Dr Henderson - Inflammation Flashcards
What are the two kinds of stimuli that can excite action potentials in primary afferent nerve fibres?
External stimuli
Internal stimuli - Released by tissue damage eg ATP and NO
What causes flare? How is this shown?
Neurogenic inflammation
Denervated or anaesthetised tissue does not show flare
What is the effect of stimulation of a nociceptor?
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 do bacterial/ viral/ fungal infections cause inflammation?
Releasing toxin
Lysing host cells = release of bradykinin and ATP
Draw the simple flow diagram depicting the response to injury, invasion and noxious stimuli
Well done
What are the major chemotactic factors?
C5a, LTB4, IL-8 and PAF
What are the direct and indirect actions of IL-1 and TNF on endothelial cells?
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
What effect do thrombin and plasmin have on the complement cascade?
They stimulate the production of c3b
What is an autocoid?
Local hormones that act upon the cell type from which they were released
What are the ways by which mast cells can become activated?
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
Where is histamine found?
Mast cells
Basophils
Enterochromaffin-like cells of oxyntic glands in the stomach
Histaminergic neurons in the CNS
What causes an increase in histamine release? How is this achieved?
Increase in intracellular calcium through binding of C3a/C5a or Fc receptor
What are the actions of histamine?
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
What are the pathophysiological roles of histamine?
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
What is the role of adrenaline in histamine release?
It increases cAMP and so inhibits histamine release
What are the drugs which inhibit degranulation of mast cells?
β2 agonists
Methylxanthines (PDE inhibitor)
Sodium cromoglycate (Ca2+ channel blockers = prevents exocytosis)
Sodium cromoglycate?
Ca2+ channel blocker - inhibits exocytosis from mast cells
Used to prevent histamine release from mast cells
What are the types of histamine receptor and to which kind of G protein are they coupled?
H1 - Gq = inflammation
H2 - Gs = gastric acid secretion
H3 - Gi = Important in CNS
H4 - Gq = Unknown role
Upon which receptor do antihistamines act?
H1
How were antihistamines improved (second generation)?
More selective for the H1 receptor and could not cross the BBB so did not cause drowsiness
Mepyramine
First generation histamine receptor antagonist
Low selectivity and had actions in the CNS = drowsiness
Promethazine
First generation histamine receptor antagonist
Low selectivity and had actions in the CNS = drowsiness
Terfenadine
Second generation histamine receptor antagonist = more selective
Could not cross BBB therefore no drowsiness
Prodrug and is metabolised to its active form fexofenadine
What is terfenadine poisoning?
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
Why can terfenadine’s break down be interfered with?
Metabolised by the 3A4 isoform of cytochrome P450 and this is susceptible to inhibition by various drugs
Fexofenadine
Third generation antagonist H1 receptor antagonist
Fewer CNS effects and no action on the heart (lower affinity for Kv11.1)
Loratidine
Third generation antagonist H1 receptor antagonist
Fewer CNS effects and no action on the heart (lower affinity for Kv11.1)
What is the other use of H1 receptor antagonists (other than anti-inflammatory)?
Anti motion sickness drugs
Dimenhydrinate?
H1 receptor antagonist - CNS effects
Used as an anti motion sickness drug
What is the effect of histamine on the GI tract?
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
Cimetidine
H2 selective antagonist used in the treatment of gastric ulceration - reduces acid secretion
Does produce drug-drug interaction
Ranitidine
H2 selective antagonist used in the treatment of gastric ulceration - reduces acid secretion
What are the older and newer treatments for peptic ulcers?
Older:
Antacids, cholinergic blockade and vagotomy
Newer:
H2 selective antagonist, proton pump inhibitor, eradication of H. pylori
Omeprazole
Proton pump inhibitor used in the treatment of gastric ulcers
Clarithromycin
Drug used to eradicate H. pylori
Metronidazole
Drug used to eradicate H. pylori
What are the peptide mediators of inflammation?
Kinins, tachykinins, cytokines and NGF
What is the role of of kallikrien?
Protease which cleaves bradykinin from high-molecular weight kininogen or low-molecular weight kininogen
How is kallikrien activated?
By tissue damage
What are the two types of bradykinin? What is the difference between them?
Bradykinin (in blood, made from high-molecular weight kininogen)
Lys-bradykinin/kallidin (in tissue, made from low-molecular weight kininogen)
Upon which receptors do bradykinin and kallidin act? What are the features of these receptors?
B(2) receptors
Constitutively expressed
Gq coupled - release IP(3), increasing intracellular calcium and activating eNOS
=smooth muscle relaxation
Draw a diagram depicting bradykinin and kallidins actions (via B(2))
WELL DOOONE
What is the role of the B(1) receptor, where is it present and what activates it?
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
What causes inactivation of bradykinin?
Removal of the C-terminal Phe (after removal of arg) by kininase II (AKA ACE)
What are the roles of kinins?
Generates plasmin from plasminogen
Causes vasodilation (smooth muscle contraction)
Activates nociceptors
What is the natural inhibitor of kallikrien?
C1 esterase inhibitor (C1-INH)
What is Hereditary Andioedema? What is the treatment?
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)
What are tachykinins?
Substances P (AKA NK1) Substance K (AKA NK2) Neurokinin B (AKA NK3)
What is the effect of activation of tachykinin receptors?
Gq coupled so an increase in Ca2+
What is unusual about cytokines?
Not stored by are produced on demand by gene transcription and released by a process of vesicle shedding
Which cells produce cytokines?
Macrophages, T cells and monocytes
Which cytokines are proinflammatory?
IL-1,2,6 and TNF-α