I&I inflammation, inflammatory mediators, and anti-inflammatory agents Flashcards
What are the 5 cardinal signs of inflammation?
- Calor
- Rubor
- Tumor
- Dolor
- Functio laesa
What are the 5 steps involved in inflammation?
- Recognition of the injurious site
- Recruitment of leukocytes
- Removal of the agent
- Regulation of response
- Resolution
Why is histamine released locally?
For local action
Why is histamine inactivated locally?
Inactivated locally to minimise systemic effects
What is histamine synthesised stored and releasef from?
-Mast cells, which express receptors for IgE, C3a and C5a on cell surface (connective tissues)
-Basophils(blood)
-Neuron in brain
-Histaminergic cells in gut (ECL, enterochromaffin-like cells)
What is histamine released by?
Released by allergic reactions (IgE-mediated), production of
complement agents (C3a and C5a), insect stings, trauma, etc.
through a rise in [Ca2+]i.
What is release of histamine inhibited by?
Release of histamine inhibited by stimulation of β-adrenoceptors
What are the different types of histamine receptors?
4 types
-H1, H2, H3 and H4
What does stimulation of H1 and H2 receptors produce?
Stimulation of H1 and H2 receptors produce many of the actions of
histamine-mediated inflammation
What are the cardiovascular effects of H1 receptor stimulation?
-Dilation of arterioles decreasing TPR
-Increased permeability of post-capillary venules, decreasing blood volume
What are the non-vasulcar smooth muscle effects of the stimulation of H1 receptors?
bronchoconstriction
What is the cardiovascular effect of the stimulation of H2 receptors?
Increase in heart rate
What is the algesia effects of the stimulation of H1 and H2 receptors
Pain, itching, and sneezing caused by stimulation of sensory nerves
(H1)
What are associated exocrine secretions in result of H1 and H2 receptor stimulation?
Increased secretions due to increased blood flow
What is the effect on gastric acid in result of the stimulation of H1 and H2 receptors?
Increased secretion
What are the most important clinical roles of histamine?
- Acute inflammation(H1 effects)
- Stimulating gastric acid secretion(H2)
What is involved in the triple response?
- Redness
- Flare(depends on nerve supply)
- Wheal(depends on soluble, chemical mediator)
What acts on histamine secreting cells and how is this involved in gastric acid secretion?
-Gastrin and Ach act on histamine secreting cells
-This secreted histamine which acts on H2 receptor on parietal cells
-This leads to gastric acid secretion
What acts on muscarinic receptor on parietal cell and what does this lead to the secretion of?
Ach acts on muscarinic receptor on parietal cell which leads to the secretion of gastric acid
What do H1 antagonists treat?
Treat acute inflammation
What are examples of first generation H1 antagonists?
Mepyramine, promethazine, diphenhydramine
What are exzmples of 2nd and third generation H1 antagonists?
-Terfenadine
-Fexofenadine
What type of drug is terfenadine and what type of actions does it have?
Pro drug
-With potential cardiac arrhythmia actions at high doses
What is terfenadine action increased with and why?
increased with grapefruit juice (which
inhibits P450-mediated drug metabolism pathways in the liver)
What type of drug is fexofenadine and what is it a metabolite of?
active, non-toxic metabolite of terfenadine
What is a major side effect of first generation H1 antagonists?
Drowsiness
What is the therapeutic effect of promethazine?
Antiemetic so for motion sickness
What are H2 antagonists used for?
Gastric problems
What are examples of H2 antagonists?
-Cimetidine
-Famotidine
What is the therapeutic action of H2 antagonists and what is it used for the treatment of?
-Reduce gastric acid secretion in the treatment of duodenal and gastric ulcers and zollinger ellison syndrome
What do H2 antagonists increase activity of and what does this lead to the breakdown of?
Increase INMT activity so more rapid breakdown of histamine
What are the side effects of H2 antagonists?
Mental confusion, dizziness, tiredness & diarrhoea sometimes
as side effects
What does cimetidine decrease activity of therefore what can this cause?
Cimetidine decreases cytochrome P450 activity so potential
for adverse drug interactions; gynecomastia
What is bradykinin generated as a result of?
Bradykinin is generated as a result of activation of:
1.Hageman factor (HF, factor XII) & production of plasma kallikrein;
2.Production of lysylbradykinin by tissue kallikreins;
3.Action of cellular proteases
What are the functions of bradykinin?
- Pain
- Increase vascular permeability
- Vasodilation
- Chemotactic to leukocytes
- Dry cough
What do platelets release and what is it involved in?
Platelets release 5-HT involved in platelet aggregation
What cells in the gastrointestinal tract are involved in the distribution of 5-HT?
The mucosal enterochromaffin cells of gastrointestinal tract
(mediates gut movement, diarrhoea)
What release excess 5-HT and what are they involved in?
Some tumours (e.g. carcinoid) secrete excess 5-HT →↑
proliferation, and cell survival
What does 5-HT promote in terms of inflammatory action?
Promotes inflammation by increasing the number of mast cells at
the site of tissue injury
What does 5-HT stimulate with mast cells?
Stimulates mast cell adhesion and migration
What does 5-HT enhance inflammatory reactions of?
Enhances inflammatory reactions of skin, lungs and gut
How do TXA2 and 5-HT work together to stimulate platelet activity and vasoconstriction?
-Activation of TXA2 receptors increases 5-HT-mediated
responses in blood vessels
-Briefly, injured arteries and arterioles constrict due to
the release of 5-HT from platelets which plugs the
injured site
What are prostaglandins, thromboxanes and leukotrienes collectively known as?
Known collectively as Eicosanoids
What family do prostaglandins and thromboxanes - prostanoids come from?
Cyclooxygenases
What family do leukotrienes and lipoxins come from?
Lipoxygenases
What are the targets of major anti-inflammatory drugs?
-NSAIDs
-Glucocorticoids
-Lipoxygenase inhibitors
-Leukotriene anatagonists
What are prostanoids genertated from?
Prostanoids are generated from arachidonic acid (AA, poly-
unsaturated fatty acid). This is rate-limiting step
What is arachidonic acid produced from?
AAs are produced from phospholipids (PLs) via 1-step/2-step
pathways
What is the 1 step pathway in the formation of arachidonic acid?
Phospholipids–> arachidonic acid
-Enzyme is phospholipase A2
What is the 2 step pathway in the formation of arachidonic acid?
Check slide 28
What enzyme is required to convert arachidonic acid to prostanoids?
Require the enzyme cyclooxygenase(COX)
What are the 2 main isoforms of COX?
COX-1 and COX-2
What state is COX-1 in?
Constitutively active
What is COX-1 responsible for?
Responsible for ‘physiological’ roles of PGs/TXs such as
regulation of peripheral vascular resistance, renal blood flow,
platelet aggregation, gastric cytoprotection
What state is COX-2 in?
Needs to be stimulated
What is COX-2 respsonsible for?
Responsible for role of PGs/TXs in inflammatory response(pain and fever)
How does prostaglandin endoperoxides PGG2 and PGH2 convert to TXA2?
With the assistance of the thromboxane synthase enzyme
How does prostaglandin endoperoxides PGG2 and PGH2 convert to classical prostaglandins PGD2, PGE2 and PGF2alpha?
With the assistance of tissue-specific isomerases/synthases
How does prostaglandin endoperoxides PGG2 and PGH2 convert to prostacylcin PGI2?
With the assistance of prostacyclin synthase
What does aspirin do in the cyclooxygenase pathway?
Inhibits formation of TXA2 from prostaglandin endoperoxides
What does mPGES-1 do in the cyclooxygenase pathway?
Blocks production of classic prostaglandins
What does epoprostenol do in the cyclooxygenase pathway?
Blocks production of prostacyclin
When is there a switch for PG synthesis and from what state to another?
There is a switch for PG synthesis from pro-inflammatory (PG & LTs) at
onset of inflammation to anti-inflammatory lipoxins and 15dPGJ2
(cyPG) during resolution
What do lipoxins recruit and for what reason?
Lipoxins recruit monocytes to clear inflamed site of necrotic
apoptotic neutrophils
What do monocytes regulate activation levels of?
Regulate activation levels of neutrophils and dampen their damaging
effects (↑phagocytosis of neutrophils)
What does monocytes acting in concert with cyPGs promote?
Promote macrophages to phagocytose and clear apoptotic cells →
resolution of inflammation
What activation does cyPGs inhibit and what does this lead to?
CypG – inhibits macrophage activation→ ↓ uncontrolled tissue
damage; ↓NF-B activation (helps to ↓ activation of inflammatory genes)
What cells specialise in making particular eicosanoids?
-Mast cells: PGD2
-Platelets: TXA2
-Endothelial cells: PGI2, PGE2
What do DP receptors do when stimulated by prostaglandins?
Vasodilatation, Decrease platelet aggregation, bronchoconstriction
What do FP receptors do when stimulated by prostaglandins?
Contraction of myometrial smooth muscle, bronchoconstriction
What do IP receptors do when stimulated by prostaglandins?
Vasodilatation, Decrease platelet aggregation, renin release
What do EP1 receptors do when stimulated by prostaglandins?
Contraction of bronchiole/GIT smooth muscle
What do EP2 receptors do when stimulated by prostaglandins?
Bronchodilation, vasodilatation, relaxation of GIT smooth
muscle, Increase intestinal fluid secretion
What do EP3 receptors do when stimulated by prostaglandins?
Contraction of intestinal smooth muscle, Increase gastric mucus
secretion, Decrease gastric acid secretion, pyrexia
What happens when TXs act on TP receptors?
Vasoconstriction, Increase platelet aggregation
What happens when LTs act on BLT (1 and 2) receptors?
Chemotaxis and proliferation of immune cells, Increase adhesion
What happens when LTs act on CysLT(1 and 2) receptors?
Bronchoconstriction, vasodilatation, Increase vascular permeability
Which is more potent between leukotrienes and histamine?
Leukotrienes
What are examples of leukotriene receptor antagonists?
Zafirlukast, montelukast, pranlukas
What are the diverse actions of eicosanoids?
-Bradykinin and 5-HT act on receptors on the endothelial cells which release TXA2
–TXA2 increases platelet aggregation and these platelets release more TXA2
–TXA2 also acts on TP receptors which increase Ca2+ leading to contraction of blood vessel
-Shear stress acts on endothelial cells which releases PGI2
–PGI2 inhibit platelet aggregation
–PGI2 act on IP receptor which increases cAMP leading to relaxation of blood vessel
What are leukotriene useful in?
– Prevention of mild to moderate asthma
– Early to late bronchoconstrictor effects of allergens
– Exercise-induced asthma and asthma provoked by NSAIDs
What can the LTs such as LTC4, LTD4, LTE4 cause?
These LTs cause airway oedema, secretion of thick mucus and smooth
muscle contraction
What are side effects involved in the use of leukotriene receptor antagonists?
– GI upset
– Dry mouth, thirst
– Rashes, oedema
– Irritability
What is an example of a cox inhibitor?
Aspirin
What does the inhibition of cox stop the synthesis of?
Inhibition of COX stops the synthesis of prostanoids (PGs and TXA)
How do prostaglandins protect the epithelial cells of the stomach against damage?
- Stimulating the secretion of HCO3- which neutralises gastric acid
- Reducing H+ secretion
- Stimulating mucus production
- Promoting vasodilation
Why can GI bleeds be associated with aspirin poisoning/overdose?
PGs protect the stomach against damage; thus GI bleed can be associated with aspirin poisoning/overdose
What are the cytoprotective effects of PGE2?
- Promotes secretion of mucus
- inhibits release of acid
