Pharmacology – II [PHL 322]

Non Steroidal Non Steroidal Anti- Inflammatory Anti- Inflammatory

Drugs (NSAIDS)Drugs (NSAIDS)

Dr. Mohd Nazam Ansari

TerminologyAnalgesic: A drug given to reduce pain without

resulting in loss of consciousness.

Antipyretic: A drug given to reduce or stop fever.

Inflammation: A basic way in which the body reacts to infection, irritation or other injury, the key feature being redness, warmth, swelling and pain.

NSAID’s: Non-Steroidal Anti-inflammatory Drugs.

Narcotic: is an addictive drug that reduces pain, dulls the senses, alters mood and behavior, and usually induces sleep or stupor.

Narcotic Analgesics1. Opiates: are the alkaloids found in opium, a

white liquid extract of unripe seeds of the poppy plant (morphine and codeine).

2. Opioids: are derivatives of opiates, they bind to opioid receptors in the central nervous system or gastrointestinal tract.

1. Endogenous opioid peptides produced in the body (endorphins, dynorphins, enkephalins)

2. Semi-synthetic opioids (heroin, oxycodone, hydrocodone)

3. Fully synthetic opioids (Demerol, methadone, fentanyl, tramadol)

NSAID’sHave antipyretic, analgesic and anti-

inflammatory activities.Not as effective as narcotic analgesics.Unlike narcotics, the site of action of NSAID’s

is peripheral tissues.Examples include:

PyrazolonPhenylbutazone IndomethacinIbuprofen

Inflammation is a defense reaction caused by tissue damage or injury

Characterized by:

1. Redness: vasodilation of capillaries to increase blood flow

2. Heat: vasodilation

3. Pain: Hyperalgesia, sensitization of nociceptors

4. Swelling: Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream)

5. Loss of function

• Inflammatory cell transmigration through endothelium and accumulation at the site of injury

Prostaglandins (PGs) are Prostaglandins (PGs) are derived from arachidonic acidderived from arachidonic acid

Cell Membrane (phospholipids) phospholipase A2

Arachidonic acid

cyclooxygenase aspirin, indomethacin

(COX1 & COX2)

Cyclic endoperoxides (PGG2, PGH2)

prostacyclin prostaglandin thromboxane synthetase synthetase synthetase

prostacyclin PGE2 PGF2 Thromboxane A2

PDX, PGI2 (vasodilator, (erythma (vasodilator

(vasoconstriction antiaggregating) edema uterus contractor) platelet

aggregation) pain, fever)

Lipoxygenase (LOX)Leukotrienes

How do they work? - NSAID v COX2

Arachidonic acidArachidonic acid

COX-1COX-1 COX-2COX-2

thromboxane / prostaglandins prostaglandins

NSAIDs

Primarily support platelet function

Primarily protect GI mucosa

Maintenance Induced

Primarily mediate inflammation, pain & fever

Effects of COX Inhibition

COX-1

Gastric ulcers

Bleeding

Acute renal failure

COX-2

Reduce inflammation

Reduce pain

Reduce fever

Beneficial actions of NSAIDs due to prostanoid synthesis inhibition

1. Analgesia: prevention of pain

2. Antipyretic: connected with influence of thermoregulatory centre in the hypothalamus

3. Anti-inflammatory action: mainly antiexudative effect

4. Antithrombotic action: in very low daily doses

5. Closure of ductus arteriosus

Shared toxicities of NSAIDs due to prostanoid synthesis inhibition

1. Gastric mucosal damage: connected with PGE inhibition

2. Bleeding: inhibition of platelet function (TxA2 synthesis)

3. Limitation of renal blood flow Na+ and water retention

4. Delay / prolongation of labourconnected with PGF2α inhibition

5. Asthma and anaphylactic reactionsconnected with PGF2α inhibition

NSAIDs: NSAIDs: Classifications Classifications based on chemistrybased on chemistry

Salicylic acid derivativesAspirin

Para-aminophenol derivativesAcetaminophen

Indole and indene acetic acids Indomethacin

Pyranocarboxylic acidsEtodolacKetorolac

Propionic acids IbuprofenNaproxenKetoprofenCarprofenVedaprofen

FenamatesMeclofenamic acidTolfenamic acid

Pyrazolones or enolic acidsPhenylbutazoneDipyrone

OxicamsPiroxicam,Meloxicam

Nicotinic acid derivativesFlunixin meglumine

Hydroxamic acid derivativesTepoxalin

Coxib-class NSAIDsDeracoxib, Firocoxib

Acetaminophen: Paracetamol

Acetaminophen (Paracetamol) is the most commonly used over-the-counter (OTC), non-narcotic analgesic.

Used as an analgesic and antipyretic.

No clinically significant anti-inflammatory effect.

Paracetamol is found in more than 600 over-the-counter drugs.

It can be found in combination with other active ingredients in many cold, sinus, and cough medications

Rapidly and completely absorbed from the GI tract.

Drug Interactions / Adverse EffectsDrug Interactions / Adverse EffectsParacetamol is remarkably free of drug interactions

at its usual therapeutic doses.

It exerts little or no pharmacologic effect on the cardiovascular, respiratory, or gastrointestinal systems, on acid-base regulation, or on platelet function.

With large doses (>4g/day), an intermediate metabolite is produced that is thought to be hepatotoxic and possibly nephrotoxic.

Alcohol induces drug-metabolizing enzymes in liver, resulting rapid metabolism of acetaminophen produces and accumulation of toxic metabolites.

The Salicylates: AspirinHas antipyretic, analgesic and anti-inflamatory activities.

It is useful as analgesics for certain categories of pain, such as headache and arthritis.

It remains the standard, first-line drug in the therapy of rheumatoid arthritis, and can provide relief of symptoms in acute rheumatic fever.

Some clinicians recommend small daily doses of aspirin for stroke or myocardial infarction because of its antiplatelet activity.

Pharmacologic effectsAnalgesic effects: Aspirin is as effective as

Acetaminophen for low- to moderate-intensity pain treatment

Antipyretic action: is rapidly effective in febrile patients, yet has little effect on normal body temperature.

Anti-inflammatory effects: the primary clinical application is in the treatment of musculoskeletal disorders, such as rheumatoid arthritis

Respiratory effects: high doses result in medullary stimulation, leading to hyperventilation and respiratory alkalosis

Pharmacologic effectsCardiovascular effects: high doses may cause

peripheral vasodilation by exerting a direct effect on smooth muscle and Toxic doses depress circulation.

Hepatic effects: aspirin can cause dose-dependent hepatic damage.

Hematologic effects: It can inhibits platelet aggregation and reduce plasma prothrombin levels.

Gastrointestinal effects: It can cause nausea and vomiting by irritating the gastric mucosal lining. It may also cause a dose-related gastric ulceration, bleeding.

Pharmacologic effectsRenal effects: It can result in salt and water

retention because of decreasing renal blood flow.

Metabolic effects: It can produce hyperglycemia and glycosuria in large doses.

Endocrine effects: In very large doses, it can stimulate steroid secretion

Uses of Aspirin• As analgesic (300 to 600 mg during 6 to 8 h) for headache,

backache, pulled muscle, toothache, neuralgias.

• As antipyretic in fever of any origin in the same doses as for analglesia. However, paracetamol and metamizole are safer, and generally preferred.

• Acute rheumatic fever. Aspirin is the drug of choice. Antirheumatic doses are 75 to 100 mg/kg/day.

• Rheumatoid arthritis. 3-5 g/day after meal is effective in most cases. Since large doses of Aspirin are poorly tolerated for a long time, the new NSAIDs (diclofenac, ibuprofen, etc.) in depot form are preferred.

• Salicylic acid is used topically to treat: plantar warts , fungal infections, corns

Aspirin Toxicity Aspirin Toxicity In adults, salicylism (tinnitus, hearing loss,

vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning.

In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

Drugs Result

Diuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effect

ACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleeding

Sulfonylurea Increase hypoglycemic risk

Cyclosporine Increase nephrotoxicity

Alcohol Increase of GI bleeding

Drug interactions with NSAIDs

COX-2 inhibitors (1) Selective COX-2inhibitors (Coxibs)• Celecoxib, Rofecoxib• Etoricoxib, Valdecoxib• Parecoxib (2) PreferentialCOX-2 inhibitors• Meloxicam• Nimesulide• Nabumetone

•Coxibs are selective COX-2 inhibitors. •They exert Anti-inflammatory, analgesic, and antipyretic action with low ulcerogenic potential.

•Coxibs can cause infertility. •The ulcerogenic potential of preferential COX-2 inhibitors (Meloxicam, and Nimesulide) is significant.

•Celecoxib is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs.

•Probably because it is a sulfonamide, celecoxib may cause rashes.

• It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin – would be expected of a drug metabolized via CYP 2C9.

Rofecoxib and valdecoxib Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke

CelecoxibCelecoxib remains on the market and is approved for:

Osteoarthritis and rheumatoid arthritisPain including bone pain, dental pain, and

headache Ankylosing spondylitis.