Ita Armyanti

Farmakologi PSPD FK
UNTAN

Muskuloskeletal2013 May 4, 2017 1

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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 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 A2
It can also be released by the
combination phospholipase C and
diglyceride lipase.

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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

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 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.

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 Membrane
Phospholipase C
Phospholipids
Phospholipase A2
Diglyceride lipase Arachidonic acid Lipooxygenase
Cyclooxygenase

Cyclic endoperoxides LTs

PGD
synthase
PGI synthase Thromboxane PGE synthase
synthase
PGD2
PGE2
PGI2 TXA2
PGE9-Ketoreductase
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PGF2
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 LTA4

LTB4 LTC4
1. Phagocyte LTD4
activation LTE4
2. Chemotaxis
Bronchoconstriction
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 PGI2:
1. Vasodilation
2. Inhibition of platelet aggregation
3. Bronchodilation
4. Glomerular filtration
TXA2:
1. Vasoconstriction
2. Stimulation of platelet aggregation
3. Is a smooth muscle mitogen
4. Intrarenal vasoconstriction during
inflammatory conditions of the kidney

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 PGE2:
1. Vasodilation
2. Patency of ductus arteriosus
3. Bronchodilation
4. Uterine contraction & dysmenorrhea
5. Cervical ripening
6. Decreased gastric acid secretion
7. Pain sensitization
8. Increased body temperature
9. Stimulate longitudinal muscle in GIT
10. Increase glomerular filtration

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 PGF2:
1. Vasoconstriction
2. Bronchoconstriction
3. Uterine contraction
4. Aqueous humor drainage
5. Contracts circular muscle in GIT
PGD2:
1. Bronchoconstriction
2. Vasodilation or vasoconstriction
3. Natural sleep

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1. Alprostadil (PGE1 analogue):
Used to maintain patency of the
ductus arteriosus in infants
with congenital heart disease
waiting for surgical correction
2. Carboprost (PGF2 analogue):
a. To terminate pregnancy
b. To control refractory
postpartum bleeding

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3. Misoprostol (PGE1 analogue):
a. Used in combination with
NSAIDs to decrease gastric acid
secretion & to inhibit ulceration
b. Induction of labor
c. Enhancing cervical ripening
d. Induction of abortion
Associated with increased risk
of uterine rupture and
perforation
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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 (PGF2 analogue):
For glaucoma

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 Involves the release of a
number of mediators
Results in pain and tissue
destruction
Treatment involves:
1. Relief of pain
2. Slowing tissue damage or
3. Arresting tissue damage

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 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 metabolized
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 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
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Most are reversible inhibitors of Coxs,
except aspirin which irreversibly
acetylates the active site of the enzyme
1. Celecoxib, rofecoxib & valdecoxib are
selective Cox-2 inhibitors
2. Aspirin, indomethacin, piroxicam &
sulindac are more effective on Cox-1
3. Ibuprofen & meclofenamic acid inhibit
the 2 isozymes equally

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 Is the prototype NSAID
Use for inflammatory conditions is
now rare
Mainly used as antiplatelet drug
Pharmacokinetics:
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
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 Salicylate is bound to albumin
and binding is saturable
Eliminated by metabolism and
elimination is zero-order
(saturable)
t 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
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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

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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

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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)
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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

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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

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4. Uric acid retention at doses of 2 g or
less daily
Uric 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 &
Reyes syndrome in children with
febrile illness
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7. Bleeding
8. Allergic reactions: rash, asthma,
nasal polyps & anaphylaxis
9. Hyperthermia: due to uncoupling
of oxidative phosphorylation
10. Electrolyte disturbances
11. Inhibition of uterine contractions
delayed labor, low birth weight,
premature closure of ductus
arteriosus
12. Photosensitivity, toxic epidermal
necrolysis
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 Very good analgesic and
antipyretic
Used for:
1. Musculoskeletal disorders
PO, IM
2. Renal colic IM
3. Dysmenorrhea IM
4. Solar keratosis
Topical
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 Salicylic acid derivative
Zero-order kinetics
Claimed to be particularly useful
for cancer pain with bone
metastasis
Pain following dental surgery

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 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
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 May also inhibit phospholipases A & C
Reduces neutrophil migration
Decreases 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 spondylitis
2. Patent ductus arteriosus
Adverse effects occur in one third of
patients

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 Similar but more severe than other
NSAIDs.
Headache (20%) + dizziness,
confusion and depression
Psychosis, hallucinations
Aplastic anemia, thrombocytopenia
Hyperkalemia
Diarrhea
Pancreatitis

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 Has significant analgesic efficacy,
used to replace morphine
Can be given IM, IV, PO
Adverse effects similar to other
NSAIDs
More renal toxicity

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

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 Also inhibits polymorphonuclear
leukocyte migration, decreases
oxygen radical production and
inhibits lymphocytes function
t very long ~ 57 hours
Used for rheumatic conditions
More toxic than other NSAIDs

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 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
polyposis
2. May prevent development of
colon, breast and prostate cancer
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 Adverse effects similar to NSAIDs
+
1. Less nephrotoxic ( reoxidized to
the inactive prodrug in the kidney
2. Steven Johnson syndrome,
epidermal necrolysis
3. Thrombocytopenia,
agranulocytosis
4. Nephrotic syndrome and
reversible renal failure
5. Cholestatic hepatic damage
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 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 effects
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 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

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1. GI bleeding and history of peptic
ulceration
2. Advanced age, poor health, long
duration of treatment & heavy
alcohol use
3. Renal Impairment
4. Heart failure, edema
5. Hypertension
6. Hypersensitivity reactions to
salicylates
7. Bronchial asthma
8. Pregnancy (?)

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1. Corticosteroids: increased toxicity
2. Biphosphonates: enhance GIT
irritation
3. 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

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 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

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 Methotrexate
Chlorambucil
Cyclophosphamide
Azathioprine
Cyclosporine
Mycophenolate mofetil

May be discussed later with

anticancer drugs and
immunosuppressants

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 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 chemotaxis
3. Stabilization of lysosomal enzymes
4. Inhibition of DNA & RNA synthesis
5. Trapping of free radicals
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 Extensively distributed to
melanin-containing tissues
Indications:
Rheumatoid arthritis: Takes 3-6
months to obtain a response
Adverse effects:
1. Ocular toxicity
2. Nightmares
3. Dyspepsia

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 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

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 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 leukocytes
Auranofin also inhibits the
release of PGE2 and LTB4.
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 Tends to concentrate in synovial
membranes, liver, kidney, spleen,
lymph nodes & bone marrow
t ~ 1 year
Excreted in urine and feces
Indications:
Active rheumatoid arthritis
slows progression of the disease

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Adverse effects:
1. Pruritic skin rash and eosinophilia
2. Stomatitis and metallic taste
3. Thrombocytopenia, leukopenia,
pancytopenia and aplastic anemia
4. Proteinuria, nephrotic syndrome
5. Enterocolitis & cholestasis
6. Peripheral neuropathy
7. Pulmonary infiltrates
8. Sweating, flushing & headache
9. Corneal deposits

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 TNF- 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

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 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 ???

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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
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 Completely absorbed after PO
administration, t ~ 19 days
Indications: Rheumatoid arthritis,
inhibits bone damage
Adverse effects:
1. Diarrhea and elevation of liver
enzymes
2. Mild alopecia
3. Weight gain
4. Increased blood pressure
5. Leukopenia and thrombocytopenia
6. Contraindicated in pregnancy
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 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
administration
Metabolized to glucuronide and
sulfate conjugates
t ~ 2-3 hours

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Indications:
1. Mild-to-moderate pain
2. Fever
Adverse 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-acetylcysteine
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 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 attack
2. Prevention of recurrent gouty episodes

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 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

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 Pharmacodynamics:
It rapidly relieves the pain and
inflammation of gouty arthritis in
12-24 hours
No direct analgesic effect
No effect on uric acid
Pharmacokinetics:
Absorbed rapidly after oral
administration and eliminated in
urine and feces as metabolites
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Therapeutic uses:
1. Acute gouty arthritis
2. Acute Mediterranean fever
3. Sarcoid arthritis
4. Hepatic cirrhosis
Adverse Effects:
1. Diarrhea, nausea, vomiting,
abdominal pain
2. Hair loss

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3. Bone marrow depression
4. Peripheral neuritis
5. Myopathy

Acute intoxication: burning

throat pain, bloody diarrhea,
shock, hematuria, oliguria
Fatal ascending CNS depression

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 All can be used except aspirin,
salicylates and tolmetin
Oxaprozin also increases uric
acid excretion and should be
avoided in urate renal stones

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 Probenecid (& sulfinpyrazone)
Decrease body pool of uric acid by
increasing its excretion
Pharmacodynamics:
Uric acid is secreted and reabsorbed
in the proximal renal tubules by
active organic acid transport proteins
These transport proteins are inhibited
by probenecid, sulfinpyrazone and
large doses of aspirin leading to
decreased net reabsorption of uric
acid Uric acid excretion

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 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 metabolized
Sulfinpyrazone is eliminated by
the kidney

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 Adverse effects:
1. GIT irritation (S > P)
2. Skin rash and allergic
dermatitis (P > S)
3. Nephrotic syndrome
4. Aplastic anemia
5. Renal stone formation

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Inhibits xanthine oxidase and thus
uric acid formation. It decreases
plasma urate levels with a
concurrent increase in the soluble
xanthine and hypoxanthine
Purine 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
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 Uses:
1. When uricosuric agents fail
2. When urinary excretion of uric
acid is high
3. Recurrent urate renal stone
formation
4. To prevent massive uricosuria
following therapy of blood
dyscrasia and cancer
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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, diarrhea
3. Peripheral neuritis
4. Necrotizing vasculitis
5. Bone marrow depression

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6. Hepatic toxicity
7. Interstitial nephritis
8. Allergic pruritic maculopapular
rash
9. Exfoliative dermatitis
10. Cataract
Drug interactions:
Inhibits the metabolism of
mercaptopurine, azathioprine,
warfarin, probenecid and
cyclophosphamide
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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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