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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.