Musculoskeletal System: Lec.8 - Mss Pharm Treatment Of Gout

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Musculoskeletal System:
Lec.8 - MSS Pharm Treatment of Gout

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Musculoskeletal System:
Lec.8 - MSS Pharm Treatment of Gout

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Musculoskeletal System:
Lec.8 - MSS Pharm Treatment of Gout

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Musculoskeletal System:
Lec.8 - MSS Pharm Treatment of Gout

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Q8:

Where does gout come from?

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An imbalance between uric acid production and excretion by the kidneys

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Q8:

Where does uric acid come from?

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Break down of purines (

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Q8:

If you have elevated uric acid levels (above 7) will you have gout?

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not necessarily, some people have elevated levels and no symptoms

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Q8:

Describe the physiology behind an gouty toe

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- urate crystals deposit in the joint.
- Crystals attract PMNs
- Deposition of the crystal in the synovial space causes release of prostiglandins and interlukins
- Prostiglandins activate PMNs
- this is then a cycle that all contributes to the inflammatory process and pain
-

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Q8:

What is a Gouty arthritis attack like?

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- the first attack my only be one joint, and may be minimal or unnoticable
- subsequent attacks may involve more joints.
- attacks will become closer and closer to one another until you finally end with chronic gout

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Q8:

Who gets gout, and is there anything that makes it worse?

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- Usually older men (but not exclusively)
- Some drugs may make it worse: thiazides and loop diuretics, salicylates as well)
- it is possible that rich foods may make it worse

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Q8:

In what ways can we treat gout?

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- Inhibit uric acid synthesis (Allopurinol)

- Eliminate the uric acid faster (probenicid & sulfinpyrazone)

- Inhibit the immune response to the uric acid crystals (NSAIDs & Colchicine)

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Q8:

What is the mechanism of action for Colchicine?

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(prevents immune responce to uric acid by....)
- Binds to intracellular protein tubulin preventing polymerization into microtubules; this prevents leukocyte migration and phagocytosis. Also inhibits LTB4 formation
- Breaks the cycle leading to inflammatory response and joint pain.
- Not analgesic or uricosuric (increased secretion of uric acid)

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Q8:

Tell us about the pharmacokinetics of Colchicine?

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NOTHING UNUSUAL!!
-Takes about 1/2 day for some relief
-Used orally except in special cases
-Metabolized by the eliver (cimetidine and erythromycin inhibit metabolism)

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Q8:

what are the 3 categories of side effects to know for drugs?

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- common
- life changing (life or death, steven's johnson syndrome, liver failure)
- weird

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Q8:

Adverse effects for Colchicine?

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- Effective dose in near dose to produce GI problems (Narrow TI) (nausea, vommiting, diarrhea colic in 80%)
- Risk of hair loss
- Bone marrow depression (BMD)
- Peripheral neuritis (if given IV)

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Q8:

Colchacine can cause death, there is no antidote, what does acute oral overdose include?

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• Burning throat pain
• Bloody diarrhea
• CV shock
• Renal shut down
• Muscular and CNS depression
• Can be fatal
• No antidote; treatment is symptomatic

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Q8:

What does chronic toxicity of Colchacine include?

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• Agranulocytosis
• Aplastic anemia
• Potential mutagenesis and teratogenesis
o Don’t use in pregnant females
(so take a CBC before treatment and periodically to make sure this is not happening)

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Q8:

What are the therapeutic usages for Colchacine?

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- Acute gouty arthritis (but must be used with high dosage, or with another drug)(if they respond then this means they have gout)
- mostly used to prevent attacks, limited by troublesome diarrhea (less of a problem at lower doses used in prophylaxis)

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Q8:

What are some other uses of Colchacine?

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- acute mediterranean fever
- sarcoid arthritis
- hepatic cirrhosis

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Q8:

How are NSAIDs used to treak gout?

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- it is fast acting, and used to treat at the onset of a gouty attack
- decreases the inflamatory process (inhibits prostiglandin synthesis)
- Profilactic use is limited (due to chronic adverse effects)
- does have some analgesic properties as well as antipyretic and anti-inflammatory effects

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Q8:

What are some NSAIDs that are used to treat Gouty Arthritis?

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- Indomethacin: Significant GI side effects

- Phenylbutazone: Metabolized to active metabolite Oxyphenybutazone (serious hematological side effects is used chronically, aplastic anemia)

- Ibuprofen: Used in high doses

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Q8:

Are antiinflamatory steroids used to treat gout?

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yes, they are great for acute treatment.
(adrenal corticosteroids)
- antiinflamatory properties
- used for acute attacks
- inter-articular injection with acute mono-articular gout
- toxcities preclude chronic systemic use (but is used systemically in systemically chronic cases where colchacine and NSAIDs dont work.)

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Q8:

example of :
Inhibitors of uric acid synthesis

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- Allopurinol (Xyloprim)

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Q8:

What is the mechanism of action of Allopurinol?

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- An analog of hypoxanthine (which comes from purine metabolism); allopurinol competitively inhibits xanthine oxidase (XO) (what XO does is it converts xantine to uric acid, this prevents the synthesis of uric acid)

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What does XO convert allopurinol to?

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it makes an active metabolite that does the same thing as the parent compound

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Q8:

How is allopurinol cleared from the body?

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- It is cleared by the kidneys by filtration (you should lower the dose of allopurinol according to decreases in GFR)

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Q8:

Pharmacokinetics of Allopurinol

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- filtered by the kidneys
- has a long half life and an active metabolite (this allows for once a day dosing)
- Allopurinol inhibits metabolism of 6-mercaptopurine and azathioprine by xanthine oxidase (therefore you will need to reduce the dose of these immunosuppressive agents if allopurinol is being used.)

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Q8:

What are the adverse effects of allopurinol?

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- Generally few side effects
- allergic rxn (2% 0f people) When in combination with ampicillin 20%)
- mostly rash but exfoliative dermatitis is possible
- may induce acute gouty attacts at first so treat in conjunction with colchicine or NSAIDs (due to liberation of uric acid from deposits)

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Q8:

What are the therapeutic uses of Allopurinol?

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- Chronic treatment of gout
(prevents further acute attacks - profilactic)
(possibly used durring chemo therapy to prevent gout onset from free damaged dna and high uric acid levels)
- protects kidneys, Gouty neuropathy
-eliminate thopi
- renal urate stones
- DOES NOT RELIEVE ACUTE GOUTY ATTACKS

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Q8:

What is Febuxostat?

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A new drug that may be approved to reduce the synthesis of uric acid (similar to Allopurinol, but fewer side effects)

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Q8:

what are Uricosurics, and give two examples

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– Uricosuric drugs (probenecid and sulfinpyrazone) are organic acids that act at anionic transport sites in renal tubules to cause a net decrease in uric acid reabsorption.

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Q8:

low doses of probenecid will do what?

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-Inhibit the secretion of uric acid ( so it will not be able to get back into the urine after being absorbed)

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Q8:

high doses of probenecid will do what?

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-Inhibit renal reabsorption of uric acid (this increases the amount that stays in the urine)

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Q8:

What is the biggest risk when using uricosuric agents?

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- The formation of uric acid crystals in the urine and deposition of uric acid in the renal tissue (causing UA nephropathy)

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Q8:

Adverse reactions of Probenecid?

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- Allergic reactions in 2-4% (most extreme being anaphylaxis)
- Should not be used in Pts already excreting large amounts of uric acid (as it may induce renal calculi)
- occasionally may cause nephritic syndrome and very rarely aplastic anemia
- contraindicated if urine flow is low

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Q8:

Therapeutic uses of Probenecid?

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- Use after gouty attacks
- use when Allopurinol is not tolerated
- Use when evidence of tophi appears
- Do not initiate use durring a gouty attack but if already on it continue
- DO NOT USE TO MANAGE hyperuricemia in association with chemo therapy (risk of uric acid nephropathy)

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Q8:

When using probenecid (or sulfinpyrazone) what should you also do?

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- increase fluid intake (keep hydrated)
- Alkalinizine urine to increase solubility (to avoid renal calculi)

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Q8:

How is Probenecid used to effect PCN?

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- sometimes used to slow renal elimination

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Q8:

What are some drug interactions of Probenecid?

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- Probenecid inhibits renal secretion of drugs (PCN, indomethacin, ect)

-Low doses of salicylates (e.g. aspirin) can inhibit probenecid effects (by interfering with active secretion of uric acid)(aspirin is contraindicated in someone taking probenecid)

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Q8:

what are the bennefits of using sulfinpyrazone (Anturane) instead of Probenecid?

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- Works pretty much the same
- GI irritation is greater than that of Probenecid
- Allergic rxns however, are uncommon

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Q8:

What are the primary drugs used for gout?

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o colchicine and NSAIDs to treat acute attacks and prophylaxis

o allopurinol to decrease AU levels by inhibiting synthesis

o probenecid to decrease UA levels by enhancing renal elimination

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Q8:

What should be used for acute gouty attacks?

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colchicine or NSAIDs may be used (NSAIDs 1st; colchicine 2nd)

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Q8:

How should chronic gout be addressed?

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therapy directed at controlling the plasma level of UA and preventing the deposition of urates in the joints, renal calculi (life long treatment). Allopurinol first; uricosurics second.