nonsteroidal antiinflammatory drugs and antipyretic- analgesics (1)

7/27/2019 Nonsteroidal Antiinflammatory Drugs and Antipyretic- Analgesics (1)

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NONSTEROIDAL

ANTIINFLAMMATORYDRUGS AND ANTIPYRETIC-

ANALGESICS


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Overview These drugs are a group of chemically dissimilar

agents that have antipyretic, analgesic and anti-

inflammatory effects.

The structure of this kind of drug differs from that

of steroidal anti-inflammatory drugs.


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Phospholipids

Phospholipase

Arachidonic Acid

5-lipoxygenase cyclooxygenase

5-HPTE PGG2

peroxidase

LTB4 LTC4

PGH2

TXA2 PGI2 PGE2 PGF2PGD2


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PGE2: Vasodilatation, pain sensitization,

gastric cytoprotection [mucous/HCO3 secretion],

fever

PGF2 : Bronchoconstriction, uterine contraction

PGI2 : Inhibition of platelet aggregation, gastric

cytoprotection

TXA2 : Platelet aggregation


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Anti-inflammatory action

NSAIDs only inhibit the symptoms of

inflammation

But they neither arrest the progress of the

disease nor do they induce remission


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Anti-inflammatory action

The decrease in vasodilator

prostaglandins (PGE2, PGI2) means less

vasodilatation and, indirectly, less odema.

The inhibition of activity of adhesion

molecule.

Accumulation of inflammatory cells is also

reduced.


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The principal pharmacological effect of NSAIDs is

due to their ability to inhibit prostaglandin

synthesis by blocking the cyclooxygenase(COX)

activity of COX-1 and COX-2.

NSAIDs - acetylation of COX

(reversible or irreversible)

COX-1: constitutive enzyme: is involved in

tissue homeostasis. COX-2: inducible enzyme: is responsible for the

production of the prostanoid mediators of

inflammation.

Mechanism of action


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NSAIDs

Prostaglandins

pGE2 pGF2

Symptoms of

inflammation

Red, swelling,

Heating, Pain

Bradykinin

Histamine

5-HT

Inflammatory

factors

+

block prostaglandinsproduction

Sites of action:

peripheral tissue


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Antipyretic action

Normal temperature: slightlyaffected

Elevated temperature: reduced The higher temperature, the more

potent

Mechanism of antipyretic action:Blocks pyrogen-induced prostaglandinproduction in thermoregulatory center(CNS)


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Heat production and heat dissipation. Infever associated with an infection, increased

oxidative processes enhance heat production .

Aspirin causes cutaneous vasodilation,

prompts perspiration, and enhance heat

dissipation.


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NSAIDs

PyrogenProstaglandins

pGE2

thermoregulatory

center

heat production Heat dissipation

set point

Fever

Antipyretic MechanismBlock prostaglandins

production

Sites of action:

Central Nervous System


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Analgesic action

Pain may arise from:

Musculature, dental work , vascular ,

postpartum conditions, arthritis ,bursitis

Sites of action:

Peripherally - sites of inflammationsubcortical sites


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NSAIDs

Prostaglandins

pGE2 pGF2

Nerve ending of

pain

Pain

Bradrkininhistamine

factors

+

block prostaglandinsproduction

Sites of action:

peripheral tissue


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CLASSIFICATION

Nonselective COX inhibitors (traditional NSAIDs)1) Salicylates : Aspirin2) Propionic acid derivatives : Ibuprofen

Naproxen

Ketoprofen

Flurbiprofen

3) Anthranilic acid derivatives: Mephenamic acid4) Aryl- acetic acid derivatives: Diclofenac

Aceclofenac

5) Oxicam derivatives: Piroxicam

Tenoxicam

6) Pyrrolo- pyrrole derivatives: Ketorolac7) Indole derivatives: Indomethacin

8) Pyrazolone derivatives: Phenylbutazone

Oxyphenbutazone


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Preferential COX-2 inhibitors

Nimesulide

Meloxicam

Nabumetone

Selective COX-2 inhibitorsCelecoxib

Etoricoxib

Parecoxib

Analgesic- antipyretics with poor antiinflammatory action1) Paraaminophenol derivative: Paracetamol (Acetaminophen)

2) Pyrazolone derivatives: Metamizol ( Dipyrone)

Propiphenazone

3) Benzoxacine derivatives: Nefopam


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Salicylates: Aspirin

Analgesic Effect

Aspirin is most effective in reducing pain of mild

to moderate intensity (headache, toothache,

dysmenorrhea, arthralgia, etc). It is not effective for severe visceral pain, e.g.

myocardial infarction or renal or biliary colic.

It acts peripherally through its effects oninflammation but probably also inhibits pain

stimuli at a subcortical site.


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Anti-inflammatory Effects:

The anti-inflammatory property of aspirin

in high dosage is responsible for treatment

various kinds of inflammation including

acute rheumatic fever, rheumatoid and

other types of arthritis.

It has been advocated as a diagnostic test

when acute rheumatic fever is suspected


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Effect on platelets Low doses of aspirin can inhibit platelet aggregation and

produce a slightly prolonged bleeding time by irreversibleinhibition of platelet COX.

Low doses of aspirin can irreversibly inhibit theproduction of TXA2in platelets without markedlyinterfering with PGI2production in endothelial cells.

In general, Aspirin should be stopped 1 week prior tosurgery to avoid bleeding complication.

Aspirin has been shown to decrease the incidence oftransient isochemic attacks, unstable angina, coronaryartery thrombosis with myocardial infarction, andthrombosis after coronary artery bypass grafting.


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1. Gastrointestinal tract This effect can be decreased with suitable

buffering(taking Aspirin with meals ). The

gastritis that occurs with Aspirin may bedue to irritation of gastric mucosa by the

undissolved tablet, or to inhibition of

production of protective prostaglandins.

Therefore, aspirin should be avoided by

individuals with peptic ulcer disease.

ADVERSE EFFECTS


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2.BloodAspirin increases bleeding

time,decreases platelet

adhesiveness,,and ,at large doses,may

cause hypoprothrombinaemia.

3.hepatotoxicity

4.Hypersensitivity:Aspirin asthma

5.Salicylate intoxication

6. Reyes syndrome


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Propionic acid derivatives:

Ibuprofen Ibuprofen is a simple derivative of Arylpropionic

acid.

In doses of about 2400 mg daily,ibuprofen is

equivalent to 4 g of aspirin in anti-inflammatoryeffect.Oral ibuprofen is often prescribed in

lower doses(


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Indole derivative:

Indomethacin Indomethacin is an indole derivative.

It enjoys the usual indications for use in

rheumatic conditions and is particularlypopular for gout and ankylosingspondylitis.In addition,it has been usedto treat patient ductus arteriosus.

It is one of the most potent COXinhibitors, and has more adverse effects.


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Pyrazolone derivative:

Phenylbutazone Phenylbutazone,a pyrazolone

derivative rapidly gained favor after its

introduction in 1949 for the treatment ofrheumatic syndromes

But its toxicities,particularly thehematologic effects (including aplastic

anemia),have resulted in its withdrawalfrom many markets

Rarely used today


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Selective COX-2 inhibitors

Celecoxib is a selective COX-2 inhibitor,

having slight action on COX-1 in

therapeutic dosage.

The incidence of gastric toxicity is much

lower with it than with non-selective COX

inhibitors.

It is used for treatment of osteoarthritis

and rheumatoidarthritis.


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Paraaminophenol derivative:

Acetaminophen Acetaminophen is the active metabolite ofphenacetin responsible for its analgesics effect.

It is a weak prostaglandin inhibitor in peripheral

tissues and possesses no significant anti-

inflammatory effects.

Acetaminophen is one of the most important drugs

used for the treatment of mild to moderate painwhen an anti-inflammatory effect is not necessary.

Phenacetin is more toxic and has no rational

indications


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Anti

pyretic

analg

esic

Anti-

inflam-

matory

Side

action

Acetaminophen ++ ++ +

Indomethacin ++++ ++++

sulindac ++++ ++

tolmetin + + ++ ++

diclofenac ++ ++ ++

Ibuprofen + +++ + +

meloxicam ---- cox2Phenylbutazone +++ +++

ketorolac +++ i.m


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Over-the-Coun ter Anti- inf lammatory Drugs

NSAIDs that can be purchased over-the-counter include:

ibuprofen,

naproxen sodium, aspirin

Ibuprofen is also available as a prescription at doses higherthan the over-the-counter medications.

Prescr ip t ion An t i -in f lammatory Drug s The following NSAIDs are available only with a doctor's

prescription:

Celecoxib,

Sulindac

Oxaprozin Salsalate

Diflunisal

indomethacin

piroxicam

piroxicam

nonsteroidal antiinflammatory drugs and antipyretic- analgesics (1)

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