Analgesic antipyretic and antiinflammatory drugs

General consideration

• The antiinflammatory ,analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated ,which nevertheless share certain therapeutic actions and side effects.

• The prototype is aspirin . Hence these compounds are often referred to as aspirin-like drugs; they are also frequently called nonsteroidal antiinflammatory drugs (NSAIDs).

• There has been substantial progress in elucidating the mechanism of action of NSAIDs. Inhibition of cyclooxygenase, the enzyme responsible for the biosynthesis of the prostaglandin (PG) and certain related autacoids, generally is thought to be a major facet of the mechanism of NSAIDs.

History

• The active ingredient in the willow bark was a bitter glycoside called salicin, first isolated in a pure form in 1829 by Lexroux, who also demonstrated its antipyretic effect.

• On hydrolysis, salicin yields glucose and salicylic alcohol. The latter can be converted into salicylic acid. Either in vivo or by chemical manipulation sodium salicylate was first used for the treatment of rheumatic fever and as an antipyretic in 1875, and the discovery of its uricosuric effects and of its usefulness in the treatment of gout soon followed.

• Hoffman prepared acetylsalicylic acid . After demonstration of its antiinflammatory effects , this compound was introduced into medicine in 1899 by Dreser under the name of aspirin.

• The synthetic salicylates soon displaced the more expensive compounds obtained from natural source. Para-aminophenol is used today.

White willow bark

Mechanism of action of NSAIDs

• Antipyretic effects– Characteristics: this kind of drugs

reduces temperature of patients with fever, but they have no effect on normal temperature.

– Mechanism of antipyretic effects• Regulation of body temperature requires a deli

cate balance between the production and loss of heat ; the hypothalamus regulates the set point at which body temperature is maintained. In fever , this set point is elevated, and NSAIDs promote its return to normal.

Pathogen or toxin(+)

neutrophils Pyrogen release

(+)hypothalamus PGs synthesis and release

(+) Temperature-regulating center in hypothalamus

Set point for temperature

Heat production ↑and a loss of heat ↓ fever

asprin

• Synthesis of prostaglandins– Synthesis of prostaglandins is accomplishe

d in a stepwise manner by a ubiquitous complex of microsomal enzymes. The first enzyme in this synthetic pathway is prostaglandin endoperoxide synthase, also called fatty acid cyclooxygenase. There are two isoforms of this enzyme,COX-1 and COX-2

– COX-1 is constitutively expressed in most cells. COX-2 is not normally present but may be induced by certain serum factors, cytokines, and growth factors.

– The cyclooxygenases have two distinct activities: endoperoxides synthase activity that oxygenates and cyclized the unesterified precursor fatty acid to form the cyclic endoperoxide PGG, and a peroxidase activity that converts PGG to PGH. PGG and PGH are chemically unstable, but they can be transformed enzymatically into a variety of products, including PGI,PGE, PGF, PGD,PGE2,PGD2,TXA, etc.

• NSAIDs nonselectively inhibit the COX-1 and COX-2 , PG synthesis is decreased, heat production ↓ and a loss of heat ↑,normal temperature.

• Therapeutic use: high fever

• Distinguishing between antipyretics and phenothiazide

Temperature

Normal fever

Mechanism of action

phenothiazides

antipyretics (-)

Inhibition of temperature-regulating center

Inhibition of PGs biosynthesis

• Analgesic effect– Characteristics

• Analgesic effect is weak and effective on mild to moderate dull pain and little effect on colicky pain of smooth muscle and sharp pain.

• Non-narcotic

Mechanism of analgesics

Injured or inflammatory tissue

PGs release

Autocoid release

Pain receptors

(+)

pain

PGs directly stimulate pain receptors and increase sensitivity of pain receptor to bradykinin etc to produce pain . NSAIDs relieve pain via inhibition of PGs biosynthesis.

• Therapeutic uses: common dull pains: headache, toothache, muscular pain , arthralgia and dysmenorrhea.

Distinguishing between narcotic and non-narcotic

analgesia

analgesia Site of action Action mechanism indications narcotic

Narcotic strong central activate opioid receptors sharp pain (+)

NSAIDs weak peripheral inhibite PGs biosythesis dull pain (-)

• Anti- inflammatory effect

PGs( PGE2,PGI2)

vasodilation

Autocoids release

Increased vascular permeability

Edema NSAIDs

diminish

pain

swelling

• Therapeutic uses: rheumatic and rheumatoid arthritis

Classification

• Salicylates: aspirin • Aminophenol derivative : acetaminophe

n• Pyrazolon: phenybutazone• Other drugs: piroxicam, meloxicam

Acetylsalicylates acid / aspirin

Pharmacokinetics

• Absorption– PO: rapidly, partly from the

stomach but mostly from the small intestine

• Distribution. – Salicylate is distributed thr

oughout most body tissues and most transcellular fluids.

– The drug readily crosses the placental barrier.

• Biotransformation :– The biotransformation of salicylate takes place

in many tissue, but particularly in the hepatic endoplasmic reticulum and mitochondria.

– Aspirin in oral small dose is metabolized in the first -order kinetics. (T1/2: 2~3h), whereas aspirin in the large dose is metabolized in the zero-order kinetics, which prolong T1/2 of aspirin and is easy to get intoxication.(T1/2: 15~30h).

• Excretion – Aspirin is excreted via kidney. pH in the urin

e affects the excretion of aspirin and alkalinization of urine increases the excretion.

Pharmacological effects

• Analgesia:– The type of pain usually relieved by aspirin a

re those of low to moderate-intensity dull pain, especially headache, myalgia, and arthralgia.

– Long term use dose not lead to tolerance or addiction, and toxicity is lower than that of opioid analgesics. The salicylates alleviate pain by virtue of a peripheral action, direct effect on the CNS also may be involved.

• Antipyresis : – Aspirin usually lower e

levated body temperatures rapidly and effectively. However ,moderate doses that produce this effect also increase oxygen consumption and metabolic rate.

• Antiinflammatory effects– Aspirin used to treat rheumatoid and rheum

atic arthritis . Aspirin may provide symptomatic relief and not provide treatment for cause of these disease.

• Aspirin inhibits platelet aggregation

platelet

Various stimuli chemical and mechanical

Activation of phospholipse A2

phospholipidsrelease

Arachidonic acidCOX1 or COX2

Unstable endoperoxide (PGG,PGH)

Thromboxane synthase

TXA2

Platelet release ADP

Platelet aggregation Aspiri

n

Therapeutic uses

• Hyperpyrexia: relieving symptom of fever in the modest dose.

• Analgesia : aspirin is valuable for the nonspecific relief of certain types of pain: headache, arthritis , dysmenorrhea, neuralgia , and myalgia.

• Treat acute rheumatic fever and rheumatoid in relatively large dose by both analgesic and antiinflammatory effects.

• Prophylaxis of thromboembolism, stroke , myocardial infarction in small dose.

Rheumatic fever

Rheumatoid arthritis

• Rx of Dysmenorrhoea• Antiplatelet aggregatory: by inhibition of synthesis

of both proaggregatory (TXA2) and anti aggregatory (PGI2) prostanoids,but effect on platelet TXA2 predominates.

• Ductus arterious closure:• Parturition• Gastric mucosal damage: Inhibition of COX-1 medi

ated synthesis of gastroprotective PGsis involved,though local action inducing back diffusion of H+ ions in gastric mucosa also plays a role.

• Anaphylactoid reaction:Aspirin precipitates asthma,angioneurotic oedema,urticaria or rhinitis in certain susceptible individuals.

Adverse reaction

• Gastrointestinal effects:– Epigastric distress, nausea, and vomiting. G

astric ulceration, exacerbation of peptic ulcer symptom , gastrointestinal hemorrhage

– Note:Aspirin –induced gastric bleeding sometimes is painless and , if unrecognized as , may lead to an iron –deficiency anemia

The prophylactin measures for the side effects including: taking aspirin with meal, taking enteric-coated aspirin

• Hepatic damage:– There usually are no symptoms, and elevate

d hepatocellular enzyme activities in plasma are the principle indication of hepatic damage.

• Prolongation of bleeding time.– Ingestion of aspirin by healthy

individuals causes a prolongation of the bleeding time.

Patients with severe hepatic damage, hypoprothrombinemia, Vit K deficiancy, or hemophilia a should avoid aspirin because the inhibition of platelet hemostasis can result in hemorrhage

• Salicylate intoxication– Mild chronic salicylate intoxi

cation is termed salicylism when fully developed, the syndrome includes headache, dizziness, ringing in ears, difficulty in hearing , dimness of vision, mental confusion, drowsiness, sweating, thirsty, etc.

• The treatment of salicylate intoxication– Salicylate medication is withdrawn as soon

as intoxication is suspected.– Gastric lavage– Intravenous infusion of NaHCO3

– Dialysis if required– Relieving symptoms

Para-aminophenol derivatives: acetaminophen

• Acetaminophen is the active metabolite of phenacetin, and is an effective alternative to aspirin as an analgesic-antipyretic agent.

• Its antiinflammatory activity is weak and thus it is not useful agent to treat inflammatory conditions.

• Acetaminophen is a suitable substitute for aspirin for analgesic or antipyretic uses. It is particularly valuable for patients in whom aspirin is contraindicated or when the prolongation of bleeding time caused by aspirin would be a disadvantage.

• Adverse effects include skin rash and drug fever, hypoglycemic coma, renal tubular necrosis and renal failure in the long-term administration, acute hepatic necrosis in the large dose.

Indomethacin• Pharmacological effect

– Prominent antipyretic, analgesic and antiinflammatory activities.

– Antiinflammatory effect from indomethacin is more potent than aspirin

• Therapeutic uses– Rheumatoid arthritis,

ankylosing spondylitis, and acute gout.

gout

Rheumatoid arthritis

ankylosing spondylitis

– Indomethacin is not routinely used for analgesia and antipyresis because of its toxicity and side effects.

– Indomethacin relieves pain ,reduces swelling and tenderness of the joint, increases grip strength, and decreases the duration of morning stiffness

Adverse reaction

• Gastrointestinal complaints: anorexia, nausea, and abdominal pain, single ulcer.

• CNS effects: severe frontal headache, dizziness, vertigo, light-headedness, and mental confusion are also frequent.

• Hematologic effect: neutrupenia, thrombocytopenia, impaired platelet functions and rarely aplastic anemia.

• Indomethacin should not be used in pregnant women, nursing mothers, persons operating mechinery , or patients with psychiatric disorders, epilepsy, or Parkinsoniasm.

Piroxicam • Piroxicam is one of the oxicam derivativ

es, a class of enolic acids that have antiinflammatory , analgesic, and antipyretic activity.

• Piroxicam is an effective antiinflammatory agent, it is about equal in potency to indomethacin as an inhibitor of prostaglandin biosythesis in vitro, and is approved in the US for the treatment of rheumatoid arthritis and osteoarthritis.

• It also has been used in the treatment of ankylosing spondylitis, acute musculoskeletal disorders ,dysmenorrhea, postoperative pain, and acute gout.

• Gastrointestinal reaction are the most common.

Ketorolac

Nsaid with potent analgesic and modest antiinflammatory effect.

Efficacy equal to morphine in post operative pain.So frequently used in post-op paindental and acute musculoskeletal pain,renal colic and migraine.

Has lower hepatotoxicity.