Download Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Haiyun Luo
–NSAIDs
Large and chemically diverse group of drugs with antipyretic, analgesic and
nti-inflammatory properties. They are among the most frequently prescribed drugs:in the
worldwide: there are 70 million people/day prescribed NSAIDs, 230 million people/day take OTC
NSAIDs. NSAIDs are also called anti-pyretic-analgesic & anti-inflammatory drugs. Aspirin is
the prototype, so ASPIRIN-LIKE DRUGs is another name for them. Their chemical structures
differ in a large range, but have no steroidal structure, so they are also called non- steroidal
anti-inflammatory drug (NSAIDs) (vs. the glucocorticosteroides).
General features of NSAIDs
Most NSAIDs are nonselective inhibitors of cyclooxygenases (COX). They decrease formation of
prostaglandins (PGs) and thromboxanes in the body. This action is a primary (but not sole)
contributor to the pharmacologic effects of NSAIDs.
Prostaglandins (PGs)
The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also
known as cyclooxygenase or COX. This enzyme converts arachidonic acid (AA) to the unstable
intermediates PGG2 and PGH2 and leads to the production of thromboxane A2 (TXA2) and a
variety of prostaglandins. There are two forms of COX, COX-1 and COX-2. COX 1 is
constitutively expressed in most tissues, and is thought to protect the gastric mucosa. COX-1 is
essential for thromboxane formation in blood platelets. COX-2 expression is stimulated by
inflammatory
mediators, eg, growth factors, cytokines, & endotoxins. Inflammation is
associated with up-regulation of COX-2 and increased formation of PGs. Some of ihe
inflammatory mediators are derived from phospholipids, with an outline of their actions and the
sites of action of anti-inflammatory drugs.
Biosysthesis of PGs
The structure of phospholipids and the sites of action of phospholipases.
The inflammatory mediators derived from phospholipids,
with an outline of their actions and the sites of action of
anti-inflammatory drugs.
Relationship between PGs and fever
Fever (also known as pyrexia, or a febrile response): is a frequent symptom that describes an increase
in internal body temperature to levels that are above normal. In moderation, fever aids in recovery
from illness, it can 1, promotes interferon activity, 2, increase metabolic rate, so tissue repair more
rapid, and 3, inhibits bacterial and viral reproduction. But excessive high temperature is troubsome,
it is even lead to delirium, convulsions, coma, death.
Pathogenesis of fever and antipyretic mechanism of NSAIDs
•Pyrogen:
A pyrogen is a substance that induces fever. They can be either exogenous or
endogenous:
The bacterial endotoxin (lipopolysaccharide, LPS) is an example of an exogenous pyrogen.
Endogenous pyrogen are the cytokines, such as interleukin 1,tomor necrosis factor-alpha produced
byphagocytic cells, which cause the increase of PGE in the thermoregulatory set-point in the
hypothalamus.
•Truma,
infection etc. →
exogenous pyrogen ↑ → endogenous pyrogen ↑ →
anterior
hypothalamus → PGEs ↑ → cAMP ↑ → resetting the thermoregulatory center → body
temporature. set point↑ →fever.
The hypothalamus regulates the set point at which body temperature is maintained. The
macrophages secrete pyrogenic cytokines (IL-1, & TNF α, etc.) during inflammation which
stimulate the synthesis of PGE2 in hypothalmic area. PGE2 elevated the set point →fever;
NSAIDs inhibit PGs synthesis → resetting body tem. set point to normal → recover
(antipyretic).
Relationship between PGs and inflammation
The inflammatory process is the response to an injurious stimulus (e.g., infections, antibodies, or
physical injuries). No matter what the initiating stimulus, the classic inflammatory response
includes redness, swelling, heat, pain, and loss of function. The ability to mount an inflammatory
response is essential for survival in the face of environmental pathogens and injury.Inflammatory
responses occur in three distinct temporal phases, each apparently mediated by different
mechanisms:
(1) an acute phase, characterized by transient local vasodilation and increased capillary
permeability;
(2) a delayed, subacute phase characterized by infiltration of leukocytes and phagocytic cells;
and
(3) a chronic proliferative phase, in which tissue degeneration and fibrosis occur.
Specific inflammatory mediators
1 Metabolites of Arachidonic acid
–Prostaglandins and thromboxane: cause vasodilation and prolong edema and pain; but also
protective (gastric mucosa);
–Leukotrienes:
are chemotaxins, vasoconstrictors, cause increased vascular permeability,
and bronchospasm. Chemotaxins are factors such as PGs and complement proteins -(C5a), that
attract WBCs to the site of the injury.
–PAF
(platelet activating factor): causes vasodilation, increased vascular permeability,
increases leukocyte adhesion →edema
2 Vasoactive amines
–Histamine: vasodilation and venular endothelial cell contraction
→ junctional widening
→ vascular permeability↑→edema; released by mast cells, basophils, platelets in response to
injury.
–Serotonin: vasodilatory effects similar to those of histamine; Stored in platelet dense-body
granules; release triggered by platelet aggregation; pain mediator.
3 Bradykinin :
–Vascular permeability↑
–Arteriolar dilation
–Non-vascular smooth muscle contraction (e.g., bronchial smooth muscle)
–Causes pain
–Rapidly inactivated (kininases)
Relationship between PGs and pain
•Inflammation
•Prostaglandins
→many mediators↑→stimulate nociceptor→ initiate pain.
lower the threshold of the C fiber nociceptors→pain sensitization →lower
concentrations of bradykinin and histamine are required to activate the nociceptor→ pain .
•NSAIDs inhibt PGs synthesis→
nociceptors return to normal→ analgesic effect.
Pharmacological effects of NSAIDs
1 analgesic effect
These drugs usually are effective only against low-to-moderate pain, such as dental pain,
headache. Although their maximal efficacy is generally much less than the opioids, NSAIDs lack
the unwanted adverse effects of opiates in the CNS, including respiratory depression and physical
dependence.
2 antiinflammatory effect
As antiinflammatory agents, NSAIDs are used in the treatment of musculoskeletal disorders,
such as rheumatoid arthritis and osteoarthritis. In general, NSAIDs provide only symptomatic
relief from pain and inflammation associated with the disease, do not arrest the progression of
pathological injury to tissue.
3 NSAIDs reduce fever in most situations.
Adverse effects of NSAIDs
•Gastrointestinal
symptoms are the most common, including anorexia, nausea, dyspepsia,
abdominal pain, and diarrhea. These symptoms may be related to the induction of gastric or
intestinal ulcers (occurring in 15% to 30% of regular users). Ulceration may range from small
superficial erosions to full-thickness perforation of the muscularis mucosa, and can be
accompanied by gradual blood loss leading to anemia or by life-threatening hemorrhage.
Adverse effects of NSAIDs
•Platelet: prolonged bleeding time, GI blood loss
•Analgesic nephropathy: a condition of slowly progressive
renal failure. Risk factors are the
chronic use of high doses of combinations of NSAIDs and frequent urinary tract infections. If
recognized early, discontinuation of NSAIDs permits recovery of renal function.
•Uterine: delayed parturition, dystocia.
•Hypersensitivity: symptoms that range from, angioedema, generalized urticaria, and bronchial
asthma to laryngeal edema, bronchoconstriction, flushing, hypotension, and shock.
Selective COX-2 inhibitors Less likely to cause the gastric toxicity. However, cardiovascular
side effects have curtailed use of some of these drugs.
Structural classes of NSAIDs
•Salicylates: aspirin
•Para-aminophenol derivatives: acetaminophen
•Acetic acid derivatives: indomethacin
•The fenamates,Ketorolac,Propionic acids,Enolic acids (oxicams)
A Salicylates: Aspirin
Aspirin is still the most widely consumed NSAID.
Pharmacokinetics
•
Rapidly absorbed from GI tract
•
Distributed throughout most body tissues
•
80-90% is bound to plasma proteins.
•
Rapidly hydrolyzed in blood and liver to salicyclic acid (half-life is approximately 15
min.)
•
Inactivation is mainly through the formation of conjugates in liver that are excreted in
the urine.
Inhibition of COX: Acetylation of a key serine within the active site. This reaction is not
reversible and is unique to aspirin.
Therapeutic uses of aspirin
1 Antipyresis
2 Analgesia
3 Anti-inflammation: rheumatoid arthritis.
4 Anti blood platelet aggregation---used for prophylaxis of heart disease
(myocardial infarction and stroke)
6 Prophylaxis of colorectal cancer
7 Treatment of Alzheimer’s Disease.
Thromboxane A2: Thromboxane A2 stimulates blood platelet aggregation, essential to the role of
platelets in blood clotting. Many people take a daily aspirin for its anti-clotting effect, attributed
to inhibition of thromboxane formation in blood platelets. This effect of aspirin is long-lived
because platelets do not make new enzyme.
Aspirin Toxicity – Salicylism
• Mild intoxication with aspirin. Commonly experienced when the daily dose exceeds 4 g
• Characterized by tinnitis, high frequency hearing loss, headache, nausea, dimness of
vision.
• Symptoms are usually reversible within 2-3 days after withdrawal of the drug.
Contraindications
•Aspirin Allergy
•GI Ulceration
•Liver or Kidney diseases
•Blood Disorders
Aspirin - Dosage
• Analgesic/antipyretic dose for adults is 325-650 mg every 4 hrs. The half-life is 2-3
hours.
•
•
•
B
Anti-inflammatory dose is usually 4-6 g daily. The half-life is usually 12 hours.
Low doses of aspirin (<100 mg daily) are used widely for their cardioprotective effects.
Fatal dose is 10-30 g. The half-life can be as long as 15-30 hours.
Acetaminophen
Acetaminophen is a suitable substitute for aspirin for analgesic or antipyretic uses; it is
particularly valuable for patients in whom aspirin is contraindicated (e.g., those with peptic ulcer,
aspirin hypersensitivity, children with a febrile illness).
•Acetaminophen is the first choice for releasing children fever.
Adverse effects of acetaminophen
•The
most serious acute adverse effect of overdosage of acetaminophen is a potentially fatal
hepatic necrosis. Renal tubular necrosis and hypoglycemic coma also may occur.
•Rash and other allergic reactions occur occasionally.
C. Acetic acid derivatives
•etodolac ,indomethacin,sulindac , As a group
are more potent than aspirin but are also less
tolerated.
Indomethacin
•Indomethacin is a more potent inhibitor of the cyclooxygenases than is aspirin, but patient
intolerance generally limits its use to short-term dosing.
•It is not used commonly as an analgesic or antipyretic unless the fever has been refractory to
other agents (e.g., Hodgkin's disease).
•Adverse effects: very high (35% to 50%) ; Diarrhea, severe frontal headache, neutropenia,
thrombocytopenia, severe depression, psychosis, and others.
Etodolac 依托度酸
•Etodolac is with some degree of COX-2 selectivity. Thus, at antiinflammatory doses, the
frequency of gastric irritation may be less than with other traditional NSAIDs.
•A single oral dose (200 to 400 mg) of etodolac provides postoperative analgesia that typically
lasts for 6 to 8 hours. Etodolac also is effective in the treatment of osteoarthritis and rheumatoid
arthritis. A sustained-release preparation is available, allowing once-a-day administration.
•Adverse Effects: GI intolerance, rashes, and CNS effects.
D. The fenamates
•They include:
mefenamic , meclofenamic , and flufenamic acids
•Therapeutically, they have no clear advantages over several other tNSAIDs and frequently cause
GI side effects.
E. Ketorolac
Ketorolac is a potent analgesic but only a moderately effective antiinflammatory drug. It is one of
the few NSAIDs approved for parenteral administration.
•Ketorolac, as a short-term alternative (less than 5 days) to opioids for the treatment of moderate
to severe pain. Unlike opioids, tolerance, withdrawal, and respiratory depression do not occur.
Like other NSAIDs, aspirin sensitivity is a contraindication to the use of ketorolac.
F. Propionic Acids derivatives
•Fenoprofen,flurbiprofen ,ibuprofen ,ketoprofen ,naproxen,
•All are nonselective COX inhibitors with the effects and side effects common to other NSAIDs.
•Ibuprofen, the most commonly used NSAID was the first member of the propionic acid class
of NSAIDs. Ibuprofen is thought to be better tolerated than aspirin and has been used in patients
with a history of gastrointestinal intolerance to other NSAIDs.
•Ketoprofen inhibits both COX (nonselectively) and lipoxygenase.
•Oxaprozin its half-life of 40 to 60 hours allows for once-daily administration.
G. Enolic acids (oxicams) Piroxicam, Meloxicam
They are nonselective COX inhibitors, although one member (meloxicam) shows modest COX-2
selectivity. The main advantage for these drugs is their long half-life, which permits once-a-day
dosing.
H. COX-2 Selective NSAIDs: Celecoxib
They were developed in an attempt to inhibit PGs synthesis by the COX-2 isoenzyme induced at
sites of inflammation without affecting the action of the constitutively active "housekeeping"
COX-1 isoenzyme found in the GI tract, kidneys, and platelets.
•COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects similar to those of
nonselective NSAIDs but with an approximate halving of gastrointestinal adverse effects.
•Likewise, COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is
mediated by the COX-1 isoenzyme. As a result, COX-2 inhibitors do not offer the cardioprotective
effects of traditional nonselective NSAIDs. Unfortunately, because COX-2 is constitutively active
within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those
associated with traditional NSAIDs. Clinical data have suggested a higher incidence of
cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and
valdecoxib, resulting in their withdrawal from the market.