Atina Hussaana

Dept. Pharmacology &

Therapy Medical Faculty of
UNISSULA
 injurious stimulus inflammatory process
noxious agents Calor Dolor

: Infection Rubor Tumo

Antibodies r
Functiolesa
Physical injuries Phase :
acute
subacute
chronic
proliferat
ive
Essential for survival in inflammatory may be exaggerated & sustained
the face of response without apparent benefit & w/
environmental pathogens severe adverse consequences
and injury
 Therapeutic Strategies

Relief of pain

Slowing or-in theory-arrest of

the tissue damaging process
 Chemistry & Pharmacokinetics

Grouped in several Varied

chemical classes pharmacokinetic
characteristics

But NSAIDs have some

general properties in
common
 Chemistry & Pharmacokinetics

Weak organic acids

except
nabumetone

Most are well

absorbed
Food doesnt
substantially
change
bioavalability

Most are highly metabolized : phase I & II ; phase II

alone Elimination : most important route renal excretion

 PHARMACODYNAMICS

antiinflammatory
analgesic antipyretic
Except paracetamol w/
very low anti inflammatory
effect

Inhibition of Prostaglandin Biosynthesis

 2 forms : cyclooxygenase-1
(COX-1) cyclooxygenase-2
(COX-2)
COX-1 : primarily constitutive
isoform
found in most normal cells and tissues
kidney, GIT, platelet homeostasis

COX-2 : induced during inflammation;

facilitate the inflammatory response
Origin
& Effects
of
PG
 Stimulus

Gangguan pd membran
sel
Phospholipase Phospholipid
inhibitors s
Corcoticosteroids Phospolipas
Arachidonic e
Fatty acid substitution
(diet) acid NSAID.
Lipoxygenase Cyclo- ASA
Lipoxygenas oxygenase
inhibitors
e

Leukotrien
Receptor level es
antagonists

LTB LTC4 / D4 / Prostaglandi Thromboxan Prostacycli

ns e n
4 E4

Alteration of
Phagocyt vascular Leukocyt
e permeability, e
attraction bronchial modulatio
Colchicin , constriction,
increased secretion n
e activatio
n Bronchospas
Inflama Inflama
m, congestion,
si si
mucus
I. NON SELECTIVE COX INHIBITORS
1. SALICYLIC ACID DERIVATIVES
- ASPIRIN, SODIUM
SALICYLATE, SALSALATE,
2. PARA AMINOPHENOL
DERIVATIVES
- ACETAMINOPHEN
( PARACETAMOL )
3. INDOLE & INDENE ACETIC
ACIDS
- INDOMETHACIN, SULINDAC
4. HETEROARYL ACETIC ACIDS
- TOL METIN, DICLOFENAC,
5. ARYL PROPIONIC ACIDS
-IBUPROFEN, NAPROXEN, FLURBIPROFEN,
KETOPROFEN, FENOPROFEN, OXAPROZIN
6. ANTHRANILIC ACIDS ( FENAMATES )
- MEFENAMIC ACID, MECLOFENAMIC ACID
7. ENOLIC ACIDS
- OXICAM ( PIROXICAM, MELOXICAM )
8. ALKANONES
- NABUMETONE
II SELECTIVE COX 2
INHIBITOR
1. DIARYL SUBTITUTED
FURANONES
- ROFECOXIB
2. DIARYL SUBTITUTED PYRAZOLES
- CELECOXIB
3. INDOLE ACETIC ACIDS
- ETODOLAC
4. SULFONANILIDES
- NIMESULIDE
 For analgesia (e.g. headache, dysmenorrhoea,
backache, bony metastases, postoperative pain)
For anti-inflammatory effects (e.g. rheumatoid
arthritis and related connective tissue disorders,
gout and soft tissue disorders)
To lower temperature (antipyretic)
 Gastrointestinal : anorexia, nausea,
dyspepsia, abdominal pain, diarrhea
gastric or intestinal ulcers ( with COX-
2- selective drugs)
Cardiovascular :
COX-2-selective- risk of heart attack
and stroke
Analgesic Nephropathy
 Pregnancy : Prolongation of gestation,
postpartum hemorrhage, closure of
the ductus arteriosus and impaired
fetal circulation in utero
Hypersensitivity: bronchial
asthma, urticaria, shock
Platelets: risk of hemorrhage
Cox -2 selective- risk of thrombosis
 the oldest NSAID
Is given orally and is rapidly absorbed; 75%
is metabolised in the liver
Also inhibits platelet aggregation CHD
Unwanted effects : gastric bleeding;
dizziness, deafness and tinnitus
('salicylism); postviral encephalitis (Reye's
syndrome) in children; respiratory alkalosis
followed by metabolic acidosis
 potent analgesic and antipyretic actions but
rather weaker anti-inflammatory effects
administered orally
mild to moderate pain:
headache, myalgia, postpartum
pain
preferred to aspirin in children with
viral infections
 Adverse Effects
therapeutic dosesa mild increase in
hepatic enzymes
larger dosesdizziness,
excitement, disorientation
15 g severe hepatotoxicity; acute
renal tubular necrosis
 analgesic +, antipyretic +, anti inflammatory
(weak)
Administered orally; parenteral
Adverse Effects : agranulositosis,
anemia aplastik, trombositopeni,
hemolisis
Nonsteroidal antiinflammatory drugs
(NSAIDs)
Negative Feedback
control of ACTH
Production. Suppression
of HPA
STRESS: Overrides the
neg. feedback
mechanism.

Adrenal cortex

Produces 30 steroid hormones

Major divisions
include:
Glucocorticoids
Mineralocorticoids
Glucocorticoids

Cortisol
(95%)
Corticostrone
Cortisone

90% bound to plasma

proteins

Circadian release
Of GCs; highest in
the early morning
and lowest in the
evening.
1. Suppress T-cell activation and cytokine production.

2. Suppress mast cell degranulation.

3. Decrease capillary permeability indirectly by inhibiting

mast cells and basophils.

4. Reduce the expression of cyclooxygenase II and

prostaglandin synthesis.

5. Reduce prostaglandin, leukotriene and platelet

activating factor levels by altering phospholipase A2
activity.
 Local (Preferred)
Intra-articular, IA
Intrabursal, IB
Intralesional, IL
Intrasynovial, IS
Soft tissue, ST
Intrarectal, IR
Topical
Nasal
Inhaled

Systemic
Oral, PO
Intramuscular, IM
Intravenous, IV
Subcutaneous, SC
 Daily administration of corticosteroids at physiological
concentrations for at least 2 weeks suppresses the
HPA resulting in decreased production of
endogenous hormones. Recovery may take up to
9-12 months.

Hepatic Metabolism:
The liver is the primary site of GC inactivation.
GCs are metabolized by cytochrome P450 3A4
enzymes
25% of GCs are excreted in bile and feces.

Renal Clearance
75 % of GC metabolites are excreted in the urine.
 Biological Half life

Mineralocorticoid potency

Glucocorticoid (anti-inflammatory)
potency
 Mineralocorticoid actvity

Corticosteroids control symptoms and DO NOT stop progression (cure) of the

 Prototype corticosteroid for anti-inflammatory
activit
Short acting GC
Clinical uses: Localized inflammatory
conditions,
i.e. Ulcerative colitis & dermatitis
Relative anti-inflammatory potency is 1
Plasma half-life is 30 min
Biological half-life is 8-12 hrs.
Administration: Oral, injectable, topical
(creams and ointments) and IR (foam).
Contraindications (IR): Systemic fungal
infection, recent ileocolostomy, intestinal
anatomoses and abscess.
 Intermediate acting GC

Clinical uses: Adjunct therapy for arthritis (short

term admin), asthma, COPD; Ulcerative colitis and
Crohns disease.; Rheumatic and dermatologic
disorders.

Relative anti-inflammatory potency is 4; It is 4x more

potent than cortisol.

Inactive on its own. It must be metabolized in the

liver to an active metabolite.
Plasma half-life is 60 min
Biological half-life is 18-36 hrs

 Anti-inflammatory Drugs
Glucocorticoids
Inhaled

Beclomethasone
Budesonide
Flunisolide
Fluticasone propionate
Triamcinolone acetonide

Metered Dose Inhaler

Oral (Quick relief of asthmatic inhalers
symptoms) zers
Prednisone
Prednisolone
* Unresponsive to 2 agonists
 Intermediate acting GC
Prenisolone acetate/sodium phosphate
Clinical uses: Opthalmic
disorders, respiratory diseases.
Plasma half-life is 60 min
Biological half-life is 18-36 hrs.
Administration: Oral,
Injectable (systemic and local).
 Intermediate acting GC
Methylprenisolone acetate/sodium succinate
Clinical uses: Rheumatoid arthritis
Intra- articular injections
, UC,severe alcoholic hepatitis.
Plasma half-life is 60 min
Biological half-life is 18-36 hrs.
Administration: Oral, Injectable
(systemic and
local).
Adverse effects: vertigo, headache,
weight gain, sodium/water retention and
 Intermediate acting GC

Triamcinolone acetonide/diacetate/hexacetonide

Clinical uses: Similar to prednisone:

Opthalmic
disorders, respiratory diseases.

Plasma half-life is 60 min

Biological half-life is 18-36 hrs.

Administration: Oral, Injectable (systemic
and local).
 Taken Daily, over a long period of time
Beclomethasone
SE: oropharyngeal candidiasis (Thrush),
Budesonide dysphonia (hoarseness), adrenal
Flunisolide suppression, bone loss, in children,
Fluticasone propionate retarded growth
Triamcinolone Reduced risk of toxicity with inhaled
acetonide Mechanisms preparations

of Action:
Reduce bronchial
hyperreactivity
Decreased synthesis and release of inflammatory mediators,
e.g, leukotrienes, prostaglandins and histamine
Decreased infiltration and activity of inflammatory cells,
e.g.
eosinophils, leukocytes)
Decreased edema of the airway mucosa and mucus
 Long acting GC
Betamethasone acetate/sodium phosphate
Clinical uses: Respiratory diseases,
Respiratory distress syndrome, local
inflammatory conditions (similar to
prednisone). Life threatening or disabling
condition.
Relative anti-inflammatory potency is 25.

Plasma half-life is 300+ min

Biological half-life is 36-54 hrs.

Administration: Oral, topical,

 Long acting GC

Dexamethasone acetate/sodium phosphate

Clinical uses: Lupus and Rheumatoid arthritis.; Life threatening or

disabling conditions.

Maximal anti-inflammatory action.

Relative anti-inflammatory potency is 25.

Plasma half-life is 110-210 min

Biological half-life is 36-54 hrs.

Administration: Oral, topical, Injectable (systemic and local).
 Adrenocortical insufficiency: Suppression of HPA

Adrenocortical excess (Cushings disease): Moon face,

buffalo hump
Diabetes Mellitus

CNS effects: psychological and behavioral changes;

of pre-existingaggravation
psychiatric disorders.

Impaired wound healing

Musculoskeletal effects: osteoporosis (brittle bones), muscle

weakness and atrophy

Cardiovascular effects: fluid retention, edema, hypertension.

Glucocorticoid Withdrawal: Should be performed slowly

Withdrawal syndrome: hypotension, hypoglycemia, myalgia and
fatigue
 Drugs that Enhance Corticosteroid
Effects
Estrogens
Oral contraceptives
Antifungal agents
Antibiotics
*all of these agents inhibit cytochrome P450 enyzymes

Drugs that Reduce Corticisteroid Effects

Antacids
Cholestyramine
*these drugs decrease the absorption of corticosteroids
Phenytoin: inhibits cytochrome P450 enyzymes