Anti-Inflammatory Drugs

• What is an inflammatory response?

  A short term, acute response that is defensive and quickly resolved.

  
• What does the inflammatory response involve?

  1. Acute microvascular changes

  
  

  2. Release of inflammatory mediators

  
  

  3. Accumulation of inflammatory cells

  
  

  4. Repair and healing
• What are the arterioles and venules involved in?

  Arterioles = blood pressure changes

  
  

  Venule = Oedema formation and cell accumulation

  
• What happens in the acute inflammatory response?

  Microvascular effects are triggered from a variety of cells and plasma in and around these vessels

  
  

  Inflammatory mediators (also known as local hormones) released
• What are the common inflammatory mediators in acute inflammation?

  -Histamine

  -Bradykinin

  -Nitric oxide

  -Eicosanoid

  -Neuropeptides

  
• What is histamine formed from and what is its major source?

  Histamine formed from histidine

  
  

  Major source: mast cells & basophils
• Is histamine preformed?

  Yes

  
  

  Preformed = already stored in cells of the body (mast cells) ready to be released
• When is histamine released?

  Released in allergic/ hypersensitivity (IgE) responses
• What do H1 receptors mediate?

  Increased blood flow,

  
  

  increased microvascular permeability,

  
  

  itch
• What 2 categories do H1 antagonists fall into?

  Sedating:chlorpheniramine, diphenhydramine, promethazine

  Non-sedating ones preferred today: loratadine, cetirizine, terfenadine, astemizole

  Sedating = causes drowsinessNon-sedating = less drowsiness
• Give some examples of conditions where anti-histamines are used.

  Allergy,

  
  

  allergic rhinitis,

  
  

  urticaria,

  
  

  hay fever

  
  

  skin irritations
• Which sensory nerves are the pain fibres?

  C and Aδ fibres
• What are the roles of the C and Aδ fibres?

  They have adualrole:

  They transmit sensory information to CNS/initiate reflexes nociception- pain and itch

  They release neuropeptides - many including substance P, CGRP and VIP (alleviate migraine)
• What does the stimulation of the sensory nerves include?

  Mechanical (pressure)

  
  

  Temperature (cold & heat)

  
  

  Chemical (mediators & capsaicin)
• What is the conducting velocity of this subset of sensory nerves?

  0.5 m/s (so it's slow as it's half the speed of normal C fibres)

  
• What distinct subset of sensory nerves mediate itch?

  ~5% of afferent C fibres in skin

  
  

  They respond to histamine but are insensitive to mechanical stimuli
• What are good anti-itch agents?

  Anti-histamines are effective

  
  

  Local anaesthetics can also be used to reduce pain/itch of course
• How can arachidonic acid be metabolised?

  Either via thecyclo-oxygenasepathway to prostaglandins & thromboxanes

  OR

  via thelipoxygenasepathway to leukotrienes

  
• What is arachidonic acid?

  the key to making proinflammatory cytokines & a 20 carbon polyunsaturated fatty acid
• What are eicosanoids?

  The name given to the arachadonic acid metabolites i.e.

  
  

  prostaglandins, thromboxanes, leukotrienes
• How are the different eicosanoids synthesised and what are their roles?

  Prostaglandins = Synthesised by the cyclo-oxygenate enzymes

  
  

  leukotrienes = synthesised by 5-lipoxygenase

  
• What does the cyclo-oxygenase pathway look like?

  1. Arachidonic acid = 4 double bonds, poly unsaturated fatty acid

  
  

  2. Oxygen is inserted to mediate the cyclic endoperoxides (PGG2 and PGH2)

  
  

  3.Both unstable with the oxygen inserted, to break up the double bonds.

  
  

  4.They are metabolised via the enzyme relevant to that tissue

  
• What inhibits arachidonic acid metabolism via cyclo-oxygenase?

  NSAIDs (which leaves the lipoxygenase enzyme unhindered to carry on as normal)
• What are the characteristics of NSAIDs?

  They inhibit prostaglandin generation & they're analgesic (alleviate pain)

  
  

  anti-inflammatory, reduce fever but can enhance bleeding
• What are some examples of NSAIDs?

  Salicylates(Aspirin)Acetic acides(Indomethacin, Diclofenac)Proprionic acides(Ibuprofen, naproxen)Oxicoms(Piroxicam, phenylbutazone)Fenamates(Meclofenamate)
• What are some mediators of arthritis?

  Primary mediator:TNFα(Cytokine)

  Other mediators: IL-1, IL-6, IL-8, IL-10, IL-17, PGE2

  
• Summarise what is used to reduce acute injury.

  - Histamine plays major role in inflammation and itch.

  
  

  -Non-sedating anti-histamines are the drug of choice.

  
  

  -NSAIDs that inhibit PG production = used for analgesic/anti-inflammatory/antipyretic properties

  
  

  -Paracetamol = reduces pain + fever

  
  

  -Ice, local anaesthetic creams and noradrenaline = important roles if routinely used

  
  

  -NSAIDS used by dentists to reduce pain but can increase bleeding

  
• What is the 'therapeutic pyramid' in rheumatoid arthritis (and a range of other inflammatory diseases)?

  
• What 2 forms does cyclo-oxygenase (COX) exist in?

  COX-1 & COX-2
• What are the differences between COX-1 & COX-2?

  COX-1:-Found in most cells

  -Constitutive

  -Involved in normal physiology, to maintain homeostasis

  E.g. in GI tract, PGs important in maintaining good blood flow

  E.g. in vasculature, TxA2 stimulates platelets to aggregate (thrombus) and PGI2 inhibits this

  COX-2:-Induced in inflammatory cells by inflammatory stimuli

  -Releases high levels of prostaglandins at inflammatory sites
• From a clinical view, which one is important to inhibit, COX-1 or COX-2?

  COX-2 as it releases high levels of prostaglandins at inflammatory sites, PG's contribute to clinical signs of inflammation
• What should patients with a cardiovascular risk taking COX inhibitors be taking/doing alongside taking it?

  If taking oral NSAIDs:

  
  

  Associated use of proton pump inhibitors, to inhibit GI reflux due to excess acid (e.g esomeprazole)

  
  

  Alternatively use prostaglandin analogues (e.g. misoprostol)

  
  

  Also, gradually increase NSAID use via topical application instead e.g. diclofenac
• What are DMARDs?

  Disease modifying anti-rheumatic drugs

  
• What is rheumatoid arthritis?

  an autoimmune disease.

  
  

  The immune system mistakenly attacks the body's own tissues, particularly the synovium (the lining of the membranes that surround joints),

  
  

  leading to inflammation, pain, and joint damage.
• What are the pros of using anti-inflammatory steroids?

  Several anti-inflammatory activities:

  -Inhibit arachidonic acid release (AA)

  -Cytokine inhibition

  -Down regulation of adhesion molecules

  -Inhibition of enzyme induction (COX, NOS)

  Several effects on immune response:

  -Inhibition of lymphocyte t-cell proliferation

  -Induces apoptosis
• What are the cons (side effects) of using anti-inflammatory steroids?

  Osteoporosis

  
  

  Increased risk of infection

  
  

  Adrenal atrophy

  
  

  Diabetes

  
  

  Infection
• What is the most common DMARD?

  Methotrexate
• What is methotrexate and when is it used?

  Folate antagonist & it's the most widely used anti-metabolite in cancer chemotherapy (but may act via other mechanisms for anti-inflammatory effects)

  It's also the most widely used disease modifying agent for RA treatment– better if used early & is used in young & oldMay be best mixed with NSAID
• Can methotrexate be toxic?

  Yes, so you have to get blood tests to monitor it
• What are examples of some biologics and when is it used?

  High molecular weight = injected

  
  

  1. Anti-TNF antibodies

  
  

  2. Soluble TNF receptor construct

  
  

  -Used when other DMARDs have failed

  
  

  -Effective for 30% of cases ; can be less successful in follow up treatments

  
  

  -Expensive

  
  

  -Well tolerated compared to other anti-inflammatory drugs

  
  

  -Patients may suffer from opportunistic infections