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Pharmacology - Year 2 AC > Week 2 - Drugs And Arthritis > Flashcards

Week 2 - Drugs And Arthritis Flashcards

1
Q

What is osteoarthritis characterised by?

A

Loss of cartilage and bone from articulating surfaces

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2
Q

What do prostaglandins D2 and I2 trigger?

A

Vasodilation

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3
Q

What does prostaglandin E2 trigger?

A

Vasodilation, pyrogenic and anti-inflammatory effects

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4
Q

What do the products of COX-2 have a role in?

A

Inflammation, fever, pain

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5
Q

Name some NSAIDS

A

Ibuprofen, aspirin, diclofenac, meloxicam, indomethacin

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6
Q

Why do NSAIDS have antipyretic effects?

A

They inhibit actions of prostaglandins on the hypothalamus

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7
Q

Why do NSAIDS have an analgesic effect?

A
  • reduce sensitivity of neurones to bradykinin

- pain transmission is blocked by COX inhibition

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8
Q

Why do NSAIDS have an anti inflammatory effect?

A

Reduce vasodilation and decrease the permeability of venules

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9
Q

What is another action of NSAIDS that hasn’t already been mentioned?

A

May scavenge oxygen radicals - decreases tissue damage

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10
Q

What does aspirin inhibit and what is the effect of that?

A

Inhibits NFkB expression

  • decreases transcription of genes for inflammatory mediators
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11
Q

What does celecoxib, diclofenac and ibuprofen decrease?

A

Decreases IL-6 and TNF-a in SF

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12
Q

What are some issues with NSAIDS?

A
  • risk of gastric ulcers/GI bleeding
  • impair coagulation
  • risk of CV events in puts with cardiac disease/hypertension
  • may induce asthma attack, angioedema, urticaria (hives) or rhinitis
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13
Q

Why are some of the problems to do with NSAIDS caused?

A

May inhibit COX-1 as well as COX-2

PGs produced by COX-1 are involved in many beneficial processes - production of GI mucus, inhibit platelet aggregation (PGI2), also generates TXA2 (promotes platelet aggregation)

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14
Q

Give an example of a well tolerated GI drug with some COX2 selectivity

A

Meloxicam

  • appears to concentrate in synovial fluid, less GI effects and doesn’t affect platelet function
  • CV complications
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15
Q

What types of joints does osteoarthritis affect?

A

Synovial joints - where bones meet to form a joint, bones surface are covered with a thin layer of cartilage and synovial fluid separates/lubricates them.

(Wrist, elbow, shoulder, knee etc).

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16
Q

Which drugs (NSAIDS) are COX-2 inhibitors?

A

Celecoxib, etoricoxib

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17
Q

Whith what patients are celecoxib and etoricoxib mainly used?

A

Used on pts at a high risk of GI side effects but with little CV risk

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18
Q

What are common side effects of COX-2 inhibitors?

A

Headache, dizziness, skin rash, peripheral oedema

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19
Q

What is given alongside NSAIDS which preserves the mucus lining of the GI tract?

A

Misoprostol

Proton pump inhibitors e.g. Omeprazole

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20
Q

What is misoprostol?

A
  • synthetic prostaglandin

- PGE1 analogue

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21
Q

What are the side effects of misoprostol?

A

Diarrhoea, vaginal bleeding, used to induce abortion (can be a side effect)

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22
Q

Where is aspirin absorbed?

A

Rapidly absorbed in the stomach (I.e. Weak acid)

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23
Q

What does aspirin displace?

A

Displaces warfarin bound to plasma proteins

  • increases plasma warfarin and potentiates warfarins anticoagulant activity (warfarin not active until free from plasma proteins)
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24
Q

Is paracetamol an NSAID?

A

No

  • analgesic, antipyretic
  • does suppress PG production

-used as a safer/long term alternative to NSAIDS/COX-2 inhibitors

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25
Q

What are non-drug treatment options for osteoarthritis?

A

Exercise, weight loss, suitable foot wear, joint supports/braces, thermotherapy/ TENS devices

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26
Q

What are drug treatment options for osteoarthritis?

A
  • paracetamol - regular dosing +- oral NSAID with PPI
  • topical NSAID or capsaicin
  • opioid analgesic
  • intra-articular corticosteroid injection
  • joint replacement surgery
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27
Q

What are drugs with potential benefit to treat osteoarthritis?

A
  • strontium ranelate - promotes osteoblasts differentiation / inhibits osteoclast activity, reduces pain but found to increase risk of MI and thrombotic events - only used when severe OA
  • glucosamine sulphate - present in cartilage and synovial fluid - differing results from clinical trials
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28
Q

Why does rheumatoid arthritis occur?

A

Antibodies are targeted towards normal proteins in the connective tissue of joints, with the result that pro-inflammatory chemicals called cytokines are released

-attacks cartilage and proteins within it

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29
Q

Where is joint inflammation especially caused in rheumatoid arthritis?

A
  • synovial membrane
  • tendon sheaths
  • bursae(filled with synovial fluid, provide a cushion between bones/tendons/muscles around a joint
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30
Q

What does RA as an autoimmune disease lead to?

A

Leads to proliferation of synovial membrane which forms a spur into the articulating surface of the bones and erosion of cartilage/bone as they rub together - inflammation –> pain

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31
Q

How is the disease progression for rheumatoid arthritis measured?

A

Measuring levels of C-reactive protein (CRP) in the blood

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32
Q

What are the drug treatment options for rheumatoid arthritis?

A
  • NSAIDS/opioid analgesics - pain
  • glucocorticoids- pain and limitation of joint damage
  • immunosuppressants - limitation of joint damage
  • DMARDS - limitation of joint damage
  • anticytokines - limitation of joint damage
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33
Q

How do immunosuppressant drugs work?

A

Reduce the production and activation of T-cells at the start of this process (however T-cells play an important role in the overall function of the immune system)

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34
Q

How do glucocorticoids work?

A

Suppress the function of macrophages, hence reduce secretion of inflammatory cytokines

35
Q

How do anticytokine drugs (anti-IL1 and anti-TNF) work?

A

Suppress the activation of osteoclasts and fibroblasts

36
Q

How do DMARDS work?

A

Act directly on the joint to block inflammatory processes

37
Q

Name some corticosteroids

A

Prednisolone, dexamethasone, fludrocortisone

38
Q

Where are glucocorticoids naturally produced in the body?

A

Adrenal cortex - hydrocortisone (cortisol)

39
Q

When are glucocorticoids used and how long for?

A

Short term - to manage flare-ups (rapidly reduce inflammation) in pts with recent onset or established disease

Long term - if other treatment options fail (must discuss complications before administering)

40
Q

What effects to glucocorticoids have on the body?

A
  • metabolic effects - increase breakdown of protein and fatty release glucose (liver/adipose tissue)
  • anti-inflammatory - inhibit production of inflammatory mediators
  • immunosuppressive - inhibit NFkB which is necessary for activation of B-cells and synthesis or cytokines
41
Q

What are mineralocorticoids mainly used for?

A

Water and electrolyte balance (e.g. Aldosterone)

42
Q

What is the advantage of using synthetic steroids?

A

Modification of natural steroids gives:

  • different split of activities/potencies
  • varying duration of action
  • useful to be able to manipulate steroid activity according to therapeutic needs
43
Q

Name the synthetic steroids

A
  • prednisolone/prednisone - mixed gluco/mineralocorticoid activity
  • dexamethasone/betamethasone/beclomethasone/budesonide - glucocorticoid activity
  • fludrocortisone (treats adrenal insufficiency) - mainly mineralocorticoid activity
44
Q

State the duration of action of the different steroids

A
  • cortisone/hydrocortisone - short acting (1-12 hours) - 2X daily cream or intra-articular injection
  • prednisolone - intermediate acting (12-36 hrs) - daily oral or intra-articular injection
  • dexamethasone - long acting (36-55 hrs) - intra-articular injection every 3-21 days
45
Q

What must steroids do before they cause a response?

A

Enter the cell (lipid/fat soluble)

46
Q

What happens to steroids when they cross the cell membrane?

A
  • bind to free rectors in the cytoplasm to form a complex
  • 2 complexes join together, enabling them to enter the nucleus
  • binds to DNA inside nucleus
  • results in genes being either switched on (mRNA produced used to make certain proteins) or off
47
Q

Name the actions that glucocorticoids have in rheumatoid arthritis

A
  • anti-inflammatory and immunosuppressant actions
  • decreased transcription of pro-inflammatory cytokines (e.g. IL-2)
  • decrease circulating lymphocytes
  • inhibit phospholipase A2 (decreases release of arachidonic acid)
  • increases synthesis of anti-inflammatory proteins (e.g. Protease inhibitors)
48
Q

Name some glucocorticoids and state their action

A

Beclomethasone, budesonide, prednisolone

-stabilise mast cells (so decreases histamine release)

49
Q

What are the unwanted effects of oral corticosteroids?

A

Cushingoid features

-buffalo hump, hypertension, muscle wasting, osteoporosis, poor wound healing, increased risk of infection, thinning of skin, increased abdo fat, moon face, metabolic effects, risk of infection

50
Q

Why is there a danger when stopping steroid treatment abruptly?

A
  • causes suppression of normal steroid synthesis
    (Due to excessive negative feedback, may precipitate acute adrenal failure)

-gradual reduction needed

51
Q

Name some disease-modifying anti rheumatoid drugs (DMARDS)

A
  • sulfasalazine
  • pencillamine
  • gold compounds
  • anti-malarials
  • anti-cytokines
  • immunosuppressants (methotrexate, ciclosporin, azathioprine, leflunomide)

(Unrelated structures and different mechanisms of action)

52
Q

What is the mechanism of action of sulfasalazine?

A
  • scavenging free radicals produced by neutrophils (to kill bacteria but they also damage surrounding tissue
  • causes remission in active RA
  • given as enteric coated tablets (poorly absorbed orally)
  • 1st choice DMARD
  • complex of salicylate (NSAID) and sulphonamide (antibiotic)
53
Q

What are the side effects of sulfasalazine?

A

GI upset, headache, skin reactions, leukopenia

54
Q

What is the mechanism of action and general info for pencillamine?

A
  • produced by hydrolysis of penicillin
  • therapeutic effects take weeks
  • lowers IL-1 generation and lowers fibroblast proliferation = decreases immune response and reduces pannus formation
  • given orally
  • peak plasma conc. = 1-2 hours
55
Q

What are the side effects of pencillamine?

A

Rashes, stomitis

Anorexia, taste disturbance, fever, N+V

56
Q

What should pencillamine not be given with?

A

Gold compounds (metal chelator)

57
Q

Name some gold compounds and state how long it takes for their effects to develop

A

Auranofin, sodium auranofin

Effects develop over 3-4 months

58
Q

How is auranofin administered and what is its mechanism of action?

A
  • oral

- inhibits induction of IL-1 + TNF-a (decreases pain and joint swelling)

59
Q

How is sodium auranofin administered and what is its mechanism of action?

A
  • deep I.m. Injection

- concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex and macrophages

60
Q

What are the side effects of gold compounds?

A

Skin rashes, flu like symptoms, mouth ulcers, blood disorders (33%)

Serious side effects:
Encephalopathy, peripheral neuropathy, hepatitis (10%)

61
Q

Name some anti-malarial drugs

A

Chloroquine

Hydroxychloroquine

62
Q

State the mechanism of action and other info about anti-malarial drugs

A
  • increases the pH of intracellular vacuoles - interferes with antigen presenting
  • induces apoptosis in T-lymphocytes
  • usually used when all other treatments fail
  • therapeutic effects take a month (50% respond)
63
Q

What are the side effects of anti-malarial drugs?

A

N+V, dizziness, blurring of vision

64
Q

Name some anticytokines

A

Adalimumab, etenercept, infliximab, rituximab, abatacept, natalizumab, tocilizumab

65
Q

What are anticytokines and when are they used?

A
  • engineered recombinant antibodies
  • use restricted to patients who don’t respond well to other DMARDS
  • can be given with methotrexate (abatacept)
  • some pts don’t respond

Given by s.c or I.v injection

66
Q

Which drugs(anticytokines) target TNF?

A

Adalimumab, etenercept, infliximab

By blocking TNF-a - acts as decoy receptors

67
Q

Which drugs(anticytokines) target Leukocyte receptors?

A

Rituximab, abatacept, natalizumab

68
Q

Which drug(anticytokine) disrupts immune signalling?

A

Tocilizumab

-blocks IL-6 receptors

69
Q

What are the side effects of anticytokine drugs?

A
  • may develop a latent disease (e.g. TB, hep b, herpes zoster etc) and opportunistic infection
  • N+V
  • abdominal pain
  • worsening heart failure
  • hypersensitivity
70
Q

Name some immunosupressants

A

Ciclosporin, azothioprine, methotrexate, leflunomide, cyclophosphamide

71
Q

State the mechanism of action and general info for ciclosporin

A
  • potent immunosuppressant but no effect on acute inflammation
  • inhibits IL-2 gene transcription –> decreases t-cell proliferation
  • poorly absorbed orally - special formulations
  • accumulates in high conc. In tissues - remains for some time
  • patients who have received transplants
72
Q

What are the side effects of ciclosporin?

A

Nephrotoxicity, hepatotoxicity, hypertension, N+V, gum hypertrophy, GI problems

73
Q

State the mechanism of action and general info for azathioprine

A

Main effect - suppression of bone marrow

  • cytotoxic: interferes with purine metabolism (purines = bases found in DNA which are necessary for synthesis of DNA during cell proliferation) so decreases DNA synthesis
  • depresses cell-mediated + antibody-mediated immune reactions by interfering with production of B-cells and presentation of antigen to t-cells (reduces proliferation of these cells)
74
Q

State the mechanism of action and general info for methotrexate

A
  • folic acid antagonist - inhibits DNA synthesis
  • blocks growth and differentiation of rapidly dividing cells
  • inhibits T-cell activation
  • patients often continue treatment for >5 years
  • often prescribed with a DMARD
  • quicker acting than other drugs
75
Q

What are the side effects of methotrexate?

A
  • possibility of blood dyscrasias (abnormalities) and liver cirrhosis (requires monitoring)
  • folate deficiency - need to make RBC –> anaemia
76
Q

State the mechanism of action and general info for leflunomide

A
  • specific inhibitor or activated T cells

- well absorbed orally - long half life

77
Q

What are the side effects of leflunomide?

A

Diarrhoea, alopecia, increased liver enzymes (risk of hepatotoxicity)

78
Q

State the mechanism of action and general info for cyclophosphamide

A
  • only used when other therapies have failed
  • prodrug - can be administered orally - activated in liver to phosphoramide mustard and acrolein
  • Acrolein - haemorrhagic cystitis
  • prevented by administering with large volumes of fluid
79
Q

What is the mechanism of action for NSAIDS?

A

Inhibit COX enzyme –> decreases prostaglandin production

80
Q

What is the mechanism of action for corticosteroids?

A

Block gene transcription and synthesis of inflammatory proteins, immunosuppressant

81
Q

What is the mechanism of action for Immunosupressants?

A

Inhibit DNA synthesis or t-cell activation

82
Q

What is the mechanism of action for DMARDS?

A

Different mechanisms - scavenge free radicals, lower IL-1 etc.

83
Q

What is the mechanism of action for anticytokines?

A

Antibodies which bind to specific immune cells cytokines to inhibit immune response

Pharmacology - Year 2 AC (14 decks)

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