Pharmacological aspects of immunology Flashcards
(26 cards)
What are the NSAIDs?
Aspirin
Propionic acid derivatives -> ibuprofen, naproxen
Arylalkanoic acids –> indometacin, diclofenac
Oxicams -> piroxicam
Fenamic acids -> mefanamic acid
Butazones -> phenylbutazon
Outline the prostaglandin H2 part of the arachidonic acid pathway
Phospholipids -> (phospholipases) -> arachidonic acid -> (cyclo-oxygenases) -> prostaglandin H2 (tissue specific synthases) -> thromboxanes (platelet aggregation / vasoconstriction) + prostaglandins (bronchial tone, vascular tone, hyperalgesia etc) + prostacyclins (vasodilatation).
What is the mechanism of action of NSAIDs?
Non-specific inhibitors of cyclo-oxygenases (COX).
3 isoforms:
COX-1 -> constitutive expression –> all tissues
(stomach, kidney, platelets, vascular endothelium).
inhibition → anti-platelet activity, side effects
COX-2 –> induced in inflammation (IL-1) -> injury, infection, neoplasia. inhibition → analgesia + anti-inflammatory actions.
COX-3 –> CNS only? may be relevant to paracetamol.
What are the indications for NSAID therapy?
Short-term management of pain (+ fever). as mild analgesics (orally + topically) -> mechanical pain of all types, minor trauma, headaches, dental pain, dysmenorrhoea.
As potent analgesics (orally, parenterally, rectally) ->
peri-operative pain, ureteric colic.
NSAIDs’ anti-inflammatory properties are used for which conditions?
Gout
Inflammatory arthritis -> ankylosing spondylitis, rheumatoid arthritis
What are the uses and limitations of aspirin?
Pain + inflammation. limited by:
GI toxicity
Tinnitus –> mechanism obscure, usually reversible.
Reye’s syndrome -> fulminant hepatic failure in children.
Anti-platelet effect
Primary + secondary prevention -> stroke + MI
Treatment of acute MI + stroke
How can NSAIDs cause GI toxicity?
In GI tract prostaglandins E2 + I2 -> decrease acid production, increase mucus production, increase blood supply.
NSAID inhibition in stomach + duodenum -> irritation,
ulcers, bleeding.
Colitis –> esp. with local preps e.g. rectal diclofenac.
Upper GI bleeding -> relative risk 4.7. biggest risk factor -> previous GI bleed, age, chronic disease (e.g. rheumatoid disease), steroids.
Consider co-administration of gastro-protection with proton pump inhibitor.
How can NSAIDs cause nephrotoxicity toxicity?
Due to changes in glomerular blood flow -> decreased GFR, Na retention, hyperkalaemia, papillary necrosis.
Acute renal failure 0.5-1%
Avoid or dose adjust in renal failure
Avoid in patients likely to develop renal failure
What effect does aspirin/NSAID have on asthmatics?
10% asthmatics experience bronchospasm -> arachidonic acid shunted down 5LPO pathway when COX is inhibited, increasing leukotrienes.
List the non-selective NSAIDs from least potent to most potent (more side effects)
Ibuprofen -> naproxen -> diclofenac -> indometacin
Side effects -> GI, renal, fluid retention
What is the effect, contraindications and mechanism of paracetamol?
Not NSAID, minimal anti-inflammatory effects, good analgesic/ anti-pyretic.
Well-tolerated, almost no contraindications.
Doesn’t bind COX1 / 2, weak inhibitor of prostaglandin,
may inhibit COX3 but relevance controversial.
Dangerous in overdose.
Outline how paracetamol is metabolised
Paracetamol normally removed via phase 2 conjugation reaction in liver -> paracetamol sulphates + glucuronide -> excretion.
If phase 2 reaction saturated -> shunted down phase 1 oxidation reaction -> NAPQI (hepatic necrosis) -> another phase 2 conjugation reaction -> NAPQI-glutathione -> excretion.
How is paracetamol poisoning/overdose treated?
NAC (N-acetylcysteine) overrides saturation of conjugation pathway + enables NAPQI to be harmlessly removed.
What is the purpose of selective COX 2 inhibitors?
Selective inhibition of COX-2 in vitro + in vivo.
Anti-inflammatory + analgesic.
Selectivity (GI, platelets) at anti-inflammatory doses.
Comparable efficacy (not superior) to non-selective NSAIDs in acute pain, dysmenorrhoea, inflammatory joint disease.
Controversy -> increased MI risk but may be due to absence of anti-platelet effect.
Only recommended in high-risk patients + after cardiovascular risk assessment.
What are the functions of cortisol (hydrocortisone)?
Endogenous glucocorticoid: Carbohydrate + protein metabolism Fluid + electrolyte balance (mineralocorticoid effects) Lipid metabolism Psychological effects Bone metabolism Profound modulator of immune response
How is the mechanism of action corticosteroids?
Steroid receptors in cytoplasms complexed with Hsp90 -> steroids cross cell membrane + bind to steroid receptor complex releasing Hsp90 -> steroid:receptor complex can now cross nuclear membrane -> in nucleus steroid receptor binds to specific gene regulatory sequences + activates transcription.
Steroids reduce immune activation by altering gene expression e.g. in T + B cells + cells of innate immune system. delayed onset of action so must be taken regularly.
What are the immunomodulation effects of steroids?
Cell trafficking -> lymphopenia, monocytopenia (redistribution), neutrophilia + impaired phagocyte migration.
Cell function -> T cell hypo-responsiveness, inhibited B cell maturation, decreased IL1, IL6, TNFa production (monocytes), widespread inhibition of Th1 + Th2 cytokines, inhibition of COX - prostaglandins, impaired phagocyte killing, ↓collagenases, elastases etc.
Don’t effect immunoglobulin levels + complement.
Outline the clinical use of steroids
Suppress inflammation of all kinds, esp. in acute disease + maintenance therapy.
Asthma, Crohn’s / UC, eczema, MS, sarcoid, allergy, rheumatoid arthritis, SLE etc.
Replacement therapy in hypoadrenalism.
Myriad preparations + routes:
Systemic -> oral + parenteral
Topical -> skin, joint injections, inhaled, enteric coated, rectal.
What are the corticosteroid drugs and their potency, lipid solubility, systemic use and typical use?
Hydrocortisone -> low potency, good lipid solubility, replacement rx + occasionally treatment, skin + joints.
Prednisolone -> medium, good, anti-inflammatory, enemas.
Beclomethasone -> medium, poor, topical use for asthma + Crohn’s.
Dexamethasone -> high, good, systemic use for cerebral oedema.
Triamcinolone -> high, poor, topical use for skin + joints
What are the side effects of steroid therapy?
Early -> weight gain, glucose intolerance, mood change, suppression of ACTH release.
Later -> proximal muscle weakness, osteoporosis, skin + body shape changes, hypertension, cataracts, adrenal suppression.
What are the effects of adrenal suppression during corticosteroid therapy?
After prolonged therapy adrenal cortex atrophies + endogenous production takes some time to recover upon cessation.
Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress e.g. infection + may precipitate an adrenal crisis -> steroid warning card, tail dose slowly, increase dose during acute illness + prior to surgery.
What is the risk of steroid therapy?
Risk related to cumulative dose.
Phagocytic defects (early risk):
bacterial infection –> S. aureus, enteric bacteria etc.
fungal infection –> candida, aspergillus.
Cell mediated defects (later risk):
intracellular pathogens -> TB, varicella, listeria, pneumocystis.
What are disease-modifying anti-rheumatic drugs (DMARDS) used for?
Targets immune system.
Rheumatoid arthritis, transplantation, myriad other autoimmune + inflammatory disorders, sometimes in higher doses for chemotherapy.
Distinguished from NSAIDs, steroids + biologics.
What are the uses and toxicities of the DMARD methotrexate?
Competitive inhibitor of DHR -> anti-folate action.
Folate needed for purine synthesis in DNA.
Reduces T cell activity + tumour synthesis in higher doses.
Rheumatoid arthritis, psoriasis, Crohn’s.
Hepatotoxicity, leucopenia, pulmonary fibrosis, teratogenic.
Weekly dosing (errors have caused major toxicity).
