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Nonsteroidal Anti-inflammatory Drugs, Disease-Modifying Antirheumatic
Drugs, Nonopioid Analgesics, & Drugs Used in Gout
Florencia D. Munsayac, MD, MBA, RMT
The Inflammatory Response
3 Phases of Inflammation:- Acute Inflammation/acute phase
- The Immune Response/sub-acute or delayed phase
- Chronic Inflammation/chronic proliferative phase
Some of the mediators of acute inflammation & their effects
Mediators Vasodilation
Vascular Permeabilit
y
Chemotaxis
Pain
Histamine ++ - -Serotonin +/- - -Bradykini
n+++ - +++
Prostaglandins +++ +++ +Leukotrien
es- +++ -
Some of the Mediators of Chronic Inflammation
Mediators Sources Primary EffectsInterleukins-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
Rheumatoid arthritis
Chronic inflammation → pain & destruction of bone & cartilage
An autoimmune disease
Goals of Therapy
- Relief of pain
- Reduction of inflammation
- Protection of articular structures
- Maintenance of function
- Control of systemic involvement
5 General Approaches
NSAIDs and simple analgesics – to control the s/s of local inflammatory process– Minimal effect on the progression of the disease
Groups of NSAIDs- Salicylic acid derivatives (Aspirin, Na salicylate, choline Mg+
+ trisalicylate, salsalate, diflunisal, sulfasalazine)- Para-chlorobenzoic acid derivatives or indoles
(Indomethacin, Sulindac)- Pyrazolone derivatives (Phenylbutazone)- Arylpropionic acid (Ibuprofen, Flurbiprofen, Ketoprofen,
Fenoprofen, Naproxen, Oxaprozin)
5 General Approaches
NSAIDs and simple analgesics – to control the s/s of local inflammatory process– Minimal effect on the progression of the disease
Groups of NSAIDs- Fenamates/Anthranilic acids (Mefenamic Acid,
Meclofenamic acid)- Enolic acids/Oxicams (Piroxicam)- Heteroaryl/Penylacetic acids (Diclofenac Sodium,
Tolmetin, ketorolac)- Alkalones (Nabumetone)- Selective COX-2 inhibitors (Celecoxib, Rofecoxib,
Meloxicam)- Para-aminophenol (Acetaminophen)
5 General Approaches
Glucocorticoids– To suppress s/s of inflammation– Retard the development & progression of bone
erosions
DMARDs– Methotrexate, sulfasalazin, hydroxychloroquine,
gold salts, or D-penicillamine– Have the capacity to decrease elevated levels of
acute phase reactants → modify inflammatory component & its destructive capacity
5 General Approaches
Biologics – TNF-neutralizing agents: infliximab, etanercept,
& adalimumab– IL-1 neutralizing agents: anakinra– Depletes B cells: rituximab– Interferes T cell activation: abatacept
Immunosuppressive & Cytotoxic agents– Leflunomide, cyclosporine, azathioprine,
cyclophosphamide Shown to ameliorate the disease process
Types of Cyclooxygenases / Prostaglandin G/H synthase
COX 1 - involved in tissue hemeostasis
COX 2 - responsible for the production of the prostanoid mediators of inflammation (IL-1 and TNF-)
COX 3
Three major types of effects of NSAIDs
Anti-inflammatory
Analgesic
Antipyretic– related to their
primary action: inhibition of arachidonate cyclooxygenase, → inhibition of prostaglandin and thromboxanes.
Other Effects of NSAIDs
Strong O2-radical scavenging effects decrease tissue damage
Inhibit platelet aggregation except COX 2 selective inhibitors
Gastric irritants
Nephrotoxicity
Hypertensive complications
hepatotoxicity
NSAIDs: Pharmacokinetics
Weak organic acid, except Nabumetone
Well absorbed
food does not change their bioavailability, except Fenoprofen & Piroxicam
Highly metabolized: CYP3A or CYP2C
Renal excretion: most important route of final elimination
Biliary excretion & reabsorption (enterohepatic circulation)
Highly protein bound (~ 98%): albumin
Found in synovial fluid
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
– Rarely used as an anti-inflammatory medication
Aspirin or Acetylsalicylic Acid (ASA)Pharmacokinetics
Rapidly absorbed from the stomach & upper small intestine
Peak plasma level: 1-2 hrs
80-90% protein bound
t1/2: 15 minutes
Cross BBB & placental barrier
Undergoes hepatic metabolism
Excretion: kidneys
Aspirin or Acetylsalicylic Acid (ASA)Mechanisms of Action
- 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
Aspirin or Acetylsalicylic Acid (ASA)Adverse Effects
Gastric upset Salicylism vomiting, tinnitus, decreased
hearing, & vertigo Hyperpnea Respiratory alkalosis later acidosis supervenes Glucose intolerance Cardiotoxicity Increases uric acid levels Elevation of liver enzymes, hepatitis, decreased
renal function, bleeding, rashes, asthma Reye’s syndrome
Aspirin or Acetylsalicylic Acid (ASA)Contraindications
Pregnancy Severe hepatic damage Vitamin K deficiency Hypoprothrombinemia Hemophilia PUD Viral (chickenpox & influenza)
Aspirin or Acetylsalicylic Acid (ASA)Drug Interactions
Indomethacin, Naproxen Ketoprofen, Fenoprofen Warfarin Sulfonylureas, Methotrexate Spironolactone Penicillin
COX-2 Selective Inhibitors
Were developed in an attempt to inhibit PG synthesis by the COX-2 iso-enzyme without affecting the action of COX-1 found in the GIT, kidneys & platelets
At usual dose: no impact on platelet aggregation
Do not offer cardio-protective effects
Suggested a higher incidence of CV thrombotic events: rofecoxib & valdecoxib
COX-2 Selective inhibitors
Drugs Celecoxib Etoricoxib
Meloxicam
Valdecoxib/Rofecoxib
Parecoxib
Lumiracoxib
Absorption 20-30%(affected by food)
83% Slowly absorb
1-2 hours 15 minutes (IV, IM)
Rapid & well absorbed
Half-life 11 hrs 20-26% 20% 8-11 hours 24 hrs
Protein binding
high
Peak Plasma concentration
1-3 hrs
Metabolism CYP2C9 liver
Excretion Affected by hepatic impairment
kidney 40% decreased in elderly
Side Effects dyspepsia Slightly less ulcerogenic
MI, CVA/HTN, CHF, Stevens-Johnson syndrome
Inc BP, MI, inc transaminases
Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative)
Drugs Diclofenac Etodolac KetorolacAbsorption rapid Rapid, well absorbed Rapid (oral, IM), IV,
oral rinse, topical
Half-life 1-2 hours 7 hours 4-6 hours
Protein-binding 99% 99% 99%
Peak Plasma Concentration
30-50 min.
Bioavailability 30-70% 80% 80%
Metabolism CYP3A4 & CYP2C9
Excretion Biliary (30%) & urine (65%)
Urine (90%)
Side effects GI distress, Occult GI bleeding, Gastric ulceration, amino-transferases
Somnolence, dizziness, HA, dyspepsia, nausea pain at injection site
Non-selective COX inhibitors (Salicylic acid derivative)Diflunisal
Derived from salicylic acid
Not metabolized to salicylic acid or salicylate
Undergoes enterohepatic cycle with reabsorption of its glucoronide metabolite
T1/2: 13 hours
Uses: cancer pain with bone metastases & pain control in dental (3rd molar) surgery
Preparation: 2% oral ointment
dosage: 500-1000mg daily in 2 divided doses
Non-selective COX inhibitors (Propionic acid derivative)
Drugs Fenoprofen Flurbiprofen
Ibuprofen Ketoprofen
Absorption Rapid, incomplete Well absorbed
Half-life 2-4 hours 0.5-4 hours 1-2 hours 1-3 hours
Protein-binding 99% 99% 99%
Peak Plasma Concentration
2 hours 1-2 hours 1-2 hours
Metabolism Extensive hepatic Extensive hepatic CYP2C8 & CYP2C9
Excretion urine urine
Side effects Interstitial nephritis, GI irritation, tinnitus, rash pruritus
GI irritation & bleeding
GIT & CNS (30%)
Drug Interactions
Probenecid
Non-selective COX inhibitors (Propionic acid derivative)
Drugs Naproxen Tiaprofen Caprofen OxaprozinAbsorption
Half-life 12 hours 1-2 hours, 2-4 hours (elderly)
10-16 hours 50-60 hours
Protein-binding high
Peak Plasma Concentration
Bioavailability
Metabolism CYP2C9, less in CYP1A2 & CYP2C8
Excretion
Side effects UGIB, allergic pneumonitis, leukocytoclastic vasculitis, pseudoporphyria
Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole)Indomethacin
Introduced in 1963
A more potent analgesic, antipyretic & anti-inflammatory agent than ASA
May also inhibit phospholipase A & C
Reduce PMN migration
Decrease T & B cells proliferation
Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole)
Drugs Indomethacin SulindacAbsorption Rapid & almost
complete90% absorption
Peak concentration 2 hours 1 hour, t1/2: 7 hours
Metabolism Liver First pass hepatic, sulfide, active metabolite
Excretion Urine, bile, feces Urine, bile, feces
Side effects GIT, CNS, hematologic, psychosis w/ hallucination
GIT, CNS, hematologic, renal, allergic reactions
Drug interaction Furosemide, thiazide, beta blockers, ACEI, probenecid
Non-selective COX inhibitors (Fenamates/Anthranilic Acid)Meclofenamate & Mefenamic acid
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
Indications: Primary Dysmenorrhea
Non-selective COX inhibitors (Alkalones) Nabumetone
The only nonacid NSAID, causes less gastric damage
Converted to the active metabolites in the liver, 6-methoxy-2 naphthylacetic acid
Given as a ketone prodrug
Dose: 1000 mg
t1/2: > 24 hrs
Does not undergo enterohepatic circulation
Causes pseudoporphyria & photosensitivity
Non-selective COX inhibitors (Pyrazolone derivative)
Drugs Phenylbutazone Azapropazone
Properties Withdrawn from the market
Structurally related to phenylbutazone
Half-life 12-16 hours
Toxicities aplastic anemia, agranulocytosis
Non-selective COX inhibitors (Oxicams/Enolic acid)19. Piroxicam
Inhibits PMN leukocyte migration, decreases O2 radical production, & inhibits lymphocyte function
Inhibits proteoglycanase & collagenase
Mean t1/2: 50-60 hrs
Dosing: o.d. or every other day
Non-selective COX inhibitors (Oxicams/Enolic acid)19. 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
Non-selective COX inhibitors (Oxicams/Enolic acid)20. Tenoxicam
Half-life: 72 hours
Similar to piroxicam
Other analgesics ACETAMINOPHEN
– Active metabolite of phenacetine
– A weak PG inhibitor
– No significant anti-inflammatory effect
– For the treatment of mild to moderate pain
– Antipyretic effect
Other analgesics ACETAMINOPHEN
Pharmacokinetics:– Administered orally– Absorption: related to rate of gastric emptying– Peak blood concentration: 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-p-
benzoquinone) is important liver & kidney toxicity– t1/2: 2-3 hrs
Other analgesics 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: N-acetylcysteine (sulfhydryl groups)
Caution: liver disease
Dosage: 325-500mg q.i.d.
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
Exert minimal direct nonspecific anti-inflammatory or analgesic effects
Frequent improvement in serologic evidence of disease activity, titers of RF & CRP and ESR decline
METHOTREXATE
MOA: inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate synthase, with secondary effects on PMN chemotaxis plus enhanced adenosine release
Absorption: 70% after oral administration
Excretion: urine & bile
Dose: 7.5 - 25mg/wk (oral, SC or IM)
Toxicities: nausea, mucosal ulcers, dose-related hepatotoxicity, “hypersensitivity” lung reaction, pseudolymphomatous reaction
Folic acid & leucovorin
SULFASALAZINE
Consists of sulfapyridine & 5-amino-salicylic 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, juvenile arthritis & ankylosing spondylitis
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
Toxicity: ocular, dyspepsia, N/V, abdominal pain, rashes, nightmares
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
Mechanisms of action:– alters the morphology and functional capabilities of human
macrophages
– inhibition of lysosomal enzyme activity
– reduction of histamine release from mast cells
– suppression of phagocytic activity of the PMN leukocytes
– 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:– Active RA– Active inflammation & erosive changes– RA with Sjogren’s syndrome – Juvenile RA
CI: history 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)
PENICILLAMINE
Pharmacodynamics:– Interact with lymphocytes membrane receptors
– Interfere with the synthesis of DNA, collagen, & mucopolysaccharides
Parmacokinetics:– 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– Dose: 125-250mg daily for 1-3 months, 1.5 hrs p.c.
PENICILLAMINE
Adverse effects:– 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 hyperplasia, alopecia, & psychologic changes
PENICILLAMINE
Contraindications:– Pregnancy– Renal insufficiency
Drug Interactions: – Gold– Cytotoxic drugs– Phenylbutazone
Biologics
Bind & neutralize TNF– Etanercept – a TNF type II receptor fused to IgG1– Infliximab – a chimeric mouse/human antibody to
TNF– Adalimumab – a fully human antibody to TNF
L-1 neutralizing agent– Anakinra
Depletes B cells– rituximab
Interferes with T cell activation– abatacept
Biologics that bind & neutralize TNF
Drugs Etanercept Infliximab Adalimumab
Peak Serum Concentration
72 hour
Route of Administration
25mg SC b.i.d. 3 or 10mg/kg at 0, 2 & 6 weeks I V infusion
40mg every other week SC
Half-life 8-12 days 10-20 days
Side Effects Injection site reactions, activation of latent pulmonary tuberculosis
Upper RTI, nausea, headache, sinusitis, rash & cough with MTX
Opportunistic infections, leukopenia, vasculitis, lupus
Biologics
Drugs Anakinra Rituximab AbataceptMOA A recombinant IL-1
receptor antagonist that competitively blocks the binding of IL-1β & IL-1
A chimeric monoclonal antibody that targets CD20 B lymphoctyes
Inhibits the activation of T cells by inhibiting the binding to CD28 and CD80/86
Route/Dose 2 I V infusions 2 weeks apart
I V infusion, 3 initial dose (day 0, week 2, week 4), then followed by monthly infusion
Half-life/Drug interaction
Not recommended to combined with anti-TNF
May be combined with MTX
13-16 days, May or may not be combined with MTX, but not with anti-TNF
Side Effects injection site reaction
related to transfusion reaction
increased risk of infection, hypersensitivity reactions
Immunosuppressive Therapy
These drugs have been reserve for patients who have clearly failed therapy with DMARDs and biologics
Effective in the treatment of RA
AZATHIOPRINE
Acts through its major metabolite, 6-thioguanine suppresses inosinic acid synthesis and B & T cell functions, immunoglobulin production & IL-2 secretion
Dosage: 2mg/kg/d
Other indications: SLE, Behcet’s syndrome, psoriatic arthritis, reactive arthritis, polymyositis
Toxicities: BM suppression, GI disturbances, increased in risk for infections and malignancy
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 concentrations & 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
CYCLOSPORINE
Acts through IL-2 & TNF-a suppression, mediated through T cell effects
Absorption: erratic
Bioavailability: 30%, grape fruit juice increases by 62%
Metabolized in the liver
Dosage: 3-5mg/kg/d
Toxicities: nephrotoxicity, HTN, hyperkalemia, hepatotoxicity, gingival hyperplasia, & hirsutism
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
Mycophenolate mafetil
Active form: mycophenolic acid
Inhibits cytosine monophosphate dehydrogenase Inhibits T-cell lymphocyte proliferation Interferes with leucocyte adhesion to endothelial cells
through inhibition of E-selectin, P-selectin, & IC adhesion molecule1
Indication: SLE, vasculitis, Wagener’s granulomatosis, RA
Dosage: 2 g/day
Adverse effects: GI, hematopoietic & hepatic
IMMUNOADSORPTION APHERESIS
Mechanism of action:– Down-regulation of B cell function through the
release of small amounts of staphylococcal protein A complexed with immunoglobulins
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)
Dramatically relieves pain, by binding to IC protein tubulin preventing polymerization into microtubules inhibition of leukocyte migration & phagocytosis
Absorption: readily, oral
Peak serum level: 2 hrs
Excretion: intestinal tract & urine
DRUGS USED IN GOUT(COLCHICINE)
Indication: gouty arthritis, acute Mediterranean fever, sarcoid arthritis, hepatic cirrhosis
Dosage: 0.5-1 mg q 2 hrs
SE: LBM, N/V, abdominal pain, hair loss, BM depression, peripheral neuritis, myopathy
Acute intoxication: burning throat pain, bloody LBM, shock, hematuria, oliguria, CNS depression
NSAIDs in GOUT
Inhibit urate crystal phagocytosis
Indomethacin 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)
Act at the anionic transport sites of the renal tubule
Employed to decrease the body pool of urates
Reabsorption of uric acid in the proximal tubule is decreased
Probenecid: completely reabsorbed by renal tubules & metabolized slowly
Sulfinpyrazone: rapidly excreted by the kidneys
Probenecid & SulfinpyrazoneAdverse Effects, CI & Cautions
AE: GI irritation, allergic dermatitis, nephrotic syndrome (probenecid), aplastic 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%, oral
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
Febuxostat
First non-purine inhibitor of xanthine oxidase
More than 80% absorbed following oral administration
Maximum concentration: 1 hour
Extensively metabolized in the liver
Excreted in the urine
Febuxostat
Pharmacodynamics:– Potent & selective inhibitor of xanthine
oxidase → reduces the formation of xanthine & uric acid
Dose: 80mg, 120mg, 300mg daily
Adverse effects: liver function abnormalities, diarrhea, headache nausea
