pharmacology of inflammation

• aspirin is derived from salicylic acid (bark of willow trees), it is acetylsalicylic acid
• Aspirin like other NSAIDs:

  • analgesic - pain relief
  • anti-inflammatory - decrease inflammation
  • anti-pyretic - decrease fever

  uniquely:

  • anti-thrombolytic - decrease heart attacks, prevent thrombosis
• inflammatory mediators (cytokines, peptides like bradykinins and neuropeptides, small molecules like 5HT and histamine) cause a pathophysiological local response -> increased blood flow, vessel leakiness and neuronal sensitisation -> cardinal signs of inflammation
• rubor - redness

  calor - heat

  tumour - swelling

  dalor - pain

  loss of function
• how do different phospholipases degrade a phospholipid?

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• how are phospholipids metabolised into PGH2

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• what is the pharmacology of COX inhibition by aspirin?

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• how do NSAIDs like diclofenac target COX?

  reversible competitive inhibitors
• how is PGH2 converted into its products? Which prostanoid receptors do they act on? CPPC of treprostinil?

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• where are the different prostanoid receptors and what do they cause?

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• because prostaglandins have many receptor sites, NSAIDs and aspirin have a diverse range of effects
• what are the desired and undesired clinical effects of NSAIDs and aspirin?

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• COX-1 enzyme:

  • from PGH2 synthase
  • constitutive ( platelets , renal , gut )
  • physiological
  • undesired effects

  COX-2 enzyme:

  • from PGH2 synthase
  • inducible ( macrophages , immune cells)
  • pathophysiological
  • desired effects
• cholesterol is an example of an endogenous steroid, what are some of its functions?


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• what are examples of steroid hormones?

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• where are different steroids made in the adrenal glands?

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• physiology of corticosteroids

  glucocorticoids:

  • maintain homeostasis
  • manage stress
  • widespread effects

  mineralocorticoids:

  • electrolyte balance
  • RAAS system
  • increased Na+ and H20 retention
  • increased K+ and H+ excretion
• Cushing’s Syndrome

  •Caused by over-exposure to  glucocorticoids •Pathological: e.g., adrenal  tumour over-producing  endogenous glucocorticoids •Iatrogenic: excessive use of  exogenous glucocorticoids


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• Therapeutic Use of Steroids: things to consider

  •Severity of illness

  •Availability of alternative therapy

  •Short term vs long term use

  ̶  Disease prognosis

  ̶  Acute vs chronic

  •Topical vs systemic

  •Steroids are the only available and effective  treatment for many conditions
• compare steroids and NSAIDs

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• other than steroids and NSAIDs what drugs can be used ?

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• what are different ways to treat gout?

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• Gout

  • Inflammatory arthritis
  • Uric acid
  • end product of purine (DNA) catabolism̶
  • eliminated in urine
  • Pathophysiology
  • ↑ uric acid
  • → deposition of urate crystals
  • → inflammation
  • large urate crystals = tophi

  
• describe the analgesic ladder

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• effects of glucocorticoids

  •Metabolic (catabolic)

  ̶  Breakdown protein / carbohydrate

  ̶  Stimulate gluconeogenesis → hyperglycaemia

  ̶  Lipids: complex effects → breakdown & deposition

  ̶  ↑ appetite → obesity

  •Cardiovascular

  ̶  ↑ blood pressure

  •Immune

  ̶  Stress protective responses

  ̶  ↓ immune/inflammatory response → ↓ wound healing, ↑ infection

  •Other

  ̶  Bone growth → osteoporosis

  ̶  Cell growth: +ve & -ve effects; pro-apoptotic

  ̶  CNS: learning, neurodegeneration, mood, behaviour, temperature …
• steroid pharmacology:

  •Steroids are lipid soluble

  ̶  Distribute throughout entire body

  ̶  Influence function of ALL cells

  •Steroids bind to steroid hormone receptors

  ̶  Cytoplasmic receptors

  ̶  ‘Ligand-activated transcription factors’

  ̶  On agonist (i.e., the steroid) binding they translocate to nucleus

  ̶  Bind to defined sequences on DNA (= glucocorticoid response elements)

  • Modify target gene transcription

  •Transactivation=↑transcription •Transrepression = ↓transcription

  ̶  Regulate other transcription factors, e.g., AP-1 and NFκB
• •Receptor classification (NR3 class)

  ̶  Glucocorticoids:  GR  (wide anatomical distribution)

  ̶  Mineralocorticoids:  MR (limited anatomical distribution)

  ̶  Sex steroids:

  •PR, progestogen; AR, androgen; ERα & ERβ, oestrogen
• how do 11beta-HSD1 and 2 affect the pre-receptor metabolism of cortisone?

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• how do steroids bind affect GR binding to HSP?

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• Protein chaperones act to promote folding, block aggregation, disaggregate proteins, and facilitate protein degradation 
• describe how GRE and nGRE interact with GRs for transactivation and transrepression

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• the binding loci for the GRE presents with a palindromic sequence making 2 identical binding sites in the DNA. The spacing between the sites determines GC orientation and activity.
• how do glucocorticoids affect inflammation?

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• effects of GCs

  •Humoral

  ̶  ↓ mediators of inflammation

  ̶  ↓ PG synthesis; ↓ histamine release; ↓ NO generation;

  ↓ complement

  •Cellular

  ̶  ↓ neutrophil migration into tissues

  ̶  ↓ T-cell activation/proliferation

  ̶  ↓ B-cell activation/proliferation and ↓ IgG production

  •Substantial and comprehensive

  ̶  Very effective anti-inflammatory agents

  ̶  Wide-ranging clinical usage
• describe mediated transrepression and activation

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