1. Drug Therapy of Gout

2. What Is Gout?
A medical condition caused by an increase in the level of uric acid >> urate crystals , causing inflammatory responses around some joints of the body ( Gouty arthritis )

3. Case presentation ( Gouty arthritis)
55 y/o male
12 hours “pain in my big toe & ankle”
went to bed last night feeling fine
felt as if had broken toe this morning
PMH of similar problems in right ankle & left wrist

4. acute synovitis, ankle & first MTP joints
Gout - acute arthritis
acute synovitis, ankle & first MTP joints
Redness and swelling are noticed around those joints in particular
The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

5. Gout - acute bursitis acute olecranon bursitis
Bursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone

6. Gouty arthritis - characteristics
sudden onset
middle aged males
severe pain
distal joints
Intense inflammation
recurrent episodes
influenced by diet ( since uric acid level is influenced by our dietary intake of purines)
bony erosions on Xray

7. Monosodium urate crystals
1-polarized light
2-red compensator
These crystals show :
1-needle shape
2-negative birefringence (Birefringence: double streams of light, usually in prisms, etc)
Diagnosis is done by taking a biopsy from the synovial fluid and then examined either by:

8. Crystal-induced inflammation (from gout to gouty arthritis )
crystal deposition
(blood stream)
hyperuricemia
protein binding
receptor binding
(Synovial joints )
cytokine release
influx of PMN’s
(Macrophages )
crystals engulfed
inflammation
PMN is critical component of crystal-induced inflammation

9. Gouty arthritis - characteristics
sudden onset
middle aged males
severe pain
distal joints
intense inflammation
recurrent episodes
influenced by diet
bony erosions on Xray
Hyperuricemia (always)

10. Hyperuricemia excretion production
hyperuricemia results when production exceeds excretion (either by over production or less excretion )

11. net uric acid loss results when excretion exceeds production
Hyperuricemia
production
excretion
net uric acid loss results when excretion exceeds production

12. Chronic tophaceous gout
tophus = localized deposit of monosodium urate crystals
** could also be in several places in the body

13. classic location of tophi on helix of ear
Gout - tophus
classic location of tophi on helix of ear

14. Gout - X-ray changes
DIP (Distal interphalangeal joint) joint destruction
phalangeal bone cysts

15. Gout - X-ray changes
bony erosions

16. Gout - cardinal manifestations
arthritis
tophi
chronic
acute & chronic
HYPERURICEMIA
Nephrolithiasis
(Kidney stones)
nephropathy
*kidneys should be functioning well in order to use classical treatment

17. Drug therapy of gout Treatment targets either :
1- Decrease Uric Acid Formation
2- Increase Uric Acid Excretion

18. The Role of Uric Acid in Gout
end product of purine metabolism
serum uric acid level dependent upon
rate of uric acid production
efficiency of renal uric acid excretion

19. Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid
One method of reducing uric acid levels , is inhibition of the enzyme xanthine oxidase
xanthine
uric acid

20. Renal handling of uric acid
Fate of uric acid in kidneys :
Uric acid
glomerular filtration
tubular reabsorption
tubular excretion
post-secretory reabsorption
net excretion
Uric acid
Uric acid
Uric acid
The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys.

21. The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys
Non steroidal anti-inflammatory Drugs are sometimes used in the treatment of Gout ( cause increase in excretion )
Aspirin on the other hand is never used

22. Gout - problems excessive total body levels of uric acid
deposition of monosodium urate crystals in joints & other tissues
crystal-induced inflammation

23. Treating acute gouty arthritis
colchicine
NSAID’s
steroids
rest, analgesia, ice, time

24. Drugs used to treat gout
Urate Lowering Drugs
For chronic cases
Acute Arthritis Drugs
steroids
NSAID’s
colchicine
allopurinol
probenecid
febuxostat?
It’s a new drug that’s being developed
rest + analgesia + time

25. Drugs used to treat gout
NSAID’s
Indomethacin (Indocin) 25 to 50 mg four times daily
Naproxen (Naprosyn) 500 mg two times daily
Ibuprofen (Motrin) 800 mg four times daily
Sulindac (Clinoril) 200 mg two times daily
Ketoprofen (Orudis) 75 mg four times daily
*Don’t memorize the doses, just the names
** Remember that Aspirin is never used

26. Colchicine - plant alkaloid
colchicum autumnale
(autumn crocus or meadow saffron)

27. Correction for the previous lecture
Colchicine is used to prevent the polymerization of the cell’s cytoskeleton by binding to TUBULIN ( not Actin)

28. Colchicine
“only effective in gouty arthritis” ( it only works on the inflammation process , and has nothing to do with uric acid levels .)
not an analgesic
does not affect renal excretion of uric acid
does not alter plasma solubility of uric acid
neither raises nor lowers serum uric acid

29. Colchicine
Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules
reduces inflammatory response to deposited crystals
diminishes PMN phagocytosis of crystals
blocks cellular response to deposited crystals

30. Crystal-induced inflammation
crystal deposition
hyperuricemia
protein binding
receptor binding
cytokine release
influx of PMN’s
crystals engulfed
inflammation
PMN is critical component of crystal-induced inflammation

31. Colchicine - indications
Dose
Indication
high
treatment of acute gouty arthritis
low
prevention of recurrent gouty arthritis
It’s better to use xanthine oxidase inhibitors for

32. Colchicine - toxicity
Associated with high doses :
gastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain)
hematologic (agranulocytosis, aplastic anemia, thrombocytopenia)
muscular weakness
adverse effects dose-related & more common when patient has renal or hepatic disease

33. Gout - colchicine therapy
more useful for daily prophylaxis (low dose)
prevents recurrent attacks
colchicine 0.6 mg qd - bid
declining use in acute gout (high dose)

34. Colchicine - Cancers
Promising studies have recently shown that Colchicine could be used for treating tumors
HOW ?
Since Colchicine prevents the formation of microtubules , this could be useful in limiting the mitotic activity of tumors cell : by preventing the formation of mitotic spindles (microtubules .)

35. Hyperuricemia - mechanisms
excessive production
inadequate excretion

36. net reduction in total body pool of uric acid
Urate-lowering drugs
block production
enhance excretion
net reduction in total body pool of uric acid

37. Gout - urate-lowering therapy
Xanthine Oxidase as an example
prevents arthritis, tophi & stones by lowering total body pool of uric acid
not indicated after first attack
initiation of therapy can worsen or bring on acute gouty arthritis
no role to play in managing acute gout

38. Drugs That Block Production of Uric Acid
Drug therapy of gout
Drugs That Block Production of Uric Acid

39. Uric acid metabolism
cell breakdown
dietary intake
purine bases
hypoxanthine
xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid
xanthine
uric acid

40. Allopurinol (Zyloprim™)
inhibitor of xanthine oxidase
effectively blocks formation of uric acid
how supplied mg & 300 mg tablets
pregnancy category C
**Drugs are characterized according to their effects on pregnancy (fetus) into several categories A,B,C,D,X.
A is the safest, X: completely dangerous and should not be given to pregnant women 
**benefits from taking the drug must outweigh it’s risks in order for it to be used.
allopurinol

41. Allopurinol - usage indications
management of hyperuricemia of gout
management of hyperuricemia associated with chemotherapy
prevention of recurrent calcium oxalate kidney stones

42. Allopurinol - common reactions
diarrhea, nausea, abnormal liver tests
acute attacks of gout
rash
*Manufactures are obliged to put a special indication on each leaflet ( a BLACK BOX) , that explains the serious side effect for that particular drug
e.g Isotretinoin is a highly teratogenic Drug that should have a BLACK BOX
**For Allopurinol you might find that BLACK BOX sometimes , because certain people have shown to have allergy for it .

43. Allopurinol - serious reactions
fever, rash, toxic epidermal necrolysis
hepatotoxicity, marrow suppression
vasculitis
drug interactions (ampicillin(antibiotic), thiazides(diuretic ), mercaptopurine, azathioprine(anti-cancer)
death

44. Stevens-Johnson syndrome
Another serious side effect , characterized by :
Mucocutaenous ulcerations
target skin lesions
mucous membrane erosions
epidermal necrosis with skin detachment
Those side effects are treated by systemic corticosteroids

45. Allopurinol hypersensitivity
extremely serious problem
prompt recognition required
first sign usually skin rash
more common with impaired renal function
progression to toxic epidermal necrolysis & death

46. Febuxostat recently approved by FDA (not on market)
oral xanthine oxidase inhibitor
chemically distinct from allopurinol
94% of patients reached urate < 6.0 mg/dl
minimal adverse events
can be used in patients with renal disease

47. PEG-uricase (Polyethelene Glycol)
Uricase: enzyme that degrades uric acid 
investigational drug
PEG-conjugate of recombinant porcine uricase
treatment-resistant gout
uricase speeds resolution of tophi
further research needed

48. Drugs That Enhance Excretion of Uric Acid
Drug therapy of gout
Drugs That Enhance Excretion of Uric Acid

49. Uricosuric therapy probenecid blocks tubular reabsorption of uric acid
enhances urine uric acid excretion
increases urine uric acid level
decreases serum uric acid level

50. Uricosuric therapy moderately effective
increases risk of nephrolithiasis
not used in patients with renal disease
frequent, but mild, side effects

51. Uricosuric therapy contra-indications history of nephrolithiasis
elevated urine uric acid level
existing renal disease
less effective in elderly patients

52. Choosing a urate-lowering drug
hyperuricemia
excessive production
inadequate excretion
xanthine oxidase inhibitor
uricosuric agent

53. Refer to the third slide
Drug therapy of gout
Case Presentation
Refer to the third slide

54. Case presentation - therapy
NSAID
steroid
NSAID
colchicine (low-dose)
Maintenance dose
Anti-inflammatory
allopurinol
Chronic condition
days 1-10
days
days 365+

55. Done by Anas Khalil
With the help of shaima shahin’s Notes