Pharmacology of inflammation / Flashcards

1
Q

What type of drug is aspirin?

A

NSAID

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is aspirin derived from?

A

Derived from salicylic acid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the cardinal signs of inflammation?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the patho-physiological localised responses of inflammation?

A

Increased blood flow
Increased blood vessel permeability
Increased neuronal sensitivity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the mediators of inflammation?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the process of arachidonic acid metabolism?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the pharmacology of aspirin?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What effects does aspirin have physiologically?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What do PGEs bind to?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are the desired effects of aspirin?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the undesired effects of aspirin?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is an endogenous steroid example?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

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

A

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

17
Q

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

A

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

18
Q

What are the physiological effects of glucocorticoids?

A

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

19
Q

What physiological role do mineralcorticoids have?

A
  • Electrolyte homeostasis
  • RAAS system
  • Increased sodium and water reabsorption in kidney
  • Increased potassium and hydrogen ion excretion in kidney
20
Q

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

A

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

21
Q

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

A

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

22
Q

What proteins are upregulated or downregulated by glucocorticoids?

A

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

23
Q

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

A

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

24
Q

What does the therapeutic use of steroids depend upon?

A

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

25
Q

What type of drug is prednisolone?

A

Corticosteroid
Specifically synthetic glucocorticoid

26
Q

What is mediated transrepression?

A

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

27
Q

What is the mechanism of action of prednisolone?

A

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

28
Q

Steroids vs NSAIDs

A

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

29
Q

What is the pathophysiology of gout?

A

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