NSAIDS I

Introduction

  • Speaker: Dr. Jeff Harrison, Professor of Pharmacology and Therapeutics.

  • Focus of the lecture: Mechanism of action of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

  • NSAIDs primarily act by inhibiting cyclooxygenase enzymes, referred to as COX inhibitors.

Objectives of the Lecture

  • Gain a basic understanding of the pathway of prostanoid biosynthesis.

  • Understand the specific isoforms of COX involved in inflammation, pain, and fever, so we know how these enzymes affect our body during different conditions.

  • Learn about the regulatory effects of cyclooxygenases on cardiovascular, renal, and gastrointestinal systems, which means looking at how these enzymes impact our heart, kidneys, and stomach.

  • Appreciate outcomes related to COX inhibition in various tissues and cells, meaning how blocking these enzymes can change the way different parts of the body work.

  • Discuss prototype NSAIDs such as aspirin and celecoxib, including their unique features, which helps us understand why different medications work in different ways.

Mechanism of Action of NSAIDs

  • Major action: Inhibition of cyclooxygenase (COX) enzymes, which are crucial for producing certain chemicals in the body called prostanoids.

  • Conversion process:

    • Arachidonic acid (a fatty acid component of cell membranes) is converted to endoperoxide intermediates. These are temporary compounds that play a role in creating prostanoids.

    • These intermediates lead to the formation of biologically active prostanoids:

      • PGD2 (Prostaglandin D2)

      • PGE2 (Prostaglandin E2)

      • PGF2α (Prostaglandin F2 Alpha)

      • PGI2 (Prostacyclin)

      • TXA2 (Thromboxane A2)

  • Nobel Prize winners: Soon Beckstrom, Benksamilson, and John Bain (1982) for elucidating structures of these molecules and their synthesis, meaning they helped us understand how these important compounds are made and how they work.

Cyclooxygenase Enzymes (COX)

  • Cyclooxygenases (COX) are also known as Prostaglandin Endoperoxide Synthases (PGHS or PTGS), which are quite a mouthful! These enzymes are important for helping the body produce pain and inflammation mediators.

  • COX exists in two forms:

    • COX-1:

      • A constitutive enzyme, which means it’s always present in the body, found in various tissues (e.g., stomach, colon, kidney, vascular smooth muscle cells, and platelets).

      • It plays a role in generating prostanoids for physiological functions, like protecting the stomach lining and helping with normal platelet function.

    • COX-2:

      • Typically an induced enzyme, meaning it is produced in response to specific signals from the body, involved in inflammation, fever, and pain.

      • It is constitutively expressed in blood vessels, kidney, and brain, meaning it is also produced regularly in those areas but can increase when needed during injury or illness.

  • Cyclooxygenases catalyze a two-step reaction mechanism:

    • Arachidonic acid is converted to PGG2 (via COX activity).

    • PGG2 is then converted to PGH2 (via peroxidase activity).

Prostanoid Pathways

  • Arachidonic acid is generated through phospholipase A2 cleaving membrane phospholipids, which is like chopping fat molecules that are found in cell membranes to release arachidonic acid.

  • After generation, arachidonic acid can flow into:

    • Cyclooxygenase pathway (NSAID target), which is where NSAIDs can block enzyme activity to reduce pain and inflammation.

    • Lipoxygenase pathway (producing lipoxins and leukotrienes), which helps regulate immune responses.

    • Cytochrome P450 pathway (producing HEETs, epoxides), which is another way our body can process environmental toxins.

  • Cellular Sources of Prostanoids:

    • Most abundant prostanoid: PGE2, very important for inflammation and pain signaling.

    • Other prostanoids: PGI2 and thromboxane involved in platelet and vascular smooth muscle functions, which help regulate blood flow and prevent blood clots.

Physiological and Pathological Functions of Prostanoids

  • Diverse physiological roles:

    • Vasodilation (widening of blood vessels) vs. vasoconstriction (narrowing of blood vessels).

    • Promotion vs. inhibition of platelet aggregation, meaning they can help blood cells stick together or prevent them from doing so.

    • Effects on kidneys: promotion of sodium/water excretion vs. sodium retention, which helps with fluid balance in the body.

  • Leukotrienes: while not the primary focus, they are involved in inflammatory responses, which means they can aggravate conditions like asthma and allergies.

Inhibition of COX Enzymes
Effects of Inhibiting COX-1 and COX-2

  • Arachidonic acid is acted on by both COX-1 (producing thromboxane A2, which promotes platelet aggregation) and COX-2 (producing prostacyclin, which inhibits platelet aggregation).

  • NSAIDs inhibit the production of prostanoids:

    • Leading to physiological implications for both platelet aggregation and vascular function, meaning it can affect blood clotting and how blood moves within the body.

Anti-inflammatory Effects of NSAIDs

  • The inhibition of COX-2 is primarily responsible for anti-inflammatory effects, which means reducing swelling and redness in areas like sprained ankles or arthritis.

  • Inflammation involves:

    • Prostaglandins, interleukins, tumor necrosis factor alpha, chemokines, histamine, bradykinin, leukotrienes, which are all substances that can promote inflammation in the body.

  • NSAIDs reduce:

    • Vasodilation, edema (swelling), and pain associated with inflammation, helping people feel better.

  • Comparatively, larger doses of NSAIDs are needed for anti-inflammatory effects than for analgesic effects (about twice the normal dosage), meaning it might take more medicine to reduce swelling than to relieve pain.

Analgesic (Pain Relief) Effects of NSAIDs

  • NSAIDs reduce pain primarily through COX-2 inhibition, targeting the pain pathways directly.

  • Key prostanoid: PGE2 sensitizes nociceptive receptors, which means it makes pain-sensing nerves more reactive.

  • Mechanism:

    • PGE2 enhances sensitivity of nociceptive receptors to other pain mediators (e.g., TRPV ligands, bradykinin), leading to increased perception of pain.

    • Drugs considered mild analgesics compared to opioids, which are much stronger and can have serious side effects.

    • Effective for surgical pain and trauma-related pain with typical dosing yielding analgesic effects (e.g., 2 tablets of aspirin or ibuprofen).

Antipyretic (Fever-Reducing) Effects of NSAIDs

  • NSAIDs exert antipyretic effects by inhibiting COX-2 in the hypothalamus, which is the part of the brain that helps regulate body temperature.

  • Mechanism:

    • IL-1 stimulates COX-2 enzymatic activity to produce PGE2, leading to increased body temperature, making you feel feverish.

    • NSAIDs inhibit COX-2, decreasing PGE2 production and normalizing body temperature, helping return the body to a normal state.

Therapeutic Actions Summary

  • The therapeutic actions discussed thus far:

    • Anti-inflammatory effects

    • Analgesic effects

    • Antipyretic effects

  • All due to inhibition of COX-2 isoform, which is crucial for their effectiveness in treating inflammation, pain, and fever.

Effects on the Cardiovascular System
Platelet Activity and NSAIDs

  • NSAIDs affect platelet activity through COX-1 and COX-2 inhibition:

    • COX-1 produces thromboxane A2 (promotes platelet aggregation), which helps form clots when you get a cut.

    • COX-2-derived prostacyclin (PGI2) inhibits platelet aggregation, preventing excessive clotting.

  • Various NSAIDs can have non-selective effects inhibiting both COX-1 and COX-2, which means they can affect both types of COX enzymes.

    • COX-2 selective inhibitors (e.g., celecoxib) inhibit COX-2 but spare COX-1 actions, which aims to reduce inflammation without affecting normal clotting too much.

Aspirin's Unique Role

  • Aspirin (acetylsalicylic acid) irreversibly inhibits COX-1 in platelets:

    • The inhibition lasts for the lifetime of the platelet (8-11 days), making aspirin effective for long-term protection against clotting issues.

    • Effective at low doses (e.g., baby aspirin 80mg), making it safer for regular use.

    • Mechanism involves covalent modification of a serine residue at position 529 on platelet COX, which means aspirin changes the enzyme in a way that it can’t work properly anymore.

  • Aspirin's low dose action can be inhibited by other NSAIDs with COX-1 inhibitory activity (e.g., ibuprofen), meaning if taken together it may reduce aspirin’s effectiveness.

  • Aspirin use is clinically significant for preventing myocardial infarctions (heart attacks) and strokes, which are serious conditions where blood flow is blocked.

Conclusion

  • This concludes the first segment on NSAIDs, summarizing the main aspects discussed about how these drugs work.

  • Upcoming lecture to discuss additional aspects and prototype drugs in the NSAID class, indicating that there is more to learn about the different types of NSAIDs and their uses in medicine.