Block 4 W3 Flashcards
Give examples of immune driven inflammation.
Allergies Graft vs. Host disease Autoimmune disease Contact dermatitis Celiac disease
What is arachidonate acid formed from?
Cellular phospholipid bilayer by phospholipase A2.
Metabolised by cyclooxygenase into prostaglandins and prostacyclin, thromboxane.
What is the role of prostacyclin, PGI2?
Vasodilator, hyperalgesic, stops platelet aggregation.
What is the role of thromboxane, TXA2?
Thrombotic, vasoconstrictor.
What is the role of prostaglandin, PGF2a?
Bronchoconstrictor, myometrial contraction.
What is the role of prostaglandin, PGD2?
Inhibits platelet aggregation and vasodilator.
What is the role of prostaglandin, PGE2?
Vasodilator and hyperalgesic.
Define NSAIDs and give examples.
Non-steroidal anti-inflammatory drugs
e.g. aspirin, ibuprofen, diclofenac
Prescribed for pain and chronic inflammation - minor aches and pains.
What are the 3 major effects of NSAIDs?
- Anti-inflammatory - blocks COX from making prostaglandins which regulate inflammation due to vasodilation and increased vessel permeability.
- Analgesic - prostaglandins sensitises spinal neurones to pain.
- Antipyretic - prostaglandin synthesis inhibited in hypothalamus so reduces firing rate that control thermoregulation.
Describe the mech of action of aspirin.
Irreversibly inactivates both isoforms of COX (1 and 2) by acetylating the catalytic serine residue in position 529.
Affects COX2 expression at both transcriptional and post-t level.
What does low dose aspirin do?
Preferentially affects thromboxane pathway -> reduced platelet aggregation.
What does high dose aspirin do?
Affects both pathways -> risk of bleeding as inhibits prostacyclin, required for inhibition of platelet aggregation.
How does ibuprofen interact with aspirin?
Block the anti-platelet effects.
What are the side effects of aspirin?
Deaf, swelling of eyes, face, lips, tongue, wheezing, cold clammy hands, hives, nausea, tachycardia, bloody stools, and vomit.
What do 2nd generation NSAIDs target?
Selective COX2 inhibitors
e.g. Coxibs
Minimised gastric problems but targeted prostacyclin which increased risk CVD.
Define NO-NSAIDs?
Nitric oxide - donating NSAID
have gastro-protective effect and increased anti-inflammatory activity.
What are the adverse events of NSAIDs caused by?
Inhibition of COX1 - useful as a housekeeping role.
What are the adverse side effects of NSAIDs?
- Abdominal discomfort, dyspepsia - reduced PG synthesis in GI -> increased gastric acid secretion, diminished mucus secretion so acid irritates GI lining.
- Stomach/duodenal ulceration - PG normally causes mucus release so NSAIDs blocks this.
- MI - COX1 expressed in endothelium -> pre-disposes to blood clots and high BP.
Define SAIDs.
Steroidal anti-inflammatory drugs -> glucocorticoids
e.g. hydrocortisone, prednisone, dexamethasone
Synthesised from cholesterol.
Used in inflammatory diseases.
Reduces phospholipase A, COX2 thus reducing prostaglandins.
What are the side effects of SAIDs?
Occurs with prolonged systemic use.
- suppresses IR
- suppresses endogenous glucocorticoid synthesis
- iatrogenic Cushing’s syndrome
- osteoporosis.
How does histamine produce the Lewis Triple response?
- reddening - vasodilation
- wheal - increased permeability
- flare - antidromic stimulation of local nerves
What is the effect of histamine systemically?
- stimulation of gastric secretion
- contraction of smooth muscle
- cardiac stimulation
- vasodilation
- increased vascular permeability
Give examples of sedating anti-histamines.
Chlorphenamine and promethazine
Give examples of non-sedating anti-histamines.
Cetrizine and fexofenadine.
Give examples of immunosuppressive drugs.
Cyclosporine
Tacrolimus - prevents transcription of IL-2
Rapamycin - inhibits mTOR and so cell cycle progression.
Describe the mech of action of basiliximab.
Monoclonal antibody.
Acts via cytokine or binds receptors directly to limit proliferation of IL-2.
Define atopy.
Predisposition for IgE mediated IR.
In type I hypersensitivity, describe the immediate reaction caused by the release of mast cells.
Histamine usual effects and chemoattractant for neutrophils and eosinophils.
Leukotrienes - bronchial spasms/constrictions, mucus secretion.
Prostaglandins effects
Th2 cytokines - activates Th2 cells and eosinophils activation.
In type I hypersensitivity, describe the late reaction caused by the release of mast cells.
Migration of eosinophils - release peroxidase causing further tissue damage.
Describe allergic rhinitis and treatments.
Type I
Hay fever due to grass or pollen.
Signs - red itchy watery eyes, runny nose.
Treatment - reduce exposure, anti-histamines, intranasal corticosteroids.
Describe asthma and treatments.
Type I
Contraction of bronchial smooth muscle -> SOB.
Treatment - reliever inhaler-salbutamol (B2 agonist), preventative inhaler-corticosteroids.
Describe allergic eczema and treatments.
Type I
Skin breached by allergens, scratching + microbial toxins influx due to unresolved skin -> release of cytokines and chemokine.
Chronic disease - Th1 cells and eosinophils.
Treatment - reduce itching, emollients, topical corticosteroids.
Describe urticaria and treatments.
Type I
Release of histamine within skin - leads to angio-oedema.
Treatment - anti-histamines, corticosteroids.
Describe anaphylaxis and treatments.
Type I
Systemic response to allergen -> rapid synthesis of prostaglandins and leukotriene:
- systemic vasodilation, increased vascular permeability
- fall in BP
- severe bronchial constriction, oedema and shock.
Treatment - norepinephrine pen -> vasoconstrictor.
Describe rhesus disease and treatments.
Type II
HDN
Treatment - routine antenatal anti-D prophylaxis (RAADP) prevents sensitisation. Anti-D antibodies neutralises any D+ RBC mother is exposed to.
Describe antibiotic allergies and treatment.
Type II
Drug binds RBC - Abs produced -> destruction of RBCs, drug acts as immunological hapten.
Treatment - removal of drug, steroids.
Describe Good-pasture syndrome and treatment.
Type II
IgG Ab recognise collagen within kidney basement membrane so binding -> complement activation.
Treatment - oral immunosuppressants and plasmapheresis.
Describe myasthenia gravis and treatment.
Type II
Abs block acetylcholine receptors at NMJ - muscle weakness of eyes and face.
Treatment - pyridostigmine, immunosuppressants biologics, thymectomy.
Describe Graves disease and treatment.
Type II
Abs bind thyroid hormone receptor causing activation -> increased thyroid hormone production.
Treatment - thionamides, radioactive iodine therapy, surgery.
Describe the mechanism of type III hypersensitivity.
Complexes are deposited in organs (kidney, vessels, synovial joints) - constant activation of complement -> tissue damage.
Vasculitis, glomerular nephritis, arthritis.
Describe systemic lupus erythematous and treatment.
Type III
Autoantigens is DNA - anti-DNA antibodies result in systemic damage to tissues i.e. kidney, skin, heart and joints.
Treatment - alkylating agent (cyclophosphamide suppressing DNA synthesis), immunosuppressants, rituximab and belimumab.
Describe rheumatoid arthritis.
Type IV
Cell-mediated joint tissue destruction due to inflammation and cartilage damage.
Treatment - NSAIDs, corticosteroids.
Describe the mechanism of type IV hypersensitivity.
Sensitisation - haptens cross epidermis -> creates neo-antigens -> presented to APCs = development of memory response.
Secondary exposure - memory Th1 cells activates inflammation, macrophages and tissue destruction.
Describe contact dermatitis and treatment.
Type IV
Nickel, poison ivy
1st contact sensitises, 2nd contact elicits dermatitis.
Treatment - trigger avoidance.
Describe multiple sclerosis and treatment.
Type IV
T cells destroy myelin sheath -> paralysis.
Treatment - immunosuppressants, biologic therapy i.e. anti-cytokine and monoclonal Abs.
