Ita Armyanti

Farmakologi PSPD FK UNTAN

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1.

2.
3.

Sebutkan 2 contoh obat yang termasuk

dalam NSAIDs, beserta mekanisme
kerjanya
Sebutkan 2 efek samping yg sering tjd
akibat pemakaian NSAIDs
Sebutkan 2 indikasi NSAIDs

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 Menghambat sintesis PG : produk dr

Prostaglandins are arachidonic acid

COX

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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2.

Cycloogygenase-1 (Cox-1):
It is constitutively expressed
Widely distributed and has a
housekeeping function. e.g gastric
cytoprotection
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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Phospholipase C

Membrane Phospholipids
Phospholipase A2

Diglyceride lipase

Arachidonic acid

Lipooxygenase

Cyclooxygenase

LTs

Cyclic endoperoxides
PGI synthase

PGI2

Thromboxane
synthase

TXA2

PGE synthase

PGE2
PGE9-Ketoreductase

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PGD
synthase

PGD2
PGF2

LTA4

LTB4

LTC4
LTD4
LTE4

1. Phagocyte activation
2. Chemotaxis

Bronchoconstriction
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1.
2.
3.
4.

PGI2:
Vasodilation
Inhibition of platelet aggregation
Bronchodilation
Glomerular filtration

1.
2.
3.
4.

TXA2:
Vasoconstriction
Stimulation of platelet aggregation
Is a smooth muscle mitogen
Intrarenal vasoconstriction during
inflammatory conditions of the kidney
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1.
2.
3.
4.

5.
6.
7.
8.

9.
10.

PGE2:
Vasodilation
Patency of ductus arteriosus
Bronchodilation
Uterine contraction & dysmenorrhea
Cervical ripening
Decreased gastric acid secretion
Pain sensitization
Increased body temperature
Stimulate longitudinal muscle in GIT
Increase glomerular filtration

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1.
2.
3.
4.
5.

1.
2.
3.

PGF2:
Vasoconstriction
Bronchoconstriction
Uterine contraction
Aqueous humor drainage
Contracts circular muscle in GIT
PGD2:
Bronchoconstriction
Vasodilation or vasoconstriction
Natural sleep

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1.

2.

Alprostadil (PGE1 analogue):

Used to maintain patency of the
ductus arteriosus in infants with
congenital heart disease waiting for
surgical correction
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.

5.
6.

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.
Epoprostenol (PGI2 analogue):
For primary pulmonary hypertension
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.
2.
3.

Relief of pain
Slowing tissue damage
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.

2.

Gastric upset, peptic ulceration &

upper GI bleeding. Fecal blood loss
Iron deficiency anemia (less with
COX-2 inhibitors)
Salicylism: At high & chronic dose.
Vomiting, tinnitus, decreased hearing,
deafness, vertigo, headache,
nervousness, confusion, retinal
disturbances
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Toxic doses:

3.

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.

5.

6.

Uric acid retention at doses of 2 g or less

daily
Uric acid excretion at daily doses of 4 g or
more
Renal function impairment, fluid retention,
interstitial nephritis, papillary necrosis
Elevation of liver enzymes, hepatic
necrosis, cholestasis, hepatitis & Reyes
syndrome in children with febrile illness

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7.
8.
9.

10.
11.

12.

Bleeding
Allergic reactions: rash, asthma, nasal
polyps & anaphylaxis
Hyperthermia: due to uncoupling of
oxidative phosphorylation
Electrolyte disturbances
Inhibition of uterine contractions
delayed labor, low birth weight,
premature closure of ductus arteriosus
Photosensitivity, toxic epidermal
necrolysis
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1.
2.
3.
4.

Very good analgesic and antipyretic

Used for:
Musculoskeletal disorders
PO, IM
Renal colic
IM
Dysmenorrhea
IM
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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1.
2.

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:
Rheumatic conditions: Gout and
ankylosing spondylitis
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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1.
2.

Is a sulfoxide prodrug
Metabolized into the active sulfide
metabolite
Undergoes enterhepatic cycling, like
many other NSAIDs
Indications similar to other NSAIDs +
Suppression of familial intestinal
polyposis
May prevent development of colon,
breast and prostate cancer
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1.
2.
3.
4.
5.

Adverse effects similar to NSAIDs +

Less nephrotoxic ( reoxidized to the
inactive prodrug in the kidney
Steven Johnson syndrome, epidermal
necrolysis
Thrombocytopenia, agranulocytosis
Nephrotic syndrome and reversible
renal failure
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.
2.
3.
4.
5.
6.
7.
8.

GI bleeding and history of peptic ulceration

Advanced age, poor health, long duration
of treatment & heavy alcohol use
Renal Impairment
Heart failure, edema
Hypertension
Hypersensitivity reactions to salicylates
Bronchial asthma
Pregnancy (?)

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1.
2.
3.
4.

5.

Corticosteroids: increased toxicity

Biphosphonates: enhance GIT irritation
Anticoagulants including warfarin
(CYP2C9)
Methotrexate: NSAIDs can decrease its
clearance severe hematologic and GI
toxicity
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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1.

2.
3.
4.
5.

Used mainly in the treatment of malaria and

will be discussed more there
Antiinflammatory mechanism is unknown:
Suppression of T lymphocyte response to
mitogens
Decreased leukocyte chemotaxis
Stabilization of lysosomal enzymes
Inhibition of DNA & RNA synthesis
Trapping of free radicals

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Extensively distributed to melanincontaining tissues

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

1.
2.
3.

Ocular toxicity
Nightmares
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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1.
2.
3.
4.
5.
6.

Completely absorbed after PO

administration, t ~ 19 days
Indications: Rheumatoid arthritis, inhibits
bone damage
Adverse effects:
Diarrhea and elevation of liver enzymes
Mild alopecia
Weight gain
Increased blood pressure
Leukopenia and thrombocytopenia
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-acetylbenzoquinoneimine.

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.
2.

Relief of acute gouty attack

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.
4.
5.

Bone marrow depression

Peripheral neuritis
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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1.
2.
3.
4.
5.

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

Uses:
When uricosuric agents fail
When urinary excretion of uric acid is
high
Recurrent urate renal stone formation
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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Hepatic toxicity
Interstitial nephritis
Allergic pruritic maculopapular rash
Exfoliative dermatitis
Cataract
Drug interactions:
Inhibits the metabolism of
mercaptopurine, azathioprine,
warfarin, probenecid and
cyclophosphamide
6.
7.
8.
9.
10.

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1.

2.
3.

Sebutkan 2 contoh obat yang termasuk

dalam NSAIDs, beserta mekanisme
kerjanya
Sebutkan 2 efek samping yg sering tjd
akibat pemakaian NSAIDs
Sebutkan 2 indikasi NSAIDs

muskuloskeletal2012

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