Download CLin_Pharm_antiinflammatory agents

Clinical Pharmacology
of Anti-inflammatory
Agents
RHEUMATIC DISEASES

Rheumatic diseases (rheumatism) are painful
conditions that affect millions. These diseases
cause inflammation, swelling, and pain in the
joints or muscles.
 Some rheumatic diseases like osteoarthritis
are the result of "wear and tear" to the joints.
Other rheumatic diseases, such as rheumatoid
arthritis, happen when the immune system
goes haywire; the immune system attacks the
linings of joints, causing joint pain, swelling,
and destruction.
Fibromyalgia
Osteoarthritis
Rheumatoid Arthritis
RA is sometimes called a crippling disease. That's because it
can result in permanent joint damage and
deformity.
RA signs and symptoms include:
 Joint pain, stiffness, and swelling
 Involvement of multiple joints (symmetrical pattern)
 Other organ involvement
 Joint stiffness, especially in the morning
 Fatigue
 Fevers
 Lumps called rheumatoid
nodules
To diagnose RA, doctor will ask about medical history and do
a physical examination. Also, X-rays and blood tests will
likely be taken. One blood test may be for rheumatoid
factor; it is positive in 70% to 80% of those with RA.
Rheumatoid Arthritis
Systemic lupus erythematosus
Ankylosing Spondylitis
Sjogren's Syndrome
Venus Williams Diagnosed With
Sjogren’s Syndrome
Therapeutic Strategies

The treatment of patients with
inflammation involves two primary goals:
first, the relief of symptoms and the
maintenance of function, which are usually
the major continuing complaints of the
patient; and second, the slowing or arrest
of the tissue-damaging process.
NSAIDs can be classified based on their chemical
structure or mechanism of action
Salicylates
 Aspirin (acetylsalicylic acid)
 Diflunisal
 Salsalate
NSAIDs
Propionic acid derivatives
 Ibuprofen
 Naproxen
 Fenoprofen
 Ketoprofen
 Flurbiprofen
 Oxaprozin
Acetic acid derivatives
 Indomethacin
 Sulindac
 Etodolac
 Ketorolac
 Diclofenac (Safety alert by FDA)
 Nabumetone
NSAIDs
Enolic acid (Oxicam) derivatives
 Piroxicam
 Meloxicam
 Tenoxicam
 Droxicam
 Lornoxicam
 Isoxicam
Fenamic acid derivatives( Fenamates )
 Mefenamic acid
 Meclofenamic acid
 Flufenamic acid
 Tolfenamic acid
NSAIDs
Selective COX-2 inhibitors (Coxibs)
 Celecoxib (FDA alert)
 Rofecoxib (withdrawn from market) - increased cardiovascular
thrombotic events
 Valdecoxib (withdrawn from market) - increased cardiovascular
thrombotic events
 Parecoxib FDA withdrawn
 Lumiracoxib TGA cancelled registration
 Etoricoxib FDA withdrawn
 Firocoxib used in dogs and horses
Sulphonanilides
 Nimesulide (systemic preparations are banned by several countries for
the potential risk of hepatotoxicity)
Others
 Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence
known as 5-LOX/COX inhibitor
Inflammation
The cell damage associated
with inflammation acts on cell
membranes to cause
leukocytes to release lysosomal
enzymes; arachidonic acid is
then liberated from precursor
compounds, and various
eicosanoids are synthesized.
The cyclooxygenase (COX)
pathway of arachidonate
metabolism produces
prostaglandins, which have a
variety of effects on blood
vessels, on nerve endings, and
on cells involved in
inflammation. The lipoxygenase
pathway of arachidonate
metabolism yields leukotrienes,
which have a powerful
chemotactic effect on
eosinophils, neutrophils, and
macrophages and promote
bronchoconstriction and
alterations in vascular
permeability.
Cyclooxygenase isoforms
The discovery of two
cyclooxygenase isoforms
(COX-1 and COX-2) led to the
concept that the constitutive
COX-1 isoform tends to be
homeostatic in function, while
COX-2 is induced during
inflammation and tends to
facilitate the inflammatory
response. On this basis, highly
selective COX-2 inhibitors
have been developed and
marketed on the assumption
that such selective inhibitors
would be safer than
nonselective COX-1 inhibitors
but without loss of efficacy.
The more an NSAID blocks COX-1, the greater is its
tendency to cause ulcers and promote bleeding. But
celecoxib (Celebrex), blocks COX-2 and has little effect
on COX-1, and is therefore further classified as a
selective COX-2 inhibitor. Selective COX-2 inhibitors
cause less bleeding and fewer ulcers than other
NSAIDs.
NSAIDs are generally indicated for the
symptomatic relief of the following conditions:














Rheumatoid arthritis
Osteoarthritis
Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic
arthritis, Reiter's syndrome)
Acute gout
Dysmenorrhoea (menstrual pain)
Metastatic bone pain
Headache and migraine
Postoperative pain
Mild-to-moderate pain due to inflammation and tissue injury
Pyrexia (fever)
Ileus
Renal colic
They are also given to neonate infants whose ductus arteriosus is
not closed within 24 hours of birth
Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also
indicated for inhibition of platelet aggregation.
Complications of NSAIDs
NSAIDs are safe drugs. However, they have many side effects. The
side effects happen more often when they are used over long periods
of time, which is common in arthritis patients. Some of the side effects
can become very serious.








Central nervous system: Headaches, tinnitus, and
dizziness.
Cardiovascular: Fluid retention hypertension,
edema, and rarely, congestive heart failure.
Gastrointestinal: Abdominal pain, dysplasia, nausea,
vomiting, and rarely, ulcers or bleeding.
Hematologic: Rare thrombocytopenia, neutropenia,
or even aplastic anemia.
Hepatic: Abnormal liver function tests and rare liver
failure.
Pulmonary: Asthma.
Rashes: All types, pruritus.
Renal: Renal insufficiency, renal failure,
hyperkalemia, and proteinuria.
Choice of NSAID


All NSAIDs, including aspirin, are about equally
efficacious with a few exceptions—tolmetin seems not to
be effective for gout, and aspirin is less effective than
other NSAIDs (eg, indomethacin) for ankylosing
spondylitis.
Thus, NSAIDs tend to be differentiated on the basis of
toxicity and cost-effectiveness. For example, the
gastrointestinal and renal side effects of ketorolac limit
its use. Some surveys suggest that indomethacin or
tolmetin are the NSAIDs associated with the greatest
toxicity, while salsalate, aspirin, and ibuprofen are least
toxic. The selective COX-2 inhibitors were not included
in these analyses.
Choice of NSAID (cont’d)


For patients with renal insufficiency, nonacetylated salicylates may
be best. Diclofenac and sulindac are associated with more liver
function test abnormalities than other NSAIDs. The relatively
expensive, selective COX-2 inhibitor celecoxib, is probably safest for
patients at high risk for gastrointestinal bleeding but may have a
higher risk of cardiovascular toxicity. Celecoxib or a nonselective
NSAID plus omeprazole or misoprostol may be appropriate in
patients at highest risk for gastrointestinal bleeding; in this
subpopulation of patients, they are cost-effective despite their high
acquisition costs.
The choice of an NSAID thus requires a balance of efficacy, costeffectiveness, safety, and numerous personal factors (eg, other
drugs also being used, concurrent illness, compliance, medical
insurance coverage), so that there is no best NSAID for all patients.
There may, however, be one or two best NSAIDs for a specific
person.
CORTICOSTEROIDS
Most of the known effects of the glucocorticoids
are mediated by widely distributed glucocorticoid
receptors
CORTICOSTEROIDS
Glucocorticoids. Anti-Inflammatory
and Immunosuppressive effects


Glucocorticoids cause vasoconstriction when applied
directly to the skin, possibly by suppressing mast cell
degranulation. They also decrease capillary permeability
by reducing the amount of histamine released by
basophils and mast cells.
The anti-inflammatory and immunosuppressive effects of
glucocorticoids are largely due to the actions described
above. In humans, complement activation is unaltered,
but its effects are inhibited. Antibody production can be
reduced by large doses of steroids, although it is
unaffected by moderate doses (eg, 20 mg/d of
prednisone).
Uses of Corticosteroids



The most commonly used corticosteroids are
prednisone, prednisolone, and
methylprednisolone. Corticosteroids can be given
orally or put directly into the bloodstream through
an intravenous needle. They can also be injected
directly into an inflamed spot. Corticosteroid
cream can be rubbed on the skin.
Corticosteroids are powerful drugs. But they are
also highly toxic. Doctors have different opinions
about how corticosteroids should be used.
Corticosteroids can't cure a disease. But they do
seem to affect the development of some
diseases, including rheumatoid arthritis (RA).
Some Commonly Used Natural and
Synthetic Corticosteroids for General Use
Short- to medium-acting glucocorticoids:
Hydrocortisone (cortisol)
Cortisone
Prednisone
Prednisolone
Methylprednisolone

Some Commonly Used Natural and
Synthetic Corticosteroids for General Use
Intermediate-acting glucocorticoids
Triamcinolone
Paramethasone
Fluprednisolone
 Long-acting glucocorticoids
Betamethasone
Dexamethasone

CORTICOSTEROIDS
Withdrawal


When stop taking corticosteroids, the doses will be slowly reduced
over a period of days or weeks. Even if patient has only been taking
steroids for a few weeks, he will still need to taper off. Corticosteroid
withdrawal can be very difficult for body. In many patients, the
disease symptoms become worse. Some people experience a
sickness that includes fevers, nausea, vomiting, low blood pressure,
and low blood sugar. Others have withdrawal symptoms that include
muscle and joint pain, weight loss, fever, and headaches. If patient
have problems coming off corticosteroids, doctor will have taper off
the drug more slowly.
Different people, and different diseases, react very differently to
corticosteroids.
Choosing the right DMARD
Current evidence suggests that combinations of
DMARDs are more effective, and probably less toxic,
than monotherapy. Methotrexate is often used as an
anchor drug, combined with hydroxychloroquine,
sulfasalazine or leflunomide. An anti-TNF-alpha drug
such as etanercept or infliximab may also be used in
combination. There is a stronger evidence base for the
disease-modifying effects of methotrexate,
sulfasalazine, leflunomide and intramuscular gold than
for hydroxychloroquine, penicillamine, oral gold,
ciclosporin or azathioprine, although these agents do
improve symptoms and some objective measures of
inflammation. The choice of first agent or combination
of agents should be based on a risk/benefit analysis for
individual patients.