(4). NSAID-musket2013

Ita ArmyantiFarmakologi PSPD FK

UNTAN

Apr 28, 2023 1Muskuloskeletal2013

1. Sebutkan 2 contoh obat yang termasuk dalam NSAIDs, beserta mekanisme kerjanya

2. Sebutkan 2 efek samping yg sering tjd akibat pemakaian NSAIDs

3. Sebutkan 2 indikasi NSAIDs

Apr 28, 2023muskuloskeletal2012 2

Menghambat sintesis PG : produk dr COX

Prostaglandins are arachidonic acid metabolites.

Arachidonic acid is a fatty acid released from membrane phospholipids by the actions of phospholipase A2It can also be released by the combination phospholipase C and diglyceride lipase.

Apr 28, 2023 3muskuloskeletal2012


1. Cycloogygenase-1 (Cox-1):• It is constitutively expressed• Widely distributed and has a

“housekeeping” function. e.g gastric cytoprotection

2. Cycloogygenase-2 (Cox-2):• Inducible• Is an immediate early response

gene product in inflammatory & immune cells


Expression is 10-18 fold stimulated by growth factors, tumor promoters, cytokines and lipopolysaccaride endotoxin.

Inhibited by dexamethasone Involved in normal development Involved in vascular prostacyclin

production.


Membrane Phospholipids

Arachidonic acid

Cyclic endoperoxides

Phospholipase A2

Phospholipase C

Diglyceride lipase

CyclooxygenaseLipooxygenase

LTs

PGI2 TXA2

PGD2PGE2

PGF2α

PGI synthase Thromboxane synthase

PGE synthase

PGDsynthase

PGE9-KetoreductaseApr 28, 2023 7muskuloskeletal2012

LTA4

LTB4 LTC4

LTD4

LTE4

1. Phagocyte activation

2. ChemotaxisBronchoconstriction


PGI2:1. Vasodilation2. Inhibition of platelet aggregation3. Bronchodilation4. Glomerular filtration TXA2:1. Vasoconstriction2. Stimulation of platelet aggregation3. Is a smooth muscle mitogen4. Intrarenal vasoconstriction during

inflammatory conditions of the kidney


PGE2:1. Vasodilation2. Patency of ductus arteriosus3. Bronchodilation4. Uterine contraction & dysmenorrhea5. Cervical ripening6. Decreased gastric acid secretion7. Pain sensitization8. Increased body temperature9. Stimulate longitudinal muscle in GIT10. Increase glomerular filtration


PGF2α:1. Vasoconstriction2. Bronchoconstriction3. Uterine contraction4. Aqueous humor drainage5. Contracts circular muscle in GIT PGD2:1. Bronchoconstriction2. Vasodilation or vasoconstriction3. Natural sleep


1. Alprostadil (PGE1 analogue):Used to maintain patency of the ductus arteriosus in infants with congenital heart disease – waiting for surgical correction

2. Carboprost (PGF2α analogue):a. To terminate pregnancyb. To control refractory postpartum bleeding


3. Misoprostol (PGE1 analogue):a. Used in combination with NSAIDs to decrease gastric acid secretion & to inhibit ulcerationb. Induction of laborc. Enhancing cervical ripeningd. Induction of abortion Associated with increased risk of uterine rupture and perforation


4. Dinoprostone (PGE2 analogue):Causes uterine contractions and is used to induce abortion during the second trimester and to empty the uterus following fetal death, missed abortion or benign hydatidiform mole.

5. Epoprostenol (PGI2 analogue):For primary pulmonary hypertension

6. Latanoprost (PGF2α analogue):For glaucoma


Involves the release of a number of mediators

Results in pain and tissue destruction

Treatment involves:1. Relief of pain2. Slowing tissue damage or3. Arresting tissue damage


Analgesic-antipyretic-antiinflammatory Drugs.

Chemically diverse group of compounds

All are weak organic acids except nabumetone which is a prodrug metabolized to an acidic active drug

Most are highly metabolizedApr 28, 2023 16muskuloskeletal2012

Broad range of pharmacokinetic characteristics

Most are highly ( > 98%) protein-bound

Used to treat muscle strain, tendinitis, bursitis, rheumatoid arthritis, osteoarthritis & ankylosing spondylitis

Antiinflammatory action is mediated via inhibition cycloxygenase-2 and thus PG synthesis


Most are reversible inhibitors of Coxs,except aspirin which irreversibly acetylates the active site of the enzyme1. Celecoxib, rofecoxib & valdecoxib are

selective Cox-2 inhibitors2. Aspirin, indomethacin, piroxicam &

sulindac are more effective on Cox-13. Ibuprofen & meclofenamic acid

inhibit the 2 isozymes equally


Is the prototype NSAID Use for inflammatory conditions is

now rare Mainly used as antiplatelet drugPharmacokinetics: Acetylsalicylic acid is rapidly

absorbed from the stomach and upper intestine

Is rapidly hydrolyzed to acetic acid and salicylate by esterases in tissues and blood


Salicylate is bound to albumin and binding is saturable

Eliminated by metabolism and elimination is zero-order (saturable)

t½ is dose-dependant:600 mg / day 3-5 hours> 3.6 g / day 12-16 hours

Alkalinization of urine increases rate of excretion of salicylates


A. Antiinflammatory: Nonselective inhibitor of both Cox

izozymes Nonacetylated salicylates may work as

oxygen radical scavengers Interfere with chemical mediators of

the kallikrein system, thus, inhibiting granulocyte adherence to the damaged vasculature, stabilizing lysosomes and inhibiting the chemotaxis of polymorphonuclear leukocytes and macrophages. Dose > 3.6 g


B. Analgesic effects:Reduces pain of mild-to-moderate severity through its effects on inflammation. It may also inhibit pain stimuli at a subcortical site


C. Antipyretic effects: Reduces elevated body temperature Antipyretic effect is probably mediated

by both COX inhibition in the CNS and inhibition of IL-1 (released from macrophages during inflammation . Dose ~ 600 mg

D. Antiplatelet effects: At single low dose (81 mg) daily due to

irreversible inhibition of platelet COX Effect lasts for the life of platelet (8-10

days)Apr 28, 2023 23muskuloskeletal2012

1. Gastric upset, peptic ulceration & upper GI bleeding. Fecal blood loss Iron deficiency anemia (less with COX-2 inhibitors)

2. Salicylism: At high & chronic dose.Vomiting, tinnitus, decreased hearing, deafness, vertigo, headache, nervousness, confusion, retinal disturbances


3. Toxic doses:• Respiratory alkalosis due to

hyperpnea through a direct effect on the medulla

• Followed by metabolic acidosis due to salicylate accumulation

• Respiratory depression• Cardiac toxicity• Glucose intolerance


4. Uric acid retention at doses of 2 g or less dailyUric acid excretion at daily doses of 4 g or more

5. Renal function impairment, fluid retention, interstitial nephritis, papillary necrosis

6. Elevation of liver enzymes, hepatic necrosis, cholestasis, hepatitis & Reye’s syndrome in children with febrile illness


7. Bleeding8. Allergic reactions: rash, asthma,

nasal polyps & anaphylaxis9. Hyperthermia: due to uncoupling

of oxidative phosphorylation10. Electrolyte disturbances11. Inhibition of uterine contractions

– delayed labor, low birth weight, premature closure of ductus arteriosus

12. Photosensitivity, toxic epidermal necrolysis


Very good analgesic and antipyretic

Used for:1. Musculoskeletal disorders PO,

IM2. Renal colic IM3. Dysmenorrhea IM4. Solar keratosis

TopicalApr 28, 2023 28muskuloskeletal2012

Salicylic acid derivative Zero-order kinetics Claimed to be particularly useful

for cancer pain with bone metastasis

Pain following dental surgery


Can be used orally or topically Less sodium and water retention

than others Less frequent GIT irritation or

bleeding AE : Aseptic meningitis particularly

in patients with SLE has been reported

Other adverse effects are similar Useful analgesic & antiinflammatory


May also inhibit phospholipases A & CReduces neutrophil migrationDecreases T cell and B cell proliferation

Probenecid prologs its half-life by inhibiting its biliary and renal secretion

Used in:1. Rheumatic conditions: Gout and

ankylosing spondylitis2. Patent ductus arteriosus Adverse effects occur in one third of

patients


Similar but more severe than other NSAIDs.

Headache (20%) + dizziness, confusion and depression

Psychosis, hallucinations Aplastic anemia, thrombocytopenia Hyperkalemia Diarrhea Pancreatitis


Has significant analgesic efficacy, used to replace morphine

Can be given IM, IV, PO Adverse effects similar to other

NSAIDs More renal toxicity


Prodrug t½ > 24 hours Less toxic to the stomach Adverse effects similar to NSAIDs May cause photosensitivity


Also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production and inhibits lymphocytes function

t½ very long ~ 57 hours Used for rheumatic conditions More toxic than other NSAIDs


Is a sulfoxide prodrug Metabolized into the active sulfide

metabolite Undergoes enterhepatic cycling,

like many other NSAIDs Indications similar to other NSAIDs

+1. Suppression of familial intestinal

polyposis2. May prevent development of

colon, breast and prostate cancerApr 28, 2023 36muskuloskeletal2012

Adverse effects similar to NSAIDs +1. Less nephrotoxic ( reoxidized to

the inactive prodrug in the kidney2. Steven Johnson syndrome,

epidermal necrolysis3. Thrombocytopenia,

agranulocytosis4. Nephrotic syndrome and reversible

renal failure5. Cholestatic hepatic damage


Celecoxib, Rofecoxib, Etoricoxib 10-20 X more selective

Meloxicam – preferential selection

Do not affect the constitutive form of COX significantly

Also has analgesic, antipyretic & antiinflammatory properties

Fewer GI adverse effectsApr 28, 2023 38muskuloskeletal2012

No impact on platelet aggregation, no cardiovascular protection

Renal toxicity similar to COX-1 inhibitors

Higher incidence of cardiovascular thrombotic events, hypertension, death from cardiac causes

Some of them were withdrawn from the market because of this adverse effect


1. GI bleeding and history of peptic ulceration

2. Advanced age, poor health, long duration of treatment & heavy alcohol use

3. Renal Impairment4. Heart failure, edema5. Hypertension6. Hypersensitivity reactions to

salicylates7. Bronchial asthma8. Pregnancy (?)


1. Corticosteroids: increased toxicity2. Biphosphonates: enhance GIT

irritation3. Anticoagulants including warfarin

(CYP2C9)4. Methotrexate: NSAIDs can decrease

its clearance severe hematologic and GI toxicity

5. Increase nephrotoxicity of aminoglycosides, amphotericin B, and other nephrotoxic agents


NSAIDs often offer symptomatic relief, reduce inflammation and pain and preserve function but have little effect on bone and cartilage destruction

DMARDs slow the progression and arrest the disease over 6 weeks to 6 months


Methotrexate Chlorambucil Cyclophosphamide Azathioprine Cyclosporine Mycophenolate mofetil

May be discussed later with anticancer drugs and immunosuppressants


Used mainly in the treatment of malaria and will be discussed more there

Antiinflammatory mechanism is unknown:

1. Suppression of T lymphocyte response to mitogens

2. Decreased leukocyte chemotaxis3. Stabilization of lysosomal enzymes4. Inhibition of DNA & RNA synthesis5. Trapping of free radicals


Extensively distributed to melanin-containing tissues

Indications:Rheumatoid arthritis: Takes 3-6 months to obtain a response

Adverse effects:1. Ocular toxicity2. Nightmares3. Dyspepsia


Rarely used because of toxicity Aurothiomalate and

Aurothioglucose IM Auranofin PO Mechanism of Action:

Alteration of morphology and function of macrophages: Inhibition of chemotactic factor-1, interleukin-8 and interleukin-1B production and vascular endothelium growth factor


Mechanism of Action (contd):IM gold compounds also alter lysosomal enzyme activity, reduce histamine release, inactivate the first component of complement and suppress phagocytic activity of polymorphonuclear leukocytesAuranofin also inhibits the release of PGE2 and LTB4.


Tends to concentrate in synovial membranes, liver, kidney, spleen, lymph nodes & bone marrow

t½ ~ 1 year Excreted in urine and feces Indications:

Active rheumatoid arthritis slows progression of the disease


Adverse effects:1. Pruritic skin rash and eosinophilia2. Stomatitis and metallic taste3. Thrombocytopenia, leukopenia,

pancytopenia and aplastic anemia4. Proteinuria, nephrotic syndrome5. Enterocolitis & cholestasis6. Peripheral neuropathy7. Pulmonary infiltrates8. Sweating, flushing & headache9. Corneal deposits


TNF-α and IL-1 are among the most important inflammatory cytokines

Are produced mainly by cells of the monocyte-macrophage lineage

Work in concert to stimulate inflammatory responses such as pain, fever and recruitment of lymphocytes

They also induce production of many other inflammatory mediators and contribute to tissue damage seen in chronic inflammation


Adalimumab, Infliximab, Etanercept Indicated for rheumatoid arthritis Main adverse effect is flare up of

macrophage-dependent infections such as tuberculosis and other opportunistic infections

Increased incidence of malignancies ???


Mechanism of action: It is converted to its active

metabolite in the intestine and plasma rapidly.

It inhibits dihydroorotate dehydrogenase reduced RNA synthesis and arrest of stimulated cells in G1 phase of cell growth Inhibition of T cell proliferation and production of autoantibodies by B cells


Completely absorbed after PO administration, t½ ~ 19 days

Indications: Rheumatoid arthritis, inhibits bone damage

Adverse effects:1. Diarrhea and elevation of liver

enzymes2. Mild alopecia3. Weight gain4. Increased blood pressure5. Leukopenia and thrombocytopenia6. Contraindicated in pregnancy


Analgesic-antipyretic but not antiinflammatory

Weak COX-1 and COX-2 inhibitor in peripheral tissues

Appears to inhibit COX-3 in the brain Pharmacokinetics:

Well absorbed following PO administrationMetabolized to glucuronide and sulfate conjugatest½ ~ 2-3 hours


Indications:1. Mild-to-moderate pain2. FeverAdverse effects: Safe at therapeutic doses Large doses dizziness, excitement &

disorientation Hepatic toxicity with centrilobular

necrosis due to accumulation of the metabolite N-acetyl-benzoquinoneimine.

May also produce acute renal tubular necrosis

Lethal dose 15 grams. Antidote: sulfhydryl (-SH) containing

agents such as N-acetylcysteineApr 28, 2023 55muskuloskeletal2012

Gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis.

It is due to deposition of monosodium urate crystals in joints and cartilage

Usually associated with high serum levels of uric acid

Uric acid calculi may deposit in the kidney as part of the disease

Aims of treatment:1. Relief of acute gouty attack2. Prevention of recurrent gouty episodes


Mechanism of action:Binds the intracellular protein, tubulin, preventing its polymerization into microtubules inhibition of leukocyte migration and phagocytosis and cell mitosis.

It also inhibits the formation of LTB4


Pharmacodynamics:It rapidly relieves the pain and inflammation of gouty arthritis in 12-24 hoursNo direct analgesic effectNo effect on uric acid

Pharmacokinetics:Absorbed rapidly after oral administration and eliminated in urine and feces as metabolites


Therapeutic uses:1. Acute gouty arthritis2. Acute Mediterranean fever3. Sarcoid arthritis4. Hepatic cirrhosisAdverse Effects:1. Diarrhea, nausea, vomiting,

abdominal pain2. Hair loss


3. Bone marrow depression4. Peripheral neuritis5. Myopathy

Acute intoxication: burning throat pain, bloody diarrhea, shock, hematuria, oliguriaFatal ascending CNS depression


All can be used except aspirin, salicylates and tolmetin

Oxaprozin also increases uric acid excretion and should be avoided in urate renal stones


Probenecid (& sulfinpyrazone) Decrease body pool of uric acid by

increasing its excretionPharmacodynamics:

Uric acid is secreted and reabsorbed in the proximal renal tubules by active organic acid transport proteinsThese transport proteins are inhibited by probenecid, sulfinpyrazone and large doses of aspirin leading to decreased net reabsorption of uric acid Uric acid excretion


Therefore, the formation of uric acid renal stones may be increased. Thus fluid intake and alkalinization of urine is necessary to maintain urine flow and decrease precipitation of uric acid.

Pharmacokinetics:Probenecid is slowly metabolizedSulfinpyrazone is eliminated by the kidney


Adverse effects:1. GIT irritation (S > P)2. Skin rash and allergic

dermatitis (P > S)3. Nephrotic syndrome4. Aplastic anemia5. Renal stone formation


Inhibits xanthine oxidase and thus uric acid formation. It decreases plasma urate levels with a concurrent increase in the soluble xanthine and hypoxanthinePurine xanthine hypoxanthine uric acid

Pharmacokinetics: ~ 80 % absorbed after oral administration, metabolized also by xanthine oxidase to alloxanthine which is also an inhibitor of the enzyme


Uses:1. When uricosuric agents fail2. When urinary excretion of uric

acid is high3. Recurrent urate renal stone

formation4. To prevent massive uricosuria

following therapy of blood dyscrasia and cancer


Adverse effects:1. Acute attack of gouty arthritis

at the beginning of treatment which can be prevented by colchicine or NSAIDs

2. GIT: Nausea, vomiting, diarrhea3. Peripheral neuritis4. Necrotizing vasculitis5. Bone marrow depression


6. Hepatic toxicity7. Interstitial nephritis8. Allergic pruritic maculopapular

rash9. Exfoliative dermatitis10. CataractDrug interactions:

Inhibits the metabolism of mercaptopurine, azathioprine, warfarin, probenecid and cyclophosphamide


1. Sebutkan 2 contoh obat yang termasuk dalam NSAIDs, beserta mekanisme kerjanya

2. Sebutkan 2 efek samping yg sering tjd akibat pemakaian NSAIDs

3. Sebutkan 2 indikasi NSAIDs



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(4). NSAID-musket2013