NSAIDs: Mechanism and Pharmacology

NSAIDs Basics

• NSAIDs, with aspirin (ASA) as the archetypal example, possesses analgesic, antipyretic and anti-inflammatory properties
• NSAIDs treat low-grade pain, bone pain (like cancer metastases), fever (from infections) and inflammation
• NSAIDs' effects depend on their varying abilities to inhibit different Cyclooxygenase (COX) enzymes

Pharmacological Mechanisms of NSAIDs

• NSAIDs work by inhibiting COX enzymes, preventing the conversion of arachidonic acid (AA) into prostaglandins (PGs) and thromboxanes (TXs)
• Aspirin inhibits COX irreversibly, while most other NSAIDs inhibit it reversibly
• Aspirin's irreversible action makes it useful in preventing cardiovascular events
• Older NSAIDs inhibit both COX-1 and COX-2 enzymes
• Newer drugs selectively target COX-2 and paracetamol has a special mechanism

Antipyretic Action of NSAIDs

• During infections bacterial endotoxins trigger macrophages to release interleukin-1 (IL-1β)
• IL-1β causes the hypothalamus to release prostaglandin E2 (PGE2) via COX-2
• Increased PGE2 raises the body's temperature set point
• The body responds by depressing temperature-sensitive neurons, causing fever
• NSAIDs reduce fever by blocking PGE2 production, resetting the body temperature
• NSAIDs does not affect normal body temperature

Analgesic Action of NSAIDs

• PGs sensitize and stimulate nociceptors
• Inflammation-related edema directly activates nociceptive nerve fibers
• PGs interact with kinins, 5-HT, and histamine
• PGs causes hyperalgesia
• NSAIDs leads to pain relief by blocking PG production
• NSAIDs are helpful for pain from inflammatory agents by inhibiting PGs-mediated vasodilation
• COX-1, COX-2 and COX-3 are inhibited in the CNS

Anti-Inflammatory Action of NSAIDs

• Prostaglandin E2 (PGE2) and Prostaglandin I2 (PGI2) are responsible for arteriole dilation, increased post-capillary venule permeability, and inflammatory mediator influx
• NSAIDs reduce inflammation by inhibiting the formation of PGE2 and PGI2, which reduces redness and swelling
• NSAIDs provide relief from symptoms only
• NSAIDs do not address the underlying cause of the cause
• COX-2 generated PGs effects develops gradually

Cardiovascular Effects of NSAIDs

• Thromboxane A2 (TXA2) plays a major role in vascular hemostasis
• TXA2 causes platelet aggregation and vasoconstriction
• NSAIDs decrease TXA2 levels by inhibiting the COX-1, which increases bleeding time
• This effect can be problematic during surgery or childbirth
• Aspirin can be used to prevent cardiovascular issues where platelet aggregation is high

Thrombo-resistance

• Thrombo-resistance is mediated by endothelial factors that prevent platelet aggregation
• Prostacyclin I2/E2 and Nitric Oxide prevent platelet aggregation
• Vessel damage causes collagen and von Willebrand factor(vWF) exposure
• Platelets then aggregate and adhere, increasing thromboxane 2(TXA2) and causing blood loss

Aspirin Benefit To Cardiovascular Disorders

• COX-2 is inducible
• COX-1 is constitutively active
• Endothelial cells create Prostacyclin (PGI2)
• Platelets create Prostaglandin(TXA2)
• Aspirin can beneficial in cardiovascular disorders when in low doses
• Benefits from PGI2 and PGE2 are not lost

Skeletal Effects of NSAIDs

• PGs with inflammatory effects (acute) worsen the swelling and pain associated with arthritis
• These inflammatory effects include arteriolar dilation, heightened microvascular permeability and increased sensitivity to pain
• NSAIDs reduce symptoms by by preventing the cause

Effects of NSAIDs on the GI Tract

• Prostaglandins(PGs), PGE2, and PGI2 help protect gastric mucosa by stimulating mucus and reducing gastric acid production
• NSAIDs reduce cytoprotective mechanisms, raising risk of bleeding and ulcers
• Gastric side effects are a common adverse reactions
• Because Cyclooxygenase (COX-1) is in gut, COX-2 inhibitors are gastric-friendly

Effects of Aspirin on Gastric Protection

• Gastrin stimulates histamine secretion
• Acetylcholine stimulates histamine secretion contributing to an acid secretion
• Prostaglandin(PGE2 stimulates mucus secreting cells to release mucus and HCO3
• Aspirin then inhibits the synthesis of vasodilation, causing heartburn and ulcers

Aspirin Effects on the GI tract

• NSAIDs are acidic
• Aspirin can cause a reduction mucus secretion
• Aspirin can cause a reduction of HCO3-
• Aspirin can cause an increase acid secretion
• Aspirin can cause an increase Leukotriene production
• Aspirin can cause an increase blood loss
• Aspirin can interfere with tissue healing by inhibiting COX-2
• Aspirin can can cause Nausea, dyspepsia through COX-1 inhibition

COX-2 Selective Agents and Cardiovascular Accidents

• Celecoxib, etoricoxib, rofecoxib, and valdecoxib are some examples
• Etoricoxib is the most selective COX-2 inhibitor
• These agents do not affect platelet thromboxane A2(TXA2), but lower prostaglandin (PGI2) levels in blood vessels
• Rofecoxib has been withdrawn
• RA/osteoarthritis should be treated with use meloxicam or etodolac
• COX-2 inhibitors and NSAIDs cause ulcers
• Diclofenac is selective for COX-2, yet limits COX-1 in the GI Tract resulting in ulcers
• Diclofenac is a poor analgesic because it inhibits COX-3 in the brain and spinal cord

Effects of NSAIDs on the CNS

• NSAIDs can reduce pyrexia
• In overdose, NSAIDs case paradoxical hyperpyrexia, stupor, and coma as well as increased metabolism and metabolic acid production
• Reye's syndrome is a risk for children taking NSAIDs when they have Influenza or Chickenpox
• Somnolence, confusion and fulminant hepatitis can be caused by NSAIDs

Reye's Syndrome

• You should avoid aspirin in children with influenza or chickenpox
• Instead, use acetaminophen
• If urine alkalinisation you can increase the excreation of aspirin

Effects of NSAIDs on the Genital Tract

• NSAIDs can treat pain and muscle spasms during menstruation
• Mefenamic acid helps reduce blood loss
• NSAIDs help in people with dysmenorrhea
• NSAIDs delay uterine contractions in childbirth
• NSAIDs increase postpartum blood loss because it prevents Prostaglandin (TXA2)

Respiratory Concerns With Aspirin

• Although Prostaglandin (PGD2, PGF2a) have constrictor and dilator effects on airway smooth muscle, NSAIDs does not effect normal airway tone
• NSAIDs should be avoided in asthmatics
• 20% of asthma patients wheeze from taking aspirin or NSAIDs because of hypersensitivity
• Aspirin stimulates respiration
• Aspirin stimulates the respiratory center and uncouples oxidative phosphorylation
• This causes respiratory alkalosis, caused by hyperventilation and CO2 loss

Aspirin Effect on Kidney and Blood Pressure

• Vasodilator Prostaglandins (E2/I2) help regulate renal blood flow
• NSAIDs can reduce renal blood flow, potentially causing chronic injury
• NSAIDs reduces the effects of some antihypertensive drugs
• NSAIDs prevent sodium excretion, increasing volume
• Blood pressure rises about 3/2 mmHg
• Small doses of aspirin don't affect it but regular use should be avoided

Additional Uses for NSAIDs

• NSAIDs decrease colonic polyps, and prevent colon cancer
• NSAIDs are being trialed for reduction in hepatic steatosis and hepatocellular
• NSAIDs may decrease risk of Alzeheimer's
• NSAIDs relieve post-operative pain
• NSAIDs ease renal colica
• Using NSAIDs and warfarin increases GI bleeding

Treatment for Ulcerative Colitis

• Ulcerative Colitis inflames the bowel
• Reduce symptoms to induce remission and maintain remission
• Use aminosalicylates as first-line treatment
• Aminosalicylates reduces inflammation
• Use Short-term treatment of flare-ups
• Use Long term to maintain remission

Sulfasalazine Action

• The body breaks down sulfasalazine into 5-aminosalicylic acid (mesalazine) and sulfapyridine
• Then it reduces synthesis of eicosanoids by blocking cyclooxygenase and lipoxygenase
• Ulcerative colitis has increase presence of cyclooxygenase and lipoxygenase

Side effects of sulfasalazine

• Indigestion, feeling or being sick, abdominal pain, or diarrhoea
• You can be dizzy, get headaches, difficulty sleeping, or tinnitus,
• Coughing may occur
• You might get itchy rash or sore mouth

Anti-Inflammatory Agents for Gout

• Gout results from uric acid accumulation in joints
• Build up causes inflammation
• Soluble uric acid can prevent issues with vessels
• You will likely pass in urine or faeces
• In people with hyperuricemia, tiny grit crystals irritates joints, causing inflammation and pain
• You can treat with naproxen, diclofenac and indomethacin

Mode of action of Allopurinol

• Allopurinol prevents xanthine oxidase and rasburicase

Mode of Action of Naproxen

• Naproxen lowers COX1/COX2 helping target inflammation mediators
• It is an analgesic, anti-inflammatory, and antipyretic
• naproxen inhibits platelet aggregation through thromboxane A2(TXA2)

Side Effects of Naproxen

• Indigestion, nausea, and blurred vision
• Diarrhoea, liver issues, water retention, and ringing in the ears
• There is a relatively neutral risk for Cardiovascular events