P8: Allergies and Anti-inflammatories Flashcards
What are the main categories of anti-inflammatory drugs?
- NSAIDs
- Glucocorticoids
- Anti-histamines
- Anti-rheumatics
- Biologics
Name some NSAIDs (3)
- Aspirin
- Ibuprofen
- Diclofenac
Name some Glucocorticoids (3)
- Betamethasone
- Hydrocortisone
- Prednisolone
Name some Anti-histamines (2)
- Loratidine
- Acrivastine
Name some Anti-rheumatics (3)
- Methotrexate
- Azathioprine
- Ciclosporin
Etanerecpt is an example of which type of anti-inflammatory drug
Biologics
NSAID mechanism of action
Primary mechanism of action is through inhibition of cyclo-oxygenase (COX)
COX breaks down Arachidonic Acid into which 3 metabolites?
- Thromboxanes
- Prostacylin
- Prostaglandins
Role of Thromboxanes
Promote thrombosis and vasoconstriction
Role of Prostacyclin
- Limits thrombosis
- Promotes vasodilation
Role of Prostaglandins
- Vasodilators
- Stimulate bronchial, GI tract, uterine smooth muscles
Where are COX-1 expressed?
COX-1 expressed in virtually all tissues
Where are COX-2 expressed?
COX-2 has very limited constitutive expression
When are COX-2 upregulated?
Rapidly upregulated during inflammation by cytokine stimulation
Name some of the many actions of Glucocorticoids (7)
Many actions but bottom line is that these all work together to stop inflammation
- 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
What are the two isoforms of Glucocorticoid Receptors?
Which binds to cortisol?
- GRα and GRβ
- Only GRα binds cortisol
What are the 5 major side effects of Glucocorticoid
- Osteoporosis
- Hypertension
- Mood disorders
- Hyperglycaemia
- Adrenal suppression
Give an example of Type I hypersensitivity
only Type I is an allergy
Asthma/Atopy/Anaphylaxis
Give an example of Type II hypersensitivity
Myasthenia gravis
Give an example of Type III hypersensitivity
Lupus
inflammation in joints
Give an example of Type IV hypersensitivity
Contact dermatitis/rheumatoid arthritis/coeliac disease/MS
What is a major effector of Type I hypersensitivity
Histamine acting on H1 receptors
What is Anaphylaxis?
- Severe, life-threatening systemic allergic reaction
- Systemic release of histamine and cytokines
- Bronchoconstriction and vasodilation causing hypotension
What is Rheumatoid Arthritis?
Chronic autoimmune disease affecting the joints
What are the two therapies for Rheumatoid Arthritis
- Disease modifying anti-rheumatic drugs (DMARDs)
- Biologic therapies (antibodies)
What does the COX1 cyclo oxygenase do
- Produces prostaglandins responsible for homeostatic function as well as during inflammation
- Maintains gastric mucosa integrity
- Regulates renal blood flow
What inhibits COX1 and COX2 enzymes and what side effects do they have?
Older NSAIDs like aspirin, ibuprofen and diclofenac
GI side effects - gastric ulcers, duodenal bleeding
Name some selective COX2 inhibitors and what side effects they have
Celecoxib and etoricoxib
Fewer effects on gastric mucosa
Cardiovascular damage - block of protective PGI2
What are the most powerful anti-inflammatory agents
Glucocorticoids, lots of side effects
What happens after glucocorticoid receptors bind to cortisol
They translocate to the nucleus to activate and repress gene transcription
Steroids that activate the glucocorticoid receptor are commonly also mineralocorticoid receptor agonists, name some GR selective steroids
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
Give examples of histamines and their characteristics
Acrivastine, Cetirizine, loratadine - orally active, long half life, no sedation
Name some older anti histamines and their characteristics
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
What are some treatments for anaphylaxis
- Administration of adrenaline, i.m., at 5 min intervals
- administration of oxygen
- administration of anti histamines, slow i.v. or i.m. injection
What is the purpose of DMARDs and where are they usually used
Diverse collection of drugs that target aspects of the inflammatory response in arthritis, used in many autoimmune diseases Egypt, lupus, crohn’s, myasthenia gravis
How does Azathioprine work and what are its side effects
Orally active prodrug, converted to mercaptopurine
Integrates into DNA, halts replication, preventing immune cell proliferation
Side effects: nausea/vomiting, carcinogen, birth defects
How does Methotrexate work and what are its side effects
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
How does Ciclosporin work and what are its side effects
Blocks activity of calcineurin, an enzyme required for cytokine production
Side effects: kidney damage, mild hepatotoxicity, gum hypertrophy
What are Anti-TNFalpha therapies used for and how do they work
Highly effective in treating rheumatoid arthritis, Crohn’s disease, ulcerative colitis
Humanised antibodies, or antibody components that target the cytokine TNFα
name some anti TNFalpha therapies and their mechanisms
Bind TNF and prevent its activity
Etanercept
TNF receptor fused to an antibody stem
Infliximab, adalimumab
Anti-TNFα antibodies
