Download Nonsteroidal Anti-inflammatory Drugs, Disease

Nonsteroidal Antiinflammatory Drugs,
Disease-Modifying
Antirheumatic Drugs,
Nonopioid Analgesics, &
Drugs Used in Gout
Dr. Florencia D. Munsayac
The Inflammatory Response
3 Phases of Inflammation:
- Acute Inflammation
- The Immune Response
- Chronic Inflammation
Some of the mediators of acute
inflammation & their effects
Mediators
Vasodilation
Histamine
Vascular
Permeability
Chemotaxis
Pain
++
-
-
Serotonin
+/-
-
-
Bradykinin
+++
-
+++
Prostaglandins
+++
+++
+
Leukotrienes
-
+++
-
Some of the Mediators of
Chronic Inflammation
Mediators
Sources
Primary Effects
Interleukins-1,
-2, and -3
Macrophages, T
lymphocytes
Lymphocyte activation,
PG production
GM-CSF
T lymphocytes,
endothelial cells,
fibroblast
Macrophage &
granulocyte activation
TNF-alpha
Macrophages
PG production
Interferons
Macrophages,
endothelial cells, T
lymphocytes
Many
PDGF
Macrophages,
endothelial cells,
fibroblasts, platelets
Fibroblast chemotaxis,
proliferation
Therapeutic Strategy
2 Primary Goals:
- The relief of pain
- NSAIDs
- Nonopioid analgesics
- Corticosteroids
- The slowing or--in theory--arrest of the
tissue damaging process
- SAARDs or DMARDs
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
8 Groups of NSAIDs:
1. Salicylic acid derivatives (Aspirin, Na salicylate, choline
Mg++ trisalicylate, salsalate, diflusinal, sulfasalazine)
2. Para-aminophenol (Acetaminophen)
3. Para-chlorobenzoic acid derivatives or indoles
(Indomethacin, Sulindac)
4. Pyrazolone derivatives (Phenylbutazone)
5. Arylpropionic acid (Ibuprofen, Flurbiprofen,
Ketoprofen, Fenoprofen, Naproxen, Oxaprozin)
6. Fenamates/Anthranilic acids (Mefenamic Acid,
Meclofenamic acid)
7. Enolic acids/Oxicams (Piroxicam, Meloxicam)
8. Heteroaryl/Penylacetic acids (Diclofenac Sodium,
Tolmetin, ketorolac)
9. Alkalones (Nabumetone)
SALICYLATES
• Aspirin or Acetylsalicylic Acid (ASA)
– Comes from the family of salicylates
derived from salicylic acid
– Prototype drug
– Developed in 1899 by Adolph Bayer
– The oldest anti-inflammatory agent
Salycilates
Pharmacokinetics
• Rapidly absorbed from the stomach &
upper small intestine
• Peak plasma level: 1-2 hrs
• 80-90% protein bound
• t1/2: 3-5 hrs
• Cross BBB & placental barrier
• Undergoes hepatic metabolism
• Excretion: kidneys
Salycilates
Pharmacodynamics
. MOA:
- Inhibits prostaglandin synthesis
- Irreversibly blocks the enzyme
cyclooxygenase (PG synthase)
. Pharmacological Properties & Therapeutic
indications:
- anti-inflammatory effects
- analgesic effects
- antipyretic effects
- Platelet effects
- Uricosuric effects
. Dosage: children: 50-75mg/kg/day
adult: 325-650mg p.o. q 4 hrs
Salicylates
Adverse Effects
• Gastric upset
• Salicylism  vomiting, tinnitus, decreased
hearing, & vertigo
• Hyperpnea
• Respiratory alkalosis  later acidosis
supervenes
• Glucose intolerance
• Carditoxicity
• Increases uric acid levels
• Elevation of liver enzymes, hepatitis, decreased
renal function, bleeding, rashes, asthma
• Reye’s syndrome
Salicylates
Contraindications
• Pregnancy
• Severe hepatic damage
• Vitamin K deficiency
• Hypoprothrombinemia
• Hemophilia
• PUD
• Viral (chickenpox & influenza)
Special Drug Characteristics
or NonAcetylated Salicylates
• Sodium salicylate, sodium
thiosalicylate, Mg salicylate &
choline salicylate
• Salisalicylate
• Methylsalicylate (oil of wintergreen)
• Diflunisal
ACETAMINOPHEN
• Active metabolite of phenacetine
• A weak PG inhibitor
• No significant anti-inflammatory
effect
• For the treatment of mild to
moderate pain
• Antipyretic effect
Acetaminophen
Pharmacokinetics
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Administered orally
Absorption: related to rate of gastric emptying
Peak blood conc: 30-60 min
Slightly protein bound
Partially metabolized by hepatic microsomal
enzyme  acetaminophen SO4 & glucuronide
• Excretion: unchanged < 5%
• A minor but highly active metabolite (N-acetyl-pbenzoquinone) is important  liver & kidney
toxicity
• t1/2: 2-3 hrs
Acetaminophen
Indications
• HA, myalgia, postpartum pain
• ASA allergy, hemophilia or hx of
PUD, bronchospasm precipitated by
ASA, & children with viral infection
• Analgesic adjunct to antiinflammatory therapy
• Gout
Acetaminophen
Adverse Effects
• Mild increase in hepatic enzymes
• Dizziness, excitement & disorientation
• Ingestion of 15gm: fatal  death caused by
hepatotoxicity with centrilobular necrosis &
sometimes with acute renal tubular necrosis
• Symptoms of early hepatic damage: N/V,
diarrhea, abdominal pain
• Antidote: acetylcysteine (sulfhydryl groups)
• Caution: liver disease
• Dosage: 325-500mg q.i.d.
INDOMETHACIN
• Introduced in 1963
• An indole derivative
• A more potent analgesic, antipyretic
& anti-inflammatory agent than ASA
• Nonselective COX inhibitor
• May also inhibit phospholipase A & C
• Reduce PMN migration
• Decrease T & B cells proliferation
Indomethacin
Pharmacokinetics
• Rapidly & almost completely
absorbed from GIT
• Peak concentration: 2 hrs
• Metabolism: liver & extensive
enterohepatic circulation
• Excretion: bile, urine, feces
Indomethacin
Drug Interaction
•Probenecid
•Furosemide
•Thiazide
•Beta adrenergic blocking agents
Indomethacin
Therapeutic Uses
• Rheumatic conditions
• Gout & ankylosing spondylitis
• Patent ductus arteriosus
• Sweet’s syndrome
• Juvenile rheumatoid arthritis
• Pleurisy
• Nephrotic syndrome
• Tocolytic agent
Indomethacin
Adverse Effects
• Gastrointestinal effects (abdominal
pain, diarrhea, GI hemorrhage,
pancreatitis)
• Headache, dizziness, confusion,
depression
• Psychosis with hallucination
• Thrombocytopenia
• Aplastic anemia
• hyperkalemia
Indomethacin
Contraindications
• Nasal polyps
• Angioedema
• Asthma
• Renal failure
• Enterocolitis
• hyperbilirubinemia
SULINDAC
• A sulfoxide prodrug
• An acetic acid derivative
• Reversibly metabolized to active
metabolite sulfide  more potent as
cyclooxygenase inhibitor ,
enterohepatic recycling prolongs
DOA: 12-16 hrs, excreted in bile
• Metabolized to an inactive sulfone
Sulindac
Pharmacokinetics
• 90% absorbed after oral
administration
• Peak concentration: 1 hr
• t1/2: 7 hrs
• First pass kinetics
Sulindac
Therapeutic Indications
• Rheumatoid arthritis
• Suppresses familial intestinal
polyposis
• Ankylosing spondylitis
• Osteoarthritis
• Acute Gout
• Tocolytic agent
Sulindac
Adverse Effects
• GI side effects: abdominal pain &
nausea
• CNS side effects: drowsiness,
dizziness, HA, nervousness
• Skin rash & pruritus
• Transient elevations of hepatic
enzymes
TOLMETIN
• A nonselective COX inhibitor
• Effective anti-inflammatory with
analgesic & antipyretic effects
• Has a short half-life: 5 hrs
• Given frequently  not often used
• Ineffective in gout  unknown
• SE: allergic IgM-related
thrombocytopenic purpura, GI &
CNS effects
DICLOFENAC
• A simple phenylacetic acid derivative
• A potent nonselective
cyclooxygenase inhibitor
• Decreases arachidonic acid
bioavailability
• Has the usual anti-inflammatory,
antipyretic & analgesic properties
Diclofenac
Pharmacokinetics
• Rapidly absorbed following oral
administration
• 99% protein bound
• 30-70% systemic bioavailability  first
pass hepatic metabolism
• t1/2: 1-2 hrs
• Accumulates in synovial fluid  t1/2 of 2-6
hrs
• Metabolized by CYP3A4 & CYP2C9
• 30% biliary clearance, urine (65%)
Diclofenac
Adverse Effects
• GI distress
• Occult GI bleeding
• Gastric ulceration
• Elevates serum aminotransferases
Preparations: ophthalmic,
dermatologic, IM administration
ETODOLAC
• A racemic acetic acid derivative
• Slightly more COX-2 selective, with
COX-2:COX-1 activity ratio of 10
• Clinical uses: postoperative
analgesia, osteoarthritis, rheumatoid
arthritis
• SE: GI irritation & ulceration (less)
Etodolac
Pharmacokinetics
• Rapidly well absorbed
• 80% bioavailability
• Strongly bound to plasma proteins
(99%)
• Enterohepatic circulation
• t1/2: 7 hrs
• Dosage: 400-1600mg/d
• Excreted in the urine
KETOROLAC
• Potent analgesic with moderate antiinflammatory & antipyretic effects
• Inhibits platelet aggregation
• Promotes gastric ulceration & renal
impairment
• Indications: postsurgical pain,
chronic pain, inflammatory
conditions of the eye, seasonal
allergic conjunctivitis  topical
Pharmacokinetics
• Rapidly absorbed after oral or IM
administration
• Also given IV
• Peak concentration: 30-50 min.
• 80% oral bioavailability
• Almost totally protein bound
• t1/2: 4-6 hrs
• Metabolized to active & inactive forms
• Excreted in the urine (90%)
FENOPROFEN
• A propionic acid derivative
• t1/2: 2-4 hrs
• Given q.i.d.
• Toxic effect: interstitial nephritis
• Adverse effects: nephrotoxicity,
nausea, dyspepsia, peripheral edema,
rash, pruritus, CNS & CVS effects
and tinnitus
FLURBIPROFEN
• A propionic acid derivative
• Inhibits COX nonselectively
• Also affect TNF-a & nitric oxide synthesis
• t1/2: 0.5-4 hrs
• Extensive hepatic metabolism
• Dosages: 200-400mg/day
• Ophthalmic formulation inhibition of
intraoperative miosis
• SE: GI symptoms, cogwheel rigidity,
ataxia, tremor & myoclonus
IBUPROFEN
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A simple derivative of phenylpropionic acid
Dose: 2400mg daily
99% protein bound
Rapidly cleared
Terminal t1/2: 1-2 hrs
Extensively metabolized in CYP2C8 & CYP2C9 in
the liver
• SE: GI irritation & bleeding
• CI: nasal polyps, angioedema, bronchospastic
reactivity to ASA, rash, pruritus, tinnitus,
dizziness, HA, aseptic meningitis, fluid retention,
agranulocytosis, aplastic anemia, ARF,
interstitial nephritis, nephrotic symdrome
KETOPROFEN
• A propionic acid derivative
• Inhibits both cyclooxygenase
(nonselective) & lipoxygenase
• Rapidly absorbed
• Elimination t1/2: 1-3 hrs
• Metabolized in the liver (glucuronide)
• DI: probenicid
• Dosage: 100-300mg/day
• Indication: RA, OA, GA, dysmenorrhea
• AE: GIT & CNS
NAPROXEN
• Is a naphthylpropionic acid
• A nonselective COX inhibitor
• Elimination serum t1/2: 12 hrs
• High albumin binding
• Metabolism: CYP2C9, less in CYP1A2 &
CYP2C8
• Prep: SR formulation, oral susp
• AE: UGIB, allergic pneumonitis,
leukocytoclastic vasculitis, &
pseudoporphyria
OXAPROZIN
• a propionic acid derivative
• t1/2: 50-60 hrs
• Does not undergo enterohepatic
circulation
• Given o.d.
• Is a mild uricosuric agent
PIROXICAM
• An oxicam
• A nonselective COX inhibitor
• Also inhibits PMN leukocyte
migration, decreases O2 radical
production, & inhibits lymphocyte
function
• Mean t1/2: 50-60 hrs
• Dosing: o.d. or every other day
Piroxicam
Pharmacokinetics
• Rapidly absorbed from the stomach &
upper intestine
• Peak plasma concentration: 1 hr
• Extensively metabolized to inactive
metabolites
• 99% protein bound
• Elimination: renal – 5% unchanged
• Toxicity: GI symptoms, dizziness, tinnitus,
HA & rash, increased incidence of PUD
and bleeding
MELOXICAM
• An enolcarboxamide
• Slightly COX-2 selective
• Slowly absorbed
• t1/2: 20 hrs
• Clearance: 40% decreased in elderly
• Dose: 7.5-15mg/d for RA & OA
• Slightly less ulcerogenic
NABUMETONE
• The only nonacid NSAID
• Converted to the active acetic acid
derivative in the body
• Given as a ketone prodrug
• t1/2: > 24 hrs
• Deos not undergo enterohepatic
circulation
• Cause less gastric damage
• Cause pseudoporphyria & phosensitivity
PHENYLBUTAZONE
• A pyrazolone derivative
• Withdrawn from the market in
North American & most European
markets
• Toxicity: aplastic anemia
agranulocytosis
MECLOFENAMATE &
MEFENAMIC ACID
• Fenamic acid derivatives
• Inhibit both COX & phospholipase A2
• Peak plasma level: 30-60 min
• t1/2: 1-3 hrs
• SE: LBM, abdominal pain (meclofenamate)
• CI: pregnancy, children
• DI: oral anticoagulants
CELECOXIB
• Highly selective COX-2 inhibitor
• Absorption: 20-30% decreased by food
• t1/2: 11 hrs
• Highly protein bound
• Metabolized by CYP2C9
• Clearance affected by hepatic impairment
• Effective dose: 100-200mg b.i.d.
• Does not affect platelet aggregation
• DI: warfarin
• AR: dyspepsia
ROFECOXIB
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A furanose derivative
A potent highly selective COX-2 inhibitor
Well absorbed
Dosage range: 12.5-50mg/d
Slightly less protein-bound (87%)
t1/2: 17 hrs
Given o.d., for OA
Metabolized by cytosolic liver enzymes
Does not inhibit platelet aggregation
Have little effect on gastric mucosal PGs
Associated with fewer gastric or duodenal
gastroscopic ulcers
CORTICOSTEROID DRUGS
• Capable of slowing the appearance of
new bone erosions
• Known to inhibit phospholipase A2
• Shown to selectively inhibit the
expression of COX-2
• SE: fracture, infections, cataracts
• Prep: oral, intra-articular
DISEASE-MODIFYING
ANTIRHEUMATIC DRUGS
(DMARDS)
• Might arrest or at least slow the
progression of bone & cartilage
destruction
• Effects may take 6 weeks to 6 months to
become evident
• Include: methotrexate, azathioprine,
penicillamine, hydroxychloroquine,
chloroquine, organic gold compounds,
sulfasalazine, leflunomide, TNF-blocking
agents, & immunoadsorption apheresis
METHOTREXATE
• A potent immunosuppressive drug
• MOA: inhibition of aminoimidazolecarboxamide
ribonucleotide (AICAR) transformylase &
thymidylate synthase, plus enhanced adenosine
release
• Absorption: 70% after oral administration
• Highly polyglutaminated
• Excretion: urine & bile
• Dose: 25mg/wk
• Toxicities: nausea, mucosal ulcers, dose-related
hepatotoxicity, “hypersensitivity” lung reaction,
pseudolymphomatous reaction
• Folic acid & leucovorin
ANKYLATING AGENTS
(CHLORAMBUCIL)
• MOA: probably through its metabolic
phenylacetic acid mustard, cross-links
DNA, thereby preventing cell replication
• Bioavailability: 70%
• Completely metabolized
• Complete excretion within 24 hrs
• Other indications: SLE, vasculitis,
• Toxicities: BM suppression, infertility,
risk of neoplasia & leukemia
ALKYLATING AGENTS
(CYCLOPHOSPHAMIDE)
• MOA: through it active metabolite,
phosphoramide mustard, cross-links DNA
& prevents cell replication, it suppresses T
& B cell functions by 30-40%
• Metabolized in the liver
• Given orally at 2mg/kg/d
• Toxicities: infertility, BM suppression,
hemorrhagic cystitis, bladder Ca 
acrolein
• Other indications: SLE
CYCLOSPORINE
• Acts through IL-2 & TNF-a suppression
• Its major actions in rheumatic diseases
appear to be mediated through T cell
effects
• Absorption: erratic
• Bioavailability: 30%
• Metabolized in the liver
• Dosage: 3-5mg/kg/d
• Toxicities: nephrotoxicity, HTN,
hyperkalemia, hepatotoxicity, gingival
hyperplasia, & hirsutism
AZATHIOPRINE
• Acts through its major metabolite, 6thioinosinic acid, to suppress inosinic acid
synthesis and B & T cell functions
• Dosage: 2mg/kg/d
• Other indications: SLE, Behcet’s syndrome
• Toxixcities: BM suppression, GI
disturbances, increased in risk for
infections and malignancy
ANTIMALARIAL DRUGS
(CHLOROQUINE,
HYDROXYCHLOROQUINE)
• Used for the treatment of RA & SLE
• MOA: unclear
• They suppress the responsiveness of T
lymphocytes to nitrogens, decrease
leukocyte chemotaxis, stabilize lysosomal
membranes, inhibit DNA & RNA synthesis
and trap free radicals
• Effects are seen after 12-24 weeks
• Other indications: juvenile chronic
arthritis, Sjogren’s syndrome, SLE
GOLD
• Prep: auranofin – oral; aurothiomalate &
aurothioglucose – parenteral
• 95% protein-bound
• Concentrate in synovial membrane, liver,
kidney, spleen, adrenal glands, LN, & BM
• Peak serum level: 2-6 hrs
• Excretion: 40% within a week, 2/3-urine;
1/3-feces
• Total body t1/2 (IM) – 1 year
Gold
Pharmacodynamics
• alters the morphology and functional capabilities
of human macrophages
• inhibition of lysosomal enzyme activity
• reduction of histamine release from mast cells
• inactivation of the first component of
complement
• suppression of phagocytic activity of the PMN
leukocytes
• inhibition of the Swartzman phenomenon
• Aurothiomalate reduces the number of
circulating lymphocytes
• Auranofin inhibits the release of PGE2 from
synovial cells and the release of leukotrienes B4
& C4 from PMN leukocytes
Gold
Indications & Contraindications
• Active RA
• Active inflammation & erosive
changes
• RA with Sjogren’s syndrome
• Juvenile RA
• CI: hx of previous toxicity from the
drug, pregnancy, serious liver &
renal impairment & blood dyscrasia
Gold
Adverse Effects
• Dermatitis - 15-20% (most common)
• Thrombocytopenia, leukopenia, pancytopenia –
1-10%
• Aplastic anemia – rare but fatal
• Proteinuria  nephrotic syn – 8-10%
• Stomatitis, metallic taste, skin pigmentation,
enterocolitis, cholestatic jaundice, peripheral
neuropathy, pulmonary infiltrates, & corneal
deposition of gold
• Nitritoid reaction (sweating, faintness, flushing,
& headache)
• GI disturbances (LBM), dermatitis
PENICILLAMINE
• A metabolite of penicillin
• Is an analog of amino acid cysteine
• Absorption: half of the orally
administered, enhanced after 1.5 hrs
p.c.
• Excretion: urine & feces in 24 hrs
Penicillamine
Pharmacodynamics
• Interact with lymphocytes
membrane receptors
• Interfere with the synthesis of DNA,
collagen, & mucoplosaccharides
Penicillamine
Adverse Effects
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Decrease RF titer
Impedes absorption of many drugs
Inhibition of wound healing
Muscle & blood vessel damage
Proteinuria – 20%
Immune complex nephritis – 4%
Leukopenia & thrombocytopenia  aplastic anemia
Skin & mucosal membrane reactions
Drug fever associated with cutaneous eruption
Any of these maybe seen: myasthenia gravis, hemolytic
anemia, thyroiditis, Goodpasture’s syndrome & SLE
• Loss of taste perception or metallic taste
• Anorexia, N/V
• Mammary hyperlasia, alopecia, & psychologic changes
Penicillamine
Containdications & Drug Interactions
• Pregnancy
• Renal insufficiency
• DI: gold, cytotoxic drugs or
phenylbutazone
• Dose: 125-250mg daily for 1-3
months, 1.5 hrs p.c.
SULFASALAZINE
• Consists of sulfapyridine & 5-aminosalicylic acid connected by diazo bond
• Metabolized by bacteria in the colon
• Have some anti-inflammatory action by O2
radical scavenging & inhibition of
prostanoids and inhibit immune
reactivity
• t1/2: 6-17 hrs
• Dose: 2-3g/d
• Uses: RA, reducing bone erosion, juvenile
arthritis & ankylosing spondylitis
ANTI-TNF-ALPHA DRUGS
(INFLIXIMAB)
• Monoclonal Ab that binds with high
affinity to human TNF-a
• Given IV infusion
• Terminal t1/2: 8-12 days
• Dose: 3 or 10 mg/kg at 0, 2, & 6 wks
• SE: upper RTI, nausea, headache,
sinusitis, rash & cough with MTX
ANTI-TNF-ALPHA DRUGS
(ETANERCEPT)
• A recombinant fusion protein that
consists of 2 soluble TNF p75 receptor
moieties linked to Fc portion of human
IgG
• It binds 2 TNF-alpha molecules
• Peak serum conc: 72 hrs
• Dose: 25mg SC twice weekly
• Uses: psoriatic arthritis, juvenile chronic
arthritis
• SE: injection site reactions – pain,
erythema, swelling, itching (20-40%)
LEFLUNOMIDE
• A77-1726 (active metabolite) inhibits
dihydroorotate dehydrogenase  decrease
de novo RNA synthesis and lower levels of
rUMP  translocation of p53 to nucleus 
inhibits autoimmune T cell proliferation
& production of autoantibodies by B cells
• Increases the mRNA level of IL-10
receptor, decreases IL-8 receptor type A
mRNA concs & blocks TNF-dependent
nuclear factor-kappa B activation
Leflunomide
Pharmacokinetics
• Orally active molecule
• MW: 270
• Absorption: rapidly & nearly 100%plasma
t1/2: 15 days
• Strong protein binding
• Enterohepatic circulation
• Excretion: bile
• DI: cholestyramine
• SE: diarrhea, elevation of liver enzymes
IMMUNOADSORPTION
APHERESIS
• Contains staphylococcal protein A
bound to silica matrix designed to
remove IgG & IgG-containing
immune complexes from plasma
• Median duration of response: 6
months
• SE: chills – 30%, musculoskeletal
pain – 15%, HA & nausea – 20-30%,
joint pains & swelling – 30%
DRUGS USED IN GOUT
(COLCHICINE)
• An alkaloid from autumn crocus, Colchicum autumnale
• Dramatically relieves pain, anti-inflammatory effects by
binding to IC protein tubulin  preventing polymerization
into microtubules  inhibition of leukocyte migration &
phagocytosis
• Absorption: readily absorb after oral administration
• Peak serum level: 2 hrs
• Excretion: intestinal tract & urine
• Indication: gouty arthritis, acute mediterranean fever,
sarcoid arthritis, hepatic cirrhosis
• Dosage: 0.5-1 mg q 2 hrs
• SE: LBM, N/V, abd pain, hair loss, BM depression, peripheral
neuritis, myopathy
• Acute intoxication: burning throat pain, bloody LBM,
shock, hematuria, oliguria, ascending CNS depression
NSAIDs in GOUT
• Inhibit urate crystal phagocytosis
• Endomethacin is the agent most
often used – 50 mg q 6 hrs  reduced
to 25mg t.i.d or q.i.d. for 5 days
• ASA, salicylates, tolmetin are not
effective for gouty episodes
• Oxaprozin, lowers serum uric acid,
but not given to patients with uric
acid stone
URICOSURIC AGENTS
(Probenecid & Sulfinpyrazone)
• Are organic acids
• Act at the anionic transport sites of
the renal tubule
• Probenecid: completely reabsorbed
by renal tubules & metabolized
slowly
• Sulfinpyrazone: rapidly excreted by
the kidneys
Probenecid &Sulfinpyrazone
Pharmacodynamics
• Employed to decrease the body pool
of urates
• Reabsorption of uric acid in the
proximal tubule is decreased
Probenecid & Sulfinpyrazone
Adverse Effects, CI & Cautions
• AE: GI irritation, allergic dermatitis,
nephrotic syndrome (probenecid),
apalstic anemia
• CI & C: stone formation
• Dosage: probenecid – 0.5 gm orally in
divided doses, sulfinpyrazone – 200
mg daily
ALLOPURINOL
• Reduce uric acid synthesis by inhibiting xanthine
oxidase and increasing uric acid excretion
• Absorption: 80% after oral administration
• Metabolized by xanthine oxidase
• Given o.d.
• Indications: chronic tophaceous gout, uric acid
urine (24hrs) > 600-700mg, allergic reactions to
probenecid & sulfinyrazone, renal impairment,
grossly elevated serum uric acid levels
• AE: N/V, diarrhea, peripheral neuritis,
necrotizing vasculitis, BM depression, aplastic
anemia, hepatic toxicity, interstitial nephritis,
allergic skin reaction, cataracts