Anti inflammatory drugs Flashcards Preview

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Flashcards in Anti inflammatory drugs Deck (64):
1

Broad reasons for using anti inflammatory drugs

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

2

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

arachidonic acid

3

What functions are eicosanoids involved in?

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

4

What are the clinical indications for use of NSAIDs?

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

5

What drug group does aspirin belong to?

non-steroidal anti-inflammatory drugs

6

What is the action of NSAIDs?

COX inhibitors

7

What are the COX groups, found in which cells?

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

8

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

- 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)

9

What are the adverse effects of NSAIDs?

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

10

What is one way to reduce mucosal damage?

An enteric NSAID has a

11

What does an enteric form mean re NSAID?

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

12

How can foecal blood loss be reduced in using NSAIDs?

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

13

What is a selective COX-2 inhibitor?

Meloxicam

14

Advantage of selective COX-2 inhibitors

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

15

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

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

16

How do NSAIDs bind to COX?

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

17

How is aspirin/ acetyl salicylic acid metabolised?

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

18

Pharmacokinetics of salicylic acid?

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

19

How does aspirin irreversibly inhibit COX?

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

20

Doses for aspirin?

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

21

What are symptoms of salicylism/aspirin toxicity?

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

22

What are the three groups of corticosteroids?

Mineralocorticoids, androgens, glucocorticoids - antiinflammation

23

Where are the corticosteroids synthesised and secreted?

adrenal cortex

24

Corticosteroids and cholesterol?

All three groups of corticosteroids are derived from cholesterol

25

What do mineralocorticoids do?

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

26

Example of a mineralocorticoid?

aldosterone

27

What do glucocorticoids do?

affect carbohydrate and protein metabolism

28

Example of a glucocorticoid?

cortisol/hydrocortisone

29

Glucocorticoid effect as a drug?

Anti-inflammatory activity in doses above normal levels

30

indications for glucocorticoids?

- adrenal insufficiency (Addison's disease)
- inflammatory/allergic conditions

31

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

adrenal insufficiency. lethargy, weakness, hypotension, dehydration

32

How are glucocorticoids used to treat Addison's disease?

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

33

How do glucocorticoids treat inflammatory and allergic conditions?

inhibit early + late manifestations of inflammation
reverse inflammatory reaction irrespective of causative factor

34

What are interactions for glucocorticoids?

generally induce CYP3A4

35

How might glucocorticoids be administered?

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

36

Mode of action of glucocorticoids?

Have nuclear receptors, binding leads to gene transcription

37

Action of steroidal anti-inflammatory drugs?

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

38

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

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

What are anti-inflammatory actions?

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

40

Side effects of glucocorticoids?

- increased susceptibility to hyperglycaemia/diabetes
- growth suppression in children/muscle wasting
- osteoporosis
- hypertension
- increased risk of infection

41

What is Cushing's syndrome caused by?

Excess production/administration of glucocorticosteroids.

42

Symptoms of Cushing's syndrome?

- (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

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

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

44

What happens in sudden withdrawal of glucocorticoids?

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

45

Effect of a single large dose of glucocorticoids?

virtually harmless

46

Effect of prolonged glucocorticoid therapy (weeks/months)?

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

47

How long until glucocorticoids take effect?

4-6hours (gene transcriptional changes)

48

Advantages of NSAIDs therapy?

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

49

Disadvantages of NSAIDs therapy?

- 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

What are DMARDs?

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

51

How are DMARDs' potency and toxicity?

potent, often toxic

52

How long until DMARDs take effect?

6-8 weeks, some up to 6 months

53

What do DMARDs do?

retard progression of disease process

54

How are DMARDs managed today?

- earlier and more aggressive intervention with DMARDs
- combination DMARD therapy
- introduction of biologic therapy if DMARDs fail

55

Time until Methotrexate takes effect?

1-3 months, first line drug in treating arthritis

56

Mechanism of action of DMARDs?

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

57

Advantages of DMARDs

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

58

Disadvantages of old DMARDs

- 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

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

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

Examples of cytokines

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

61

Effects of IL-1?

- 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

Effects of TNF-alpha?

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

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

*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

Anti-interleukins and mechanisms of action?

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