of a nociceptor?

A

APs travel to the CNS causingthe perception of pain

APs also invade branch terminals of the afferent nerve fibre, from which they release neuropeptides substance P and CGRP

These activate mast cells = inflammatory factors eg histamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How do bacterial/ viral/ fungal infections cause inflammation?

A

Releasing toxin

Lysing host cells = release of bradykinin and ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Draw the simple flow diagram depicting the response to injury, invasion and noxious stimuli

A

Well done

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the major chemotactic factors?

A

C5a, LTB4, IL-8 and PAF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the direct and indirect actions of IL-1 and TNF on endothelial cells?

A

Direct - Increase in permeability of the junctions between endothelial cells

Indirect - Trigger production of further inflammatory mediators (bradykinin, PGE2) which cause further increases in vascular permeability and vasodilation and activation of sensory neurons

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What effect do thrombin and plasmin have on the complement cascade?

A

They stimulate the production of c3b

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is an autocoid?

A

Local hormones that act upon the cell type from which they were released

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the ways by which mast cells can become activated?

A

By components of the complement cascade or by an allergen binding to an immunoglobulin and in turn an Fc receptor on the mast cell membrane

Also activated by Substance P or CGRP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Where is histamine found?

A

Mast cells
Basophils
Enterochromaffin-like cells of oxyntic glands in the stomach
Histaminergic neurons in the CNS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What causes an increase in histamine release? How is this achieved?

A

Increase in intracellular calcium through binding of C3a/C5a or Fc receptor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are the actions of histamine?

A

Contraction of smooth muscle

Dilation of small arterioles

Increased permeability of posst-capillary venules

Sensitises nerve endings, leading to itching

Classic triple response of Lewis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the pathophysiological roles of histamine?

A

Involved in various allergic conditions eg allergic rhinitis and urticaria

Response include swelling, itching, nasal congestion and watery eyes

Can cause anaphylaxis

May play a role in chronic inflammatory conditions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the role of adrenaline in histamine release?

A

It increases cAMP and so inhibits histamine release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the drugs which inhibit degranulation of mast cells?

A

β2 agonists
Methylxanthines (PDE inhibitor)
Sodium cromoglycate (Ca2+ channel blockers = prevents exocytosis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Sodium cromoglycate?

A

Ca2+ channel blocker - inhibits exocytosis from mast cells

Used to prevent histamine release from mast cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the types of histamine receptor and to which kind of G protein are they coupled?

A

H1 - Gq = inflammation
H2 - Gs = gastric acid secretion
H3 - Gi = Important in CNS
H4 - Gq = Unknown role

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Upon which receptor do antihistamines act?

A

H1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

How were antihistamines improved (second generation)?

A

More selective for the H1 receptor and could not cross the BBB so did not cause drowsiness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Mepyramine

A

First generation histamine receptor antagonist

Low selectivity and had actions in the CNS = drowsiness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Promethazine

A

First generation histamine receptor antagonist

Low selectivity and had actions in the CNS = drowsiness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Terfenadine

A

Second generation histamine receptor antagonist = more selective

Could not cross BBB therefore no drowsiness

Prodrug and is metabolised to its active form fexofenadine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is terfenadine poisoning?

A

Under conditions of reduced activity of cytochrome P450, terfenadine is not metabolised sufficiently and can affect the heart via block of HERG channel (Kv11.1) = potentially fatal arrhythmias

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Why can terfenadine’s break down be interfered with?

A

Metabolised by the 3A4 isoform of cytochrome P450 and this is susceptible to inhibition by various drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Fexofenadine

A

Third generation antagonist H1 receptor antagonist

Fewer CNS effects and no action on the heart (lower affinity for Kv11.1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Loratidine

A

Third generation antagonist H1 receptor antagonist

Fewer CNS effects and no action on the heart (lower affinity for Kv11.1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is the other use of H1 receptor antagonists (other than anti-inflammatory)?

A

Anti motion sickness drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Dimenhydrinate?

A

H1 receptor antagonist - CNS effects

Used as an anti motion sickness drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What is the effect of histamine on the GI tract?

A

Parietal cells express H2 receptors, stimulation of which causes a rise in cAMP that in turn regulates activity and location of the H+/K+ pump

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Cimetidine

A

H2 selective antagonist used in the treatment of gastric ulceration - reduces acid secretion

Does produce drug-drug interaction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Ranitidine

A

H2 selective antagonist used in the treatment of gastric ulceration - reduces acid secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What are the older and newer treatments for peptic ulcers?

A

Older:
Antacids, cholinergic blockade and vagotomy

Newer:
H2 selective antagonist, proton pump inhibitor, eradication of H. pylori

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

Omeprazole

A

Proton pump inhibitor used in the treatment of gastric ulcers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Clarithromycin

A

Drug used to eradicate H. pylori

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Metronidazole

A

Drug used to eradicate H. pylori

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

What are the peptide mediators of inflammation?

A

Kinins, tachykinins, cytokines and NGF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What is the role of of kallikrien?

A

Protease which cleaves bradykinin from high-molecular weight kininogen or low-molecular weight kininogen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

How is kallikrien activated?

A

By tissue damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What are the two types of bradykinin? What is the difference between them?

A

Bradykinin (in blood, made from high-molecular weight kininogen)

Lys-bradykinin/kallidin (in tissue, made from low-molecular weight kininogen)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

Upon which receptors do bradykinin and kallidin act? What are the features of these receptors?

A

B(2) receptors

Constitutively expressed
Gq coupled - release IP(3), increasing intracellular calcium and activating eNOS
=smooth muscle relaxation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

Draw a diagram depicting bradykinin and kallidins actions (via B(2))

A

WELL DOOONE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

What is the role of the B(1) receptor, where is it present and what activates it?

A

B(1) - Gq coupled = same effects as B(2) ie activation of eNOS and smooth muscle relaxation

Up-regulated in inflammation

Activated by the bradykinin which has had its C-terminal arginine removed by kininase I

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What causes inactivation of bradykinin?

A

Removal of the C-terminal Phe (after removal of arg) by kininase II (AKA ACE)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What are the roles of kinins?

A

Generates plasmin from plasminogen
Causes vasodilation (smooth muscle contraction)
Activates nociceptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

What is the natural inhibitor of kallikrien?

A

C1 esterase inhibitor (C1-INH)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

What is Hereditary Andioedema? What is the treatment?

A

A rare acute inflammatory condition caused by low levels of C1-INH (C1 esterase inhibitor) and characterised by episodes of severe swelling

A kallikrien inhibitor ecallantide (Kalitor) has been developed (mimic the binding domain of an antibody)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

What are tachykinins?

A
Substances P (AKA NK1)
Substance K (AKA NK2)
Neurokinin B (AKA NK3)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What is the effect of activation of tachykinin receptors?

A

Gq coupled so an increase in Ca2+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What is unusual about cytokines?

A

Not stored by are produced on demand by gene transcription and released by a process of vesicle shedding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

Which cells produce cytokines?

A

Macrophages, T cells and monocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

Which cytokines are proinflammatory?

A

IL-1,2,6 and TNF-α

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

Which cytokines inhibit the production of other cytokines?

A

IL-4 and 10

54
Q

Nerve Growth Factor?

A

Released from activated macrophages

Potent cause of pain in osteoarthritis

55
Q

Glucocorticoid?

A

Inhibit the transcription of genes involved in inflammation

56
Q

Tanezumab?

A

Antibody which targets NGF

Potent analgesic in osteoarthritis - so effective that patient overuse their joints!

57
Q

Draw the cleavage sites of phospholipases

A

WEFEWF

58
Q

How are lipid-derived mediators of inflammation made?

A

Produced on demand from membrane phospholipids via the action of phospholipases

59
Q

What are the common features of the fatty acids on the glycerol backbone?

A

FA at location 1 is saturate

FA at location 2 is often arachidonic acid (cis double bonds at 5, 8, 11 and 14 positions)

60
Q

What is generated by the action of phospholipase A2?

A

Arachidonic acid and lyso-phosphatidylcholine

61
Q

What happens to arachidonic acid in inflammation?

A

It is converted to inflammatory mediators by cyclo-oxygenase enzymes or by 5-,12- or 15-lipoxygenase

62
Q

What is activation of PLA2 dependent on?

A

A rise in intracellular calcium and activation of GPCRs such as B1 or B2 (= phosphorylation of PLA2)

63
Q

12-HETE

A

Chemotactic messenger employed in the migration of leukocytes to the site of injury

64
Q

Leukotrienes?

A

Produced predominantly by inflammatory cells such as mast cells and macrophages

65
Q

What is the role of LTB4?

A

Stimulates neutrophil and macrophage adherence, chemotaxis and proliferation and cytokine production by macrophages and lymphocytes

66
Q

What are the cysteinyl-leukotrienes? What do they do?

A

LTC4, LTD4 and LTE4

‘slow reacting substances of anaphylaxis’

Constrict coronary vessels but increase blood flow and vascular permeability elsewhere

Powerful spasmogens

67
Q

In what conditions are cysteinyl-leukotrienes important?

A

Asthma and other inflammatory disorders

they cause bronchospams

68
Q

Zileuton

A

A 5-lipoxygenase inhibitor used to prevent the production of cysteinyl-leukotrienes in asthma/ other inflammatory disorders

69
Q

Zafirlukast

A

A specific cysteinyl leukotriene receptor antagonist used in the treatment of asthma and other inflammatory conditions

70
Q

What stimuli result in the production of cysteinyl leukotrienes?

A
Exercise, dry cold air
Adenosine
Allergens
Aspirin in NSAID-intolerant patients
PAF
SO2
71
Q

How is platelet activating factor produced? What is its role?

A

By replacing the carboxylic acid linker at position 1 with an ether bond

It is a potent platelet aggregator
Also a vasodilator and chemotactic agent for leukocytes

72
Q

How is platelet activating factor degraded?

A

Rapidly degraded in vivo by acetyl hydrolase which removed the 2-position acteyl group

73
Q

What molecule is made by the replacement of the carboxylic acid at position 1 with an ether bond?

A

Platelet activating factor

74
Q

What are prostanoids derived from?

A

Arachidonic acid by cyclo-oxygenase enzymes

75
Q

What is the life span of a prostanoid?

A

~1min

76
Q

What is the role of cyclooxygenase?

A

It catalyses two distinct reactions

Firstly a cyclo-oxygenase reaction leading to PGG and secondly a peroxidase reaction resulting in PGH2

77
Q

What is the action of NSAIDs?

A

Inhibit COX’s production of PGG

78
Q

Draw the pathway of prostaglandin production and action in platelets

A

AA => PGH2

Txs converts this to TxA(2)

Transported out of cell by PGT

Acts on TPβ receptor on vascular smooth muscle to cause vasoconstriction
Acts on TPα receptor on platelets to cause aggregation

79
Q

Draw the pathway of prostaglandin production and action in endothelial cells

A

AA => PGH(2)

PGH(2) => PGI(2) via the action of PGIS

PGI(2) then acts upon IP receptor on vascular smooth muscle to cause vasodilation
PGI(2) also acts on IP receptors on platelets to cause declumping

80
Q

Draw the pathway of prostaglandin production and action in mast cells

A

AA => PGH(2)

PGH(2) => PGD(2) via the action of PGDS

PGD(2) transported out of the cell by PGT

PGD(2) then acts upon DP2 receptors on Th2 lymphocytes to cause chemotaxis

PGD(2) also acts upon DP1 receptors on lung epithelial cells to cause allergic asthma

81
Q

Draw the pathway of prostaglandin production and action in most cells

A

AA => PGH(2)

PGH(2) => PGE(2) via PGES

PGE(2) transported out of the cell by PGT

PGE(2) then acts on…
EP(4) receptors on osteoclasts = bone reabsorption
EP(3) receptors on OVLT neurons = fever generation
EP(2) receptors on ovarian cells = maturation for ovulation/fertilisation
EP(2/4) receptors on spinal neurons = Pain response

82
Q

What is the role of COX1?

A

Constitutively expressed and is involved in the secretion of stomach acid as well as the production of prostanoids in tissues

83
Q

What are the inflammatory effects of prostaglandins?

A

Swelling - PGI(2) acting on IP receptors

= increase in cAMP = smooth muscle relaxation = ^ blood flow

Fever - PGE2 locally produced in the hypothalamus acting locally on neurones via EP3 receptor

= v cAMP

Pain - PGE(2) effects on EP(2/4) receptors

= increase in cAMP = enhances sensory fibre response to other painful signals (hyperalgesia)

84
Q

What is the action of prostanoids on blood vessel and in platelet aggregation?

A

PGI(2) produced by endothelial cells has vasodilatory and anti aggregatory action

TXA(2) produced by platelets has vasoconstrictor and pro-aggregatory actions

= produce during endothelial damage to alter the balance in favour of platelet aggregation to seal damage vessels

TXA(3) derived from eicosapentaenoic acid (from fish oil) has lower pro-aggregatory actions so lower probability of thrombus

85
Q

What happens when there is damage to the endothelium?

A

Balance is altered in favour of aggregation

= release of TXA(2) and reduced release of PGI(2)

86
Q

How do fish oils help to reduce the propensity of heart attacks?

A

Contain eicosapentaenoic acid

Replaces eicosatetranoic acid during prostaglandin synthesis and so produces products containing an extra bond

= reduced pro-aggregatory action of thromboxane A3 compared to A2

87
Q

What is the effect of prostaglandins on tumour growth?

A

Believed to enhance tumour growth (in some cases) probably by inhibiting apoptosis, promoting invasion and stimulating angiogenesis

Relates to increase risk of stomach cancer with chronic helicobacter pylori infection

88
Q

What are non-inflammatory/non thrombotic effects of prostaglandins?

A

Smooth muscle => contraction or relaxation of smooth muscle (non vascular)

In the kidney => regulates renin release
=> modifies tubular reabsorption

In the stomach => stimulates mucus and bicarbonate secretion
=> Inhibits acid secretion from parietal cells

89
Q

Where is COX present in the cell?

A

Attached to the endoplasmic reticulum

90
Q

How to COX-2 selective drugs achieve their selectivity?

A

This is due to the fact that they are too bulky to enter the narrower COX-1 channel

91
Q

Why is paracetamol toxic at high doses?

A

It is normally eliminated by conjugation, but some of it is converted in the liver to N-acetyl-p-benzoquinone (NAPQI)

NAPQI is normally conjugated to glutathione but in overdose there is insufficient NAPQI

NAPQI oxidises thiol groups on proteins, killing cells

92
Q

Why is paracetamol overdose often fatal?

A

Sign do not appear until 24-48hrs = serious hepatic damage can already have taken place

93
Q

For whom can the toxic dose for paracetamol be lower?

A

In those with induced liver enzymes through regular use of drugs or alcohol, in people who are malnourished (low levels of glutathione)

94
Q

What are the adverse effects of NSAIDs? (non including those specific to aspirin)

A

Nephropathy, prolonged gestation, GI damage, ulceration, bleeding and anaemia

95
Q

What are the side effects specific to aspirin?

A

Salicylate poisoning, Reye’s syndrome, hypersensitivity reactions

96
Q

What are the pharmacological strategies employed to reduce the GI effects of NSAIDs?

A
Enteric coating
NSAID prodrug
NSAID + NO
NSAID + misoprostol
NSAID + proton pump inhibitor
NSAID + Vit C
Selective COX-2 inhibitors
Inhibition of COX and 5-LOX
97
Q

How does an enteric coating aim to reduce the GI side effects of NSAIDs?

A

Reduces topical damage (Released more slowly)

Doesn’t work (Sorensen HT et al)

98
Q

How does an NSAID prodrug aim to reduce the GI side effects of NSAIDs?

A

Minimises level of active drug in gastric mucosa

99
Q

How does using NSAID + NO aim to reduce the GI side effects of NSAIDs?

A

Slow release of gastroprotective NO

100
Q

How does an NSAID + misoprostol aim to reduce the GI side effects of NSAIDs?

A

PG substitute

101
Q

How does use of an NSAID + proton pump inhibitor aim to reduce the GI side effects of NSAIDs?

A

Prevents acid secretion (reduces risk of gastric ulceration/ GI bleeding)

102
Q

How does using an NSAID + Vit C aim to reduce the GI side effects of NSAIDs?

A

Antioxidant effect

103
Q

Celecoxib

A

COX-2 selective NSAID - selectivity due to bulky side groups

Increased risk of ulcer rupture due to COX-2’s role in healing

104
Q

Ibuprofen

A

Weakly COX-1 selective NSAID

105
Q

Rofecoxib

A

COX-2 selective NSAID - selectivity due to bulky side groups

Increased risk of ulcer rupture due to COX-2’s role in healing

Also increased risk of MI (withdrawn)

106
Q

Paracetamol

A

Antipyretic and analgesic

May act on COX-3 isoform in brain

Shown to selectively inhibit COX-2 ( Hinz, Chermina and Bruce 2007)

AM404 may act through endogenous cannabinoig system to reduce amanaditine reuptake = activation and desensitization

AM404 can also inhibit Na+ channels (like local anaesthetics)

Also acts on spinal TRPA1 = depolarising block

107
Q

What is the metabolic pathway for the synthesis of serotonin its breakdown?

A

Tryptophan
tryptophan hydroxylase
5-hydroxytryptophan
L-aromatic acid decarboxylase
5-HT

                            Monoamine oxidase

                           Aldehyde dehydrogenase

5-HIAA

108
Q

Name the types of antiemetic drugs

A

5-HT antagonists eg ondansetron
D2 antagonist eg metoclopramide, phenothiazines
Muscarinic antagonist eg scopolamine
Non-selective H1 antagonist eg mepyramine

109
Q

Ondansetron

A

Anti emetic drug

5-HT antagonist

110
Q

Metoclopramide

A

D2 antagonist used as an antiemetic

111
Q

Phenothiazines

A

D2 antagonists used as antiemetics

112
Q

Scopolamine

A

Muscarinic receptor antagonist used as antiemetic

113
Q

Mepyramine

A

Non-selective H(1) antagonist used as an antiemetic

114
Q

Draw the areas of the body and receptors involved in emesis

Add on where antiemetic drugs act

A

DIAGRAM IN NOTES

kkkk

115
Q

What are the three theories as to the cause of migraines?

A

Vascular hypothesis

Brain hypothesis

Sensory nerve hypothesis

116
Q

What are the three phases of a migraine?

A

The premonitory phase

The aura phase

The headache phase

117
Q

How did the vascular hypothesis originate?

A

When it was found that interfering with the meningeal blood vessels during surgery caused headache.

118
Q

What is the Vascular Hypothesis of migraines?

A

Theory suggests that constriction of intracerebral arteries produces aura and rebound extracerebral vasodilation produces headache

119
Q

What happens in the premonitory phase of a migraine?

A

Symptoms include fatigue, irritability, difficulty concentrating, mood change, yawning, stiff neck, phonophobia and nausea

120
Q

What happens in the aura phase of a migraine?

A

Cortical spreading depression causing activation of nociceptive pathways - hypothesised that CSD can be a direct cause of headache

121
Q

What is the evidence again cortical spreading depression as the cause of headache?

A

Studies into the timing of migraine relative to aura indicates that headache and other migraine symptoms commonly occur simultaneously with aura

122
Q

What is the evidence and counter evidence for the involvement of vasodilation in migraine?

A

Studies showed that both the middle meningeal artery and middle cerebral artery were slightly dilated on the same side as migraine evoked by infusion of calcitonin gene-related peptide

BUT

MRI studies show that migraine headache was not correlated with any significant dilation of cerebral or meningeal arteries

123
Q

What might be the reason for the discrepancy in evidence regarding the role of vasodilation in migraines?

A

May the result of different techniques or a reflection of different triggers that were used to evoke migraine

124
Q

What is the brain hypothesis of migraines?

A

Links migraine to a wave of cortical spreading depression ie neural inhibition associated with ionic imbalances

125
Q

What is the sensory nerve hypothesis of migraines?

A

Sensory nerve hypothesis suggests that activation of trigeminal nerve terminals innervating meningeal blood vessels release neuropeptides eg CGRP causing neurogenic inflammation and vasodilation of meningeal blood vessels

126
Q

Explain the stage of Cortical Spreading Depression and Trigeminovascular Nociception

A

CSD is initiated by local elevations of extracellular K+ above a critical level as a result of hyperactive neuronal circuits in the cerebral cortex

CSD is a slowly propagating wave of strong neuronal and glial depolarisation

Other noxious mediators such as H+, NO, AA and 5-HT are released (aswell as neurotransmitters)

These substance may activate trigeminal nociceptors innervating pial blood vessels and via axon collaterals, dural trigeminal afferents

= meningeal afferents after disruption of the BBB, leading to activation of central trigeminovascular neurons

= release of proinflammatory vasoactive neuropeptides (including CGRP, substance P and neurokinin A)

= neurogenic inflammation in the dura (and sensitisation)

127
Q

What is the role of 5-HT in migraines

A

Thought to be involved because 5-HT(1D) agonists are remarkably effective in suppressing migraine

128
Q

What are the drugs treatments for migraines?

A

To terminate the attack:-

NSAIDs, triptans (5-HT(1) agonists) eg sumatriptans; alkaloids (nonspecific 5-HT(1) agonists) eg ergotamine

Preventative:-

Valproic acid; β-adrenoceptor blockers; Ca2+ channel blockers

129
Q

Sumatriptan?

A

Triptan 5-HT(1) agonist used in the treatment of migraines

130
Q

Ergotamine?

A

Ergot alkaloid - non-specific 5-HT(1) agonists used in the treatment of migraines

131
Q

Valproic acid

A

Used as a preventative measure against migraines

May act through the blockade of voltage dependent sodium channels and increased GABA levels

132
Q

What are the potential target receptors in the treatment of migraines?

A

5-HT(1B) receptors => vascular smooth muscle constriction

5-HT(1D) receptors => on sensory nerves = inhibition of peptide release from trigeminal neurons (CGRP etc)

Also development of CGRP antagonists