Drugs for Gout

(1)

Drugs for Gout

Dr Jameel Ahmad MD,DCH Assistant Professor

Dept of Pharmacology

JNMC AMU Aligarh

(2)

Case presentation

• 55 y/m went to bed last night feeling well, felt as he has broken toe this morning &

also pain at ankle

• Past h/o/ of similar episode

• O/E:

MTP joint & Ankle red, swollen & tender

• Right elbow also swollen

• Serum uric acid = 11.5 mg/dl-

• 24-hour uric acid excretion

= 300 mg

(3)

GOUT: A metabolic disease most often affecting middle-aged to elderly men & postmenopausal women.

body pool of Urate with hyperuricemia.

Deposition of MSU crystals in joints & connective tissue, Tophi Risk for deposition in kidney interstitiumUric acid

nephrolithiasis

Plasma urate level:

> 7mg/dl (M) > 6 mg/dl ( F)

Uricase urate oxidase) catalyzes the following overall reaction:

(4)

Hyperuricemia

production

excretion

hyperuricemia results when production

exceeds excretion

(5)

Hyperuricemia

production

excretion

net uric acid loss results when excretion

exceeds production

(6)

• Overproducers 10%

• Underexcretors 90%

• Underexcretors but Overproducers

HGPRT(hypoxanthine-guanine phospho-ribosyl transferase)>Deficiency

HGPRTase: Salvage purines from degraded DNA to reintroduce into purine synthetic pathways HPRT mutations Lesch-Nyhan syndrome

PRPP Synthetase(5'-phosphoribosyl-1'-pyrophosphate synthetase) >Excess

• Influenced by diet

(7)

(8)

• Humans do have a gene for urate oxidase, but it is nonfunctional.

• Uric acid is the end product of catabolism of purines

• Uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals

• Acute hyperuricemia in patient receiving chemotherapy(Tumor lysis syndrome)

• Rasburicase is a recombinant version of urate oxidase an enzyme that metabolizes uric acid to allantoin

• Lyophilized powder intended for intravenous

administration following reconstitution with a diluent.

(9)

Hyperuricemia

Primary hyperuricemia:

Genetic defect in purine metabolism.

Secondary hyperuricemia:

• Leukemias, lymphomas : due to increased nucleic acid turn over.

• Chemotherapy /radiation: Due to enhanced cell death &

nucleic acid metabolism

• Drugs causing hyperuricemia

• Anticancer drugs

• Thiazides

(10)

Gout - cardinal manifestations

nephrolithia sis

nephropathy

arthritis tophi

HYPERURI CEMIA

acute &

chronic

(11)

Secretion of A^-, BH⁺of bound and

unbound drug Filtration @

Bowman’s capsule

H₂O H₂O

H₂O

Proximal tubule (PT) Descending thin limb (DTL)

Ascending thin limb (ATL)

Thick ascending limb (TAL) Distal

tubule (DT)

Collecting tubule (CT)

H₂O

H₂O H₂O H₂O

H₂O

+ADH

-ADH

(12)

Renal handling of uric acid

•Glomerular filtration

•Tubular reabsorption

•Tubular excretion

•Post-secretory reabsorption

•Net excretion

(13)

Gout - acute arthritis

Acute

synovitis, Ankle & first

MTP joints

(14)

Chronic tophaceous gout

tophus = localized

deposit of monosodium

urate crystals

(15)

Gout - tophus

classic location of tophi on

helix of ear

(16)

FLARE INTERVALS FLARE INTERVALS



Silent tissue Silent tissue

deposition & Hidden deposition & Hidden

Damage

(17)

Gout - X-ray changes

DIP joint

destruction

phalangeal

bone cysts

(18)

Gout - X-ray changes

bony

erosions

(19)

SYNOVIAL FLUID

Birefringent needle-shaped MSU crystals

(20)

Laboratory Diagnosis

• Diagnosis confirmed by needle aspiration of acutely or chronically involved joints or tophaceous deposits

• D/D: Acute septic arthritis/Palindromic rheumatism &

• Psoriatic arthritis

• During acute gouty attacks: birefringent needle-shaped MSU crystals (intracellularly & extracellularly)

•

• Synovial fluid cell counts : 2000 to 60,000/L

• Effusions appear cloudy due to the increased numbers of leukocytes.

• Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid

• Bacterial infection can coexist with urate crystals in synovial fluid;

(21)

(22)

Stages of Classic Gout

• Asymptomatic hyperuricemia

– Majority of people with hyperuricemia never develop symptoms.

– Only 10% of hyperuricemic pts. develop gout.

• Acute Intermittent Gout (Gouty Arthritis)

– Episodes of acute attacks. Symptoms may be confined to a single joint or patient may have systemic symptoms.

• Intercritical Gout

– Symptom free period interval between attacks. May have hyperuricemia and MSU crystals in synovial fluid

• Chronic Tophaceous Gout

– Results from established disease and refers to stage of deposition of

urate, inflammatory cells and foreign body giant cells in the tissues.

Deposits may be in tendons or ligaments.

– Usually develops after 10 or more years of acute intermittent gout.

(23)

• Therapeutic goals include:

• Relieving acute attacks

• Preventing future attacks

• Lower serum urate levels.

(24)

Drugs for gout

• For acute gout:

– NSAIDs

– Colchicine – Steroids

• For Chronic gout:

• Uricosurics: Probenecid, Sulfinpyrazone, Benzbromarone

• Synthesis inhibitor: Allopurinol, Febuxostat

(25)

Acute gout

• NSAIDs: Antiinflammatory & Analgesic

– Strong anti-inflammatory drugs: Indomethacin Piroxicam, Naproxen, Diclofenac, Etoricoxib

– Naproxen , Piroxicam also inhibit chemotactic migration of leucocytes

– Indomethacin: Potent PG synthesis inhibitor; reduce neutrophil motility

.

Short term use

• Also used as cover therapy for with uricosuric agents or allopurinol in chronic gout

• Indomethacin: 50 mg, 8 h25 mg 8 H for 5-7 days

• No Salicylates (Asprin)???

(26)

• Colchicine: Alkaloid Colchicum autumnale

• No analgesic, No uricosuric, No synthesis inhibitor

• Pharmnacological action action

• Inhibition of

– leucocyte migration – Phagocytosis

– lysosomal enzymes Release

– Antimitotic (highly dividing cells: Inflammatory & GIT) – Neurogenic stimulation of gut

(27)

(28)

Pathophysiology of Gout Pathophysiology of Gout

Diet DNA of dying cells

Purines Bases

Salvag ed

Hypoxanthine

Xanthine

Uric Acid

Allantoin Xanthine Oxidase Xanthine Oxidase Xanthine Oxidase Xanthine Oxidase

Uricase

(29)

Uric Acid Supersaturate

Forms Mono Sodium Urate Crystal

Crystals engulfed by Macrophages

Acute Attack Resolves Acute Attack Resolves

IL-1& TNF-α

Activate Synovial Cells Activate Synovial Cells Inflammatory Response Inflammatory Response

Chronic Gouty Arthritis Chronic Gouty Arthritis

Tophi Lysozyme

(30)

Drug classes

• Drugs decreasing Uric acid Synthesis:

 Purine- Allopurinol

 Non-Purine- Febuxostat

• Drugs increasing Uric acid Excretion (Uricosuric):

 Probenecid

 Sulfinpyrazone

• Drugs increasing metabolism of Uric acid

 Rasburicase

 Pegloticase

(31)

Acute Gout

Drug inhibiting Neutrophil Migration: Colchicine

Drugs inhibiting Pain and Inflammation: NSAIDs & Corticosteroids

Chronic Gout

Drugs Inhibiting Uric Acid Synthesis: Allopurinol & Febuxostat

Drugs Increasing Uric Acid Excretion: Probenecid, Sulphinpyrazone

(32)

Uric Acid Supersaturate

Forms Mono Sodium Urate Crystal

Crystals engulfed by Macrophages

Acute Attack Resolves Acute Attack Resolves

IL-1& TNF-α

Activate Synovial Cells Activate Synovial Cells Inflammatory Response Inflammatory Response

Chronic Gouty Arthritis Chronic Gouty Arthritis Lysozyme

Colchicine

Not analgesic or anti-inflammatory or decreases Uric acid levels MOA:

1.Prevent Granulocyte migration 2.Inhibit Lysozyme

3.Inhibit releases of Glycoprotein  lactic acid 4.Bind to “Tubulin” causing depolymerization of microtubules esp Neutorphils (Druken

Walk)

Dose: 1mg followed by 0.5 mg Three times a day

ADRs:

Diarrhea

Nausea, Vomiting

Agranulocytosis, Hematuria, Respiratory depression

(33)

Allopurinol Allopurinol

Purines Bases

Salvag ed

Hypoxanthine

Xanthine

Uric Acid

Uricase

Allopurinol (t_1/2 2hr)

Alloxanthine(t_1/2 24hr) Non Competitive Inhibitor

Competitive Inhibitor ADRs

1.May ppt Acute attack of Gouty arthritis

 Dissolution of tophi

2.Hypersensitivity reactions 3.GIT distress

Dose: 100 mg/day

Febuxostat Febuxostat

More Potent and Selective Xanthine Oxidase Inhibitor ADRs:

Liver dysfunction, Diarrohea

Suitable for patients intolerant to Allopurinol

(34)

Probenecid Probenecid

Purines Bases

Salvag ed

Hypoxanthine

Xanthine

Uric Acid

Uricase

MOA: Inhibit active resorption of Uric acid from renal tubules 250 mg twice daily

ADRs

Less- GIT distress, dyspepsia

Renal Stones: Prevented by drinking large amount of water Nephrotic syndrome

Drug interaction

Low dose aspirin- Blocks uricosuric action

Inhibit Urinary excretion of penicillins, cepholosporins, Methotrexate,

(35)

Rasburicase Rasburicase Pegloticase Pegloticase

Purines Bases

Salvag ed

Hypoxanthine

Xanthine

Uric Acid

Uricase

Recombinant Uricase or Uric acid oxidase

(36)

Acute Gout

Drug inhibiting Neutrophil Migration: Colchicine

Drugs inhibiting Pain and Inflammation: NSAIDs & Corticosteroids

Chronic Gout

Drugs Inhibiting Uric Acid Synthesis: Allopurinol & Febuxostat

Drugs Increasing Uric Acid Excretion: Probenecid, Sulphinpyrazone

(37)

(38)

(39)

Pharmacokinetics

• Oral absorption & I.V.

• Enterohepatic circulation

• Peak conc: 1-2 H

• High conc. Kidney, liver,

• Poor concentration: heart, brain, skeletal

muscle

(40)

Adverse effects

– Gut susceptible to toxicity: Nausea, Vomiting , diarrhea, abdominal pain, hemorrhagic gastropathy

– kidney damage

– Bone marrow suppression: Agranulocytosis, Aplatic anemia – Chronic use: Myopathy,

– Hepatic necrosis, DIC,

– Ascending paralysis, seizures

– Death is due to muscular paralysis, respiratory failure Use

– Acute gout attack: Colchicine >Effective& Faster acting (NSAIDs) but high toxicity

– Response is dramatic

– Dose: 0.6 mg/hour---HOW LONG??? 0.6mg 8H – I.V. 2mg in 20 ml NS

– Prevention of recurrent gout particularly in early stages of antihyperuricemic therapy

– Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours

(41)

• Prophylactic use

• Diagnostic

• Not effective in other arthritis(RA,OA)

• Colchicine Vs. NSAIDs

(42)

(43)

(44)

Corticosteriods

– Indicated in refractory cases & not tolerating Colchicine/NSAIDs

– Treatment of severe symptomatic gout

– Prednisone (30–50 mg/d), tapered over 7–10 days

– Intra-articular injection of – Hydrocortisone 50 mg – Triamcinolone acetonide :

– 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee)

“They don’t arrest disease progression”

(45)

Treatment of chronic gout

• Life style modification

– Control of body weight

– low-purine diet: meat, seafood – increase in liquid intake

– limitation of ethanol use

• Drug therapy started

• High plasma uric levels

• Many episodes of acute gout

• Presence of tophi, nephropathy

(46)

Uric acid synthesis inhibitor Allopurinol & Febuxostat

MOA of Allopurinol

• Hypoxanthine analogue

• Inhibits xanthine oxidase

• Oxypurinol {alloxanthine}, this is non competitive inhibitor of XO

• Increased concentration of hypoxanthine, xanthine, soluble purines, efficiently excreted out

• Dissolution of tophi

• “Acute attack may be precipitated”

(47)

(48)

Pharmacokinetic

• Oral absorption

• Peak concentartion 1-1.5 H

• T

_1/2

: 1-1.5

• Allopurinol Oxypurinol (T

_1/2

: 30H)

• Clinical uses:

• Primary hyperuricemia

• Secondary hyperuricemia

• Drug induced hyperuricemia

• overproducers, urate stone formers, and patients

with renal disease

(49)

– Co-administartion Allopurinol with colchicine/ NSAIDs for 3-6 months

– Should not be used in acute gout

• Goal of therapy: reduce plasma uric acid concentration<6mg/

dl

• Fluid intake more than 2 liter/d, also alkalinize the urine

• Start with 100 mg, increments of 100mg/wk, maintain at 300mg/d daily dose.

• Severe cases: 400mg-600mg/d in divided doses

• Colchicine 0.5 mg twice a week for prophylaxcis

(50)

• ADRs:

• Hypersensitivity:

• Cutaneous reactions: Pruritic, erythematous, urticarial

• Stevens Johnson Syndrome & Necrolysis

• Gastrointestinal intolerance,

• Peripheral neuritis,

• Necrotizing vasculitis

• Depression of bone marrow,

• Rarely aplastic anemia

• Xanthine stone formation

• Contraindication???

•

Stop or No allopurinol

Asymptomatic hyperuricemia First appearance of skin rash

(51)

I do not recommended for the treatment of hyperuricemia Allopurinol should be discontinued at the first appearance

of skin rash or other signs of an allergic reaction

In an asymptomatic person with hyperuricemia, the efficacy of long-term drug treatment is unproved

In some individuals, uric acid levels may be elevated up to

2 standard deviations above the mean for a lifetime

without adverse consequences.

(52)

• Drug interactions

– Inhibit degradation of Mercaptopurine & Azathioprine, doses should be reduced

– Interfere with hepatic inactivation of warfarin &

theophylline

– Probenecid+ allopurinol complex: probenecid decreases t1/2 of allopurinol & allopurinol increases t1/2 of

probenecid

– High incidence of skin rash with ampicillin

• Other uses:

• Adjuvant treatment of kala azar(Inhibits Leishmania by altering its purine metabolis)

• Cautions: mercaptopurines & azathioprine) if concomitantly dose is reduced by about 75%.

(53)

ALLOPURINOL – Black Box Warning

THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF ASYMPTOMATIC HYPERURICEMIA

ALLOPURINOL SHOULD BE DISCONTINUED AT

THE FIRST APPEARANCE OF SKIN RASH OR

OTHER SIGNS OF AN ALLERGIC REACTION

(54)

Renal handling of uric acid

(1) Glomerular iltration (2) Tubular reabsorption (3) Secretion, and

(4) Postsecretory reabsorption

-Over 90% of individuals with sustained hyperuricemia have a defect in the renal handling of uric acid.

-Gouty individuals excrete ~40% less uric acid than nongouty

(55)

Uricosuric drugs

• MOA

:

– Block active transport of organic acids across renal tubules by blocking: organic acid transport protein

– Uricosuric compounds directly inhibit URAT1 on the apical side of the tubular cell

– All that is reabsorbed (as uric acid): its excretion is enhanced – All that is secreted (as some drugs penicillin): inhibition of

excretion

• Drugs :

– Probenecid

– Sulfinpyrazone – Benzbromarone

• More effective in under-excretors & patients with good renal function

• Used as adjuvant or second line agent with Allopurinol

(56)

• Probenecid:

– Uricosuric action

– Inhibits the excretion of penicillin, also cephlaosporins, sulfonamides, methotrexate

– Also inhibits biliary excretion of rifampicin

• Adrs:

• Gastrointestinal irritation (common), rashes(rare), Nephrotic syndrome , high doses convulsions, respiratory failure ,

• Uses:

– Chronic gout & Hyperuricemia

• More effective in under-excretors

• As second line or adjuvant to Allopurinol

• Co-adminstration of NSAIDs/ colchicine for 3 months

• Ineffective in renal failure

– Prolong the duration of action of penicillin

(57)

• SULFINPYRAZONE

– Similar to probenecid

– Used only in chronic gout & hyperuricemia

– 98% bound to plasma proteins, so displacement reactions with warfarin, sulfonylureas

– Gastric irritation most common side effect

• BENZBROMARONE

– Potent uricosuric even acts in decreased renal function

– In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used

– Uricosuric initiated in gouty 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.

– Caution: essential to maintain a large urine volume

(58)

In most mammals/birds, uricase converts uric acid to the more soluble allantoin

RASBURICASE

Rasburicase recombinant urate oxidase, an enzyme which occurs in many mammals, but not in humans

Uric acid  allantoin

Allantoin is an inactive metabolite of purine metabolism, and is five to ten times more soluble than uric acid

(59)

• In the general population the prevalence of hyperuricemia ranges between 2.0 and 13.2%, and the prevalence of gout is between 1.3 and 3.7%.

• Complications of gout correlate with both the duration and severity of hyperuricemia

• Uric acid nephrolithiasis: ~50% with serum urate levels of (13 mg/

dL)

• Urate nephropathy

• Uric acid nephropathy

• Hyperuricemia is present in ~5% of the population and in up to 25%

of hospitalized individuals

• Recommended for individuals receiving cytolytic therapy for neoplastic disease

• Every patient of hyperuricemia must receive drug treatment ???

(60)

• Treatment for acute gout

• Treatment of chronic gout

• Treatment of gout

• Explain basis of therapeutic use of Allopurinol in chronic gout

• Allopurinol ALONE should not be used in acute gout

• Uricosuric should not be used in acute gout

• Low doses of Aspirin is contraindicated in gout

• Explain basis of therapeutic use of colchicine in chronic gout

• Short note on Allopurinol, Febuxostat

• Penicillin is given along with Probenecid???

• Aspirin in MI

• Rasburicase is being used gout

(61)

• A bus driver presented with soft tissue injury with pain.

Which of the drugs should not be prescribed

• Celecoxib

• Indomethacin

• Naproxen

• Aceclofenac

• NSAID acting through cox-3 inhibition is ???

• The most common limiting adverse effect of colchicine is???

• ANY QUESTTION ???