Lecture 16- Pharmacological aspects of Immunology Flashcards
NSAIDS:
Large chemically diverse family of drugs
- Aspirin
- propionic acid derivates- ibuprofen, naproxen
- Arylalkanoic acid- piroxicam
- Oxicams- piroxicams
- Fenemic acid- mefanamic acid
- Butazones- phenylbutazones
which pathways does the NSAIDs work on?
Eicosanoid pathways
Describe the mechanism of action of NSAIDs?
arcachidonic acid—->prostaglandins H2 via Cox enzyme
- NSAID block this enzyme
- Preventing the building up of:
- thromboxanes
- Prostaglandins
- Prostacyclins
Explain the function of Thromboxanes, prostaglandins, and prostacyclins?
Thromboxanes: -Platelet aggregation and vasoconstriction -Prostaglandins: Bronchial tone vascular tone and hyperalgesia -Prostacyclins: Vasodilation
Which COX enzymes does the NSAID block and what is the normal function?
COX-1: all tissues express it- stomach, kidney, platelets, vascular endothelium Inhibition: antiplatelet activity -COX-2: Induced inflammation (IL-1) caused by: injury, infection and neoplasia Inhibition: Analgesia and anti-inflammatory actions COX-3: CNS only? May be relevant to paracetamol only
what are the indication for NSAID therapy?
Short-term management of pain (and fever) and anti-inflammation
1) As mild analgesics (orally and topically):
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
2) As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic
Why has aspirin is no longer used for pain-relief and inflmmation?
Use for pain and inflammation limited by
- GI toxicity
- Tinnitus – mechanism obscure, usually reversible
- Reye’s syndrome (fulminant hepatic failure in children)
What are the current uses of aspirin?
Anti-platelet effect:
- Primary and secondary prevention eg stroke and MI
- Treatment of acute MI and stroke
How is GI toxicity caused by NSAIDS?
In the GI tract prostaglandins E2 and I2:
-Decrease acid production
-Increase mucus production
-Increase blood supply
NSAIDS block the production of prostaglandins
what is the consequences of NSAID use on the stomach and dueodenum and colon?
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Colitis: esp with local preps
Which NSAIDs have the highest risk for upper GI bleeds?
1) Azapropazone = 23.4
2) Piroxicam = 18.0
Small differences between others…
what is the biggest risk factor for the GI bleeds and what are the other risk factors?
1) Biggest risk factor for GI bleed = previous GI bleed
Other risk factors:
-Age
-Chronic disease (e.g.rheumatoid disease)
-Steroids
How does the NSAIDS cause the nephrotoxicity?
Primarily related to changes in glomerular blood flow causing:
1) Decreased glomerular filtration rate
2) Sodium retention
3) Hyperkalaemia
4) Papillary necrosis
How does aspirin cause bronchospasm?
-Due to increased production of leukotrienes
How can the NSAID toxicity be prevented?
- Use of NSAID esstential? alternatives?
- Consider other risk factors
- Give with a PPI (gastroprotection)
Which NSAIDS to use?
From least to Most risk of SE:
Ibuprofen>Naproxen>Diclofenac>Indometacin
Describe paracetamol use and mechanism of action?
-Not NSAID
-Minimal anti-inflammatory
-Good analgesic/antipyretic
-very well tolerated
-Mechanism of action not well understood:
does not bind to CoX-1 or 2- weak inhibitor
-May Inhibit COX-3
-Dangerous in overuse
Describe the metabolism of paracetamol?
Normal metabolism:
Paracetamol………….>Paracetamol sulphate and glucuronide via phase II conjugation reaction and excreted
Describe the metabolism of paracetamol in an overdose?
Paracetamol converted to N-acetyl–p-benzoquinoneimine
(NAPQI) via phase I oxidation reaction causes hepatic necrosis
NAPQI goes through phase II conjugation reaction to form: NAPQI - glutathione
which is then excreted
What is the treatment option in paracetamol poisoning?
-N-acetylcysteine (glutathione precursor) used in paracetamol poisoning
Describe the use of selective COX-2 inhibitors?
- Selective inhibition of COX-2 in vitro and in vivo
- Anti-inflammatory and analgesic in humans
- Objective evidence of selectivity (GI, platelets) at > anti-inflammatory doses
Are the selective COX-2 inhibitors better than NSAIDs?
- COX-2 Comparable efficacy (not superior) to non-selective NSAIDs in
- Acute pain
- Dysmenorrhoea
- Inflammatory joint disease
- Controversy due to apparent increased risk of MI – but may have been a result of absence of anti-platelet effect
Why is the COX-2 superior than NSAIDS?
-Rates of GI SE and peptic ulceration low
Describe the functions of cortisol?
-Cortisol (hydrocortisone) – predominant endogenous glucocorticoid:
Carbohydrate and protein metabolism
Fluid and electrolyte balance (mineralocorticoid effects)
Lipid metabolism
Psychological effects
Bone metabolism
Profound modulator of immune response
Describe the mechanism of action for cortiscosteriods?
- Steroid receptors are bound to heat shock protein HSP90
- Steroid crosses the cell membrane and bind to the steroid receptor releasing HSP90
- The steroid receptor complex can now leave the cross the nuclear membrane
- In the nucleus, steroid receptor binds to specific gene regulatory sequence and activates transcription
Describe immunomodulation caused by steroids?
1) Cell trafficking
-Lymphopenia, monocytopenia (redistribution)
-Neutrophilia and impaired phagocyte migration
2) Cell function
-T cell hyporesponsiveness
-Inhibited B cell maturation
-Decreased IL1, IL6 and TNFa production (monocytes)
-Widespread inhibition of Th1 and Th2 cytokines
I-nhibition of COX - prostaglandins
-Impaired phagocyte killing
-↓collagenases, elastases etc
What does the steroid not affect?
- Immunoglobulin levels
- Complement
what are the clinical uses for the steroid use?
-To suppress inflammation of all kinds, particularly in acute disease but also in maintenance therapy
Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis etc etc
-Replacement therapy in hypoadrenalism
Describe the preparation and routes for the steroid use?
- Systemic (oral and parenteral)
- Topical (skin, joint injections, inhaled, enteric coated, rectal)
What are the early SE of steroid therapy?
Early:
- Weight gain
- Glucose intolerance
- Mood change
- Suppression of ACTH release
What are the late SE of steroid use?
Later:
- Proximal muscle weakness
- Osteoporosis
- Skin changes
- Body shape changes
- Hypertension
- Cataracts
- Adrenal suppression
Describe the adrenal suppression during corticosteroid therapy?
- High dose exogenous steroids suppress endogenous production within 1 week
- After prolonged therapy, the adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation
What are the consequences of abrupt withdrawal of steroids after prolonged use?
-Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis
How can the adrenal crisis be prevented?
-Steroid warning card
Tail dose slowly
Increase dose during acute illness and prior to surgery
Explain the risk of infection due to steroid use?
-Risk is related to cumulative dose
-Phagocytic defects
Bacterial infection – S. aureus, enteric bacteria etc
Fungal infection – candida, aspergillus
These are risk factors in early use of steroids
Explain the infection risk of prolonged use steroid which occurs later?
-Cell mediated defects Intracellular pathogens TB Varicella Listeria Pneumocystis
Explain what DMARDs are?
- A diverse group of drugs that target the immune system
- Derive name from use in rheumatoid arthritis,
- Also used in transplantation and other autoimmune and inflammatory disorders;
- for cancer chemotherapy (higher doses)
Describe the mechanism of action of methotrexate?
- Competitive inhibitor of dihydrofolate reductase (DHR), therefore anti-folate action
- Folate needed for purine synthesis in DNA
- This reduces T cell activity, and also (in higher doses) tumour synthesis
What are the main indications for the methotrexate use?
- Rheumatoid arthritis
- Psoriasis
- Crohns disease
Describe main toxicities caused by methotrexate?
- Hepatotoxicity
- Leucopenia
- Pulmonary fibrosis
- Teratogenic
Describe the mechanism of action of azathioprine and uses?
- Inhibits thiopurine S methyltransferase (TPMT): inhibits purine synthesis
- Similar indications to methotrexate;
- more widely used in transplantation compared to methotrexate
Describe the toxicities caused by azathioprine use?
Toxicities similar to methotrexate; GI upset very common when starting
Describe the mechanism of ciclosporin and its uses?
- Inhibits calcineurin, which in turn reduces T lymphocyte activity
- Similar indications to aza/ metho, but used more in Dermatology and transplantation
What are the main toxicities of ciclosporin?
- Nephrotoxic
- Hepatotoxic
- Gum hyperplasia
- Hirsuitism
