Pharmacology of inflammation /

Question 1

What type of drug is aspirin?

Answer 1

NSAID

Question 2

What is aspirin derived from?

Answer 2

Derived from salicylic acid

Question 3

What does aspirin do clinically in common with other NSAIDs, and what is its unique effect?

Answer 3

In common with other NSAIDs:
- Analgesic: pain relief
- Anti-pyretic: decrease fever
- Anti-inflammatory: decrease inflammation
Unique property:
- Anti-thrombotic: reduce heart attacks

Question 4

What are the cardinal signs of inflammation?

Answer 4

Rubor - redness
Calor - heat
Tumor - swelling
Dolor - pain
Loss of function

Question 5

What are the patho-physiological localised responses of inflammation?

Answer 5

Increased blood flow
Increased blood vessel permeability
Increased neuronal sensitivity

Question 6

What are the mediators of inflammation?

Answer 6

Peptides/proteins: bradykinins, neuropeptides (substance P, CGRP, nuerokinin A), Complement (C3a, C5a, Coagulation (hageman factor, thrombin)
Cytokines: interleukins, chemokines, interferons
Small molecules: histamine
Free radicals: nitric oxide
Lipids: Eicosanoids, PAF

Question 7

What is the structure of arachidonic acid, and where is it found?

Answer 7

Poly-unsaturated fatty acid
Sometimes part of glycerol as the fatty acid chain
> Hydrophobic tail in the phospholipid bilayer

Question 8

What is the process of arachidonic acid metabolism?

Answer 8

Membrane phospholipids > (PLA2 breaks it down) > Arachidonic acid > (COX) > Prostaglandin G2 > (COX) > Prostaglandin H2
Prostaglandin H2 - PGH2 - forms all types of PGEs via different enzymes

Question 9

What is the pharmacology of aspirin?

Answer 9

Targets cyclo-oxygenase - COX - COX1 & 2
Irreversible inhibitor

Question 10

What effects does aspirin have physiologically?

Answer 10

Inhibits COX2 enzymes which produce PGEs which normally mediate sensitising nerve endings, potentiate action of vasodilators, and mediates thermoregulatory centre response to infection

Question 11

What do PGEs bind to?

Answer 11

Prostanoid receptors which are GPCRs
Cells and tissues express different receptors for PGEs

Question 12

What are the desired effects of aspirin?

Answer 12

Anti-inflammatory: prevents PGE2 mediated vasodilation - increase blood supply & fluid extravasation
Anti-pyretic: prevents PGE2 mediated thermoregulation in hypothalamus
Analgesic: prevents PGE2 mediated sensitisation of nerve endings
Anti-thrombotic (unique to aspirin): reduces TxA2 production in platelets

Question 13

What are the undesired effects of aspirin?

Answer 13

GIT ulceration, bleeding: PGE2 protects gastric lining - decreases gastric acid secretin, increases mucus/HCO3- secretion
Adverse renal effects: PGE2 and PGI2 regulate renal BF
Anti-haemostatic: decrease in TxA2 production in platelets

Question 14

What are the two subtypes of COX enzymes, and what do they do?

Answer 14

COX-1: PGH2 synthase, constitutive: platelets, gut, kidney, endothelium etc., physiological function, produces the undesired effects when NSAIDs inhibit
COX-2: PGH2 synthase, inducible; macrophages, inflammatory cells, pathophysiological, inhibited by NSAIDs

Question 15

What is an endogenous steroid example?

Answer 15

Originates from within the body
Cholesterol
- Present in lipid membranes
- Synthetic precursor for Vit D, bile acids, steroid hormones
- Can lead to atheroclerosis - statins inhibit HMG CoA reductase - enzyme in cholesterol synthesis

Question 16

Where are steroid hormones produced and what hormones do they produce?

Answer 16

Adrenal cortex: Corticosteroids - glucocorticoids (anti-inflam/immunosuppressant, metabolic effects), mineralcorticoids (fluid and electrolyte balance), sex steroids
Gonads: sex steroids

Question 17

What are the parts of the adrenal gland, and what steroid hormones do they release?

Answer 17

CORTEX
- Zona glomerulosa -> mineralcorticoids
- Zona fasciculata -> glucocorticoids
- Zona reticularis -> sex steroids
MEDULLA
-> Adrenaline

Question 18

What are the physiological effects of glucocorticoids?

Answer 18

METABOLIC
- breakdown protein/carbohydrate
- stimulate gluconeogenesis > hyperglycaemia
- lipids > breakdown and deposition
- increase appetite > obesity
CV
- increase blood pressure
IMMUNE
- stress protective responses
- decreased immune/inflam responses > slowed wound healing, increased infection
OTHER
- decrease bone density > osteoporosis
- pro-apoptotic effect on cells

Question 19

What physiological role do mineralcorticoids have?

Answer 19

• Electrolyte homeostasis
• RAAS system
• Increased sodium and water reabsorption in kidney
• Increased potassium and hydrogen ion excretion in kidney

Question 20

Pharmacology of steroids - solubility, receptors, receptor classification for types of steroids?

Answer 20

Lipid soluble - distribute throughout entire body - influence function of ALL cells
Bond to cytoplasmic steroid hormone receptors
> on agonist binding (the steroid), they translocate to nucleus, bind to sequences on DNA, modify target gene transcription
Glucocorticoid receptors: GR
Mineralcorticoid receptors: MR
Sex steroid receptors - progesterone: PR , androgen: AR, oestrogen: ERa, ERB

Question 21

Why does cortisol (a glucocorticoid) that has a higher affinity to MR receptors not bind to MR?

Answer 21

Pre-receptor metabolism
Cortisol is converted to cortisone by a dehydrogenase enzyme
This happens at stress levels
Normal basal levels cortisol is not converted to cortisone, and does bind to MR

Question 22

What proteins are upregulated or downregulated by glucocorticoids?

Answer 22

Upregulated:
Annexin A1
Anti-inflammatory cytokines
Down-regulated:
COX2
iNOS - inducible NO synthase
proinflammatory cytokines

Question 23

What are the effects of glucocorticoids on immune and inflammatory responses?

Answer 23

Humoral:
decreases mediators of inflammation
decreases PG synthesis > decreases histamine release > decreases NO generation
decreases complement
Cellular:
decreases neutrophil migration into tissues
decreases T-cell activation/proliferation
decreases T cell activation/proliferation and IgG production
Comprehensive
Effective anti-inflammatory agents

Question 24

What does the therapeutic use of steroids depend upon?

Answer 24

Severity of illness
Availability of alternative therapies
Short term vs long term use - acute vs chronic, disease prognosis
Topical vs systemic
Steroids are only available and effective treatment for many conditions

Question 25

What type of drug is prednisolone?

Answer 25

Corticosteroid
Specifically synthetic glucocorticoid

Question 26

What is mediated transrepression?

Answer 26

Mode of action of glucocorticoids
Repression by GRs of gene transcription of pro-inflammatory molecules e.g. cytokines, chemokines, which are activated by other transcription factors

Question 27

What is the mechanism of action of prednisolone?

Answer 27

Primary target - Glucocorticoid receptor (GR)
Binds to GR, GR will then act by transrepression to decrease expression of pro-inflammatory mediators e.g. COX2, TNF-a, Il-2
Binds to GR, Gr will then act by mediated transactivation to increase expression of Annexin A1, and any anti-inflammatory mediators
Secondary target - mineralcorticoid receptor (MR)
Binds to MR, MR will then act by transactivation to increase expression of Na/K ATPase, and increase sodium retention

Question 28

Steroids vs NSAIDs

Answer 28

Steroids:
very potent, severe and predictable adverse affects, non-selective action, still best drugs for many conditions
NSAIDs:
limited but real effects, limited but real adverse effects, targeted action - COX, decreased PGs, still first line in many treatments

Question 29

What is the pathophysiology of gout?

Answer 29

Increased uric acid - end product of purine catabolism normally excreted in urine
Deposition of urate crystals
Inflammation
Large urate crystals = tophi