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BSMS204 Theme I Immunology > 14. Pharmacological aspects of immunology > Flashcards

14. Pharmacological aspects of immunology Flashcards

1
Q

NSAIDS examples

A

Aspirin Paracetamol Propionic acid derivatives - e.g. ibuprofen, naproxen Arylalkanoic acids – e. g indometacin, diclofenac Oxicams - e.g. piroxicam Fenamic acids - e.g. mefanamic acid Butazones - e.g. phenylbutazone Coxibs e.g. celecoxib

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2
Q

What do NSAIDS do?

A

All inhibit cyclo-oxygenase Three isoforms of cyclo-oxygenase COX-1 - Constitutive expression COX-2 – Induced in inflammation COX-3 – CNS only?

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3
Q

COX-1

A

Constitutive expression – all tissues Stomach, Kidney, Platelets, Vascular endothelium Inhibition → anti-platelet activity, side effects

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4
Q

COX-2

A

– Induced in inflammation (IL-1) Injury, infection, neoplasia Inhibition → analgesia and anti-inflammatory actions

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5
Q

COX-3

A

CNS only? Inhibited specifically by paracetamol → antipyretic and analgesic actions

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6
Q

Indications for NSAID therapy

A

Short-term management of pain (and fever) As mild analgesics (orally and topically) - mechanical pain of all types - minor trauma - headaches, dental pain - dysmenorrhoea As potent analgesics (orally, parenterally, rectally) - peri-operative pain - ureteric colic As anti-inflammatories (?) - gout - Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis

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7
Q

Aspirin

A

Use for pain and inflammation limited by: - GI toxicity - Tinnitus – mechanism obscure, usually reversible - Reye’s syndrome (fulminant hepatic failure in children) Anti-platelet effect - Prophylaxis of ischaemic heart disease - Treatment of acute MI

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8
Q

Non-NSAID antiplatelet drugs

A

Clopidogrel and dipyrimidole

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9
Q

Paracetamol

A

Doesn’t bind COX1 or 2. No significant anti-inflammatory action No significant GI toxicity Analgesic/ anti-pyretic Dangerous in overdose

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10
Q

Paracetamol metabolism

A
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11
Q

Eicosanoid pathways

A
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12
Q

What is used to treat paracetamol poisoning?

A

N-acetylcystein / methionine (glutathione precursors) used in paracetamol poisoning

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13
Q

NSAID GI toxicity

A

In the GI tract prostaglandins E2 and I2

  • Decrease acid production
  • Increase mucus production
  • Increase blood supply

NSAID inhibition in stomach and duodenum

  • Irritation
  • Ulcers (gastric 15-30%, duodenal 10%)
  • Bleeding

Similar effect in the colon

  • Colitis – esp with local preps e.g. rectal diclofenac
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14
Q

Things to ask about when prescribing NSAIDS

A

Upper GI bleeding

  • Relative Risk 4.7 all users
  • Azapropazone = 23.4
  • Piroxicam = 18.0
  • Small differences between others…

Biggest risk factor for GI bleed = previous GI bleed

Also

  • Age
  • Chronic disease (e.g.rheumatoid disease)
  • Steroids
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15
Q

NSAID nephrotoxicity

A

Primarily related to changes in glomerular blood flow

  • Decreased glomerular filtration rate
  • Sodium 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

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16
Q

Asthma and aspirin

A

About 10% of asthmatics experience bronchospasm following NSAID – perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited

17
Q

Which NSAID? - non-selective NSAIDS

A
18
Q

Preventing NSAID toxicity

A

Is an NSAID the answer (paracetamol, opioids?)

In terms of GI toxicity

Treatment with

  • Gastroprotective drugs (misoprostil – PGE1 analogue, or proton pump inhibitor)

Avoid in renal failure, dose adjust if necessary

19
Q

Selective COX-2 inhibitors

A

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

The ‘coxibs’

  • celecoxib
  • etoricoxib
  • rofecoxib
  • valdecoxib
  • etc
20
Q

Efficacy of coxibs

A

Numerous clinical trial data

Comparable efficacy (not superior) to non-selective NSAIDs in

  • Acute pain
  • Dysmenorrhoea
  • Inflammatory joint disease
21
Q

GI side effects of coxibs

A

that rates of peptic ulceration and GI symptoms much lower with coxibs than NSAIDS but not lower than control

22
Q

Do Coxibs increase risk of MI?

A

Cox-2 inhibitors – no activity as antithrombotics

Two studies published in 2005

↑ rates of MI in clinical trials of celecoxib and rofecoxib

Data not fully disclosed by companies?

Relative risk

  • small (1.56 for celecoxib higher for others)
  • acute (first three months)
23
Q

Corticosteroid drugs

A

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
24
Q

How do steroids work?

A

Steroids reduce immune activation by crossing cell membrane

binding their receptors intracellularly

then entering nucleus altering gene expression in numerous cell types

including T cells, B cells and cells of the innate immune system.

Their onset of action is delayed and they must be taken regularly

25
Q

Immunomodulation by steroids: cell trafficking

A

Lymphopenia, monocytopenia (redistribution)

Neutrophilia and impaired phagocyte migration

26
Q

Immunomodulation by steroids: cell function

A

T cell hyporesponsiveness

Inhibited B cell maturation

Decreased IL1, IL6 and TNFa production (monocytes)

Widespread inhibition of Th1 and Th2 cytokines

Inhibition of COX - prostaglandins

Impaired phagocyte killing

↓collagenases, elastases etc

27
Q

Steroids inflammatory modulation: things they don’t affect

A

Immunoglobulin levels

Complement

28
Q

Clinical use of steroids

A

To suppress inflammation

  • Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis etc etc

To suppress specific immunity

  • Graft rejection

Replacement therapy in hypoadrenalism

29
Q

Steroid preparations

A

Different routes of administration

  • Systemic (oral and parenteral)
  • Topical (skin, joint injections, inhaled, enteric coated, rectal)

Different drugs

  • Different potencies
  • Different pharmacokinetics (esp lipid solubility and half-life)
30
Q

Corticosteroids as drugs

A
31
Q

Side-effects of steroid therapy

A

Predictable from steroid actions

Early

  • Weight gain
  • Glucose intolerance
  • Mood change
  • Suppression of ACTH release

Later

  • Proximal muscle weakness
  • Osteoporosis
  • Skin changes
  • Body shape changes
  • Hypertension
  • Cataracts
  • Adrenal suppression
32
Q

Adrenal suppression during corticosteroid therapy

A

High-dose exogenous corticosteroids suppress endogenous production within 1 week

After prolonged therapy, adrenal cortex starts to atrophy and endogenous production takes some time to recover upon cessation

Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis

  • Steroid warning card
  • Tail dose slowly
  • Increase dose during acute illness and prior to surgery
33
Q

Steroids increase the risk of infection

A

71 Placebo controlled trials of prednisolone

Consistently report increased risk of infection which is related to total cummulative dose

E.g for prednisolone > ~700mg (= 10 – 20 days of a standard dose)

34
Q

Risk of infection

A

Phagocytic defects - risk occurs early

  • Bacterial infection – S. aureus, enteric bacteria etc
  • Fungal infection – candida, aspergillus

Cell mediated defects

  • Intracellular pathogens
    • TB
    • Varicella
    • Listeria
    • Pneumocystis
35
Q
A

BSMS204 Theme I Immunology (22 decks)

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