Inflammation Flashcards
What is an antacoid?
Mediators of inflammation produced locally around the site of stimulus to inflammation
What are the conceptual challenges in developing new anti-inflammatory drugs?
Cost
Lack of oral availability
How do histamine a fulfil Dale’s criteria for a pharmacological mediator?
Present in histaminergic neurones Store in granules Upon antigen-IgE cross-linking, granules are released Effects shown at H receptors Terminated by histaminase
How does histamine contribute to a local inflammatory response?
Causes vasodilation of the small arteriolar and precapillary sphincters
Causes the release of CGRP and other vasodilatory by anti-dromic impulses in sensory nerve fibres
How does histamine contribute to anaphylaxis?
Causes smooth muscle contraction in bronchi
Name 3 chemical mediators which regulate acid secretion from parietal cells
Histamine (+)
Gastric (+)
Prostaglandins E(2) and I(2) (-)
Describe ranitidine.
H(2) antagonist
Heals duodenal ulcers
Describe terfenidine.
H1 non sedative antagonist
No entry to CNS
Describe diphenhydramine.
H1 antagonist
Used to treat motion sickness
Can cross BBB
What is an eicosanoid?
Locally produced lipids Work in the 10(-12)M range Small t(1/2) Metabolised into active prostaglandin
Describe the biosynthesis of PGE(2)
Phospholipid is converted into arichidonic acid by phospholipase A(2)
arichidonic acid is converted to PGG(2) by cyclooxygenase
PGG(2) converted to PGH(2) by cycloendoperoxides
PGH(2) converted to PGE(2) by PG isomerise reductase
How is the biosynthesis of PGE(2) targeted by anti-inflammatory drugs?
Lipocortin inhibits phospholipase A(2)
NSAIDS inhibit cyclooxygenase
What are the main side-effects of NSAIDs?
Gastro-intestinal bleeding
What is the biological mechanism behind NSAID gastrointestinal bleeding?
NSAIDs block cox-1, inhibiting PGE(2) production
Reducing PGE(2) increases acid production
Acid irritates gastrin mucosa increasing susceptibility to ulceration
They prolong bleeding by reducing the platelet stickiness
How do cox-2 inhibitors avoid gastrointestinal bleeding?
Cox-2 doesn’t affect platelet stickiness
Why is aspirin used for platelet inhibition and not other NSAIDs?
Aspirin is the only NSAID which irreversibly inhibits cyclooxygenase. This means much lower doses can be used and less frequently
Uses of prostaglandin analogues.
Abortion
Labour induction
Postcoital contraception
Peptic ulcer treatment
Main causative agents of peptic ulcer formation.
H. pylori
NSAIDs
Stress
Diet
What is the HPA axis?
Hypothalamic- pituitary- adrenal axis
A complex set of direct feedback interactions among the 3 endocrine glands
Regulates glucocorticoids i.e cortisol
How does the HPA axis contribute to the regulation of inflammation?
Glucocorticoids are anti-inflammatory
They suppress the production of antacoids
Inhibitor of induction and effector phases of immune response
Omeprazole
Proton pump inhibitor
Treats peptic ulcers
Inhibits H/K ATPase of parietal cell
Decreases gastric acid secretion
Aluminium hydroxide.
Antacid
Neutralises gastric acid
Sucralfate.
Coating agent
Provides protection to GI epithelium
Misoprostol.
Prostaglandin
Inhibits acid production
Dicyclomine.
Anti cholinergic agent
mAChR inhibitor
Decrease acid secretion
How do steroidal anti-inflammatory drugs affect prostaglandin production?
Inhibit the expression of cox-2, reducing the amount of PGE(2)
How do NSAIDs affect prostaglandin production?
Inhibits cox-2, reducing the amount of PGE(2)
List the 5 cardinal signs of inflammation
Pain- dolor Redness- rubor Immobility- functo leasa Swelling- tumor Heat- calor
Describe the mechanism of action of glucocorticoids.
Bind to intracellular receptors, causing them to dimerise and move to the nucleus
The complex inhibits the transcription of genes for cox-2 and NO synthase, cytokines, interleukins, and cell adhesion molecules
What are the therapeutic affects of glucocorticoids?
Hydrocortisone:
Decreases egress of neutrophils from blood vessels and reduced activation of neutrophils, macrophages, and mast cells
Decreased activation of T(helper) cells
What are the adverse effects of glucocorticoids?
Decreased fibroblast function, reduced healing and repair
Reduced activity of osteoblasts but increased activity of osteoclasts, develop osteoporosis
What effects are encounter after administration of high doses and cessation of glucocorticoid treatment?
Suppression of the response to infection Osteoporosis Hyperglycaemia Muscle wasting Acute adrenal insufficiency
List the pathological characteristics of asthma
Inflammation of airways
Bronchial hyperactivity
Reversible airways obstruction
Give two symptomatic relievers
Salbutamol- beta 2 agonist- bronchodilation
Theophylline- activates PKC- bronchodilation
Give two pathology modifying drugs
Cromoglycate
Nedocromil
What is a biologic?
A medicinal preparation created by a biological process
Discuss the use of therapeutic antibodies to treat inflammatory diseases.
Treats patients who do not respond to glucocorticoids
Do not need glucocorticoids, avoiding side effects
High cost
Requirement of long term administration
Has to be injected
Compare infliximab with etanercept (TNF- alpha blockers)
Etanercept cannot neutralise receptor bound TNF when infliximab can
Infliximab can also lyse cells in the inflammatory process
