Nonsteroidal Anti- inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Dr. Florencia D. Munsayac.

Nonsteroidal Anti-inflammatory 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 Vascular

PermeabilityChemotaxis Pain

Histamine ++ - -

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 ANTI-INFLAMMATORY 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)10. Selective COX-2 inhibitors (Celecoxib, Rofecoxib, Etodolac,

Nimesulide)

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

SalycilatesPharmacokinetics

• 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

SalycilatesPharmacodynamics

. 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

SalicylatesAdverse 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

SalicylatesContraindications

• 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

AcetaminophenPharmacokinetics

• 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-p-

benzoquinone) is important liver & kidney toxicity

• t1/2: 2-3 hrs

AcetaminophenIndications

• HA, myalgia, postpartum pain• ASA allergy, hemophilia or hx of PUD,

bronchospasm precipitated by ASA, & children with viral infection

• Analgesic adjunct to anti-inflammatory therapy

• Gout

AcetaminophenAdverse 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

IndomethacinPharmacokinetics

• Rapidly & almost completely absorbed from GIT

• Peak concentration: 2 hrs• Metabolism: liver & extensive

enterohepatic circulation • Excretion: bile, urine, feces

IndomethacinDrug Interaction

• Probenecid• Furosemide• Thiazide • Beta adrenergic blocking agents

IndomethacinTherapeutic Uses

• Rheumatic conditions• Gout & ankylosing spondylitis• Patent ductus arteriosus• Sweet’s syndrome• Juvenile rheumatoid arthritis• Pleurisy• Nephrotic syndrome• Tocolytic agent

IndomethacinAdverse Effects

• Gastrointestinal effects (abdominal pain, diarrhea, GI hemorrhage, pancreatitis)

• Headache, dizziness, confusion, depression

• Psychosis with hallucination• Thrombocytopenia• Aplastic anemia• hyperkalemia

IndomethacinContraindications

• 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

SulindacPharmacokinetics

• 90% absorbed after oral administration

• Peak concentration: 1 hr• t1/2: 7 hrs• First pass kinetics

SulindacTherapeutic Indications

• Rheumatoid arthritis• Suppresses familial intestinal

polyposis• Ankylosing spondylitis• Osteoarthritis• Acute Gout• Tocolytic agent

SulindacAdverse 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

DiclofenacPharmacokinetics

• 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%)

DiclofenacAdverse 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)

EtodolacPharmacokinetics

• 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 anti-inflammatory & 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• 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

PiroxicamPharmacokinetics

• 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• 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, 6-thioinosinic 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

GoldPharmacodynamics

• 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

GoldIndications & 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

GoldAdverse 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

PenicillaminePharmacodynamics

• Interact with lymphocytes membrane receptors

• Interfere with the synthesis of DNA, collagen, & mucoplosaccharides

PenicillamineAdverse 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 hyperlasia, alopecia, & psychologic changes

PenicillamineContaindications & 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-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, 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

LeflunomidePharmacokinetics

• 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 &SulfinpyrazonePharmacodynamics

• Employed to decrease the body pool of urates

• Reabsorption of uric acid in the proximal tubule is decreased

Probenecid & SulfinpyrazoneAdverse 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