PHARM - Anti-Inflammatory Drugs I: The Arachidonic Acid Pathway and NSAIDS - Week 5 Flashcards
Describe two means of chemical signalling between cells and give examples for each (5).
Release of molecules by other cells
-neurotransmitters
-hormones
-local mediators
-exosomes
Membrane-bound molecules
-immune system
What are exosomes?
Extracellular vesicles
Name 5 kinds of important local mediators and their composition.
Histamines - small amine
Prostaglandins - lipid-derived
Leukotrienes - lipid-derived
Bradykinin - a peptide
Nitric oxide - a gas
In what two cells are histamines largely stored in and released from? Where are these cells found?
Mast cells
-found in tissue, particularly mucosal surfaces/skin
Basophils
-blood
What relation do enterochromaffin-like cells have with histamines?
They regulate stomach acid secretion using histamine
Describe the triple response of Lewis and what each one occurs due to.
Occurs due to the release of histamine
Reddening - due to capillary dilation
Flare - redness in the surrounding area due to arteriolar dilation
Wheal - due to exudation of fluid from capillaries and venules
List 7 biological effects of histamine.
Vasodilation - hypotension
Increased vascular leak - hypovolaemia
Bronchospasm
Pain/itch - sensory nerve activation
Mucus secretion
Increased wakefulness
Gastric acid secretion
How does histamine induce pain/itch?
Sensory nerve activation
List the four major histamine receptors.
H1, H2, H3, H4
What is the major histamine receptor for allergic inflammation? What drug class targets this receptor and in what way?
H1 receptor
Anti-histamines are antagonists to this receptor.
Name four conditions that anti-histamines are useful in treating.
Hayfever - allergic rhinitis
Urticaria
Anaphylaxis
Angioedema
Can anti-histamines be useful in treating colds or athsma?
No
Are H1 receptor antagonists reversible or irreversible?
List the three classes of this drug.
Sedative
Non-sedative
Newer non-sedative
Which class of anti-histamines lacks anti-muscarinic activity and what is a consequence of this?
Non-sedative - lacks GIT effects but can cause sudden ventricular arrhythmia (rare)
What can be said of the newer non-sedative class of anti-histamines?
Reduced risk of unwanted cardiac effects
What is the active constituent of aspirin? What is it derived from?
Salicylate - derived from willow bark.
Name three effects of salicylate.
Anti-pyretic (fever)
Analgaesic
Anti-inflammatory
How did prostaglandins get their name?
The active components were thought to be from the prostate gland and was first derived and isolated from semen ( ͡° ͜ʖ ͡°)
What do prostaglandins have structural similarity to?
Arachidonic acid
What defines an eicosanoid?
20 carbon containing compounds
What umbrella term do prostaglandins and thromboxanes fall under?
Prostanoids
Are eicosanoids stored? Explain.
No, they are produced on demand
Which cells produce prostaglandins?
Most of them
Briefly describe the generation of eicosanoids and name two stimuli that can induce this process.
A cytokine/inflammatory mediator acts on its receptor to begin the process. Mechanical trauma may also induce it.
This increases Ca2+ levels, which activates phospholipase A2, which liberates arachidonic acid from the cellular membrane.
Where is arachidonic acid liberated from, and what is the rate-limiting step?
From the cell membrane - the action of phospholipase A2 is the rate-limiting step.
Are levels of free phospholipase A2 high or low in resting cells?
Very low
How does phospholipase A2 act?
It cleaves a phospholipid at its second carbon atom to result in the release of arachidonic acid
Name three derivatives of arachidonic acid (4) and two enzymes responsible for its conversion.
Cyclo-oxygenase to form prostanoids
-prostaglandins
-thromboxanes
Lipoxygenase to form leukotrienes
How many major cyclo-oxygenase enzymes are there and which of the two do most cells have? Which one do inflammatory cells have?
2 enzymes, COX1 and COX2
Most cells have COX1
Inflammatory cells have COX2
Which cells mainly use lipoxygenase?
Inflammatory cells
How do eicosanoids produce their effects?
Selective G-protein coupled receptors and subsequent second messengers.
What effect do prostaglandins have on vascular smooth muscle?
Vasodilation
What effect do thromboxanes have on vascular smooth muscle?
Vasoconstriction
What effect do leukotrienes have on bronchial smooth muscle?
Constriction
What effect do prostaglandins have on uterine smooth muscle?
Contraction
What effect do prostaglandins have on gastrointestinal smooth muscle?
Contraction
What effect do prostaglandins and thromboxanes have on platelet aggregation?
Prostaglandins - anti-aggregatory
Thromboxanes - pro-aggregatory
What effect do leukotrienes have on leukocytes?
Chemoattractant
Haemostasis is the balance between what two hormones?
PGI2 (prostaglandin) and TXA2 (thromboxane)
PGI2 is a vasodilator and anti-thrombotic
TXA2 is a vasoconstrictor and pro-thrombotic
What effect do prostaglandins have on gastric secretion?
Inhibits gastric acid secretion
What effect do prostaglandins have on the kidney (3)?
Increases renal blood flow and increases excretion of water and sodium.
List three therapeutic uses for eicosanoids.
Glaucoma (latanoprost)
Gastric ulceration
Uterine contraction
Do leukotrienes induce vasodilation?
No
Which of the following induce chemotaxis (2):
Histamine
Bradykinin
Prostanoid
Leukotriene
Histamine
Bradykinin
Which of the following induce pain:
Histamine
Bradykinin
Prostanoid
Leukotriene
Bradykinin
Which of the following most induce vascular permeability (2):
Histamine
Bradykinin
Prostanoid
Leukotriene
Histamine
Leukotriene
Which of the following acts synergistically with other mediators:
Histamine
Bradykinin
Prostanoid
Leukotriene
Prostanoid
Describe what is meant by hyperalgaesic and give two hormones that fall under this term.
Increases sensitivity of receptors to painful stimuli
PGE2 and PGI2 (prostaglandins)
Briefly describe how fever occurs in 5 steps.
Inflammation
Neutrophil activation
Cytokine release
PGE2 release in the hypothalamus
Temperature raised
What do NSAIDs target?
COX enzyme
What three effects do NSAIDs have?
Anti-pyretic
Analgaesic
Anti-inflammatory
