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Gout drugs
pharmacologic treatment of gout
25
Pharmacology
Professional
03/27/2012

Additional Pharmacology Flashcards

 


 

Cards

Term

 

 

 

Epidemiology of Gout

Definition

about 1% of western population suffers gout

 

7-9:1 male predominance

 

classically assoiciated with "indulgent" lifestyle--rich food and drink (especially red meat and alcohol) and smoking

 

associated with obesity, hypertension, and hyperlipidemia

 

 

 

 

Term

 

 

 

Gout Pathology

Definition

arthritis, nephropathy

 

chronic underlying hyperuricemia w/acute flares of arthritis, chronic and/or acute renal damage

 

monosodium urate crystal deposition in joints, cartilage, renal parenchyma, and subcutaneous tissues (tophi)

 

crystal formation encouraged by high levels of uric acid, low pH, low temperature, possible tissue factors

 

 

Term

 

 

 

Acute Gout

Definition

arthritis flare, usually one joint red and inflammed, often the great toe (podagra)

 

mediated by monosodium urate crystal precipitation in synovial space, crystals often detectable with synovial fluid aspiration

 

monosodium urate crystals are needle shaped and yellow if parallel to slow wave

 

Term

 

 

 

Uric Acid Handling at Nephron

Definition

uric acid=weak organic acid

 

freely filtered at glomerulus

 

simultaneously secreted and reabsorbed from proximal tubule--only about 10% of filtered uric acid is excreted

 

reabsorption by URAT-1 protein in organic anion transporter family (competition for transporter with other organic acids)

Term

 

 

 

Kidney manifestations of Gout

(extra-articular damage)

Definition

1. Gouty nephropathy: chronic renal insufficiency due to deposition of crystals in parenchyma over time, leads to hypertension

 

2. Obstructive nephropathy caused by acute intratubular crystal precipitation-->acute renal failure (acute tubular necrosis)

 

3. Nephrolithiasis--formation of kidney stones in renal pelvis/ureter

Term

 

 

 

Hyperuricemia

Definition

serum uric acid >7mg/dL in men

>6mg/dL in women

 

may be asymptomatic but predisposes to gout

 

overproduction or underexcretion of uric acid

 

80-90% of gout patients are (genetically predisposed) underexcretors

 

 

Term

 

 

 

Causes of Underexcretion of Uric Acid

Definition

drugs: diuretics, aspirin, ethambutal, L-dopa, cyclosporine, alcohol, nicotine

 

medical disorders: especially poorly controlled diabetes

 

idiopathic renal retention of uric acid

 

renal damage (glomerular or tubular)

 

high levels of competing organic acids like lactate and beta hydroxybutyrate

Term

 

 

 

Causes of Overproduction of Uric Acid

Definition

increased rate of de novo purine (adenine and guanine) synthesis

 

enzyme defects: decreased HGPRT activity (Leish-Nyan Syndrome) or increased PRPP synthetase activity

 

increased nucleic acid synthesis due to increased rate of cellular turnover, i.e. polycythemias or tumor lysis syndrome (myeloproliferative/lymphoproliferative disorders and cancer chemotherapy)

Term

 

 

 

Podagra

Definition

acute gouty inflammation of the big toe

 

extremely painful

 

joint is red and warm, must distinguish from septic arthritis

 

initial presentation of gout about half the time

Term

 

 

 

Tophi

Definition

subcutaneous nodules comprised of uric acid crystals 

 

found in patients with chronic gout

Term

 

 

 

 

Inflammatory Mechanism of Gouty Arthritis

Definition

synoviocytes and macrophages attempt to phagocytose monosodium urate crystals in joint

 

crystals rupture phagocytic cell membranes --> inflammatory cytokine release: IL-1, LTB4, prostaglandins)

 

cytokines attract and activate neutrophils and macrophages which attempt phagocytosis of crystals

 

cycle repeats with amplifying tissue damage and inflammation

Term

 

 

Purine Metabolism

Definition

1. phosphoribosylpyrophosphate synthestase (PRPP synthetase) converts ribose 5-P and ATP-->PRPP and glutamine       RATE LIMITING step

 

PRPP synthetase overexpression--increased uric acid levels ultimately

 

intermediate steps (PRPP-->5-phosphoribosyl-1-amine  -->inosinic acid)

 

2.  cellular and dietary purine nucleotides are in equilibrium with inosinic acid 

 

3. Inosinic acid-->Inosine

 

4. Inosine is in equilibrium with Hypoxanthine

 

5. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) converts hypoxanthine-->inosinic acid (allowing salvage synthesis of purines)

 

HGPRT deficiency=Leish-Nyan syndrome and leads to elevated uric acid levels

 

6. and 7. Xanthine oxidase converts hypoxanthine to xanthine to uric acid

Term

 

 

Xanthine Oxidase Inhibitors

Definition

increase levels of hypoxanthine, leading to increased HGPRT activity and increased purine salvage

 

decrease levels of uric acid

 

Allopurinol (and active metabolite oxypurinol)

 

Febuxostat

 

treatment of choice for chronic gout management

Term

 

 

 

Uricosuric Agents

Definition

Inhibit uric acid reabsorption at kidney

 

decrease serum urate concentration

 

by increasing uric acid excretion may cause crystal precipitation in urine and stone formation in the kidneys--use with caution in renal patients, advise patients to increase water intake

 

Probenecid and Sulfinpyrazone

Term

 

 

 

Aspirin Dual Effect

Definition

low doses of acetylsalicylic acid can cause hyperuricemia (selective inhibition of uric acid secretion at nephron)

 

high doses can decrease serum uric acid levels by interfering with reabsorption of uric acid at nephron (aspirin acts as a uricosuric aagent at higher doses)

Term

 

 

 

Colchicine

Definition

older drug used for acute gouty arthritis, could improve symptoms within 1 hour and resolve flare-up by 12 hours, oral or IV

 

largely replaced by NSAIDs (safer)

 

MOA: binds to intracellular protein tubulin, prevents polymerization into microtubules, lack of microtubule remodeling inhibits migration and phagocytosis attempts by leukocytes responsible for inflammation of acute gout

 

toxic effects (overdose): abdominal pain, nausea, and diarrhea--discontine colchicine immediately!

 

 

Term

 

 

 

Indomethacin (Indocin)

Definition

NSAID used to treat acute gouty arthritis

 

MOA: blocks prostaglandin synthesis, inhibits crystal phagocytosis, reduces inflammation

Term

 

 

 

Naproxen (Naprosyn, Anaprox, Aleve)

Definition

NSAID used to treat acute gouty arthritis

 

MOA: inhibits phagocyte migration and crystal phagocytosis

Term

 

 

 

Sulindac (Clinoril)

Definition
NSAID used for acute gouty arthritis
Term

 

 

Probenecid (Benemid, Probalan)

Definition

Uricosuric agent (inhibits uric acid reabsorption by kidney) used to control hyperuricemia in chroic, tophaceous gout

 

developed in '50s to prolong penicillin levels

 

toxicity: GI irritation, mild skin rash, renal damage due to crystal precipitation in urine

 

precautions: increase water intake and slowly titrate up to desired dose to prevent tubular damage and stone formation in kidneys, avoid in patients with renal failure

Term

 

 

 

Rasburicase (Elitek)

Definition

recombinant uricase, an enzyme found in most non-human mammals which converts uric acid to the more solluble compound allantoin

 

new drug used to treat hyperuricemia due to tumor lysis syndrome

 

IV, single course only! due to high risk of anaphylaxis

 

Adverse rxns: allergy/anaphylaxis

 

Contraindicated for patients with glucose-6-phosphate dehydrogenase deficiency b/c can cause hemolysis and methemoglobinemia

Term

 

 

 

 

Sulfinpyrazone (Anturane)

Definition

Uricosuric agent (inhibits uric acid reabsorption by kidney) used to control hyperuricemia in chronic, tophaceous gout

 

 

toxicity: GI irritation (10-15%), skin rash with fever, renal damage due to crystal precipitation in urine

 

precautions: increase water intake and slowly titrate up to desired dose to prevent tubular damage and stone formation in kidneys, avoid in patients with renal failure

Term

 

 

 

Allopurinol (Zyloprim)

Definition

purine xanthine oxidase inhibitor used to treat gouty nephropathy, chronic tophaceous gout, renal urate stones, and hyperuricemia secondary to hematologic disorders or cancer chemotherapy

 

drug of choice for prevention in chronic gout, oral

 

MOA: inhibits xanthine oxidase, decreasing levels of uric acid, causing more xanthine and hypoxanthine to be excreted in the urine (more soluble vs. uric acid), diverting hypoxanthine to purine salvage pathways, also decreases PRPP levels intracellularly

 

active metabolite oxypurinol (alloxanthine) also inhibits xanthine oxidase

 

IMPORTANT INTERACTIONS: increased toxicity if combined with the immunosuppresive/chemotherapeutic drugs 6-mercaptopurine and azathioprine, metabolism inhibited by oral anticoagulants, increased risk of rash if combined with ampicillin

 

Toxicity: allergic skin rxn.,  GI intolerance

 

Precautions: avoid in patients using 6-mercaptopurine or azathioprine or reduce dosages

Term

 

 

 

Febuxostat (Uloric)

Definition

newer non-purine xanthine oxidase inhibitor used to treat gouty nephropathy, chronic tophaceous gout, renal urate stones

 

oral, potent selective xanthine oxidase inhibitor

 

well tolerated in patients who can't tolerate allopurinol

 

Adverse rxns: diarrhea, nausea, vomiting, increased liver transaminases

 

DRUG INTERACTIONS: increased toxicity with 6-mercaptopurine and azathioprine like allopurinol

Term

 

 

 

Pegloticase (Krystexxa)

Definition

PEGylated uric acid specific uricase

 

uricase=enzyme which converts uric acid to more soluble allantoin in most non-human mammals

 

newer drug for treatment of chronic gout in patients unresponsive to or contraindicated for traditional therapy  i.e. a renal transplant pt. on azathioprine (allopurinol and fevuxostat interact with azathioprine, probenecid and sulfinpyrazone can damage kidney)

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