Pharmacology of anti-inflammatories and immunosuppressants

Question 1

What is inflammation?

Answer 1

Immune response to an infection via the complement cascade activation

Question 2

What is a metabolite?

Answer 2

Substance important in a metabolic reaction.

Question 3

What is the role of NSAIDs?

Answer 3

Reduce pain, inflammation and fever.

Question 4

What are the charactersitics of inflammation?

Answer 4

Redness, swelling, pain, loss of function and inflammation

Question 5

What is acute inflammation?

Answer 5

Short immune response to infection or physical trauma and/or cell necrosis.

Question 6

What is diapedesis?

Answer 6

During inflammation, neutrophils bind to the vascular endothelium and move between gaps to enter the infected tissue.

Question 7

What is the mechanism of acute inflammation?

Answer 7

Neutrophils enter infected tissue via diapedesis, release cytokines to recruit more WBCs for phagocytosis, release oxygen radicals to kill infected cells that leads to tissue damage. This results in the activation of the complement cascade to induce inflammation.

Question 8

What is the role of bradykinin?

Answer 8

Vasodilation, nocioception for pain, plasma extravasation (increased vascular permeability that allows plasma containing WBC to leak)

Question 9

What is the role of nitric oxide?

Answer 9

Vasodilation

Question 10

What are the mediators of acute inflammation?

Answer 10

Serotonin and histamine released by platelets and histamin released by basophils. Synthesised mediators are leukotrienes, bradykinins and nitric oxide produced by WBCs such as neutrophils.

Question 11

What are the cellular sources of inflammatory mediators?

Answer 11

Dendritic cells which co-stimulate WBCs, Neutrophils which release bradykinins and leukotrienes, platelets which release histamine and serotonin, basophils which release hsitamin. FIbroblasts produce cytokines.

Question 12

What is the role of lipoxins?

Answer 12

Control the proliferation of immune cells for proliferation that induces inflammation.

Question 13

What is the function of resolvins?

Answer 13

Reduce pro-inflammatory cytokines such as TNF and inhibit macroglia activation.

Question 14

What is the role of protectins?

Answer 14

Reduce T cell migration and the production of inflammatory cytokines for microglial cells.

Question 15

What is the role of maresins?

Answer 15

Increases tissue regneration and reduces pain.

Question 16

What is chronic inflammation?

Answer 16

Failed resolution of infection which leads to continuous immune response over 8 weeks

Question 17

How can enzymes be targeted by drugs?

Answer 17

Via their ligand binding site or allosteric site

Question 18

How can inflammatory mediators be synthesised?

Answer 18

Phospholipase A2 frees stores of arachidionic acid which is converted into porstaglandin by COX-1. It is converted into prostacyclin and thromboxane A2 by prothrombinase enzyme.

Question 19

How do NSAIDs work?

Answer 19

They inhibit COX-1 for the formation of prostaglandin, thromboxane and prostacyclin from the precursor arachidionic acid and COX-2 for the formation of lipoxin and leukotrienes’

Question 20

What are COX isozymes?

Answer 20

COX-1 and COX-2.

Question 21

What is the role of COX-1 enzyme?

Answer 21

Constantly active and the production of prostaglandin, prostacylcin and thromboxane A2.

Question 22

What is COX-2 enzymes?

Answer 22

Must be induced by inflammation and production of lipoxin the mediatior of inflammation and leukotriene an inflammatory mediatior.

Question 23

What are NSAIDs?

Answer 23

Non-steroidal anti-inflammatory drugs used to releive symtpoms of inflammation. It includes aspirin, ibuprofen, diclofenac, isofetanil

Question 24

What is NF-kB?

Answer 24

Inflammatory mediator

Question 25

What is aspirin?

Answer 25

NSAID which irreversibly inactivates COX-1 and COX-2 for the generation of inflammatory mediators.

Question 26

Mechnaism of aspirin action

Answer 26

Arachidionic acid moves through hydrophic channels to bind to COX-1 for catalysation to form the prostaglandin mediator. Aspirin enters through this channel and causes acetylation of the serine protease at position 521 to prevent arachidionic acid binding.

Question 27

How can NSAIDs affect platelets and vascular endothelial cell?

Answer 27

Platelets have no nucleus therefore irreversible inhibiton of COX-1 by aspirin means it cannot generate the agonist thromboxane A2 for adhesion/aggregation. Vascular endothelium has nuceli to generate new COX-1 enzymes.

Question 28

How does aspirin change with body weight?

Answer 28

Lower weight requires lower dose and vice versa.

Question 29

How does ibuprofen affect aspirin?

Answer 29

Ibuprofen reversibly binds to COX-1 and COX-2 and cancels out aspirin’s affects. This is important when considering aspirin’s use as an anti-platelet.

Question 30

What are the side effects of aspirin?

Answer 30

GI bleeding and discomfort, haemorrhagic stroke

Question 31

What is Coxibs?

Answer 31

COX-2 specific drugs to minimise gastric problems by general COX targeting by NSAIDs.

Question 32

What are the side effects of Coxibs?

Answer 32

Hyperkalemia, bleeding and toxicity of the kidenys.

Question 33

What are NO-NSAIDs?

Answer 33

Anti-inflammatory drugs with a gastro-protective effect.

Question 34

What are glucocorticoids?

Answer 34

Suffix -one such as dexamethasone which are Steroids synthesised from cholesterol which act in the prescence of acetylcholine to reduce the transcription of inflammatory mediators.