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Applied Pharmacology Year 2 > Arthritis Drugs – NSAIDs and analgesics > Flashcards

Arthritis Drugs – NSAIDs and analgesics Flashcards

1
Q

Itis

A

inflammation

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2
Q

Arthro

A

joint

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3
Q

Osteoarthritis (1)

A

Osteo - bone

Primary
“Wear and tear”
Related to aging

Secondary
Trauma
Disease or obesity

Pain through inflammation

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4
Q

Rheumatoid arthritis

A

Rheum - flowing in a stream

Systemic auto-immune disorder
May affect other tissues

Pain through inflammation

Rheumatologists treat a range of other disorders

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5
Q

Osteoarthritis (2)

A

Disease affecting synovial joints
Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure

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6
Q

Why is cartilage degraded?

A

Upregulation of cytokines?
IL-1β inhibits type II collagen synthesis of hyaline cartilage
Destroy environment surrounding cartilage cells → changes to cartilage structure
Cathepsin-B can cleave aggrecan
↑Matrix metalloproteinases → breakdown of collagen → cartilage degradation

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7
Q

Risk factors

A 
Gender (more common in women)
Obesity
Age (> 40)
Genetic (e.g. collagen gene mutations)
Previous joint injury/ disease
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8
Q

Prostaglandins

A

PGD2/ PGI2 → vasodilation
PGE2 → vasodilation, pyrogenic + (under certain conds.) anti-inflammatory effects

Potentiate effects of histamine, bradykinin
Increased permeability of venules → oedema
Increased sensitivity of C fibres (PAIN!)

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9
Q

COX-1

A 
‘Constitutive’
Expressed in most tissues (inc platelets)
Housekeeping’ enzyme
Protects GI mucosa
Control of renal blood flow
Initiation of labour
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10
Q

COX-2

A

‘Inducible’
Inflammatory cells – induced by injury, infection, cytokines
Prod. inflamm. mediators

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11
Q

COX-3

A

?

Found in CNS of some species

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12
Q

The NSAIDs

A

Non-Steroidal Anti-Inflammatory Drugs (~ 50 on global market)
Aspirin
Ibuprofen*
Diclofenac
Meloxicam
Indomethacin
Many are available OTC
Most widely prescribed drugs for arthritis
Diff formulations (e.g. tablets, suspensions, gels, injections)

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13
Q

Actions of NSAIDs

A

Antipyretic
inhibit actions of PGs on hypothalamus
Analgesic
reduce sensitivity of neurons to bradykinin
effective against pain of muscular/ skeletal origin
Anti-inflammatory
reduce vasodilation and decrease permeability of venules

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14
Q

Other actions of NSAIDs

A

May scavenge oxygen radicals → ↓ tissue damage
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators
Celecoxib, diclofenac and ibuprofen - ↓ IL-6 and TNF-α in SF

N.B. only suppress signs + symptoms of inflammation – do not ↓ cytokine rel or ↓ toxins which cause tissue damage in chronic disease.

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15
Q

NSAIDs (contd)

A

Variation in individual responses/ tolerance to drugs
~ 60% people respond to any NSAID
Others usually respond to certain NSAIDs
Pain relief almost immediate → full analgesic effect within a week (anti-inflamm. effect takes longer)

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16
Q

Problems with NSAIDs

A

Risk of gastric ulcers
Impair coagulation
Use with caution in elderly (GI bleeding can be serious/ fatal)
Risk of CV events in patients with cardiac disease/ hypertension
May induce asthma attack, angioedema, urticaria or rhinitis

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17
Q

Why the problem?

A

Many inhibit COX1 as well as COX2
PGs produced by COX1 are involved in many beneficial processes:
Production of GI mucus (protective)
Blocking ↑ risk of ulcer
Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregation*

COX also generates TXA2, which promotes platelet aggregation.

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18
Q

Solving the problem

A 
COX1 and COX2 differ in structure
Should be possible to produce selective drugs
Observed that best tolerated (GI) drugs had some COX2 selectivity
E.g. meloxicam
But rofecoxib (early COX-2 inhibitor) withdrawn, as some patients died from CV complications (↓ PGI2 → platelet aggregation?)
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19
Q

COX2 Inhibitors

A

E.g. celecoxib, etoricoxib
Used mainly in patients at high risk of serious GI side effects (but with little CV risk*)
Common side-effects: headache, dizziness, skin rash, peripheral oedema

*i.e. due to possible CV side-effects

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20
Q

An Alternative Strategy

A 
Misoprostol (synthetic PG)	
Given alongside NSAIDs
Preserves mucous lining of GI tract
Protects against ulceration
Other uses?
Side-effects: diarrhoea (can be severe), vaginal bleeding
 N.B. Precautions in women of childbearing age!
Proton Pump Inhibitors (e.g. omeprazole)
Reduce acid secretion
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21
Q

Aspirin

A

Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i.e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!

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22
Q

Paracetamol: A Special Case

A 
Paracetamol is NOT an NSAID
Why?	
It has no anti-inflammatory effect	
But...
It is analgesic, antipyretic
It suppresses PG production
Actions may involve COX, but in CNS (COX3?)
May stimulate serotonergic pathways involved in inhibition of pain sensation
Often grouped together with NSAIDs
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23
Q

Paracetamol – side effects

A 
Few side-effects
Chronic use of large doses → kidney damage
Toxic doses (10 – 15g) → potentially fatal liver damage (occurs 24 – 48hr after O.D.)
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24
Q

Osteoarthritis – treatment options

A 
Weight loss
Exercise – strengthens core muscles/ improves aerobic fitness
Suitable footwear + pacing
Joint supports/ braces
Thermotherapy/ TENS devices
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25
Q

Drugs used to treat osteoarthritis

A

Paracetamol – regular dosing ± oral NSAID (with PPI*)
Topical NSAID or capsaicin (esp knee/ hand)
Opioid analgesic – for further relief
Intra-articular corticosteroid injection → temporary benefit
Joint replacement surgery (hip, knee, ankle)

26
Q

Drugs with potential benefit (1)

A

Strontium ranelate
promotes osteoblast differentiation/ inhibits osteoclast activity*
reduces pain*
Indicated for prevention of fractures in severe osteoporosis (OP)
BUT
- found to ↑ risk of MI and thrombotic events so use restricted to treatment of severe OP**

27
Q

Drugs with potential benefit (2)

A

Glucosamine sulphate
major constituent of ECM
Present in cartilage + synovial fluid
Demonstrated positive effects both in vitro + in vivo (animal models)
Differing results from clinical trials – measured pain and structural improvement
Overall no sig benefit but poss long-term side effects
Not recommended by NICE!

28
Q

Rheumatoid arthritis

A

Causes joint inflammation, especially:
Synovial membrane
Tendon sheaths
Bursae*

Leads to proliferation of synovial membrane + erosion of cartilage/ bone

Symptoms: Joints swollen + stiff (morning stiffness > 30 mins), can be painful

29
Q

Rheumatoid arthritis (contd)

A

Affects ~ 1% UK population → 1 in 3 likely to develop severe disability
Autoimmune disorder → 2- 4 x more common in women

Most commonly diagnosed between 40 and 60 years of age

30
Q

Rheumatoid arthritis: Treatment Options

A 
NSAIDs/ opioid analgesics
Glucocorticoids
Immunosuppressants
Disease Modifying Antirheumatic Drugs (DMARDS)
Anticytokines
31
Q

Glucocorticoids

A

Naturally produced in the body – where?
Used short-term – to manage flare-ups (rapidly reduce inflammation) in patients with recent-onset or established disease
Long-term – if other treatment options failed - must discuss complications

32
Q

Actions of Adrenal Steroids

A 
Two main types of action:
Glucocorticoid
metabolic effects
anti-inflammatory
immunosuppressive

Mineralocorticoid
water & electrolyte balance

33
Q

Natural steroids

A

Hydrocortisone/ corticosterone
show both (MC + GC) activities
enzyme in MC-sensitive tissues (e.g. kidney) converts these to MC-inactive compounds – why?

Aldosterone
mineralocorticoid only

34
Q

Synthetic steroids

A

Modification of natural steroids gives:
Different split of activities/potencies
Varying duration of action

i.e. useful to be able to manipulate steroid activity according to therapeutic needs

35
Q

Splitting activities

A

Modification of natural steroids gives:

Mixed gluco-/ mineralocortiocoid activity
prednisolone, prednisone
Glucocorticoid activity
dexamethasone, betamethasone beclomethasone, budesonide
Mainly mineralocorticoid activity
fludrocortisone

36
Q

Duration of action of steroids

A

Short-acting (1 -12 hrs)
Cortisone/ hydrocortisone
Twice daily cream or intra-articular injection

Intermediate-acting (12 – 36 hrs)
Prednisolone
Daily oral or intra-articular injection

Long-acting (36 – 55 hrs)
Dexamethasone
Intra-articular injection every 3 - 21 days

37
Q

Glucocorticoid actions in R.A.

A

anti-inflammatory, immunosuppressant actions:
↓ transcription of pro-inflammatory cytokines (e.g. IL-2)
↓ circulating lymphocytes
inhibit phospholipase A2 → ↓ release of arachidonic acid…………….
↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors)

used for asthma and ARTHRITIS….
beclomethasone, budesonide, prednisolone – stabilise mast cells (so ↓ histamine rel.)

38
Q

Unwanted effects of oral corticosteroids

A 
Buffalo hump
Moon face
Hypertension
Increased abdominal fat
Thinning of skin
Increased risk of infection
Muscle wasting
Poor wound healing
Osteoporosis
39
Q

Methods of reducing side effects

A

Lower plasma concentrations → fewer side effects

Choose route of admin to achieve this (e.g. topical admin.)

40
Q

Danger of stopping steroid treatment abruptly

A

Patients on course of steroid therapy > 1 month must not suddenly stop treatment

Patients on long-term therapy advised to carry card

41
Q

Disease Modifying Antirheumatoid Drugs (DMARDs)

A

Drugs with unrelated structures + diff mechanisms of action
Therapy started upon definite diagnosis of R.A. → slow onset of disease
Most important examples:
Sulfasalazine, gold compounds, penicillamine, immunosuppressants (e.g. methotrexate, ciclosporin, azathioprine, leflunomide), anticytokines

42
Q

Sulfasalazine

A

Common 1st choice DMARD in UK
Complex of salicylate (NSAID) + sulphonamide (antibiotic)
Thought to act by scavenging free radicals prod by neutrophils
Causes remission in ‘active’ R.A.
Given as enteric-coated tablets (poorly absorbed orally)
Side-effects: GI upset, headache, skin reactions, leukopenia

43
Q

Penicillamine

A

Prod by hydrolysis of penicillin
75% patients respond but therapeutic effects take weeks
Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response
Given orally – peak plasma conc → 1-2 hrs
Side-effects: rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v
Should not be given with gold compds – metal chelator!

44
Q

Gold compounds (sodium aurothiomalate/ auranofin)

A

Auranofin (oral) → inhibits induction of IL-1 + TNF-α → ↓ pain + joint swelling
Sodium auranofin – deep i.m. injection
Concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex & macrophages
Effects develop over 3 – 4 months
Side-effects: skin rashes, flu-like symptoms, mouth ulcers, blood disorders (33%)
Serious side-effects: encephalopathy, peripheral neuropathy + hepatitis (10%)

45
Q

Anti-malarials (chloroquine/ hydroxychloroquine)

A

↑pH of intracellular vacuoles → interferes with antigen-presenting
Induces apoptosis in T-lymphocytes
Usually used when other treatments fail
Therapeutic effects take a month
~ 50% patients respond
Side-effects: n+v, dizziness, blurring of vision – requires screening

46
Q

Anticytokine Drugs

A

Engineered recombinant antibodies → v. expensive!
Use restricted to patients who don’t respond well to other DMARDs
Can be given with methotrexate
E.g. adalimumab, etenercept, infliximab – target TNF; rituximab, abatacept, natalizumab – target leukocyte Rs; tocilizumab - blocks IL-6 Rs → disrupt immune signaling

47
Q

Anticytokine Drugs (contd)

A

Proteins – how does this restrict admin?
Given by s.c. or i.v. injection
Some patients do not respond
Side-effects: may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity

48
Q

Immunosuppressants

A

Rheumatoid arthritis is an AUTOIMMUNE disorder

Suppressing the immune system will therefore suppress (but not cure) disease

49
Q

Ciclosporin

A

1st discovered in fungus
Potent immunosuppressant but no effect on acute inflammation
Inhibits IL-2 gene transcription → ↓ T cell proliferation
Poorly absorbed orally – special formulations (capsules/ oral solutions)
Accumulates in high conc in tissues (i.e. remains for some time)

50
Q

Side-effects

A

Nephrotoxicity*
Hepatotoxicity
Hypertension
Also: nausea/ vomiting, gum hypertrophy, GI problems

51
Q

Azathioprine

A

Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis
Depresses cell-mediated + antibody-mediated immune reactions
i.e. targets cells in induction phase of immune response
Main specific effect: suppression of bone marrow – impact of this?

52
Q

Methotrexate

A

Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells – other uses?
Inhibits T cell activation
Patients often continue treatment for > 5 years
Side-effects: possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – why is this a problem?
Often prescribed with a DMARD

53
Q

Leflunomide

A

Specific inhibitor of activated T cells
Well absorbed orally; long t½
Side-effects: diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity

54
Q

Cyclophosphamide

A

Only used when other therapies have failed
Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)

55
Q

Immunosuppressants: general problems

A

Glucocorticoids + other IS drugs:
Increase risk of infection
Increase risk of cancer

56
Q

NSAIDs

A

Aspirin, ibuprofen, meloxicam, celecoxib

Inhibit COX enzyme →
↓ PG prod

57
Q

Corticosteroids

A

Prednisolone, dexamethasone, fludrocortisone

Block gene transcription + synthesis of inflammatory proteins, immunosuppressant.

58
Q

Immunosuppressants

A

Ciclosporin, azothioprine, methotrexate, leflunomide, cyclophosphamide

Inhibit DNA synthesis or T cell activation.

59
Q

DMARDS

A

Sulfasalazine, pencillamine, gold compds, anti-malarials

Diff mechanisms: scavenge free radicals, ↓ IL-1, etc

60
Q

Anticytokines

A

Etenercept, infliximab, rituximab, abatacept

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

Applied Pharmacology Year 2 (2 decks)

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