NONSTEROIDAL ANTIINFLAMMATORYDRUGS

Antiinflammatory drugs

Steroid- Glucocorticoids

Nonsteroidal-Aspirin like

INTRODUCTION

ANALGESICANTIINFLAMMATORYANTIPYRETIC

They are also called

“Nonnarcotics,Nonopiodids,or Aspirin like analgesics”

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

1. Overview

Definition: NSAIDs are chemically diverse class of drugs

(>70 NSAIDs in use) that have anti-inflammatory, analgesic, and antipyretic properties.

Among the most frequently prescribed drugs

-worldwide: 70 million people/day prescribed NSAIDs 230 million people/day take OTC NSAIDs

-USA: 80 billion aspirin tablets consumed/year constitute 4% of all prescriptions

CLASSIFICATION A) Nonselective Cox inhibitors

1.Salicylates- Aspirin

2.Pyrazolone derivatives- Phenylbutazone, oxyphenbutazone

3.Indole derivatives- Indomethacin, Sulindac

4.Propionic acid derivatives- Ibuprofen, Naproxen, Ketoprofen

5.Anthranilic acid derivatives- Mephenaimic acid

6.Aryl-acetic acid derivatives- Diclofenac sodium

7.Oxicam derivatives- Piroxicam, Tenoxicam

8.Pyrrole derivatives- Ketorolac

B) Preferential cox-2 inhibitor Nimesulide, Meloxicam.

C) selective cox- 2 inhibitors-Celecoxib, Rofecoxib,Valdecoxib

D) Analgesics- Antipyretics-Paracetamol, Metamizol, Nefopam

(non opiod analgesic which donot inhibit PG synthesis)

NSAIDs and Prostaglandins

PGs, Prostacyclins,TXA2-Arachidonic acid Cyclooxygenase- Cox-1-Constitutive

(House keeper), Mucus secretion, Haemostasis, renal functions

Cox-2 Inducible-

Inflammatory response

Sites-brain, JG cells (constitutive)

COX-2 Hypothesis (1990s)

Normal Tissue Inflammation Site

Physiolgical ProstaglandinProduction

PathologicalProstaglandinProduction

COX-1Constitutive

COX-2Inducible

Arachidonic Acid

Normal Functions Inflammation, pain, fever

NSAIDsCOX-2

Inhibitors

CytokinesGrowth factorsILs,TNF

+

Properties of Prostaglandins

Properties of Prostaglandins•Physiological Functions of Prostaglandins

Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin, Histamine and substance P

Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema, erythema)

Protection of the gastric mucosa: PGI2

Maintenance of renal blood flow: PGE2

Fever: PGE2

Platelets: PGI2 and PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation

Uterus: PGD2 contracts uterus

Other: PGE2 keeps ductus arteriosus open following birth

Analgesia

PGs---induce hyperalgesia by increasing sensitivity of afferent nerve endings to chemical and mechanical stimuli and thus amplify action of other algesics-bradykinins, histamine, TNF-alpha, ILs.

PGs in CNS lowers threshold of central pain circuit.

NSAIDS block this pain sensitizing mechanism therefore effective against inflammation asso. Pain

The opioids are the drugs of choice for the

treatment of moderate-to-severe pain, the NSAIDs are

most frequently used for mild-to-moderate pain.

Prostaglandins by themselves do not cause pain but lower the threshold of the C fiber nociceptors.

As a result, lower concentrations of bradykinin and histamine are required to activate the nociceptor.

Antipyresis

Fever in infection is produced by pyrogens, TNF, ILs, interferon-induce production of PGs in hypothalamus-raise its temp. set point.

NASIDs block the action of pyrogens.(cox-2).

Fever also can occur through non PG mediated mech.—incomplete explanation ???

Anti-inflammatory Inhibition of PG synthesis at the site of injury.

Anti-inflammatory action of each drug corresponds with their potency to inhibit COX.

NSAIDs -also inhibit expression/ activity of adhesion molecules, growth factors like GM-CSF,IL-6,and lymphocyte transformation factors-affected.

NSAIDs-Stabilises leucocytes lysosomal membrane, and antagonizes certain act.. Of kinkins

Dysmenorrhea

Increase levels of PGs in menstrual blood flow, endometrial biopsies, and their metabolites is seen in dysmennorhic women.—myometrial ischaemia –menstrual cramps.

NSAIDs-lowers uterine PGs--relief

Antiplatelet

Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly.

Ductus arteriosus closure

PGE2, PGI2-

responsible for maintaining patency in foetal circulation.

Parturition

Sudden increase in PG synthesis by uterus triggers labour and facilitate progression.

NSAIDs –delay and retard labour

Gastric mucosal damage

Inhibition of synthesis of gastro protective PGS (E2,I2)- decrease in mucus,HCO3,increases acid secretion, may promote mucosal ischemia.

Ion trapping with NSAIDs also play role.

Renal effects Conditions like hypovoleumia, decrease renal perfusion,

and Na+ loss- induce renal PG synthesis –leading to vasodilatation, inhibition of cl - reabsorption…

NSAIDs-

1. Cox dependent impair renal bl.flow.—decrease in gfr-renal insufficiency.2. JG Cox 2 dependent Na and water retention.3. Rare ability to cause papillary necrosis on habitual intake.

Renal effects more marked in pts ofCHF, Hypovolemia, hepatic cirrhosis renal disease, pts on diuretics and antihypertensive----edema

Anaphylactoid reaction

Aspirin precipitates

Bronchial asthma, angioneurotic swelling…

Aspirin

Aspirin is acetyl salicylic acid converted in body to salicylic acid.

MOA-aspirin inhibits COX irreversibly by acetylating one of its serine residue.

Pharmacological actions1.Analgesic- relives pain related to inflammation, tissue

injury, connective tissue etc.

MOA: -obtunding peripheral receptors -prevents PGs mediated nerve ending sensitization. -raises threshold for pain perception in central sub

cortical regions.

2.Antipyretic- resets the hypothalamic thermostat.

3.Antiinflammatory-signs of inflammation like pain, tenderness, swelling, vasodilatation and leukocyte infiltration are suppressed.

Metabolic effects:At anti-inflammatory doses: 1.↑ heat loss 2.↓ blood sugar

Respiration:At anti-inflammatory doses - increased respiratory rate.In salicylate poisoning- resp.depression

Acid base balance and electrolyte balance-Initially Increased Co2 production and its washout resp.alkalosis.-Later Co2 retention –resp. acidosis (high doses)-Followed by metabolic acidosis.-dehydration occurs in poisoning.

CVS: At toxic doses –depresses VMC, BP falls, CHF may precipitate

Urate excretion: Dose related effect….

BloodTXA2 inhibition.

GIT-

Epigastric distress, nausea and vomiting

Ion trapping

Back diffusion of H+ ions

Focal necrosis of mucosal cells

Acute ulcers

Adverse effects Side effects

Nausea, vomiting ,gi distressGastric mucosal damage, peptic ulceration.

Hypersensitivity

Anti-inflammatory doses- Salicylism-(3-6g/day)

Dizziness, tinnitus, vertigo, reversible impairment in hearing and vision, excitement ,mental confusion, hyperventilation, electrolyte imbalance.

In children- Liver damageReye’s syndrome-hepatic encephalopathy esp. in

children having viral infection.

Acute salicylate poisoning-More common in childrens, fatal dose for adults 15-16g

Precautions and contraindications

Peptic ulcer Sensitive pts Children suffering from influenza, chickenpox Chronic liver diseases Diabetics CHF, lower cardiac reserve Pregnancy

Delayed labor, more postpartum bleed, premature closure of ductus arteiosus

G6PD deficiency

Interactions

Aspirin displaces warrfarin, naproxen,sulfonylurese, phenytoin from its pp binding sites-toxicity of these agents.

Inhibits tubular secretion of uric acid and antagonizes action of uricosuric agents.

Blunts action of diuretics

Pharmacological actions

Analgesia Antipyretic AntiinflammatoryDysmenorrheaAntiplatelet Ductus arteriosus closure

Parturition

Uses of aspirin 1. As analgesic-condn. Aspirin 300mg-600mg 6-8.hlly

2. As antipyretic- in various infections, PUO

3. Acute rheumatic fever-

4. Rheumatoid arthritis- 5. Osteoarthitiis-

6. Postmyocardial infraction & poststroke patients. Aspirin 60-100mg/day

7. Other- pregnancy induced hypertension preeclamcia to delay labour to close patent ductus arteriosus

Indole derivatives- Indomethacin

• Potent anti-inflammatory, antipyretic, analgesic.• Inhibit neutrophil motility.• High incidences of GIT and CNS side effects.

• Uses:1. RA not responding to Aspirin.2. Ankylosing spondilytis.3. Acute exacerbation of destructive orthopathies.4. Psoriatic arthritis5. Malignancy asso. refractory fever.6. DOC- PDA- dose:0.1-0.2mg/ kg12 hourly7. Bartter’s syndrome.

Propionic acid derivatives- Ibuprofen, Naproxen, Ketoprofen

Analgesic Antipyretics

Antiiflammatory

Inhibit PG synthesis (Nonselective COX in.)

Naproxen being most potent & better tolerated anti-inflammatory drug.

Longer acting twice dosing require.

They inhibit platelet aggregation & prolong bleeding time.

Pharmacokinetics-

Ibuprofen 400-800mg TDS Naproxen 250mg BD…(Gout) Ketoprofen 50-100mg BD Flubiprofen- ocular anti inflammatory

- Better tolerated orally and the incidences of adverse reactions are low.

- Highly protein bound drugs like aspirin can displace warrfarin, sulfonylurese, phenytoin from its pp binding sites…..toxicity of these agents.

Adverse effects

Better tolerated than aspirin Gastric discomfort Gastric erosion N & V Dizziness Blurring of vision Tinnitus & depression Rashes & hypersensitivity reaction

uses Simple analgesics and antipyretic (as low dose aspirin) Dysmenorrhea as inhibit PGs OTC RA, ankylosing spondilytis OA Musculoskeletal pain Soft tissue injuries Fractures Tooth extraction Postpartum & postoperatively

Anthranyllic acid derivatives- Mephenaimic acid

Analgesic, antipyretic, anti-inflammatory. inhibit COX antagonizes certain actions of PGs.

M.A. : exerts peripheral as well as central analgesic action.

S/E- diarrhea epigastric distress skin rash, dizziness

Uses- analgesic, effective in dysmenorrhea

Dose- 250-500mg TDS

Aryl acetic acid derivative- Diclofenac sodium

Similar in efficacy to Naproxen.Anti inflammatory action- reduces

neutrophil chemotaxis and superoxide production.

Dose:50mg BDUses-same as Ibuprofen.

Oxicam derivatives-Piroxicam, Tenoxicam

Long acting potent NSAIDs similar to Indomethacin.

Decreases production of IgM rheumatoid factor. Reduces leucocytes proliferation and ratio of T -

helper cells to T- suppressor cells. Meloxicam new congener of Piroxicam is

selective for COX II 10 times more than COX I.

Pyrrole derivatives- Ketorolac Novel analgesic, modest anti inflammatory drug. In post operative pain it has equaled efficacy of

Morphine but do not have morphine like side effects.

Uses:1. Post operative pains2. Acute musculoskeletal pain3. Renal colic4. Migraine5. Pain due to metastasis.

Dose-10-20mg 6hrly

preferential cox2 inhibitor Nimesulide

Used mainly short lasting painful conditions-

sport injuries, sinusitis, ear nose disorders, dental surgery, bursitis, low backache, dysmenorrhea, po. pain, o.a.

S/E - fulminant hepatitis

bronchospasmDose-100mg.

Cox-1 vs. Cox-2The reality.Arachidonic acidArachidonic acid

COX-2COX-2

““Inducible”Inducible”

ProstaglandinsProstaglandins

Pathological PhysiologicalPathological Physiological

InflammationInflammation Pain Pain FeverFever

COX-1COX-1“Constitutive”“Constitutive”

ProstaglandinsProstaglandins

GI cytoprotectionGI cytoprotection Platelet activityPlatelet activity Renal functionRenal function

Renal functionRenal function VascularVascular Tissue repairTissue repair

ARACHIDONIC ACID

Platelet TXA2

Endothelial PGI2

(Prostacyclin)

VasoconstrictionPlatelet Aggregation

VasodilationAnti-Platelet Aggregation

COX -1 COX -2

Thromboxane A2 vs. Prostacyclin

Aspirin

COX-1

Thromboxane

Prostacyclin Thromboxane

COX-2 inhibitors

Decreased CV events

Prostacyclin

Increased CV events

COX-2

Why do Cox-2 inhibitors increase risk for heart disease?#1. Because they adversely effect the ratio of thromboxane to prostacyclin

Selective COX2 inhibitors Celecoxib 100-200mgBD Rofecoxib 12.5-25mg OD Valdecoxib 20mg BD

Low ulcerogenic potential -TXA2 level were not reduced -Other Side effects are low

Pedal edema & rise in B.P occurs as a result of salt and water retention due to inhibition of constitutive COX II in JG cells. This may precipitate CHF.

COX II inhibition –inhibits PGI2 –prothrombotic influence….increased cardiovascular events. QT changes in ECG

Use- for long term use as analgesic in chronic pain.

Paracetmol

AcetaminophenGood & promptly acting antipyretic.Analgesic- central action

peripheral actionNegligible anti-inflammatory action.Poor inhibitor of PG synthesis in

peripheral tissuesMore active on COX in brain

In contrast to aspirin- does not stimulate respiration does not affect acid base balance. or cellular metabolism. No effect on CVS. platelets. GIT-insignificant effects

P/K- metabolism by glucuronic acid conjugation.

S/E- safe drug at antipyretic dose. Analgesic nephropathy (at toxic doses) Papillary necrosis Tubular atrophy Renal fibrosis Renal failure

Acute paracetmol poisoning- - small children - having low hepatic glucuronide conjugating ability. - if large doses >250mg/kg

Manifestations-• Nausea , vomiting.• Abdominal pain• Liver impairment- hepatic necrosis• Impaired consciousness• Renal tubular necrosis

Rx- Gastric lavage, activated charcoal

N-acetylcysteine 150mg/kg i.v over 15 mins followed by same dose over 20 hrs.

Choice of NSAIDs Mild to moderate pain with inflammation-

Paracetmol, Low dose Ibuprofen

Acute musculosketal, OA, injury associated with inflammation-

Diclfenac, Rofecoxib.

Postoperative- Ketorolac.

Gastric intolerance – Cox2 inhibitors.

Pt. with allergy to aspirin & other NSAIDs - Nimesulide.

Non-Opioid Analgesics

1. A suggested treatment algorithm (American Journal of Medicine 105, 53S-60S, 1998)

Moderate-to-severe pain

Moderate pain

Mild-to-moderate pain Acetaminophen or Ibuprofen

NSAIDs or Tramadol

Opioids or Tramadol