Biochemistry of Arachidonic Acid

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair the renin-angiotensin-aldosterone system (RAAS) pathway, leading to decreased potassium excretion and increased potassium retention, resulting in hyperkalemia.

Acetylsalicylic acid, also known as aspirin, is an irreversible COX inhibitor. Its acetyl group forms a stable bond with COX enzymes, preventing their activity for the life of the platelet.

Aspirin's affinity for COX-1 is much higher than for COX-2. This means it preferentially inhibits COX-1, which plays a role in platelet aggregation and gastric mucosal protection.

High doses of aspirin can lead to an increased anion gap metabolic acidosis (AGMA), which causes the respiratory system to compensate by increasing breathing rate to expel CO2. This leads to a decrease in blood CO2 levels, increasing blood pH and causing respiratory alkalosis.

Aspirin and ibuprofen should not be used concurrently due to their competition for COX-1 binding sites. This can lead to increased risk of gastrointestinal bleeding and other adverse effects.

The conversion of arachidonic acid into leukotrienes, a class of inflammatory mediators. This process involves a series of enzymatic steps beginning with the action of 5-lipoxygenase (5-LOX).

An unstable intermediate formed during the synthesis of leukotrienes. It is converted into either LTA4 or 5-HETE.

A highly unstable intermediate formed during leukotriene synthesis. It can be further converted into LTB4 or LTC4.

A potent chemoattractant for neutrophils, promoting their migration to sites of inflammation.

A group of leukotrienes that contain cysteine. They are potent bronchoconstrictors and play a central role in allergic reactions.

A decrease in the production of prostaglandin E1 (PGE1), which normally protects the stomach lining, leading to increased gastric acid secretion and damage.

NSAID's can inhibit COX enzymes, including COX-1, which is involved in the production of prostacyclin (PGI2). This inhibition can lead to vasoconstriction of renal arterioles, decreasing glomerular filtration rate (GFR).

A class of medications that inhibit cyclooxygenase (COX) enzymes, leading to reduced production of prostaglandins. They are widely used to treat pain, fever, and inflammation.

5, 8, 11, 14 -- eicosatetraenoic acid

• 5, 8, 11, 14 correspond to the location of double bonds

• Eicosa = 20 carbons

The plasma membrane (from the lipid portions)

Vascular Injury

• Inflammation (acute or chronic)

• Norepinephrine

• Infection

1. Physiologic stimuli (above) leads to PLA2 (phospholipase A2) activation; keep in mind that calcium is also required for PLA2 activation!

2. PLA2 cleaves arachidonic acid from the membrane phospholipids.

1. COX (cyclooxygenase) pathway

2. LOX (lipoxygenase) pathway

1. Arachidonic acid interacts with COX, forming an unstable intermediate known as PGG2 (prostaglandin G2). This occurs via a bis-oxygenation reaction!

2. PGG2 interacts with COX forms PGH2!

3. PGH2 is more stable.

COX-1 "housekeeping" COX; constitutively active (always active); involved with protective functionalities

• PGE1 gastric protection

  • Increased bicarbonate in the intraluminal environment of the stomach

  • Increased mucus production

• PGI2 (prostacyclin) vasodilation, mild anti-coagulatory functionality

• TXA2 increased platelet aggregation; increased intracellular calcium concentration; vasoconstriction CLOTTING, COAGULATION

Aspirin (acetylsalicylic acid)

Etodolac is a NSAID that selectively inhibits COX-2. Due to its unique chemical structure, it effectively penetrates synovial joints, making it ideal for treating joint pain and inflammation.

Indomethacin is a highly effective NSAID that primarily inhibits COX-1. Its strong COX-1 inhibition has been linked to the closure of the patent ductus arteriosus (PDA) in newborns.

Nabumetone is similar to naproxen in its action. It's converted into its active form, 6-methoxy-2-naphthylacetic acid (6-MNA), in the liver. It inhibits both COX-1 and COX-2 enzymes equally.

When diclofenac is taken orally, it undergoes significant first-pass metabolism in the liver. This means that a large portion of the drug is broken down before it reaches its target, leading to a lower bioavailability (only 50%). This also increases the risk of liver damage.

Ibuprofen is a NSAID that preferentially inhibits COX-1 over COX-2. It has a short half-life, making it suitable for treating acute pain and allowing for frequent dosing.

Naproxen effectively inhibits both COX-1 and COX-2 enzymes. It has a longer half-life than ibuprofen, making it more suitable for managing chronic pain conditions.

Meloxicam is a COX-2 selective NSAID. It has a high risk of causing Steven-Johnson Syndrome (SJS) when used concurrently with certain medications like carbamazepine or lamotrigine.

Celecoxib is a highly selective COX-2 inhibitor. It's a good choice for managing long-term arthritic pain, musculoskeletal pain, and chronic pain conditions. It has a low risk of gastrointestinal side effects. It's recommended to avoid combining celecoxib with other NSAIDs.