Pharmacology – II [PHL 322]

Non Steroidal Anti- Inflammatory

Drugs (NSAIDS)

Dr. Mohd Nazam Ansari

Terminology Analgesic: 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 Analgesics 1. 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’s Have 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: Pyrazolon

Phenylbutazone

Indomethacin

Ibuprofen

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 derived 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 acid

COX-1 COX-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 labour

connected with PGF2α inhibition

5. Asthma and anaphylactic reactions

connected with PGF2α inhibition

NSAIDs: Classifications based on chemistry Salicylic acid derivatives

Aspirin Para-aminophenol derivatives

Acetaminophen Indole and indene acetic acids

Indomethacin Pyranocarboxylic acids

Etodolac Ketorolac

Propionic acids Ibuprofen Naproxen Ketoprofen Carprofen Vedaprofen

Fenamates Meclofenamic acid Tolfenamic acid

Pyrazolones or enolic acids Phenylbutazone Dipyrone

Oxicams Piroxicam,Meloxicam

Nicotinic acid derivatives Flunixin meglumine

Hydroxamic acid derivatives Tepoxalin

Coxib-class NSAIDs Deracoxib, 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 Effects Paracetamol 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: Aspirin Has 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 effects

Analgesic 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 effects

Cardiovascular 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 effects

Renal 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 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-2

inhibitors (Coxibs)

• Celecoxib, Rofecoxib

• Etoricoxib, Valdecoxib

• Parecoxib

(2) Preferential

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

Celecoxib remains on the market and is approved for: Osteoarthritis and rheumatoid arthritis Pain including bone pain, dental pain, and

headache Ankylosing spondylitis.