Antipyretic, analgesic and anti-inflammatory drugs

Department of pharmacology Zhang xiaojie

OverviewThis kind of drug is a group of chemically dissimilar agents that have antipyretic, analgesic and anti-inflammatory effects.Nonsteroidal anti-inflammatory drugs ( NSAIDs ) Share similar pharmacological effects, mechanism of action and adverse effects.

All inhibit the biosynthesis of prostaglandins (PGs)

Prostaglandin, PGProstaglandins are a family of unsaturated eicosenoic fatty acids containing a five-carbon ring and two side chains, widely exists in most tissues and body fluids of humans and mammals, playing a very important role in homeostatic functions PGE2PGF2a

Production and Actions of Prostaglandins membrane phospholipids phospholipase A2 glucocorticoid lipoxygenase Arachidonic acid COX NSAIDs PGI2 synthetase (vascular endothelium) PGG2 5-HPETE PGH2

iosmerase reductase TXA2 synthetase (platelet) leukotrienes PGI2 PGE2 PGF2 TXA2 Allergy inhibit platelet aggregation induce inflammation vasoconstriction platelet aggregation vasodilation cause fever and pain bronchial constriction vasoconstriction bronchial constriction hyperalgesia vasodilation vascular permeability hyperalgesia Induce inflammation

cyclooxygenase

Biological Effects of Prostaglandins PGE2: vasodilation, protect gastric mucosa induce inflammation, fever and pain PGF2: bronchial constriction and vasoconstriction PGI2: vasodilation, inhibit platelet aggregation TXA2: platelet aggregation and vasoconstriction.

Cyclo-oxygenase (COX), is the key enzyme for synthesis PGs, include two isoforms :COX-1constitutive enzyme, involved in tissue homeostasis

COX-2inducible enzyme, responsible for the production of the prostanoid mediators of inflammation, pain and fever

Comparison between COX-1 and COX-2 COX-1 COX-2 production constitutive induced function physiological pathological protection of the gastric mucosa facilitate inflammatory regulation of platelet aggregation cause fever and pain regulation of renal blood flow regulation of peripheral vascular resistance

Most currently available traditional NSAIDs inhibit both COX-1 and COX-2 with little selectivity NSAIDs,s inhibition of COX-2 is the base of their therapeutic effects while their inhibition of COX-1 is the reason of their adverse reactions (GIT) But this is not absolute the antithrombosis effect of aspirin is based on its inhibition of COX-1 According to the selection of COX they are classified into selective COX-2 inhibitor and non-selective COX inhibitor

Common pharmacological effectsThese drugs show the same pharmacological effects -- antipyretic effect -- analgesic effect -- anti-inflammatory effect

Pharmacological Actions of NSAIDsAntipyretic effect Mechanism: Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

Characteristics They only decrease the body temperature of those who have a fever and no effect on normal ones

The higher temperature, the more potent

ProstaglandinsPGE2thermoregulatory centerheat production heat loss set point FeverPathogen (virus,bacteria,endotoxin,Ag-Ab)neutrophilic granulocyteEndogenous pyrogens (IL-1,IL-6,TNF-

The Difference between NSAIDs and ChlorpromazineInhibit the thermoregulatory center and make it out of function

Cause the body temperature to alter with the environment temperature

Not only decrease the body temperature of those who have a fever but also the normal ones

2. Analgesic EffectCause of pain: in injury tissue or inflammation, some chemical algesiogenic substances are produced and released such as bradykinin and so on together with PGs.

Bradykinin: cause pain through stimulating the algesireceptors directly. PG: (1) hyperalgesia (2) PG(E1 E2 F2) also have algesiogenic effect

Mechanism: inhibit the synthesis of PGs in periphery

The Cause of Pain

Inflammation BK,histamine et,al algesireceptor pain Injury PGs hyperalgisia NSAIDs

Analgesic Effect

Characteristics

Only effective to mild to moderate pain little effect on sharp pain and viscera angina No euphoria and no respiratory inhibition

No addiction and no tolerance

3.Anti-inflammatory Effectinflammation is the defensive reaction to lesion factors of live tissues having vascular system

phospolipids Lesion PLA2 factor neutrophilic arachidonic acid granulocyte cytokines induce COX-2 IL-1,6,8 TNF PGs BK adhesive molecules inflammation

Anti-inflammatory EffectThe role of PGs in inflammation1. cause vasodilation and tissue edema2. coordinate with bradykinin to cause inflammationMechanism of anti-inflammatory effect(1) Reducing biosynthesis of prostaglandins by inhibiting COX(2) inhibition of the expression of some cell adhesion molecules

Characteristics Symptomatic Treatment NSAIDs only relieve the main clinical symptoms (erythema, edema, fever, pain and dysfunction) of inflammation have no effect on the autoimmunological process of rheumatic and rheumatoid arthritis.

Classification of NSAIDs Non-selective COX inhibitor Selective COX-2 inhibitor

Salicylates: aspirin Para-aminophenol: acetaminophen Pyrazoly ketons : phenylbutazone Other organic acids :Indomethacinselectivitychemical structure

SalicylatesAspirinSodium salicylate

Salicylic acid

Acetylsalicyclic acid

AspirinProcess in the body1. Absorption rapidlytpeak= 0.5~2 hrs p.o.In stomach and small intestine (mainly in the latter)2. Distribution widely almost throughout the body.synovial fluid, cerebrospinal fliud,pass placenta.PPBR=80%~90%

3. Metabolism Hydrolyzed rapidly to acetic acid and salicylate by esterases plasma t1/2 =15 min. Salicylates are metabolized by cytochrome P450 in the liver,most of the product are bound to Glycines few of them are bound to glucuronic acids.

Aspirinaspirin p.o.

Process in the Body4.Excretion The metabolites are mainly excreted by kidney. low dose: most are excreted in the form of bound, few in the form of free salicylate.in large dose: many of them will be excreted in the form of free salicylate.

Process in the BodyUrine pH have a strong influence on the excretion amount of free salicylate from kidney

Alkaline pH : free SA up to 85% Acidic pH : free SA low as 5%

So we can reduce the blood concentration of free salicylate through alkalizing the urine

Pharmacological Effects1. Antipyretic and analgesic effect strong and rapid, in low dose (300-600mg)

2. Ant-inflammatory and antirheumatic effect (1) relatively weaker (2) need large dose (3-6g)

3.Inhibit platelet aggregation and prevent thrombosisInhibition of platelet COX-1-derived TXA2 can inhibit platelet aggregation Endothelial COX-1 derived PGI2 can dilate vessel and inhibit platelet aggregation Aspirin administrated in low dose can covalently modifies and irreversibly inhibits platelet COX. The enzyme is inhibited for the lifetime of the platelet (~8 -11 days) remarkably but have no apparent influence on PGI2 . So PGI2> TXA2Clinical Indications low dose, long term use produce therapeutic efficacy in stroke and MI (reduces mortality and prevents recurrent events).

The Effect of Aspirin on Platelet Cyclooxygenase-1Platelet cyclooxygenase-1 is a dimer. Arachidonic acid substrate gains access to the catalytic site (red area) through a hydrophobic channel that leads into the core of the enzyme (Panel A). Aspirin blocks the access of arachidonic acid to the catalytic site by irreversibly acetylating a serine residue at position 529 in platelet cyclooxygenase-1 (Panel B).

Clinical Uses1. Antipyresis and analgesia headache, toothache, myalgia, neuralgia, dysmenorrhea and fever of influenza2. Anti-inflammation and antirheumatismdiagnosis and therapy of acute rheumatic feverrheumatic and rheumatoid arthritis to relieve the symptoms High dose needed (5-8 g/day). But many pts cannot tolerate these doses (GIT); so, proprionic acid derivatives, ibuprofen, naproxen tried first

3. Antithrombosis

Ischemic cardiopathy including stable and variant angina pectoris and progressive myocardial infarction patients. It can reduce mortality and re-ischemiaIn transient ischemic attack patients to prevent cerebral thrombosisin angioplasty, bypass transplant operations to prevent thrombosis

Other Effects(1) Alzheimer,s disease(AD): AD is related to the over-expression of COX-2 in brain Aspirin 100mg p.o. daily has repression effect on AD

(2) Pregnancy-induced hypertension syndrome and preeclampsia: is related to the increase of the ratio of TXA2 to PGI2 in blood Aspirin 40-100mg p.o. daily can reduce the incidence of PIH and the danger of preeclamapsia

Adverse Reactions1. Gastrointestinal reactionsshort-term: nausea, vomit, abdominal painlong-term: gastritis, ulcer, gastrorrhagiaMechanism:irritate gastric mucosa directlyirritate chemoreceptor trigger zone(CTZ)Inhibit the gastric mucosa protection effect of PGE2 Methods:Take it after meal Take enteric coating tablets Take it along with antacids and misoprostol

2. Blood Coagulation DisordersIn usual dose: inhibit platelet coagulation and prolong the bleeding time Contraindications: Hemophilia Severe hepatic damage Vitamin K deficiency one week before operation ante partum

3. AllergyUrticaria, allergic shock, angioneurotic edema

Aspirin-asthma: Asthma induced by the administration of aspirin or other NSAIDS in some asthma patients.Mechanism: It is not caused by allergic reaction based on antigen-antibody reaction. COX PGS Lipoxygenase leukotrienes

Allergy

Treatment: Adrenaline has no effect on it, but we can treat it with antihistamines and glucocorticoids.

Controundications: nasal polyp, asthma, chronic urticaria, histroy of hypersensitivity

Adverse Reactions4. Salicylism When the dose of aspirin is too high, 5/d, the patients may suffer from headache, dizziness, nausea, vomiting, tinnitus, sight and hearing failure.Severe patients may suffer from hyperventilation, acid-base in balance, even mental confusion, these are all called salicylism.Treatment: sodium bicarbonate iv.drip

Adverse Reactions5. Reyes syndromeOccur rarely but can result death in childrenSevere hepatic dysfunction with complication of encephalopathyContraindicated in children and young adults less than 20 years old with fever associated viral illness

Substitute aspirin with acetaminophen for children fever, Reyes syndrome has disappeared

Drug Interactions Compete the banding site to plasma albumin

Replace dicoumarol() enhance its anticoagulation effect even cause hemorrhage

Replace tolbutamideand cause hypoglycemia

Replace glucocorticoids ()enhance its anti-inflammatory effect also enhance its effect of inducing ulcer

Acetaminophen & Phenacetin Inhibit the synthesis of PG in CNS but has little effect on the COX in peripherySimilar antipyretic and analgesia to aspirinWeak anti-inflammatory propertiesUsed in usual dose with few adverse reactions, if used overdose, it can cause hepatic injury. Phenacetin it is transformed into toxic metabolites by the liver which can change hemoglobin into methemoglobin and cause hemolysis.

Therapeutic uses Acetaminophen provides an effective alternative when aspirin is contraindicated (e.g., in patients with peptic ulcer or hemophilia) and when the anti-inflammtory action of aspirin is not required.

IndomethacinPharmacologic effects :Inhibit COX nonselectively .Inhibit phospholipase A and C.Decrease T cell and B cell proliferation.(10-40 time more potent anti-inflammatory than aspirin)

IndomethacinTherapeutic uses: Because of its toxicity and side effect, it is not routinely used for analgesia or antipyresis. The major uses of indomethacin are in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and acute gout.

IndomethacinAdverse effect: Gastrointestinal complaint:CNS effects: 25%-50%Hematologic reactions:Hypersensitivity reactions: asthma (aspirin- sensitive patients may exhibit cross-reactions to indomethacin).

Naproxen and IbuprofenThey have prominent anti-inflammatory action.Therapeutic uses: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute tendinitis, dysmenorrhea, et al.Adverse effect: gastrointestinal effects, dermatologic problems, thrombocytopenia. apply to long-term treatment because they are better-tolerated.

Phenylbutazone Powerful anti-inflammatory effectsWeak analgesic & antipyretic activitiesPromote excretion of uric acidUsed for acute gout, rheumatic & rheumatoid arthritisMore adverse reactionCan induce activities of drug metabolize-ECan displace other drugs from plasma proteins

Selective COX-2 inhibitorCelecoxib and Rofecoxibmore selective for COX-2 than for COX-1.Adverse effects are slighter than other NSADs.Long-term studies of the incidence of clinically significant gastrointestinal ulcers and bleeding are not yet completed.Rofecoxib withdrawn from market in 2004

Clinical uses of the NSAIDsFor analgesia in painful conditions (e.g. headache, dysmenorrhoea, backache, bony metastases of cancers, postoperative pain):The drugs of choice for short-term analgesia are aspirin, Acetaminophen and ibuprofen; more potent, longer-acting drugs (diflunisal, naproxen, piroxicam) are useful for chronic painThe requirement for narcotic analgesics can be markedly reduced by NSAIDs in some patients with bony metastases or postoperative pain

Clinical uses of the NSAIDs For anti-inflammatory effects in chronic or acute inflammatory conditions (e.g. rheumatoid arthritis and related connective tissue disorders, gout and soft tissue diseases) For many NSAIDs, the dosage required for chronic inflammatory disorders is usually greater than for simple analgesia and treatment may need to be continued for long periods; Treatment could be initiated with an agent known to have a low incidence of side-effects. If this proves unsatisfactory, more potent agents should be used

Clinical uses of the NSAIDsTo lower body temperature Acetaminophen is preferred because it lacks gastrointestinal side-effects and, unlike aspirin, has not been associated with Reyes syndrome in childrenThere is substantial individual variation in clinical response to NSAIDs and considerable unpredictable patient preference for one drug rather than another