QURATULAIN MUGHALBATCH IV

DOCTOR OF PHYSICAL THERAPYISRA UNIVERSITY

NONSTEROIDAL ANTI-INFLAMMATORY DRUG

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NSAIDs

These are non-opioid analgesia.

In addition they have anti-inflammatory, antipyretic and uricosuric properties-without addiction liability.

NSAIDs inhibit the prostaglandins(PG) synthesis by inhibiting the enzyme cyclo-oxygenase(COX).

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CLASSIFICATION

NSAIDs can be classified based on their mechanism of action.

A.Nonselective cox-1 inhibitorsB.Selective cox-2 inhibitors

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MECHANISM OF ACTION

NSAIDs inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes.

COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2)

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A. Nonselective cox inhibitors

1.Salicylic acid derivatives2. Para-aminophenol derivatives3.Pyrazolone derivatives4.Indole acetic acid derivatives5.Arylacetic acid derivatives6.Propionic acid derivatives7.Anthranilic acids (fenamates)8.Oxicams9.Alkanones

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1.SALICYLIC ACID DERIVATIVES

Aspirin, sodium salicylate, diflunisal.

Salicytes are salts of salicylic acid.e.g. methyl salicylate, sodium

salicylate, acetyl salicylate acid (aspirin).

Aspirin is taken as the prototype.

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PHARMACOLOGICAL ACTIONS

1. ANALGESIA: Good analgesic and relieves pain of

inflammatory origin without euphoric and hypnosis.

Pain originating from the integumental structures such as muscles, bones, joints, and pain in connective tissues is relieved.

But in vague visceral pain, aspirin is relatively ineffective.

No development of tolerance and dependence.

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2.ANTIPYRETIC ACTION10

In fever, salicylates bring down the temperature to normal level.

But, in normal individuals, there is no change in temperature.

Inhibits the PG synthesis in hypothalamus and reset the thermostat at the normal level.

Enhanced sweating and cutaneous vasodilation promote heat loss and assist in ant.ipyretic action

3.ANTI-INFLAMMATORY ACTION11

At higher doses of 4-6gm/day ,aspirin acts as anti-inflammatory agent.

Sign of inflammation like tenderness, swelling, erythema and pain are all reduced or suppressed.

But the progression of disease in RA and RF or OA is not affected.

PG inhibition which cause inflammation, erythema and pain.

4.RESPIRATION12

In therapeutic dose of 4-6 g/day salicylates increase consumption of oxygen by skeletal muscles.

The co2 production increase, which stimulates the respiratory center.

Also stimulates the medullary respiratory center.

Both these action cause the respiratory depth and rate increase.

These effects are dose dependent.

5.ACID-BASE AND ELECTROLYTE BALANCE

In respiratory alkalosis, pH becomes alkaline.This is compensated by increased excretion of

HCO3 in urine.With respiratory depression the pH decreases

and there is acidosis.Toxic doses also depress the vasomotor center

and cause the renal dysfunction resulting in accumulation of strong acids of metabolic origin like lactic, pyruvic and acetoacetic acids.

With high dose dehydration occurs.

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6.METABOLIC EFFECTS

Salicylates enhance the cellular metabolism.More O2 is used and more CO2 is produced

specially in skeletal muscles-leading to increased heat production.

Glucose utilization is increased leading to mild hypoglycemia.

In toxic dose, hyperpyrexia, protein catabolism, negative nitrogen balance and hyperglycemia due to central sympathetic stimulation which adrenaline levels.

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7.GIT

Aspirin is gastric irritant.Irritation of gastric mucosa leads to epigastric

distress, nausea and vomiting.In higher dose gastric erosion, ulceration and GI

bleeding can occur.MECHANISM: Salicylates increase gastric acid

secretion and suppress the protective effect of prostaglandins by inhibiting their synthesis (we know that PGs increase mucous production in the stomach and protect from ulceration).

It platelet aggregation which the tendency to bleed.

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8.CVS

In therapeutic doses no significant CVS effects are seen.

In toxic doses it depress the VMC and thus depress the circulation.

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9.IMMUNOLOGICAL EFFECTS

In higher doses, salicylates suppress several antigen-antibody reactions.

It inhibits antibody production. Ag-Ab aggregation and antigen induced release of histamine.

These effects might also help in rheumatic fever.

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10.URIC ACID EXCRETION

Uric acid is excreted by secretion from distal tubules.

In a dose of 1-2g/day, aspirin increase plasma urate level b/c it inhibit urate secretion by the distal tubules.

Large dose of >5g/day increase the urate excretion b/c it inhibit the reabsorption of urate by the proximal tubules causing uricosuria.

But, its uricosuria effect can’t be used for treatment of gout b/c high doses are required and such doses result in many adverse effects.

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11.BLOOD

Even in small doses aspirin inhibits TXA2

synthesis by platelets.It therefore interferes with platelet

aggregation and prolongs the bleeding time.Even a single dose can irreversibly inhibit

TXA2 synthesis in the platelets.b/c platelets have no nuclei, they can’t

synthesize cyclooxygenase and fresh platelets have to be formed to restore TXA2 activity.

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12.LOCAL EFFECTS

Salicylic acid when applied locally is a keratolytic.

It also has a mild antiseptic and fungistatic properties.

Salicylic acid is also a irritant for the broken skin.

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PHARMACOKINETICS

Salicylates are absorb from the stomach and upper small intestine.

But aspirin is such as poorly soluble, hence not well-absorbed.

When administered as microfine particles, absorption increases.

Thus the particles size, pH of GIT, solubility of preparation and presence of food in the stomach influence the absorption.

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CONTINUE..

Salicylic acid and methylsalicylates are absorbed from the intact skin.

They are extensively bound to plasma proteins.

Aspirin is broken down in liver, plasma and other tissues to release salicylic acid which is the active form.

Plasma t1/2 of aspirin is 3-5hour.Salicylates are excreted in urine.

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ADVERSE EFFECTS

Nausea, epigastric distress, vomiting, erosive gastritis, peptic ulcer, increased occult blood loss in stools are common.

Allergic reactions are manifested as rashes, urticaria, angio-edema, and asthma.

NephrotoxicityHepatotoxicityIn pregnancy it delays the onset of labor due

to inhibition of PG synthesis.

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PRECAUTIONS AND CONTRAINDICATION

Peptic ulcerLiver diseasesBleeding tendenciesPregnancyStop salicylates one week before surgery

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USES

FeverAnalgesicInflammationOsteoarthritisPostmyocardial infraction

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DRUG INTERACTION

Salicylates compete for protein binding sites and displace other drug resulting in toxicity with:

warfarinNaproxenphenytoin andsulfonylureas.

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2.PARA-AMINOPHENOL DERIVATIVES

Paracetamol or acetaminophenACTION:AnalgesicAntipyreticWeak anti-inflammatory

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PHARMACOKINETICS

ABSORPTION: orally, 30% protein boundMETABOLISM: by hepatic microsomal

enzymes (glucuronide and glutathione conjugation)

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MECHANISM

A small portion of paracetamol is metabolized to a toxic compound-N-acetyl-benzoquinone-imine

Which destroy generally by conjugation with glutathione

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B.SELECTIVE COX-2 INHIBITORS

CELECOXIB AND ROFECOXIB:Both diaryl subsituted compounds are highly

selective COX-2 inhibitors.They have good anti-inflammatory, analgesic

properties but don’t affect platelet aggregation.

Both tolerated b/c of milder gastric irritation.Both cause hypertension and edema

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USES

Acute painful condition like:Postoperative pain, dysmenorrhea and dental

painOsteoarthritis Rheumatoid arthritis

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