NSAIDS Flashcards
NSAIDS
The antiinflammatory, analgesic, and antipyretic drugs are heterogeneous group of compounds, often chemically unrelated (except a large number of them are organic acids), which share certain therapeutic actions and side effects. ASPIRIN is the prototype for the NSAIDS.
THE INFLAMMATORY PROCESS
Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents.
- inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair.
- when healing is complete, the inflammatory process usually subsides. However, inflammation is sometimes inappropriately triggered by an innocuous agent, such as pollen, or by an autoimmune response, as in asthma or rheumatoid arthritis—in these cases the defense reactions themselves may cause progressive tissue injury.
Inflammation
is triggered by the release of chemical mediators from injured tissues and migrating cells.
Specific chemical mediators vary with the type of inflammation process
-amines—- histamine and 5-hydroxytryptamine
-lipids——prostaglandins
-small peptides——bradykinin
-large peptides——-interleukin 1
PROSTAGLANDINS
unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure ( sometimes referred to as eicosanoids)
-Prostaglandins and related compounds are produced in small quantities by almost all tissues.
-they generally act locally on the tissues in which they are synthesized, and are rapidly metabolized to inactive products at their site of action—they do not circulate in the blood in significant concentrations
-thromboxanes, leukotrienes, hydroperoxyeicosatetraenoic acids (HPETEs)
and hydroxyeicosatetraenoic acids (HETEs) are related lipids, synthesized from the same precursors as are the prostaglandins, using interrelated pathways
ARACHIDONIC ACID
a 20 carbon fatty acid, is the primary precursor of the prostaglandins and related compounds
- Arachidonic acid is present as a component of the phospholipids of cell membranes, primarily phosphatidyl inositol and other complex lipids.
- Free Arachidonic acid is released from tissue phospholipids by the action of phospholipase A2 and other acyl hydrolases, by a process controlled by hormones and other stimuli
There are two major pathways in the synthesis of the eicosanoids from arachidonic acid
CYCLOOXYGENASE PATHWAY
LIPOXYGENASE PATHWAY
CYCLOOXYGENASE PATHWAY
All eicosanoids with ring structures (prostaglandins, thromboxanes, and prostacyclins, are synthesized by the cyclooxygenase pathway.
-two isoforms have been identified (A) COX-1—ubiquitous and constitutive. (B) COX-2 is induced in response to inflammatory stimuli
LIPOXYGENASE PATHWAY
Several lipoxygenase can act on arachidonic acid to form 5-HPETE, 12 HPETE, and 15 HPETE which are unstable peroxidated derivatives that are converted to the corresponding hydroxylated derivatives (HETEs) or to leukotrienes or lipoxins, which depends upon the tissue involved
actions of prostaglandins
The actions of prostaglandins are mediated by their binding to a wide variety of distinct membrane receptors that operate by G proteins that either activate or inhibit adenylate cyclase or stimulate phospholipase C.
NSAIDS
NSAIDS are a group of chemically dissimilar agents that differ in their antipyretic, analgesic and anti-inflammatory activities. It is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process. NSAIDS act primarily by inhibiting the cyclooxygenase enzymes but not the lipoxygenase enzymes. Cyclooxygenase-2 (COX-2) is found in inflammatory cells and inhibition of this enzyme is responsible for the beneficial effect of these drugs. Aspirin is the prototype of the group; it is the most commonly used and the drug to which all other anti-inflammatory drugs are compared. About 15% of patients show intolerance to aspirin and these patients may benefit from other NSAIDS. Some of the newer NSAIDS are superior to aspirin in certain patients because they have greater anti-inflammatory activity and/or cause less gastric irritation, or can be taken less frequently. The newer NSAIDS, however, are considerably more expensive than aspirin and some have proved to be more toxic.
Aspirin (acetylsalicylate)
SALICYLATES: weak organic acids; ASPIRIN is unique among NSAIDS in irreversibly acetylating (inactivating) cyclooxygenase (NOTE: all other NSAIDS are reversible inhibitors); aspirin is readily deacetylated by esterases in the body producing salicylate which has anti-inflammatory, analgesic, and antipyretic effects; diflunisal is not metabolized to salicylate and doesn’t cause salicylate toxicity; diflunisal is 3-4 times more potent than aspirin as an analgesic and anti-inflammatory, but has no antipyretic properties (NOTE: diflunisal does not enter the CNS and therefore cannot relieve fever)
aspirin moa
for antipyretic and analgesic effects are due to blockade of prostaglandin synthesis at the thermoregulatory centers in the hypothalamus and at peripheral sites; blockade of prostaglandin synthesis by both acetylsalicylate and salicylate prevents sensitization of pain receptors to mechanical and chemical stimuli
for anti-inflammatory effects: by blocking COX, prostaglandin synthesis is diminished and inflammation mediated by prostaglandins is inhibited.
analgesic effects
PGE2 is thought to sensitize nerve endings to
the action of bradykinin, histamine, and other chemical mediators
released locally by the inflammatory process; NSAIDS block PGE2
formation and repress the sensation of pain
antipyretic effects
fever occurs when the set-point of the anterior
hypothalamic thermoregulatory center is elevated; this can be caused
by PGE2 and is blocked by NSAIDS; aspirin resets the “thermostat”
toward normal and rapidly lowers the body temperature of febrile
patients by increasing heat dissipation as a result of peripheral
vasodilation and sweating; aspirin has no effect on normal body temperature
respiratory actions
at therapeutic doses, aspirin increases alveolar ventilation (NOTE: salicylates uncouple oxidative phosphorylation which leads to elevated CO2 and increased respiration) with no effect on pH; higher doses of aspirin work directly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis that is usually adequately compensated for by the kidney; toxic doses of aspirin may cause respiratory paralysis and a respiratory acidosis ensues due to continuous CO2 production (note: that the decrease of pH is also due to metabolic acidosis—organic acid)
