James Ivan A. Baluran
Pharmacology Laboratory (A1)
Clinical Case: Gout
Group 1
Clinical Questions:
1. What is gout?
● Gout is an inflammatory disease in which MSU crystals deposit into a joint,
making it red, tender and swollen within hours. When this happens, it is called a
Gouty Attack. The underlying cause of gout is hyperuricemia, which results in
sharp needle-like crystals in areas with slow blood flow like the joints and the
kidney tubules. Overtime repeated gouty attacks can cause destruction of the
joint tissue which results in arthritis.
2. What are the risk factors for gout?
● Male
● Alcohol consumption
● Hypertension
● Obesity
● Diabetes
● Dyslipidemia
● Hyperuricemia due to underexcretion or overproduction
3. What are the four clinical phases of gout?
a. Asymptomatic
● Hyperuricemia with no symptoms
● May last ≥ 10 years
b. Acute Gouty Arthritis
● Acute severe pain with overlying erythema, decreased range of motion,
swelling, warmth
● Possibly fever
● Symptoms are more likely to occur at night, typically waking the patient.
● Symptoms peak after 12–24 hours and regress over days to weeks.
● Desquamation of the skin overlying the joint may be seen during the
recovery from an acute gout flare.
c. Intercritical stage
● Asymptomatic
● May last up to several years
d. Chronic Gouty Arthritis
● Progressive joint destruction
● Tophi formation
a. Multiple painless hard nodules with possible joint deformities
○ May appear yellow or white because of overlying
attenuated skin
○ Ulceration and discharge (chalky white substance) may
occur
●
b. Bone tophi: urate crystal deposition in bones (e.g., elbows, knees,
extensor surfaces of forearms)
c. Soft tissue tophi: urate crystal deposition in the pinna of the
external ear, subcutis, tendon sheaths (e.g., at the Achilles
tendon), or synovial bursae (e.g., olecranon bursa)
Renal manifestations with uric acid nephrolithiasis and uric acid
nephropathy
4. What are the diagnostic criteria for gout?
Diagnostic criteria for gout:
● Male sex.
● Previous arthritis attack.
● Onset within 1 day.
● Joint redness.
● First metatarsophalangeal joint involvement.
● Hypertension or 1 or more cardiovascular diseases.
● A serum uric acid level higher than 5.88 mg/dL.
5. What are the workup approach considerations for gout?
The workup approach consideration for gout are :
a)Synovial Fluid AnalysisWhen a patient presents with acute inflammatory monoarticular arthritis, aspiration of the
involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of
gout or pseudogout on the basis of identification of crystals.
b)Serum Uric AcidMeasurement of serum uric acid is the most misused test in the diagnosis of gout. The presence
of hyperuricemia in the absence of symptoms is not diagnostic of gout. In addition, as many as
15% of patients with symptoms from gout may have normal serum uric acid levels at the time of
their attack. Thus, the diagnosis of gout can be missed if the joint is not aspirated.
Approximately 25% of the population has a history of elevated serum uric acid, but only a
minority of patients with hyperuricemia develop gout. Thus, an abnormally high serum uric acid
level does not indicate or predict gout. As noted, gout is diagnosed by the presence of urate
crystals in the synovial fluid or soft tissues. More importantly, some patients who present with a
hot swollen joint and an elevated serum uric acid level in fact have infectious arthritis, which
may be mismanaged if their synovial fluid is not examined.
c)Urinary Uric Acid
A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being
considered. If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular
diet, they are over excretors and thus overproducers of uric acid.
d)Blood studies
Blood studies may reveal abnormalities associated with gout or common comorbid
conditions.The WBC count may be elevated in patients during the acute gouty attack,
particularly if it is polyarticular. Hypertriglyceridemia and low levels of high-density lipoprotein
(HDL) are associated with gout. Glucose measurement is useful because patients with gout are
at increased risk for the development of diabetes mellitus.
e)Radiography
Plain radiographs may show findings consistent with gout.Erosions with overhanging edges
generally are considered pathognomonic for gout.
f)Ultrasonography
Ultrasonographic findings in established gout include the following :
-A “double-contour” sign, consisting of a hyperechoic, irregular line of MSU crystals on the
surface of articular cartilage overlying an adjacent hyperechoic bony contour
-“Wet clumps of sugar,” representing tophaceous material, described as hyperechoic and
hypoechoic heterogeneous material with an anechoic rim
-Bony erosions adjacent to tophaceous deposits
g)Histology
Chronic tophaceous gouty deposits frequently show large pale pink acellular areas, which
represent dissolved urate crystals, surrounded by histiocytes and multinucleated giant cells.
Pharmacology Guide Questions:
1. How is gout managed?
Gout is managed in the following 3 stages
1. Treating the acute attack
2. Providing prophylaxis to prevent acute flares
3. Lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue
deposition of urate crystals
The American College of Rheumatology (ACR) published guidelines on the treatment and
prophylaxis of acute gouty arthritis and the management of hyperuricemia.While those
guidelines do describe treatment targets, more recent publications have focused more closely
on the treat-to-target concept, although for the most part these recommendations are based on
underlying principles and expert opinion rather than trial data.
As a general rule, asymptomatic hyperuricemia should not be treated, though ultrasonographic
studies have demonstrated that urate crystal deposition into soft tissues occurs in a minority of
patients with asymptomatic hyperuricemia.Patients with levels higher than 11 mg/dL who over
excrete uric acid are at risk for renal stones and renal impairment; therefore, renal function
should be monitored in these individuals.
Urate-lowering therapy appears to reduce the incidence of kidney damage in gout. In a
retrospective study of 16,186 patients with initial serum uric acid levels above 7 mg/dL, Levy
and colleagues found that patients with gout who remained on urate-lowering therapy were less
likely to develop kidney damage leading to chronic kidney disease than those who were
untreated. All patients were followed for 36 months from their first documented high serum uric
acid level.
Patients 65 years of age and older were more likely to have three or more flares. Other risk
factors for gout flares included the following:
1.
2.
3.
4.
5.
6.
Male gender
Failure to attain serum uric acid goal
Presence of three or more comorbidities
Use of diuretics
No changes in initial urate-lowering therapy dose
Nonadherence to urate-lowering therapy
Tophi should not be surgically removed unless they are in a critical location or drain chronically.
Surgery may be indicated for tophaceous complications, including infection, joint deformity,
compression (eg, cauda equina or spinal cord impingement), and intractable pain, as well as for
ulcers related to tophaceous erosions. Delayed healing is noted in 50% of patients.
2. Current treatment guidelines
a. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
i.
Aspirin
1. Aspirin is a salicylate that exhibits analgesic,
anti-inflammatory, and antipyretic activities. Additionally, it
also inhibits platelet aggregation.
a. Indication: Rheumatic disorders, Fever, Mild and
Moderate pain
b. Mechanism of Action: It is a selective and irreversible
inhibitor of cyclooxygenase-1 (COX-1) enzyme
resulting in direct inhibition of the biosynthesis of
prostaglandins and thromboxanes from arachidonic
acid.
c. Dosage:
Adult: 4-8 g daily in divided doses for acute
i.
disorders. 5.4 g daily in divided doses for
chronic conditions.
d. Adverse Effects:
i.
Significant: Salicylate sensitivity, tinnitus.
Rarely, Reye’s syndrome. Hypersensitivity
ii.
reactions (e.g. Stevens Johnson syndrome,
angioedema), gastrointestinal bleeding and
perforation.
ii.
iii.
Other non-selective COX inhibitors (Ibuprofen, Naproxen,
Indomethacin, Ketorolac)
1. Nonselective NSAIDs vary primarily in their potency, analgesic
and anti-inflammatory effectiveness, and duration of action.
Ibuprofen and naproxen have moderate effectiveness;
indomethacin has greater anti-inflammatory effectiveness; and
ketorolac has greater analgesic effectiveness.
a. Indication: Rheumatic disorders, mild to sever pain
b. Mechanism of action: Inhibit both cyclooxygenase
isoforms and thereby decrease prostaglandin and
thromboxane synthesis throughout the body. Release of
prostaglandins necessary for homeostatic function is
disrupted, as is release of prostaglandins involved in
inflammation.
c. Dosage:
i.
Naproxen:
1. 500 mg BID
ii.
Indomethacin: 25-50 mg TID
iii.
Ketorolac: Maximum dose: 40 mg/day
iv.
Ibuprofen: 800 mg BID
v.
Diclofenac: 50 mg TID
d. Adverse effects
i.
Most prominent: GI irritations, gastrointestinal and
renal damage,
Selective COX-2 inhibitors (Celecoxib, Etoricoxib, Valdecoxib)
1. nonsteroidal anti-inflammatory drug (NSAID). It works by reducing
hormones that cause inflammation and pain in the body. The
COX-2-selective inhibitors have less effect on the prostaglandins
involved in homeostatic function, particularly those in the
gastrointestinal tract
a. Indication: Rheumatoid arthritis, gout, menstrual pain
b. Mechanism of action: selectively inhibits
cyclo-oxygenase-2 activity (COX-2), reducing hormones
that cause inflammation and pain in the body.
c. Dosage:
i.
Celecoxib: 800 mg followed by 400 mg 12 hours
later, then 400 mg BID
ii.
Etoricoxib:The normal dosage for acute gout is
120 mg once a day for up to eight days.
d. Adverse effects: stomach or intestinal bleeding, fatal.
Renal damage, myocardial infarction and stroke (rofecoxib
and valdecoxib)
b. Uricosuric agents
Drugs employed to decrease the body pool of urate in patients
with tophaceous gout or in those with increasingly frequent gout attacks.
In a patient who secretes large amounts of uric acid, the uricosuric agents
should not be used.
Probenecid & Sulfinpyrazone
a. Indication:
Patients with underexcretion of uric acid when allopurinol
or febuxostat is contraindicated or when tophi are present.
Therapy should not be started until 2–3 weeks after an acute
attack.
b. Mechanism of Action:
Inhibit active transport sites for reabsorption and secretion
in the proximal renal tubule so that net reabsorption of uric acid in
the proximal tubule is decreased.
c. Dosage:
i.
Probenecid started at a dosage of 0.5g orally in divided
doses (progress to 1g daily after 1 week.
ii.
Sulfinpyrazone started at a dosage of 200 mg orally daily,
(progress to 400-800 mg daily in divided doses
d. Adverse Effects: GI irritation, rash, nephrotic syndrome
(Probenecid), and both may rarely cause aplastic anemia
c. Corticosteroids
Corticosteroids are man-made drugs that closely resemble cortisol, a
hormone that your adrenal glands produce naturally. Corticosteroids are
often referred to by the shortened term "steroids.” Corticosteroids
(cortisone-like medicines) are used to provide relief for inflamed areas of
the body. They lessen swelling, redness, itching, and allergic reactions.
a. Indication: rheumatoid arthritis, inflammatory bowel disease (IBD), asthma, allergies
and many other conditions.
b. Mechanism of action: Corticosteroids enter the cell and bind to cytosolic receptors that
transport the steroid into the nucleus. The steroid-receptor complex alters gene
expression by binding to glucocorticoid response elements (GREs) or
mineralocorticoid-specific elements .Tissue-specific responses to steroids are made
possible by the presence in each tissue of different protein regulators that control the
interaction between the hormone-receptor complex and particular response elements.
c. Dosage: Oral: 10 to 60 mg/day given in a single daily dose or in 2 to 4 divided doses;
Low dose: 2.5 to 10 mg/day; High dose: 1 to 1.5 mg/kg/day (usually not to exceed 80 to
100 mg/day). Glucocorticoid-Responsive Conditions: 5-60 mg/day PO in single daily
dose or divided q6-12h
d. Adverse Effect: weight gain or swelling of the legs (edema),High blood pressure, Loss
of potassium, Headache,Muscle weakness, Puffiness of the face (moon face), Facial
hair growth,Slow wound healing, Glaucoma, Cataracts, Ulcers in the stomach and
duodenum,Loss of diabetes control
d. Xanthine Oxidase Inhibitors
i.
Allopurinol- preferred and standard-of-care therapy for gout during the
period between acute episodes.
a. Indications: Allopurinol is often the first-line agent for the
treatment of chronic gout in the period between attacks
and it tends to prolong the intercritical period.
b. Mechanism of Action: Xanthine oxidase inhibitor; inhibits
conversion of hypoxanthine to xanthine to uric acid;
decreases production of uric acid without disrupting
synthesis of vital purines.
c. Dosage: The initial dosage of allopurinol is 50–100 mg/d.
d. Adverse Effects: In addition to precipitating gout (the
reason to use concomitant colchicine or NSAID), GI
intolerance (including nausea, vomiting, and diarrhea),
peripheral neuritis and necrotizing vasculitis, bone marrow
suppression, and aplas- tic anemia may rarely occur.
II. Febuxostat- is a potent and selective inhibitor of xanthine oxidase, thereby
reducing the formation of xanthine and uric acid without affecting other enzymes in the
purine or pyrimidine metabolic pathway.
A. Indications: Febuxostat is approved at doses of 40 or 80 mg for the
treatment of chronic hyperuricemia in gout patients.
B. Mechanism of Action: Xanthine oxidase inhibitor; inhibits conversion of
hypoxanthine to xanthine to uric acid; at therapeutic dosages, decreases
production of uric acid without disrupting synthesis of vital purines and
pyrimidines.
C. Dosage: The recommended starting dose of febuxostat is 40 mg daily.
D. Adverse Effect:Gout flares, xanthine deposition, Increased serum
AST/ALT, increased TSH
e. Selective Uric Acid Reabsorption Inhibitor (SURI)
i.
Brand names: Duzallo, Lesinurad, Zurampic
a. Indication: Selective uric acid reabsorption inhibitor
(SURI) is a class of medication prescribed for excessive
uric acid in the blood (hyperuricemia) associated with gout.
b. Mechanism of Action: Selective uric acid reabsorption
inhibitor (SURI) inhibits uric acid transporter 1 (URAT1)
and organic anion transporter 4 (OAT4), increasing urinary
excretion of uric acid, lowering plasma urate
concentrations, and eventually reducing urate deposits in
the tissue.
c. Dosage: 200 mg once daily. Should be taken with food.
Take in the morning.
d. Adverse effects:
i.
Significant: Gout flares, increased serum creatinine,
renal failure, nephrolithiasis.
ii.
Gastrointestinal disorders: Gastroesophageal reflux
disease.
iii.
Immune system disorders: Rarely, hypersensitivity
reactions (e.g. photosensitivity).
iv.
Infections and infestations: Influenza.
v.
Nervous system disorders: Headache.
f.
Rheumatologics
i.
DMARDs: RA is a progressive immunologic disease that causes
significant systemic effects, shortens life, and reduces mobility and quality
of life. The conventional synthetic agents include small molecule drugs
such as methotrexate, azathioprine, chloroquine and hydroxychloroquine,
cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil and
sulfasalazine.
ii.
Methotrexate:
Methotrexate, a synthetic nonbiologic antimetabolite, is the first-line csDMARD
for treating RA and is used in 50–70% of patients. It is active in this condition at
much lower doses than those needed in cancer chemotherapy.
Dosage and Indications: It is recommended to start treatment with 7.5
mg weekly. According to patient response, methotrexate is increased to the most
common dosing regimen for the treatment of RA, which is 15–25 mg weekly.
Notably there is an increased effect up to 30–35 mg weekly, although with
increased toxicity. The drug decreases the rate of appearance of new erosions.
Evidence supports its use in juvenile chronic arthritis, and it has been used in
psoriasis, PA, AS, polymyositis, dermatomyositis, Wegener’s granulomatosis,
giant cell arteritis, SLE, and vasculitis.
Mechanism of Action: Methotrexate’s principal mechanism of action at the low
doses used in rheumatic diseases probably relates to inhibition of
amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and
thymidylate synthetase. AICAR, which accumulates intracellularly, competitively
inhibits AMP deaminase, leading to an accumulation of AMP. The AMP is
released and converted extracellularly to adenosine, which is a potent inhibitor of
inflammation. As a result, the inflammatory functions of neutrophils,
macrophages, dendritic cells, and lymphocytes are suppressed. Methotrexate
has direct inhibitory effects on proliferation and stimulates apoptosis in immune
inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to
rheumatoid synovitis.
Adverse Effect: Nausea and mucosal ulcers are the most common toxicities.
Additionally, many other side effects such as leukopenia, anemia, stomatitis, GI
ulcerations, and alopecia are probably the result of inhibiting cellular proliferation.
Sulfasalazine
Mechanism of Action: Sulfasalazine, a csDMARD, is metabolized to
sulfapyridine and 5-aminosalicylic acid. The sulfapyridine is probably the active
moiety when treating RA (unlike inflammatory bowel disease. Some authorities
believe that the parent compound, sulfasalazine, also has an effect. Suppression
of T-cell responses to concanavalin and inhibition of in vitro B-cell proliferation
are documented. In vitro, sulfasalazine or its metabolites inhibit the release of
inflammatory cytokines produced by monocytes or macrophages—eg, IL-1, -6,
and -12, and TNF-α.
Indications and Dosage: Sulfasalazine is effective in RA and reduces
radiologic disease progression. It has also been used in juvenile chronic arthritis,
PsA, inflammatory bowel disease, AS, and spondyloarthropathy-associated
uveitis. The usual regimen is 2–3 g/d.
Adverse Effect: Approximately 30% of patients using sulfasalazine
discontinue the drug because of toxicity. Common adverse effects include
nausea, vomiting, headache, and rash. Hemolytic anemia and
methemoglobinemia also occur, but rarely. Neutropenia occurs in 1–5% of
patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive
double-stranded DNA (dsDNA) are occasionally seen, but drug-induced lupus is
rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility
in women. The drug does not appear to be teratogenic
Hydroxychloroquine
Mechanism of Action: Chloroquine and hydroxychloroquine are non
biologic drugs mainly used for malaria and in rheumatic diseases as csDMARDs.
The following mechanisms have been proposed: suppression of T-lymphocyte
responses to mitogens, inhibition of leukocyte chemotaxis, stabilization of
lysosomal enzymes, processing through the Fc-receptor, inhibition of DNA and
RNA synthesis, and the trapping of free radicals.
Indications and Dosage: Antimalarials are approved for RA, but they are
not considered very effective DMARDs. Dose-loading may increase the rate of
response. There is no evidence that these compounds alter bony damage in RA
at their usual dosages (up to 6.4 mg/kg per day for hydroxychloroquine or 200
mg/d for chloroquine). It usually takes 3–6 months to obtain a response.
Antimalarials are used very commonly in SLE because they decrease mortality
and the skin manifestations, serositis, and joint pains of this disease. They have
also been used in Sjögren’s syndrome.
Adverse Effects: Although ocular toxicity may occur at dosages greater
than 250 mg/d for chloroquine and greater than 6.4 mg/kg/d for
hydroxychloroquine, it rarely occurs at lower doses. Nevertheless,
ophthalmologic monitoring every 12 months is advised. Other toxicities
include dyspepsia, nausea, vomiting, abdominal pain, rashes, and
nightmares. These drugs appear to be relatively safe in pregnancy.
Leflunomide
Mechanism of Action: Leflunomide, another csDMARD, undergoes
rapid conversion, both in the intestine and in the plasma, to its active metabolite,
A77-1726. This metabolite
inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide
synthesis and the arrest of stimulated cells in the G1 phase of cell growth.
Consequently, leflunomide inhibits T-cell proliferation and reduces production of
autoantibodies by B cells. Secondary effects include increases of IL-10 receptor
mRNA, decreased IL-8 receptor type A mRNA, and decreased
TNF-α–dependent nuclear factor kappa B (NF-κB) activation.
Indications and Dosage: Leflunomide is as effective as methotrexate in
RA,including inhibition of bony damage. In one study, combined treatment with
methotrexate and leflunomide resulted in a 46.2% ACR20 response compared
with 19.5% in patients receiving methotrexate alone.
Adverse Effects: Diarrhea occurs in approximately 25% of patients given
leflunomide, although only about 3–5% of patients discontinue the drug because
of this side effect.
Elevation in liver enzymes can occur. Both effects can be reduced by decreasing
the dose of leflunomide. Other adverse effects associated with leflunomide are
mild alopecia, weight gain, and increased blood pressure. Leukopenia and
thrombocytopenia occur rarely. This drug is contraindicated in pregnancy.
g. Corticotropic Hormones:
ACTH. Adrenocorticotropic hormone (corticotropin). Parenteral
administration of ACTH 1-39 was reported, more than 50 years ago, to be clinically
effective in controlling the symptoms of gouty arthritis. However ACTH 1-39
treatment was rarely used because of the intense suppression of the
hypothalamic-pituitary-adrenal (HPA) axis observed following repeated
administrations.
Mechanism of action. The mechanism of action was initially proposed to
explain the anti-inflammatory properties of ACTH1-39. However, recent
controlled clinical studies have confirmed the efficacy of ACTH1-39 itself,
suggesting the involvement of a mechanism separate from adrenal gland
activation. These clinical data highlight the anti-inflammatory properties of
ACTH but do not allude to a specific mechanism of action. Systemic
administration of ACTH 1-39 produces dose dependent reduction of
several parameters of MSU crystal-induced joint inflammation.
Dosage: ACTH 1-39 5 μg
Adverse effect: Intense suppression of HPA axis
3. Non-pharmacologic Interventions
●
●
Healthy Diet
○ Avoid food that may trigger a gout flare, including foods high in purines ( like red
meat , organ meat and seafood ), also limit alcohol intake especially the beer and
hard liquor instead drink plenty of water.
Exercise regularly and lose weight
○ Losing weight reduces pressure on joints. Maintaining a healthy weight can
relieve pain, improve function and slow the progression of arthritis. Low impact
activities such as walking , bicycling and swimming are easy on the joints, have a
low risk of injury and do not put too much stress on the joints.
References :
● Gout | Arthritis | CDC)
● Gout - Diagnosis and treatment - Mayo Clinic
● Getting, S.J., Christian, H.C., Flower, R.J. and Perretti, M. 2002. Activation of
melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic
hormone efficacy in gouty arthritis. Arthritis & Rheumatism. 46 (10), pp.
2765-2775
● Katzung’s Basic & Clinical Pharmacology 4th edition