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Pharmacology > Anti-inflammatories > Flashcards

Anti-inflammatories Flashcards

1
Q

What are NSAIDs?

A

they inhibit the production of inflammatory mediators such as prostaglandins and thromboxanes
- cyclooxygenases (COX) are enzymes which synthesis these paracrine mediators
- NSAIDs inhibit COX enzymes so inhibit the production of PGs and thromboxanes
- therefore they prevent paracrine signalling between cells at sites of inflammation

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2
Q

how are paracrine mediators produced?

A

arachidonic acid is produced from membrane phospholipids
- it acts as a second messenger and as a substrate for lipoxygenases and cyclooxygenases which leads to generation of paracrine mediators
- lipoxygenase pathway produces leukotrines
- cyclooxygenase pathway forms PGs and thromboxanes

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3
Q

what are prostaglandins?

A
  • PGs are created by cells and act only in the surrounding area before they are broken down
  • PGs control neighbourhood processes such as vasodilation (PGE2), aggregation of platelets during clotting (PGD), constriction of uterus during labour (PGF) and a hyperalgesic (makes you more sensitive to pain) (PGE2)
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4
Q

what is the role of PGs?

A
  • deliver and strengthen pain signals to induce inflammation
  • chemoattractants - recruit immune cells
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5
Q

what do NSAIDs result in?

A
  1. anti-inflammatory - modify the inflammatory reaction
    - decrease vasodilation and in turn oedema
    - effective against headaches as they reduce the vasodilator effect of PGs on cerebral tissue
  2. analgesic - reduce pains
    - decrease production of PGs in damaged and inflamed tissue which sensitises nociceptors to inflammatory mediators e.g. bradykinin, 5-HT
  3. antipyretic - lowers raised temperature
    - thermostat in hypothalamus is activated by IL-1 induced COX2 production of PGe
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6
Q

what is the structure of the COX enzyme?

A
  • made up of 2 identical subunits, each with 2 catalytic sites
  • 2 active sites are collectively termed as prostaglandin synthase:
    • one side has a cyclooxygenase active site
    • the other side has a peroxidase site which activates haem groups in
      the COX reaction
  • enzyme complex is a dimer of 2 subunits, so there are 2 cyclooxygenase sites and 2 peroxidase sites in close proximity
  • each subunit has a carbon-rich knob which anchors the complex to the ER membrane
  • cyclooxygenase active site is buried deep inside the protein which is accessible through a tunnel in the knob which acts as a funnel to guide arachidonic acid into the enzyme
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7
Q

what are the types of COX enzymes?

A
  1. COX1: constitutive expression
    - important for platelets, stomach, kidney and colon
  2. COX2: inducible expression
    - most cells, especially inflammtory cells after stimulation with cytokines, growth factors or tumour promoters
    - immediate-early response gene

3 COX3: in CNS, target for paracetamol?

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8
Q

what is the action of NSAIDs?

A
  • COX1 and COX2 inhibitors prevent the cyclooxygenation reaction of arachidonic acid to prevent production of PGs
  • aspirin inhibits expression of transcription factor NF-kappaB which has a key role in triggering gene transcription of inflammatory mediators
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9
Q

how are NSAIDs selective?

A
  • COX1 contains isoleucine residue while COX2 contains valine residues, allowing the creation of NSAIDs which are selective to COX1 or COX2
  • COX2 is inducible, so is only produced when there is tissue damage
  • COX1 is constitutive so maintains homeostatic mechanisms e.g. PGs in the GI tract maintain the mucus layer to protect GI cells from acid
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10
Q

how may NSAIDs have unwanted side effects?

A

if PG production is inhibited by COX1-inhibitors, the mucus layer in the GI tract is reduced, so acid from the stomach may harm GI cells, leading to ulcers

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11
Q

what is the action of aspirin?

A

suicide inhibitor:
- aspirin is composed of an acetyl group which attaches to salicylic acid
- when aspirin attacks cyclooxygenase, its acetyl group covalently binds to the serine residue in COX to permanently deactivate the enzyme
- this prevents arachidonic acid from reaching the cyclooxygenase site through the tunnel
- aspirin therefore blocks the active site

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12
Q

what are the 2 isoforms of COX?

A

COX1: constitutive, expressed in most cells including platelets, has a housekeeping role in homeostasis

COX2: induced in inflammatory cells when activated and produces prostanoid mediators of inflammation

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13
Q

do NSAIDS show a lot of selectivity? how do types of NSAIDs differ?

A

no, they show little selectively.

main differences are in toxicity, duration of action and pain tolerence

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14
Q

what are the side effects of NSAIDs?

A
  1. Gut - PGs normally inhibit acid secretion to protect mucosa, so NSAIDs prevent this
    - causes diarrhoea, dyspepsia, nausea, vomiting, gastric bleeding and ulceration
    - co-administration of misoprostal (PG analogue) helps
    - can be relieved by use of COX2-selective drugs
  2. Renal function: PGs maintain renal blood flow, so NSAIDs may cause issues with renal function, leading to renal failure
  3. liver damage: the metabolite of paracetamol in the phase 1 reaction is toxic to liver
    - patients must be careful if cytochrome p450 is induced as an overdose may cause liver failure
  4. bronchospasm/asthma attacks
  5. skin rashes
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15
Q

what is the risk of GI complications with NSAIDs?

A

35-45% users sustain some form of GI damage

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16
Q

what are the advantages of COX1/COX2-selective NSAIDs?

A

COX2-selective NSAIDS such as rofecoxib (Vioxx), valdecoxib, parecoxib and celecoxib can reduce burden of GI toxicity:
- analgesic and anti-inflammatory]

COX1-selective NSAIDs may be antithrombotic and can help prevent stroke (COX1 is involved in clot formation)

17
Q

what are the disadvantages of COX1/COX2-selective NSAIDs?

A

COX2-selective drugs may cause increased arterial blood pressure, increased atherogenesis, or increased thrombotic tendency
- there is evidence for these NSAIDs to have cardiovascular toxicity if COX2 is consistently inhibited
- increased blood pressure and increased salt retention -> kidney failure

COX1-selective drugs are not suitable with someone with a bleeding disorder, as these drugs prevent clot formation

18
Q

aspirin vs paracetamol:

A

aspirin:
- Anti-platelet action
- Reduced risk of colonic and rectal cancer
- Reduced risk of Alzheimer’s
- Weak acid, rapid and efficient absorption in the ileum
- Suicide inhibitor (irreversible)

paracetamol
- Analgesic-antipyretic due to CNS effects
- Weak anti-inflammatory
- Cox3/1 selective
- Well absorbed, metabolized in liver
- Less side-effects than aspirin with long term use, but large doses may increase kidney damage
- N-acetyl-p-benzoquinone imine is hepatotoxic in uncongugated form
- Competitive Inhibitor

19
Q

what is ibuprofen?

A

same as aspirin except it is a competitive inhibitor

20
Q

what are the clinical uses of NSAIDs?

A
  • antithrombotic = aspirin (for patients with high risk of arterial thrombosis)
  • analgesia:
    short term: aspirin, paracetamol, ibuprofen,
    long-term = naproxen (codeine)
  • anti-inflammatory = ibuprofen, aspirin and naproxen
  • antipyretic (reduces fever) = paracetamol
21
Q

what is rheumatoid arthritis?

A
  • chronic inflammatory condition and autoimmune disease
  • possibly genetic
  • 3x more prevalent in women than in men
  • affects joints, inflammation of synovium and erosion of cartilage and bone
  • treated with DMARDs (reverse/halt the disease) and NSAIDs (alleviate symptoms)
  • no cure
  • smoking is a risk factor
22
Q

what are the mediators involved in the pathogenesis of rheumatoid arthritis?

A
  • T cells activate macrophages which release cytokines involved in driving the inflammatory response:
    e.g. IL-1 and TNF-alpha
23
Q

how can rheumatoid arthritis be treated?

A
  • methotrexate: low doses have cytotoxic and immunosuppresant activity (high doses for chemotherapy)
    • folic acid is the antagonist
  • DMARDs: mixed group of drugs with different mechanisms of action
    • clinical effects are slow, so NSAIDs are provided as cover during
      induction phase
24
Q

give examples of some DMARDs:

A
  1. sulfasalazine: sulfa drug used for chronic inflammatory bowel disease
    - bacteria in colon produce 5-aminosalicylic acid which acts as a free radical to decrease damage by neurtrophils
  2. penicillamine (d-isoform): metabolite of penicillin, used as a heavy metal chelator in poisoning
  3. gold compounds e.g. auranofin: inhibits induction of IL-1 and TNF-alpha
25
Q

what is the role of immunosuppressant drugs?

A

they inhibit the induction phase of the inflammatory response:
- cyclosporin and glucocorticoids inhibit transcription of pro-inflammatory cytokines such as IL-2

26
Q

what is the mechanism of action of cyclosporin?

A

inhibits IL-2 synthesis to cause decrease in T cell proliferation:
1. cyclosporin binds to cyclophilin, a cytosolic immunophilin protein
2. the drug-immunophilin complex bind to and inhibit calcineurin to prevent activation/signalling via transcription factor NF-kappaB, which is regulated by calcium signalling in T cells
- calcineurin is a phosphatase regulated by calcium and targets NF-kappaB transcription factor to produce cytokines
3. inhibition of calcineurin means NF-kappaB can no longer drive the production and secretion of cytokines IL-2, IL-1 and TNF-alpha

27
Q

what is the mechanism of action of glucocorticoids?

A

they act at the level of gene transcription by binding to DNA itself:
- they act as repressors of transcription of genes that make pro-inflammatory cytokines
- they affect IL-1, TNF-alpha and INF-gamma synthesis
- effective in induction and effector phases of the immune response
- they also inhibit NF-kappaB

28
Q

how are biopharmaceuticals used as anti-inflammatory drugs?

A

Humanised monoclonal antibodies:
- can bind to cytokines and prevent their inflammatory response
- high affinity and selectivity for target
- they neutralise the action of soluble or membrane-bound pro-inflammatory cytokines
- long half-life
- the antibodies are engineered with human sequences to prevent rejection

Soluble receptors:
- proteins engineered that mimic the binding site of a known cytokine receptor
- protein is injected into body and cytokine binds to it but has no downstream inflammatory activity

29
Q

what are the issues with biopharmaceuticals’ use in anti-inflammatory drugs?

A

very expensive

30
Q

what is COPD? How is it treated?

A

chronic obstructive pulmonary disease:
- disease driven by macrophages
- symptoms: breathlessness and eventually respiratory failure
- emphysema
- treatment: B2 agonists, muscarinic antagonists and corticosteroids
- cannot be cured

31
Q

what is asthma?

A
  • shortness of breath especially when exhaling
  • symptoms: cough, wheezing, inflammation of airways, bronchial hyperactivity, reversible airway obstruction
32
Q

how can asthma be treated?

A
  • bronchodilators: salbutamol is a B2-adrenoreceptor agonist (GPCR via Gs and adenylyl cyclase) on airway smooth muscle to relax the airways
    • polymorphisms in B2-adrenoreceptors cause reduced efficacy of bronchodilators
  • anti-inflammatory agents: prednisolone and omalizumab reduce cytokine production
33
Q

what are the types of respiratory allergies?

A
  1. allergic rhinitis (hayfever) - issue in upper airways
    - allergen activates mast cells in the nasal mucosa
    - nasal congestion, sneezing and allergic conjunctivitis
  2. allergic asthma (atopic) - issue in lower airways
    - allergen activates mast cells in lower respiratory tract
    - early/immediate phase reactions are reversible airway obstructions
    - bronchial hyperactivity - abnormal sensitivity to many stimuli, causing bronchoconstriction
    - acute attacks are reversible but can progress to chronic state
    - patients have an increased no. in mast cells in the bronchi
34
Q

what is involved in the late phase reactions of asthma?

A
  • cytokines and leukocyte infiltration (especially eosinophils), leading to inflammation
  • some patients develop chronic asthma: chronic inflammation, tissue damage and airway remodelling
  • 50% of asthma patients suffer with this
35
Q

what causes asthma?

A
  • associated with overactivity of T-helper cells as they drive the immune response and production of antibodes to the allergen
  • antibody is bound to mast cells and eosinophils
  • when receptors are activated from allergen binding to antibody, histamine is released and binds to smooth muscle receptors to cause constriction
  • histamine drives production of PGs which also cause bronchoconstriction
36
Q

what are mast cells and their role in asthma?

A

mediators of type 1 hypersensitivity reactions
- cause: smooth muscle contraction, increased vascular permeability, mucous secretion, platelet activation, stimulation of nerve endings and recruitment of eosinophils
- they secrete cytokines and chemokines during the immediate phase to set the scene for the late phase of an asthma attack
- IgE has natural role in allergic reaction

37
Q

what is the pathology associated with chronic inflammation of the airways?

A
  • clogged airways are full of mucus which restricts oxygen exchange
  • thickening and growth of smooth muscle cells affects the stretchiness of airways, so future allergen responses are worse
  • increase in mucus-producing cells
38
Q

what are the unwanted side effects of prednisolone steroid use?

A

Cushing’s syndrome:
- hypertension
- moon face
- poor wound healing
- muscle wasting
- increased abdominal fat

39
Q

what are the new therapies for treating asthma?

A
  • humanised antibodies and soluble receptors to IgE (omalizumab), cytokines and chemokines (biopharmaceuticals)
  • prostaglandin D2-R antagonists: PG D2 is synthesised in mast cells by PGD synthase
    • PGD2 acts on DP1 receptors on vessels to mediate vasodilation, and
      also on DP2 receptors to attract T-helper2 cells and eosinophils
    • therefore PGD2-R antagonists prevent the vasodilation and
      recruitment
  • antagonists of DP1 and DP2 receptors, and inhibitors of PGDs are in clinical development for asthma therapy

Pharmacology (10 decks)

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