Obat Anti inflamasi

dr. Rohmania Setiarini

Mediators of
inflammation

Anti-inflammatory Drugs
Nonsteroidal Anti-inflammatory Drugs
(NSAIDs)
Steroidal Anti-inflammatory Drugs
Pharmacological control of inflammation:
Preventing the release of inflammatory
mediators
Inhibiting their actions
Treating pathophysiologic responses to them

NSAIDs
Major action:
inhibit Cyclooxygenase (COX)
Pharmacological effects
Suppress inflammation
Relieve pain
Reduce fever

Uses
Mild to Moderate Pain
Inflammation
Fever

Prostaglandin
Biosynthesis,
Function, and
Pharmacologic
Inhibition.

Phospholipase
-----

Steroids

Arachidonic acid
Cyclooxygenase
NSAIDs

Lipoxygenases
Lipoxygenase inhititors

-----

Prostaglandins
PGF2

PGE2

-----

PMNs
PGI2
Lymphokines

algesic

pyrexia

vasodilation

The events of the inflammtory response and mechanisms of anti-flammatory

Prostaglandins (PGs) are derived from arachidonic acid

Cell Membrane (phospholipids)

phospholipase A2

Lipoxygenase (LOX)
Arachidonic acid
Leukotrienes
indomethacin

cyclooxygenase

aspirin,

(COX1 & COX2)

Cyclic endoperoxides (PGG2, PGH2)

prostacyclin
synthetase
prostacyclin
PDX, PGI2

prostaglandin
synthetase

(vasodilator,
(vasoconstriction
antiaggregating)
platelet aggregation)

PGE2

PGF2
(erythma

edema
pain, fever)

thromboxane
synthetase
Thromboxane A2
(vasodilator
uterus contractor)

NSAIDs:

Classifications based on chemistry

Salicylic acid derivatives

Aspirin

Para-aminophenol derivatives
Acetaminophen

Indole and indene acetic acids

Indomethacin

Fenamates

Meclofenamic acid
Tolfenamic acid

Pyrazolones or enolic acids

Phenylbutazone
Dipyrone

Pyranocarboxylic acids

Oxicams

Propionic acids

Nicotinic acid derivatives

Etodolac
Ketorolac

Ibuprofen
Naproxen
Ketoprofen
Carprofen
Vedaprofen

Piroxicam
Meloxicam

Flunixin meglumine

Hydroxamic acid derivatives

Tepoxalin

Coxib-class NSAIDs
Deracoxib
Firocoxib

NSAIDs: Cyclooxygenase
Cyclooxygenase has 2 forms:

COX-1 (good COX) : found in all tissues

Mediates housekeeping chores

Protect gastric mucosa
Support renal function
Promote platelet aggregation

COX-2 (bad COX) : found at sites of tissue injury

Mediates inflammation and sensitize receptors to painful

stimuli
Also present in brain- mediates fever and contributes to
perception of pain
Mediates a cytoprotective effect in damaged GI mucosa

COX INHIBITORS
Cyclooxygenase-1 (COX-1):
-constitutively expressed in wide variety of cells all over the
body.
-"housekeeping enzyme"
-ex. gastric cytoprotection, hemostasis
Cyclooxygenase-2 (COX-2):
-inducible enzyme
-immediate-early gene product in inflammatory and immune
cells
-dramatically up-regulated during inflammation (10-18X)

NSAIDs: effect of COX inhibition

COX-1 inhibition

Results largely in harmful effects

Gastric erosion and ulceration
Bleeding tendencies
Acute renal failure

COX-2 inhibition

Results in beneficial effects

Suppression of inflammation
Alleviation of pain
Reduction of fever

Classification of Cyclooxygenase Inhibitors

Drugs with anti-inflammatory properties
NSAIDsNonsteroidal anti-inflammatory drugs: 2
types
First generation (inhibit both COX1 and COX2)
Non-selective COX inhibitors
- aspirin
Second generation (inhibit COX2 only)
Preferential COX2 inhibitors (partial specificity for COX2)
- celecoxib
Selective COX2 inhibitors (full specificity for COX2)
- rofecoxib

Drugs without inflammatory properties

Acetaminophen

NSAIDs: mechanism of
action
NSAIDs

act to block the first step of prostaglandin

synthesis
by binding to and inhibiting cyclooxygenase

Dose and drug dependent

The major therapeutic, toxic, and potency
of NSAIDs
all relate to their ability to inhibit
prostaglandin synthesis

NSAIDs: Pharmacokinetics
As weak acids, well absorbed after PO
Small volume of distribution (10%)
Highly protein binding (90%)
Clearance:
hepatic metabolism both phase I and II
Conjugated metabolites -> urine

NSAIDs: Pharmacological
effects
Analgesia, antipyretic, and control of
inflammation

Aspirin is a unique NSAID, the only NSAID inhibits clotting of blood for a
prolonged period (4 to 7 days), ideal for preventing blood clots that cause
heart attacks and strokes

NSAIDs: Adverse reactions

Gastrointestinal system
GI ulceration
Hematopoietic system
Bleeding
All NSAIDs are able to impair platelet activity
Platelet aggregation defects caused by aspirin can last up
to 1 week
Renal system
Analgesic nephropathy
In kidney, vasodilatory and tubuloactive prostaglandins are
protective
Both COX1 and COX2 mediate renal effects of
prostaglandins

Side effects of NSAIDs

Gastrointestinal
Direct irritation : acidic molecules
Indirect irritation: inhibit COX-1, reduce protective
prostaglandins
S/S: nausea, vomiting, dyspepsia, gastric
ulcer/bleeding,

Side effects of NSAIDs

Renal
Decrease prostaglandins constriction of afferent
arteriole decreased renal perfusion
alter renal function
S/S: salt and fluid retension, hypertension
Caution: NSAID with ACE inhibitor, diuretic
Rare: ARF, ATN, nephrotic syn.

Mechanism of GI
toxicity

Risk Factors For NSAID-Mediated GI Bleedin

Concomitant
Corticosteroid Or
Anticoagulant
Use

65 y Of
Age

Previous
History Of
Ulcers Or GI
Bleeds

Risk
Factors
Alcohol
Consumption

Smoking
Piper et al. Ann Intern Med. 1991;114:735.
Shorr et al. Arch Intern Med. 1993;153:1665.
Silverstein et al. Ann Intern Med. 1995;123:241.

Wolfe et al. NEJM;1999, 30(24)1888-1899

Risk Factors For NSAID-Mediated

Adverse Renal Effects
Concomitant
Use Of Diuretics
Or ACE
Inhibitors

65 y Of
Age

Intrinsic
Renal
Disease

Risk
Factors
Volume
Depletion

Congestive
Heart
Failure

Hepatic
Disease
(cirrhosis)

NSAIDs: Acute Renal

Toxicity
Drug

Relative Risk

Indomethacin, ketorolac

High

Naproxen, diclofenac,
piroxicam, ibuprofen

Medium

Aspirin

Low

Acetaminophen

None

Non-Selective COX inhibitors

Acetaminophen
Aspirin
Etodolac
Flunixin Meglumine
Ketorolac
Naproxen
Phenylbutazone
Piroxicam
Tolfenamic acid
Vedaprofen

Preferential COX-2 inhibitors

(Partial specificity for COX-2)

Carprofen (Rimadyl, Pfizer)

Meloxicam

Selective COX-2 inhibitors

(no significant effect on COX-1)

Deracoxib (Deramaxx,
Novartis)
Firocoxib (Previcox, Merial)

Robenacoxib
Novartis)

Mavacoxib

(Onsior,

(Trocoxil, Pfizer)

Dual COX and LOX inhibitors

Tepoxalin
Ketoprofen

 the chronic use of some COX-2-specific inhibitors has

been associated with an increase in cardiovascular as
well as cerebrovascular events particularly in patients
with an elevated risk of thrombosis.
This increased risk may be due to the COX-2-mediated
reduction in synthesis of prostacyclin, which is a natural
inhibitor of platelet activation.

SomeCorticosteroids
RelativeAnti
Inflammatory
Activity

RelativeSalt
Retaining
Activity

Oral,parenteral,
topical

Cortisone

Oral

0.8

0.8

Prednisone

Oral

0.3

Triamcinolone

Oral,injectable,
topical,inhaled

Dexamethasone

Oral,injectable,
topical

30

Oral

250

Agent
Cortisol(hydro
cortisone)

Fludrocortisone
(mineralocorticoid

Forms
Available

Obat yang
mempengaruhi
hemostasis tulang
dr. Rohmania Setiarini

Calcium
Calcium exists in three forms:
50% ionized
40% bound to protein (especially to albumin)
10% complexes to anions.
Approximately 100-250mg of daily intake is
absorbed from the proximal intestine with an
equal amount excreted by the kidney.
98% filtered calcium is reabsorbed.

Calcium metabolism
Control of serum calcium and
phosphorus depends on the
hormones
1. Vitamin D
2. Parathyroid hormone
3. Calcitonin

Bone remodeling involves dynamic

interaction of osteoclast and osteoblast.

 Calcium and Phosphate are the two major

constituents of the bone.
Normal extra cellular concentrations of
calcium is required for proper functioning
of nerves, muscles and blood coagulation.
The balance between bone resorption and
bone formation is usually maintained up
to fourth decade.

Calcium
An adequate intake of Calcium and
Vitamin D is essential for:
1. optimal bone formation in
children
2. prevention of osteoporosis in
adults.

Calcium drugs
Calcium carbonate requires stomach
acidity for absorption.
Calcium citrate does not requires
acidity.
Calcium gluconate is the preferred i.v
preparation.
Calcium and Vitamin D are used for:
A. Prevention and treatment of
osteoporosis
B. Hypocalcemia.
The most common adverse effect of

Calcium metabolism
1. PTH net effect is to increase plasma
calcium and decrease phosphate
concentration.
Kidney :
. PTH stimulates reabsorption of
calcium by the renal tubules.
. PTH decrease the reabsorption of
phosphate from renal tubules this
plasma phosphate concentration,
which in turn plasma calcium.

Calcium metabolism
PTH : Bone :
PTH increase bone resorption by
stimulating osteoclast activity which
enables the bone calcium to enter
the extra cellular pool (high dose)
PTH : GIT
It increase calcium and phosphate
absorption by activating the
synthesis of 1,25 dihydroxyvitamin
D-3 (Calcitriol).

Calcium metabolism
2. Vitamin D : It is a prohormone.
. Vitamin D-3 (cholecalciferol) and
Vitamin D-2 (ergocalciferol) are
the major forms of vitamin D.
. Vitamin D-3 is produced in the
skin from 7-dehydrocholesterol
under the influence of ultra-violet
light.
. Vit-D-3 is an inactive precursor of
active 1,25 dihydroxyvitamin D-3
(Calcitriol).

Calcium metabolism
Vitamin D : Net effect is to
increase plasma calcium and
phosphate concentration.
The hydroxylation of Vitamin D-3 at the 25
position in the liver results in 25
Hydroxyvitamin-D3(Calcidiol).
PTH stimulates the renal hydroxylation at
position 1 resulting in 1, 25 Dihydroxyvitamin D3 (Calcitriol).

Calcium metabolism
Vitamin D :
Calcitriols primary effect is on the
small intestine where it increase
dietary calcium and phosphate
absorption.
Vitamin D promotes mineralization
bone formation.
Calcium and phosphate excretion
may be decreased by renal
tubules.

Calcium metabolism
Vitamin D :
It inhibits parathyroid hormone
secretion from the parathyroid
gland.
Vitamin D affects the immune
system by promoting phagocytosis,
anti-tumor activity, and
immunomodulatory functions.

Vitamin D is used to prevent and

treat:
osteoporosis
Rickets: vit. D deficiency in children
osteomalacia

In renal failure, it is advisable to

use the active form, calcitriol as
they cannot synthesize it.
Calcipotriol, synthetic derivative
of vitamin D, is used in psoriasis.

3. Calcitonin : It is released in
response to increased plasma
calcium and it decrease plasma
calcium.
. It is secreted by the parafollicular
cells of the thyroid gland.
. It is administered parenterally or
nasal inhalation.
. Salmon calcitonin is 100 times
more potent than human

Calcitonin : Principal effects are to

lower serum calcium and
phosphate
It inhibits osteoclast activity,
decrease bone resorption thus lowers
serum calcium and phosphate and
reduce bone pain.
It decrease the reabsorption of
calcium and phosphate from the
renal tubules.

Calcitonin : It increase BMD in spine

Used in pagets disease of bone(enlarged
and deformed bones)

Osteoporosis
Hypercalcemia
Usually reserved for post
menopausal women (who cannot
take estrogen).

PTH

Vitamin Calciton
D
in

Intestine

Ca & PO4
absorption

Ca & P04
absorption

Kidney

Ca & P04
excretion
bone
resorption (H)
bone
formation (L)

Bone

Net
effect

Ca & PO4
excretion
bone
resorption
(H)

bone
formation
plasma Ca plasma
plasma Ca
PO4
plasma
PO4

---- Ca & PO4

excretion
bone
resorption

plasma
Ca
plasma
PO4

Phosphate
Phosphate helps maintain acid-base

equilibrium.
Buffers and allows for renal H+ excretion.
Helps regulate calcium metabolism, and is
an active intermediate of energy
metabolism (ATP).
Approximately 67% of an oral dose is
absorbed from the intestine.
Excretion is via the kidney.

Biphosphonates :
Alendronate (Fosamax)
Risedronate (Actonel)
Ibandronate (Boniva)
Zoledronate (Zometa)

Calcium metabolism
Biphosphonates :
It adsorbs to hydroxyapatite and
become a part of the bone structure.
They are slowly released from the
bone during the bone remodeling.
Biphosphonates prevent bone
resorption by inhibiting osteoclast
activity
Prevent attachment of osteoclast to bone.

Biphosphonates :
Used in steroid induced
osteoporosis, pagets disease
and hypercalcemia of
malignancy
Biphosphonate result in
esophagitis and GIT distress.

Miscellaneous agents :
Estrogens are considered as first line of
therapy for prevention of osteoporosis in
postmenopausal women.
Estrogens decrease bone resorption by:
inhibiting IL-1, TNF and CSF from monocytes
decrease osteoclast differentiation / activation
which slows bone loss in women.

Raloxifene, selective estrogen receptor

modulator, can be used for prevention of
osteoporosis in women with breast /
endometrial cancer.

Fluoride :
It is well established for the
prophylaxis of dental caries.
It stimulates new bone formation.
It increase the bone crystal size and
render the bone more resistant to
resorption.

Bone
Plicamycin :
A cytotoxic antibiotic is an
inhibitor of osteoclast and block
the action of PTH.
Used to treat Pagets disease.
Glucocorticoids :
It decrease osteoblast activity
and cause osteoporosis.

Thiazides
Treatment of bone mineral disorders.
Reduce Renal Ca excretion.
Increases effectiveness of PTH.
Block Na reabsorption, increasing Ca
exchange (distal tubule).
Reduce incidence of stone formation.