Gout And Rheumatoid Arthritis: Pharmacology

Front 1

Gout Def

Back 1

arthritis due to deposition of monosodium urate crystals (MSU) in and about joints and tendons

precipitate from plasma which is hypersaturated with urate

MSU crystals induce severe local inflammation

Front 2

Therapeutic Objectives for Gout

Back 2

1. treatment of acute pain and inflammation

2.prophylaxis of recurrence

3. prevention of permanent joint and organ damage

Front 3

Therapeutic Strategies for Gout

Back 3

1. Anti-inflammatory interventions/analgesia

2./3. Reduction of plasma urate levels and total body urate pool

Front 4

2 Diagrams on pg. 3

Back 4

flow of uric acid and drugs used

Front 5

Where do these play a role?

1. Allopurinol
2. Oxypurinol
3. Probenecid Sulfapyrazone
4. Colchicine
5. NSAIDs
6. Low Dose Aspirin, Diuretics

Back 5

1. Xanthine oxidase inhibitor
2. Xanthine oxidase Inhibitor
3. Decrease tubular reabsorption
4. Decrease Granulocytes
5. Decrease inflammation

Front 6

Diagnosing Gout

Back 6

often sudden onset
nocturnal
monoarticular
small peripheral joint
fever
precipitating factor

Front 7

Gout Differentials:

Back 7

critical: bacterial infection of joint

pseudogout, aseptic monoarthritis, trauma

Front 8

Gout Risk Factors

Back 8

high purine intake
obesity
alcohol
metabolic factors
drug therapy
kidney failure

Front 9

Is plasma urate level a reliable predictor of gouty attacks

Back 9

NO: plasma levels may be above 9mg/dL and may persist for years without gouty attack

but in a gouty attack the total body pool of urate is usually increased up to 30 fold (normal is 1g)

Front 10

What does deposition of MSU crystals depend on?

Back 10

solubilizers present in plasma
plasma pH
tissue perfusion, and tissue temperature

Front 11

What is the aqueous solubility of urate?

Back 11

<7mg/dL

Front 12

Inflammation in Gouty Goint

Back 12

flow in packet pg. 4

Front 13

Colchine

Back 13

plant alkaloid, binds tubulin, causes depolymerization
cytostatic effect in leukocytes
inhibits inflammatoin and provides pain relief

NO effect on MSU crystals or plasma urate

Front 14

Colchine PK

Back 14

oral, or IV

unchaged excretion via feces or urine

enterohepatic circulation

many PK interactions (P-gp)

Front 15

Cochine AE

Back 15

related to cytostatic properties

Acute: GI, abdominal pain, diarrhea (frequent)
Chronic: Long term use not recommended
alopecia, agranulocytosis, aplastic anemia, myopathy, neuropathy

CI in pregnancy or severe second disease

Front 16

Allopurinol

Back 16

uricostatic

inhibit xanthine oxidase which decreases uric acid and increases hypoxanthine and xanthine

hypoxanthine and xanthine are better soluble than UA and reduces the risk of UA precipiation and it also increases elimination of hypo adn xanthine via renal

Front 17

Allopurinol AE

Back 17

GI upset; may increase uric acid levels at onset of therapy

Front 18

Allopurinol USE

Back 18

management of chronic gout

NOT in 1st 1-2 weeks after an acute episode

Front 19

Uricosuric Agents

Back 19

Probenecid
Sulfinpyrazone
Benzbromarone

block tubular reabsorption of uric acid at therapeutic concentrations

Front 20

What happens at low doses of uricosouric agents?

Back 20

may block tubular excretion of uric acid, making things worse

Front 21

Uricosouric Agents PK

Back 21

probenecid inhibits tubular secretion of
penicillin
naproxen, ketoprofen, and indomethacin

Front 22

Uricosouric AE

Back 22

mild

sulfinpyrazone: GI

Front 23

Treatment of Acute Gout

Back 23

1. establish diagnosis (microscopically ID MSU crystals)

2. Decide on NSAID or Colchicine
Colchicine: p.o. 1mg q 2h until response is seen or AE limits use: don't exceed 7mg in 48 hours

3. Pain should decrease within 12h and cease within 2 days

4. additional opioid analgesic may be required

5. splinting of joint may be helpful

6. DO NOT initiate treatment with drugs that lower serum urate before symptoms have been fully controlled

Front 24

Aims of Treatment for Chronic Hyperuricemia

Back 24

prevent recurrent attacks

lower plasma urate levelss to normal
minimize body total urate pool
resolve tophaceous MSU deposits in tissues/joints
prevent organ damage

decreasing urate levels may take months to years and could be life long maintanence

Front 25

Protocol for Hyperuricemia Treatment

Back 25

high fluid turnover (>3L/day)

start in symptom/free interval

avoid purine rich foods

Rx allopurinol and or uricosuric drug

NSAID or colchicine at onset to prevent recurrent attack

weight reduction in symptom free times

alkalinazation of urine but don't over do it (calcium oxalate stones in alkaline urine)

Front 26

Rheumatoid Arthritis Diagnosis

Back 26

any 4 of the following:
morning stiffness for >1hr
arthritis of three or more joints for >6 weeks
arthritis of hand joints
symmetric arthritis for >6 weeks
Rheumatoid nodules
Serum rheumatoid factor positive
Radiographic changes typical of RA

Front 27

Rheumatoid Arthritis Objective of Treatment

Back 27

control pain
control infllammation
protection/conservation of joint and muscle function
prophylaxis of organ damage

Front 28

Rheumatoid Arthritis Treatment modalities

Back 28

1. rest, motion exercise, physiotherapy, diet, heat, cold
2.Symptomatic treatment with NSAID
3.Disease modifying drugs (start early after diag)
4.Immunosuppresant drugs

corticosteroids, surgery, novel/experimentl drugs

Front 29

AE of NSAID

Back 29

GI bleed in 2-4% of patients

cost 4 billion per year

Front 30

Low Risk GI bleed NSAID

Back 30

Paracetamole
Ibuprofen

Front 31

Intermediate Risk GI bleed NSAID

Back 31

Aspirin
Diclofenac
Diflunisal

Front 32

High Risk GI Bleed NSAID

Back 32

Piroxicam
Indomethacin
Ketoprofen

Front 33

Disease Modifying Drugs

Back 33

DMARDS

methotrexate, chlorambucil, cyclophosphamide, gold compounds, hydroxychloroquine, penicillamine, Sulfasalazine, Azathioprine, Cyclosporine, Mycofenolate

Front 34

Common Features of DMARDS

Back 34

mechanisms poorly understood
none is effective in more than 60% of patients
effectivity is largely unpredicatble
therapeutic effects take 2-4 months to develop
if one has been ineffective in a patient once, it is considered ineffective in this case for the future

Front 35

Methotrexate

Back 35

low dose use (DMARD)

aminopterin analogue, designed to inhibit dihydrofolate reductase, used in high doses as cytostatic drug

Front 36

Methotrexate PK

Back 36

oral, s.c, im, iv

t1/2=7h

renal elimination 60%

enterohepatic recirculation

Front 37

Methotrexate PD in RA

Back 37

inhibition of
1. AICAR (aminoimidazolecarboxamide)-transformylase and thymidilate synthetase---->polymorphnuclear chemotaxis is decreased

2. dihydrofolate reductase-->lymphocyte and macrophage function decrease

Front 38

Mehtotrexate (DMARD) AE

Back 38

int.: nsaid reduce Clren: combinatino with other sulfas (cotrimoxazole) potentiates bone marrow toxicity

GI, stomatitis, hair loss

Teratogen

Front 39

Methotrexate (DMARD) USE

Back 39

7.5-15mg once a week combined with 1mg folic acid daily (stomatitis)

expect effect 6-8 weeks

monitor leuko, thromob, liver enzymes, creatinine, urinary status

Front 40

Advantage of Methotrexate vs. other DMARD

Back 40

probably best response rate
less adverse effects than other DMARDs
well tolerated in long term treatment
well tolerated in DMARD combination treatment

Front 41

Biological Response Modifiers

Back 41

reduce the activity of tumor necrosis factor

kineret (adalimumab)
enbrel (etanercept)
remicade (infliximab)

usually given in combo with MTX
cost 10,000/yr

used initially for refractive cases but now trend towards early treatment