Non-steroidal Anti-inflammatory drugs (NSADs)

Gafacom March 17, 2023

Non-steroidal Anti-inflammatory drugs (NSADs)

Non-steroidal Anti-inflammatory drugs (NSAIDs) are a group of medications commonly used to reduce pain, inflammation, and fever. They work by blocking the production of certain enzymes called cyclooxygenase (COX) that are involved in the body’s inflammatory response. By reducing inflammation, NSAIDs can help to relieve pain and swelling associated with conditions such as arthritis, menstrual cramps, headaches, and muscle strains.

Examples of NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, and celecoxib. These drugs are available over-the-counter (OTC) or by prescription, depending on the strength and formulation. Some NSAIDs, such as aspirin, also have blood-thinning properties and can be used to prevent heart attacks and strokes in certain individuals.

While NSAIDs are generally safe when used as directed, they can have side effects, particularly when used long-term or at high doses. These side effects can include stomach ulcers, bleeding, kidney damage, and an increased risk of heart attack or stroke. It’s important to follow the recommended dosages and speak to a healthcare provider before taking NSAIDs regularly or for an extended period of time.

Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents. Inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair. Analgesic drugs relieve pain without causing loss of consciousness. The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti inflammatory activities. 



Role of prostaglandins in pain

Prostaglandins are a group of hormone-like substances that play an important role in many physiological processes in the body, including inflammation, blood flow, and the formation of blood clots. They are produced by cells throughout the body, but are particularly abundant in the lining of the stomach, the kidneys, and the reproductive system.

Prostaglandins are synthesized from a type of fatty acid called arachidonic acid, which is released from the cell membrane when cells are activated or damaged. They act locally and affect nearby cells, rather than traveling in the bloodstream.

There are many different types of prostaglandins, each with different functions. For example, some prostaglandins cause inflammation and pain, while others promote blood clotting or help to maintain the lining of the stomach.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, work by inhibiting the activity of the enzyme cyclooxygenase (COX), which is involved in the synthesis of prostaglandins. By reducing the production of prostaglandins, NSAIDs can help to reduce inflammation, pain, and fever. However, this inhibition can also lead to unwanted side effects, such as stomach ulcers, bleeding, and kidney damage.

Synthesis of prostaglandins

There are two major pathways in the synthesis of the eicosanoids from arachidonic acid, the cyclooxygenase(enzyme) and the lipoxygenase(enzyme)pathways

Cyclooxygenase(enzyme) pathway

The cyclooxygenase (COX) pathway is the main pathway involved in the synthesis of prostaglandins. The pathway begins with the release of arachidonic acid from the cell membrane in response to cellular activation or damage. Arachidonic acid is then converted into prostaglandins through a series of enzymatic reactions.

The first step in the COX pathway is the conversion of arachidonic acid into prostaglandin H2 (PGH2) by the enzyme COX. COX exists in two forms: COX-1 and COX-2. COX-1 is expressed in many tissues and plays a role in maintaining normal physiological function, while COX-2 is induced in response to inflammation and is responsible for the production of prostaglandins that cause pain, swelling, and fever.

After PGH2 is produced, it is further converted into specific types of prostaglandins, depending on the cell type and the tissue involved. For example, prostaglandin E2 (PGE2) is produced in response to inflammation and is responsible for causing fever and pain. Prostaglandin I2 (PGI2), also known as prostacyclin, is produced by blood vessel cells and plays a role in regulating blood flow and preventing blood clots.

Lipoxygenase (LOX) pathway

It’s important to note that lipoxygenase (LOX) pathway is not directly involved in the synthesis of prostaglandins. Instead, it is a separate pathway involved in the synthesis of a group of molecules called leukotrienes. Leukotrienes are involved in the body’s inflammatory response and can contribute to conditions such as asthma and allergies.

The LOX pathway begins with the release of arachidonic acid from the cell membrane, similar to the COX pathway. Instead of converting arachidonic acid into prostaglandins, LOX enzymes convert arachidonic acid into a molecule called leukotriene A4 (LTA4). LTA4 is then converted into different types of leukotrienes depending on the cell type and the tissue involved.

LOX enzymes are divided into several types based on their specific functions and the types of leukotrienes they produce. For example, 5-lipoxygenase (5-LOX) is primarily involved in the production of leukotrienes that cause inflammation and contribute to conditions such as asthma and arthritis.

While LOX and COX pathways are separate, they are both involved in the body’s inflammatory response and can be targeted by some medications. For example, some medications, such as leukotriene receptor antagonists, can help to reduce inflammation by blocking the effects of leukotrienes. However, these medications are not typically used to treat the same conditions as NSAIDs, which target the COX pathway to reduce pain and inflammation.

Therapeutic uses of prostaglandins

Prostaglandins have a major role in modulating pain, inflammation, and fever. They also control many physiological functions, such as acid secretion and mucus production in the gastrointestinal (GI) tract, uterine contractions, and renal blood flow.

Mechanism of action: inactivate cyclo-oxygenases, enzymes required for the production of prostaglandins. 

ASA and traditional NSAIDs inhibit both COX 1 and COX 2

COX 1 is present in all tissues esp. GI, kidneys, endothelial cells and in platelets while COX 2 is Found in brain, bone, kidneys, GI tract, and the female reproductive system Overall, prostaglandins produced by COX 2 are associated with pain and inflammation. Prostaglandins important in:

  • Protection of kidneys and stomach
  • Regulate vascular tone and platelets in CV system

Acetaminophen

Equal in effectiveness to ASA in analgesic and antipyretic effects. Ethanol induces drug-metabolizing enzymes in liver. Resulting rapid metabolism of acetaminophen produces enough toxic metabolite to exceed glutathione. Need glutathione to inactivate toxic metabolites. 

Acetaminophen Poisoning

Toxicity occurs with 20g or more. Creates toxic metabolite that is inactivated by glutathione. Over Dose supply of acetaminophen cause glutathione depletion, hence toxic metabolite are produced which damages liver cells. Not to exceed 4g/day

Treatment of overdose—gastric lavage, Activated charcoal, antidote is Mucomyst (acetylcysteine). Provides cysteine, a precursor to glutathione.

List of some common Non-Steroidal Anti-inflammatory drugs

  • Aspirin (acetylsalicylic acid)
  • Ibuprofen (Advil, Motrin)
  • Naproxen (Aleve, Naprosyn)
  • Diclofenac (Voltaren, Cataflam)
  • Indomethacin (Indocin)
  • Meloxicam (Mobic)
  • Celecoxib (Celebrex)
  • Ketoprofen (Orudis)
  • Piroxicam (Feldene)
  • Nabumetone (Relafen)
  • Etodolac (Lodine)
  • Sulindac (Clinoril)
  • Mefenamic acid (Ponstel)
  • Flurbiprofen (Ansaid)
  • Oxaprozin (Daypro)

Keywords

  • non-steroidal anti-inflammatory drugs
  • list of common NSAIDs
  • mechanism of action of NSAIDs
  • side effects of NSAIDs
  • Prostaglandin synthesis
  • uses of prostaglandins
  • role of prostaglandins in pain
References
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