P8: Allergies and Anti-inflammatories

Question 1

What are the main categories of anti-inflammatory drugs?

Answer 1

• NSAIDs
• Glucocorticoids
• Anti-histamines
• Anti-rheumatics
• Biologics

Question 2

Name some NSAIDs (3)

Answer 2

• Aspirin
• Ibuprofen
• Diclofenac

Question 3

Name some Glucocorticoids (3)

Answer 3

• Betamethasone
• Hydrocortisone
• Prednisolone

Question 4

Name some Anti-histamines (2)

Answer 4

• Loratidine

- Acrivastine

Question 5

Name some Anti-rheumatics (3)

Answer 5

• Methotrexate
• Azathioprine
• Ciclosporin

Question 6

Etanerecpt is an example of which type of anti-inflammatory drug

Answer 6

Biologics

Question 7

NSAID mechanism of action

Answer 7

Primary mechanism of action is through inhibition of cyclo-oxygenase (COX)

Question 8

COX breaks down Arachidonic Acid into which 3 metabolites?

Answer 8

• Thromboxanes
• Prostacylin
• Prostaglandins

Question 9

Role of Thromboxanes

Answer 9

Promote thrombosis and vasoconstriction

Question 10

Role of Prostacyclin

Answer 10

• Limits thrombosis

- Promotes vasodilation

Question 11

Role of Prostaglandins

Answer 11

• Vasodilators

- Stimulate bronchial, GI tract, uterine smooth muscles

Question 12

Where are COX-1 expressed?

Answer 12

COX-1 expressed in virtually all tissues

Question 13

Where are COX-2 expressed?

Answer 13

COX-2 has very limited constitutive expression

Question 14

When are COX-2 upregulated?

Answer 14

Rapidly upregulated during inflammation by cytokine stimulation

Question 15

Name some of the many actions of Glucocorticoids (7)

Many actions but bottom line is that these all work together to stop inflammation

Answer 15

• Induction of neutrophil apoptosis
• Promotion of macrophage phagocytosis
• Suppression of T cell activity
• Direct small vessel vasoconstriction
• Suppression of cytokine release
• Decreased production of prostanoids and leukotrienes
• Reduced production of ROS from neutrophils and macrophages

Question 16

What are the two isoforms of Glucocorticoid Receptors?

Which binds to cortisol?

Answer 16

• GRα and GRβ

- Only GRα binds cortisol

Question 17

What are the 5 major side effects of Glucocorticoid

Answer 17

• Osteoporosis
• Hypertension
• Mood disorders
• Hyperglycaemia
• Adrenal suppression

Question 18

Give an example of Type I hypersensitivity

only Type I is an allergy

Answer 18

Asthma/Atopy/Anaphylaxis

Question 19

Give an example of Type II hypersensitivity

Answer 19

Myasthenia gravis

Question 20

Give an example of Type III hypersensitivity

Answer 20

Lupus

inflammation in joints

Question 21

Give an example of Type IV hypersensitivity

Answer 21

Contact dermatitis/rheumatoid arthritis/coeliac disease/MS

Question 22

What is a major effector of Type I hypersensitivity

Answer 22

Histamine acting on H1 receptors

Question 23

What is Anaphylaxis?

Answer 23

• Severe, life-threatening systemic allergic reaction
• Systemic release of histamine and cytokines
• Bronchoconstriction and vasodilation causing hypotension

Question 24

What is Rheumatoid Arthritis?

Answer 24

Chronic autoimmune disease affecting the joints

Question 25

What are the two therapies for Rheumatoid Arthritis

Answer 25

- Disease modifying anti-rheumatic drugs (DMARDs) | - Biologic therapies (antibodies)

Question 26

What does the COX1 cyclo oxygenase do

Answer 26

- Produces prostaglandins responsible for homeostatic function as well as during inflammation - Maintains gastric mucosa integrity - Regulates renal blood flow

Question 27

What inhibits COX1 and COX2 enzymes and what side effects do they have?

Answer 27

Older NSAIDs like aspirin, ibuprofen and diclofenac GI side effects - gastric ulcers, duodenal bleeding

Question 28

Name some selective COX2 inhibitors and what side effects they have

Answer 28

Celecoxib and etoricoxib Fewer effects on gastric mucosa Cardiovascular damage - block of protective PGI2

Question 29

What are the most powerful anti-inflammatory agents

Answer 29

Glucocorticoids, lots of side effects

Question 30

What happens after glucocorticoid receptors bind to cortisol

Answer 30

They translocate to the nucleus to activate and repress gene transcription

Question 31

Steroids that activate the glucocorticoid receptor are commonly also mineralocorticoid receptor agonists, name some GR selective steroids

Answer 31

Prednisolone - orally active, high potency Betamethasone + dexamethasone - long action duration, high potency insignificant MR effects Hydrocortisone - moderate effectiveness, topical administration due to weak MR effects

Question 32

Give examples of histamines and their characteristics

Answer 32

Acrivastine, Cetirizine, loratadine - orally active, long half life, no sedation

Question 33

Name some older anti histamines and their characteristics

Answer 33

Promethazine - strong sedative effect due to CNS actions Diphenhydramine - sedative, anti muscarinic effects used for motion sickness Mepyramine - topical cream for insect bites, marginally effective

Question 34

What are some treatments for anaphylaxis

Answer 34

- Administration of adrenaline, i.m., at 5 min intervals - administration of oxygen - administration of anti histamines, slow i.v. or i.m. injection

Question 35

What is the purpose of DMARDs and where are they usually used

Answer 35

Diverse collection of drugs that target aspects of the inflammatory response in arthritis, used in many autoimmune diseases Egypt, lupus, crohn's, myasthenia gravis

Question 36

How does Azathioprine work and what are its side effects

Answer 36

Orally active prodrug, converted to mercaptopurine Integrates into DNA, halts replication, preventing immune cell proliferation Side effects: nausea/vomiting, carcinogen, birth defects

Question 37

How does Methotrexate work and what are its side effects

Answer 37

Inhibits enzymes in purine metabolism, preventing immune cell activation Prevents expression of T cell adhesion molecules, limiting access to tissue Side effects: hepatotoxic, leukopenia, teratogen, abortifacient

Question 38

How does Ciclosporin work and what are its side effects

Answer 38

Blocks activity of calcineurin, an enzyme required for cytokine production Side effects: kidney damage, mild hepatotoxicity, gum hypertrophy

Question 39

What are Anti-TNFalpha therapies used for and how do they work

Answer 39

Highly effective in treating rheumatoid arthritis, Crohn’s disease, ulcerative colitis Humanised antibodies, or antibody components that target the cytokine TNFα

Question 40

name some anti TNFalpha therapies and their mechanisms

Answer 40

Bind TNF and prevent its activity Etanercept TNF receptor fused to an antibody stem Infliximab, adalimumab Anti-TNFα antibodies