Non-steroidal anti-inflammatory drugs (NSAIDs) Definition, classification, pharmacological actions, dose, indications, contraindications. Aspirin and paracetamol.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Definition, classification, pharmacological actions, dose, indications, contraindications

• NSAIDs are a group of dissimilar chemical compounds with common therapeutic effects. Common therapeutic effects are analgesic, antipyretic, and anti-inflammatory. The extent of these effects is not the same in each drug.

• Glucocorticoids are major anti-inflammatory drugs. They are chemically steroids. Drugs under NSAIDs are not chemically steroids but show anti-inflammatory effects along with analgesic and antipyretic effects. Thus these drugs are called non-steroidal anti-inflammatory drugs.

• Opioids show analgesic effects by acting on the central nervous system. NSAIDs also have an analgesic effect without producing CNS depression. Thus NSAIDs are also called non-narcotic analgesics or non-opioid analgesics.

• Non-narcotic analgesics are also called analgesic antipyretic drugs. The following are the main differences between narcotic analgesics and non-narcotic analgesics.

• Non-narcotic analgesics are effective in superficial pain of somatic origins. They are not effective in visceral pain (deep organ pain). Opioid analgesics are used for deep visceral pain.

• Non-narcotic analgesics do not cause respiratory depression at a normal dose. A high dose develops respiratory depression. Narcotic analgesics develop respiratory depression at a normal dose.

Inflammation: Inflammation is the protective/defensive response of the body to tissue injury. Inflammation naturally subsides after the body completes the healing procedure. Sometimes body fails to heal injury naturally. In this condition, the body's defense mechanism causes progressive tissue injury. This requires the administration of NSAIDs.

Classification

Conventional NSAIDs: They are nonselective COX inhibitors

• 1. Salicylates: Aspirin, Diffunisol

• 2. Arylacetic acid derivatives: Diclofenac

• 3. Indole and Indene acetic acid: Indomethacin, sulindac, etodoloc, fenamate

• 4. Arylpropionic acid derivatives: Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, naproxen, oxaprozin

• 5. Pyrazolone derivatives: Phenylbutazone, oxyphenbutazone, Azapropazon ecarprofen, metamizole

• 6. Anthraquinone acid derivatives: Mefenamic acid

• 7. Oxicam derivatives : piroxicam, tenoxicam

• 8. Pyrollo Pyrrole derivatives: ketorolac

• 9. Preferential COX-2 inhibitors: Nomsulide, meloxicam, nabumetone

Selective COX-2 Inhibitors: celecoxib, rafecoxib, valdecoxib

• Analgesic –antipyretics

• 1. Paraamino derivatives: paracetamol

• 2. Pyrazolone derivatives: propiphenazone, metamizol

• 3. Benzoxazocine derivatives: nefopam

NSAIDs Mechanism of action: cyclooxygenase (COX) enzymes convert arachidonic acid to prostaglandins. NSAIDs inhibit COX enzymes. Prostaglandin effects are pain, fever, edema, platelet aggregation, gastric acid secretion inhibition to produce epigastric distress and renal blood flow maintenance. NSAIDs do not inhibit the synthesis of prostaglandins from arachidonic acid.

Aspirin

Mechanism of action:

• Aspirin produces antipyretic and anti-inflammatory effects mainly by blocking the synthesis of prostaglandin. COX enzyme converts arachidonic acid to prostaglandins. Acetylsalicylic acid (Aspirin) competes with arachidonic acid to COX. Acetylsalicylic acid binds irreversibly with the COX enzyme to make COX inactive. Thus available arachidonic acid in cells will not be converted to prostaglandins. In this reaction, acetylsalicylic acid is deacetylated to form salicylates. Salicylates have analgesic, antipyretic, and anti-inflammatory effects. Excess of salicylates inside the body causes salicylate intoxication (Salicylicism).

• Acetylsalicylic acid + COX Acetylated COX + Salicylate

• Nerve-ending sensitivity to pain stimuli (both mechanical and chemical stimuli) decreases in the absence of prostaglandins in peripheral cells.

• Acetylsalicylic acid also blocks the synthesis of thromboxane in platelets. This inhibits platelet aggregation to produce an antithrombotic effect.

Pharmacokinetics: Most aspirin remains unionized in the stomach. But it is absorbed partly from the stomach. Most aspirin remains ionized in the small intestine but is absorbed from the upper part of the small intestine. Most aspirin is absorbed from the intestine due to its large surface area. Enzyme esterase rapidly hydrolyses acetylsalicylic acid (Aspirin) to acetic acid and salicylate. Inside the blood and liver, at the therapeutic dose of aspirin, 80% to 90% of salicylates bind with plasma proteins like albumin. Salicylates are metabolized in the endoplasmic reticulum and mitochondria of the liver by conjugation. Both salicylates and water-soluble conjugates are excreted in the urine.

Pharmacological Effect

• 1. Analgesic: Prostaglandins induce hypersensitivity to pain (hyperalgesia). Aspirin decreases the synthesis of PGE2.

• 2. Antipyretic: Fever-producing agents are released from white blood cells (WBC) during infection, malignancy, inflammation, or hypersensitivity. They stimulate the synthesis of PGE2 in some parts of the brain and anterior hypothalamus. It raises body temperature. Aspirin and all NSAIDs block the synthesis of PGE2 and reset the hypothalamus thermostat to maintain normal body temperature. This normalizes body temperature by increasing heat loss through sweating and peripheral vasodilation. Aspirin does not reduce normal body temperature to produce hypothermia.

• 3. Anti-inflammatory: Aspirin inhibits COX at the site of inflammation to reduce the formation of prostaglandins at the site of inflammation. Thus aspirin reduces inflammation caused by prostaglandins. It is not effective in inflammation caused by chemical mediators other than prostaglandins.

• Aspirin stops granulocyte adherence and prevents damage to blood vessels. This also stabilizes lysosomes to stop migration into the inflammatory sites. Due to these properties, aspirin is most effective in controlling inflammation and pain in rheumatoid arthritis.

• 4. Anti-aggregator: (Anti-aggregator effect on platelets): COX converts arachidonic acid to Prostaglandins, prostacyclin (PGE2), and thromboxane (TXA2). Thromboxane increases platelet aggregation. A low dose of aspirin inhibits thromboxane synthesis in platelets. There will decrease in platelet aggregation. Thus aspirin acts as increases bleeding time (prolongs bleeding time).

• 5. Respiratory effect: A therapeutic dose of aspirin increases metabolic rate in skeletal muscles. This utilizes glucose, consumes oxygen, and releases carbon dioxide. All of these cause an increase in the rate of respiration.

• The higher dose of aspirin directly stimulates the respiratory center in the medulla..

• 6. Acid-base balance and Electrolyte balance: Therapeutic dose develops hyperventilation by increasing blood carbon dioxide level. Hyperventilation promotes carbon dioxide washout and develops respiratory alkalosis by decreasing carbon dioxide levels in the blood. This affects the electrolyte balance of the body.

• The toxic dose of aspirin depresses the respiratory center that will retard carbon dioxide washout from blood. This leads to respiratory acidosis.

• 7. Toxic dose of aspirin causes vasomotor depression. This impairs renal function. That will lead to the accumulation of various acids like sulphuric acid, phosphoric acids, etc produced as a by-product of metabolism.

• 8. Gastrointestinal effect: Aspirin and its metabolites irritate the mucous membrane of GIT. This develops epigastric distress, nausea, and vomiting. Gastric mucosa irritation can be explained by the following mechanism.

• Unionized aspirin does not diffuse into blood circulation they remain trapped in the mucosal layer. This increases H+ concentration.

• Combine the effect of prostaglandin secretions inhibition and an increase in acidity in the mucosal layer causing mucosal cells and blood capillaries in gastric wall damage (necrosis). This irritates the gastric wall and develops epigastric distress, gastritis, peptic ulcer, and blood loss in stool daily. Vomiting of stomach content with blood (Hematoemesis) may develop occasionally.

• 9. Cardiovascular effect: A therapeutic dose of aspirin does not affect cardiac function. A higher dose increases the body's metabolic rate which increases the body's oxygen demand. Heart rate increases to supply more blood to body systems to fulfill body oxygen demand. Toxic dose depresses the respiratory center and vasomotor center. Vasomotor center depression leads to a fall in blood pressure (Hypotension).

• 10. Renal effect: Prostacycline (PGI2) maintains renal blood flow even in the presence of vasoconstrictors. Aspirin inhibits cyclooxygenase (COX) which decreases PGI2 and PGE2 levels in the kidney. This leads to a decrease in renal blood flow which causes a decrease in glomerular filtration. Water and sodium retention and a decrease in urine excretion. This develops oedema.

• 11. Hepatic effect: Aspirin is contraindicated in chronic hepatic disease. Aspirin should not be administered to children and adolescents suffering from chickenpox, influenza viral disease, and just after influenza vaccination.

• 12. Reye’s syndrome is a rare but serious condition. It causes hepatic steatosis (fatty changes in the liver) and altered mental status during recovery from viral infection. Aspirin or salicylate administration during viral infection increases the risk of Reye’s syndrome because aspirin inhibits fatty metabolism in the liver.

• 13. Gestation and Labour: Prostaglandins play a role in developing uterus contraction and labor pain. Aspirin prolongs the gestation period and labor pain by blocking the secretion of prostaglandin.

• 14. Metabolic effect: Toxic doses of aspirin develop hyperthermia. A large dose of aspirin increases the rate of glucose metabolism that generates ATP. This ATP increases body temperature. i.e. hyperthermia.

• 15. Bronchoconstriction: Aspirin and all NSAIDs inhibit COX and promote arachidonic acid conversion to leukotrienes Leukotrienes lead to bronchoconstriction in asthmatic patients and the nasal polyp.

Therapeutic Uses:

• 1. Salicylates provide mild to moderate pain relief, such as headache, myalgia, neuralgia, arthritis, and dysmenorrhea. It cannot control pain from deeper (visceral) organs. NSAIDs with opioids are used to relieve pain associated with malignancy (cancer).

• Dose: The adult oral dose is 350mg to 650mg every four hours to produce analgesic and antipyretic effects. In four to six divided doses, children's oral dose is 50 mg to 75 mg/kg/day. This dose should not exceed 3.6gm daily. Aspirin and other NSAIDs cannot counter pain induced by direct administration of prostaglandins.

• 2. Antipyretic

• 3. Anti-inflammatory agent,

• 4. Symptomatic relief from Rheumatoid arthritis. Aspirin is superior to either NSAIDs or newer NSAIDs to manage rheumatoid arthritis.

• 5. Antithrombic drug, as a prophylactic agent in unstable angina, Transient ischaemic attack.

• 6. Pre-eclampsia treatment: Preeclampsia is pregnancy-induced high blood pressure. Excess of TXA2 develops pre-eclampsia.

• 7. Anti-colon cancer: Chronic use of aspirin decreases the chance of colon cancer development.

• 8. Topical application: Methylsalicylate liniment is used externally as a skin counter-irritant. Methyl salicylate may get absorbed from the skin. It may be fatal.

Drug interaction:

• 1. Acetazolamide and ammonium chloride exaggerate aspirin toxicity.

• 2. Alcohol increases aspirin GIT toxicity and increases gastric bleeding.

• 3. Tolbutamide, chlorpropamide, methotrexate, and phenytoin are displaced from protein binding by aspirin. Thus aspirin increases the pharmacological effects of these drugs.

• 4. Antacids decrease aspirin absorption from GIT.

• 5. Aspirin inhibits the action of heparin and other oral coagulants that increase bleeding.

• 6. Aspirin inhibits the excretion of penicillins by competing with renal excretion.

• 7. Aspirin antagonises furosemide and thiazide diuretic effect. It also inhibits the action of spironolactone.

Salicylism (Salicylate intoxication or Salicylate poisoning): Ingestion of 10-gram aspirin or 5 gm methyl salicylate used as counter-irritant liniment may produce salicylate intoxication. This may be fatal in children. 15-30gm aspirin is fatal in adults. Salicylism is salicylate poisoning due to an acute or chronic overdose of salicylate-containing compounds. Ex aspirin, topical salicylates such as methyl salicylate (Oil of wintergreen), bismuth subsalicylate.

PREFERENTIAL COX2 INHIBITORS (Nimesulide)

Nimesulide: It is a sulphonamide derivative that possesses high affinity with COX-2 and low affinity with COX-1. It inhibits inflammation by several mechanisms. These are:

• 1. It inhibits prostaglandins in tissue by inhibiting mainly COX2.

• 2. It also possesses an antihistaminic effect by competitively inhibiting histamine release. Thus it also acts as an antiallergic.

• 3. It inhibits the synthesis of superoxide anions by activated neutrophils.

• 4. It directly scavenges free radicals generated from the phagocytic process.

• 5. Platelet-activating factors (PAF) are synthesized by platelets, neutrophils, monocytes, basophils, etc that increase arachidonic acid metabolism. Nimesulide reduces the generation of PAF.

• It has anti-inflammatory, antipyretic, and analgesic effects. It is used to treat painful inflammation, rheumatoid arthritis, osteoarthritis, migraine, migraine prevention, pain, fever, menstrual cramps (dysmenorrhoea), ear nose, and throat complications, dental pain, and dental surgery pain. Side effects are less than other NSAIDs and its analgesic, anti-inflammatory, and antipyretic effects are almost equal to other NSAIDs. But it produces a fatal effect on the liver. Thus it has been banned in several countries. It is advised to avoid its use and other NSAIDs should be recommended.

Meloxicam: It is similar to piroxicam. There is no clinical proof that it is better than other NSAIDs.

SELECTIVE COX2 INHIBITORS: COX-1 is considered a physiological housekeeper. It is present in blood vessels, stomach mucus walls, and kidneys. NSAIDs block COX-1enzyme to decrease prostaglandin secretion in these organs. Prostaglandins promote platelet function, and mucus function, in the stomach and promote vasodilation in the kidney increasing blood flow in the kidney. Thus NSAIDs effect inhibiting COX1 enzyme generates various side effects like an increase in bleeding time, ulceration, renal disorders, etc. Selective COX-2 inhibitors do not have these side effects. However, selective COX-2 inhibitors are not preferred due to increased cases of heart attack and stroke caused by their long-term use. Examples are Celecoxib, Rofecoxib, Valdecoxib.

PARA-AMINOPHENOL DERIVATIVES (Phenacetin and paracetamol)

• Phenacetin and paracetamol (Acetaminophen): These drugs are antipyretic and analgesic. They are antipyretic analgesics but they are not NSAIDs. Phenacetin develops serious kidney injury termed analgesic abuse nephropathy. Thus phenacetin has been banned. Paracetamol is much less toxic than phenacetin. Paracetamol does not have as many side effects as aspirin and other NSAIDs. However, paracetamol is effective in blocking prostaglandin synthesis in vascular endothelial cells, neurons, and CNS. Thus paracetamol acts as antipyretic and analgesic.

• Paracetamol has a poor anti-inflammatory effect, moderate analgesic effect, and a good antipyretic effect. It also raises the pain threshold in the CNS which contributes to its analgesic effect. It adjusts the temperature regulatory center in the hypothalamus which contributes to its antipyretic effect. Thus paracetamol is CNS acting antipyretic analgesic drug.

• Pharmacokinetics: It is rapidly and completely absorbed from GIT and uniformly distributed through the body. Peak plasma concentration is achieved in 30-60 minutes, the half-life of the drug is 2 hours and plasma protein binding is 25% to 50%. Paracetamol is metabolized in the liver by conjugation with glucuronic acid, sulphuric acid, and cysteine. Metabolites are excreted in the urine.

• Side effects: Paracetamol does not have serious side effects at the therapeutic dose level. Some rare side effects are skin rashes, minor allergic reactions minor alterations in leukocyte count. A prolonged large dose may cause renal tubular necrosis, hypoglycemia, and coma. But these are also rare.

• Therapeutic uses: Antipyretic and analgesic.It is prescribed if an anti-inflammatory effect is not required.

Paracetamol Poisoning

The therapeutic dose is safe but overdose causes hepatotoxicity that may be fatal. In adults, more than 10gm or more than 150 mg/kg of body weight causes paracetamol poisoning. Children are more susceptible to paracetamol poisoning. Paracetamol 250mg/kg body weight is associated with serious hepatic necrosis and liver failure.

• Symptoms: Symptoms of paracetamol poisoning can be divided into the following four stages.

• 1. Stage 1 (0-24 hrs): It may be asymptomatic or only GIT upset.

• 2. Stage 2 (24 hrs – 48 hrs): Nausea and vomiting. Abdominal pain, gall bladder, kidney, and a small part of the intestine, tenderness, hepatic necrosis, and renal necrosis.

• 3. Stage 3 (48hrs-96hrs): Hepatic failure, jaundice, encephalopathy, coagulopathy

• 4. Stage 4: Death due to liver failure)

• Treatment: Poisoning detected at an earlier stage requires vomiting or gastric lavage to withdraw unabsorbed paracetamol from the stomach. Activated charcoal is administered orally to block the absorption of paracetamol. This measure is practiced within 4 hours of paracetamol poisoning. N Acetylcysteine (NAC) is administered through an intravenous route in a dose of 150mg/kg body weight for 15 minutes. The same dose is repeated for the next 20 hours. NAC is not administered orally because activated charcoal in the stomach blocks its absorption. NAC is administered with 5% glucose by the I.V. route. Continue NAC administration till the patient starts to recover

  Alok Bains