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pharmacology > Anti inflammatory drugs > Flashcards

Anti inflammatory drugs Flashcards

1
Q

Broad reasons for using anti inflammatory drugs

A
  1. anaphylaxis is life threatening
  2. autoimmune damage e.g. RA
  3. pain, especially chronic
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2
Q

What’s the major molecule involved in producing inflammatory mediators?

A

arachidonic acid

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3
Q

What functions are eicosanoids involved in?

A

platelet aggregation, uterine motility, vasoconstriction/vasodilation, bronchodilation/bronchoconstriction, inflammation, gastric function, allergic response

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4
Q

What are the clinical indications for use of NSAIDs?

A
  • mild-moderate pain due to tissue injury
  • fever (antipyretic)
  • platelet aggregation
  • migraine
  • arthritis
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5
Q

What drug group does aspirin belong to?

A

non-steroidal anti-inflammatory drugs

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6
Q

What is the action of NSAIDs?

A

COX inhibitors

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7
Q

What are the COX groups, found in which cells?

A

COX-1: house keeping (platelet aggregation, vascular flow, renal function), found in most cells
COX-2: induced in activated inflammatory cells

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8
Q

In terms of COX inhibition, what is the effect of aspirin at different doses?

A
  • low dose aspirin = selective for COX-1
    e.g. prevent platelet aggregation and thrombosis, prevent heart attack and stroke
  • high dose aspirin = non selective, (platelets)
    (most other NSAIDs are non selective)
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9
Q

What are the adverse effects of NSAIDs?

A

GIT peptic ulcers due to lack of prostaglandin inhibition of gastric acid secretion, leading to enhanced mucosal blood flow and increased secretion of mucus
Platelet aggregation inhibited = increased bleeding time, GIT blood loss
allergic = bronchospasm, rhinitis due to increased synthesis of leukotrienes

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10
Q

What is one way to reduce mucosal damage?

A

An enteric NSAID has a

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11
Q

What does an enteric form mean re NSAID?

A

Coating over the drug allows it to bypass the stomach and be released in the duodenum

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12
Q

How can foecal blood loss be reduced in using NSAIDs?

A

Reduce 3-8ml faecal blood loss by 50% by using a soluble rather than compressed formulation

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13
Q

What is a selective COX-2 inhibitor?

A

Meloxicam

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14
Q

Advantage of selective COX-2 inhibitors

A

Lower risk of GIT effects, but at higher doses there is a higher risk of cardiovascular events

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15
Q

How is the structures of COX-1 and COX-2 different?

A

COX-2 has a side pocket, shape of COX-2 enzyme channels allows for larger molecules to bind: size and shape of the molecule depends on whether it is a COX-1 or COX-2 inhibitor

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16
Q

How do NSAIDs bind to COX?

A

NSAIDs enter hydrophobic channel forming reversible hydrogen bonds (@ arginine 120), preventing fatty acids from entering

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17
Q

How is aspirin/ acetyl salicylic acid metabolised?

A

aspirin is a prodrug that is converted to salicylic acid in the liver: 30% of the prodrug is lost to first pass metabolism

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18
Q

Pharmacokinetics of salicylic acid?

A

pKa of 3.5 (weak acid)
dose-dependent kinetics - is saturable
t 1/2 = 2-4hours in low doses
t 1/2 = 15-30 hours in high doses

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19
Q

How does aspirin irreversibly inhibit COX?

A

Enters active site with -OH, irreversibly acetylates a serine @ position 530

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20
Q

Doses for aspirin?

A

0.5-1mg/kg = low dose, e.g. anti-platelet
5-10mg/kg = moderate dose, e.g. analgesic, antipyretic
>30mg/kg = high dose, e.g. anti-inflammatory
normal tablet has 300mg

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21
Q

What are symptoms of salicylism/aspirin toxicity?

A

Tinnitus, deafness, headache, mental confusion, convulsions, coma and death
- requires CV and respiratory support, correct acid-base abnormalities and eliminate salicylate/prevent further absorption

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22
Q

What are the three groups of corticosteroids?

A

Mineralocorticoids, androgens, glucocorticoids - antiinflammation

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23
Q

Where are the corticosteroids synthesised and secreted?

A

adrenal cortex

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24
Q

Corticosteroids and cholesterol?

A

All three groups of corticosteroids are derived from cholesterol

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25
Q

What do mineralocorticoids do?

A

affect water and electrolyte balance (Na+/K+)

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26
Q

Example of a mineralocorticoid?

A

aldosterone

27
Q

What do glucocorticoids do?

A

affect carbohydrate and protein metabolism

28
Q

Example of a glucocorticoid?

A

cortisol/hydrocortisone

29
Q

Glucocorticoid effect as a drug?

A

Anti-inflammatory activity in doses above normal levels

30
Q

indications for glucocorticoids?

A
  • adrenal insufficiency (Addison’s disease)

- inflammatory/allergic conditions

31
Q

What is Addison’s disease, what are the symptoms?

A

adrenal insufficiency. lethargy, weakness, hypotension, dehydration

32
Q

How are glucocorticoids used to treat Addison’s disease?

A

as replacement therapy: glucocorticoid in conjunction with a synthetic mineralocorticoid that mimics aldosterone effects

33
Q

How do glucocorticoids treat inflammatory and allergic conditions?

A

inhibit early + late manifestations of inflammation

reverse inflammatory reaction irrespective of causative factor

34
Q

What are interactions for glucocorticoids?

A

generally induce CYP3A4

35
Q

How might glucocorticoids be administered?

A

lots
systemic = oral, intramuscular, intravenous
topical = creams, eye drops, metered dose inhaler (MDI)

36
Q

Mode of action of glucocorticoids?

A

Have nuclear receptors, binding leads to gene transcription

37
Q

Action of steroidal anti-inflammatory drugs?

A

interact with protein ‘annexin-1’ that inhibits phospholipase A2. So no arachidonic acid is produced and no leukotrienes are produced

38
Q

Why are steroidal anti-inflammatory drugs more potent than NSAIDs?

A

work at an earlier stage of mediator (leukotriene, prostaglandin, and thromboxane) production: steroidal anti-inflammatory drugs prevent arachidonic acid and leukotriene production, NSAIDs prevent thromboxane and prostaglandin production

39
Q

What are anti-inflammatory actions?

A

Decreased oedema, leucocyte activity, fibroblast function, eicosanoid production, cytokines production, NO synthesis, histamine release from basophils

40
Q

Side effects of glucocorticoids?

A
  • increased susceptibility to hyperglycaemia/diabetes
  • growth suppression in children/muscle wasting
  • osteoporosis
  • hypertension
  • increased risk of infection
41
Q

What is Cushing’s syndrome caused by?

A

Excess production/administration of glucocorticosteroids.

42
Q

Symptoms of Cushing’s syndrome?

A
  • (redistribution of body fat from extremities to neck, face and abdomen): buffalo hump, thin arms and legs, increased abdominal fat, moon face
  • other symptoms: euphoria/emotional instability, hypertension, thinning of skin, poor wound healing, easy bruising, avascular necrosis of femoral head, cataracts, benign intracranial hypertension, red plethoric cheeks
  • osteoporosis, tendency to hyperglycaemia, negative nitrogen balance, increased appetite, increased susceptibility to infection, obesity
43
Q

Relative potency of prednisolone and dexamethasone relative to hydrocortisone (natural glucocorticoid)? Therefore in what type of situation would they be used?

A

prednisolone 4x as potent
dexamethasone 30x as potent
life threatening situations

44
Q

What happens in sudden withdrawal of glucocorticoids?

A

adrenal insufficiency (Addison’s disease), due to suppression of endogenous steroids

45
Q

Effect of a single large dose of glucocorticoids?

A

virtually harmless

46
Q

Effect of prolonged glucocorticoid therapy (weeks/months)?

A

usually associated with problems - need to use lowest effective dose for shortest period of time

47
Q

How long until glucocorticoids take effect?

A

4-6hours (gene transcriptional changes)

48
Q

Advantages of NSAIDs therapy?

A
  • control of inflammation and pain
  • reduced swelling
  • improved mobility, flexibility and range of motion
  • improved quality of life
  • relatively low-cost
49
Q

Disadvantages of NSAIDs therapy?

A
  • does not affect disease progression
  • GI toxicity common
  • renal complications
  • hepatic dysfunction
  • CV complications e.g. through COX 2
  • treat symptoms not the cause
50
Q

What are DMARDs?

A

unrelated to each other, different chemical structures and different modes of action

51
Q

How are DMARDs’ potency and toxicity?

A

potent, often toxic

52
Q

How long until DMARDs take effect?

A

6-8 weeks, some up to 6 months

53
Q

What do DMARDs do?

A

retard progression of disease process

54
Q

How are DMARDs managed today?

A
  • earlier and more aggressive intervention with DMARDs
  • combination DMARD therapy
  • introduction of biologic therapy if DMARDs fail
55
Q

Time until Methotrexate takes effect?

A

1-3 months, first line drug in treating arthritis

56
Q

Mechanism of action of DMARDs?

A

affect antigen presenting cells, cytokines (less synovial inflammation, production of ECM programs, destructive symptoms, effect on bone)
methotrexate affects T and B cells

57
Q

Advantages of DMARDs

A 
slow progression of disease
improve functional disability 
decrease pain 
interfere with anti-inflammatory processes
retard joint erosion
58
Q

Disadvantages of old DMARDs

A
  • lacking adequate safety profile
  • unable to control disease activity in large groups of patients, variable effects
  • newer biologic agents could address this by acting on cytokines
59
Q

Features of cytokines: what, released by what, bind to what and type of action

A

LMW proteins (30KDa) acting on immune cells
released by immune cells during inflammation to promote proliferation and growth of those immune cells
bind to TRK (“track”) receptors to alter gene expression
actions are local (para/autocrine) and synergistic

60
Q

Examples of cytokines

A

ILs, chemines, interferons, colony stimulating factors, growth factors, tumour necrosis factor (TNF)

61
Q

Effects of IL-1?

A
  • activates monocytes/macrophages, (inflammation)
  • induce fibroblast proliferation (synovial pannus formation -new granular tissue in cartilage space)
  • activates chondrocytes (cartilage breakdown)
  • activates osteoclasts (bone resorption)
62
Q

Effects of TNF-alpha?

A

interferes with synovial producing cells/synoviocytes (pain, joint swelling)
interferes with osteoclasts (bone erosion)
interferes with chondrocytes, increasing cartilage degradation (narrowing of joint space)

63
Q

3 examples of Anti-TNF agents? Common mechanism of action?

A

infliximab, etanercept, adalimumab
binds to TNF-alpha, prevents binding of TNF-alpha to TNF receptors on inflammatory cells, results in suppression of downstream cytokines and suppression of leucocyte migration and activation

64
Q

Anti-interleukins and mechanisms of action?

A

rituximab - B-cell depletion
basiliximab - recombinant monoclonal antibody directed against IL-2 receptor a-chain preventing actions of IL-2
anakinra - competitive IL-1 receptor antagonist

pharmacology (17 decks)

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