NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic properties. Their therapeutic actions are thought to stem primarily from their ability to block the formation of certain prostaglandins through inhibition of the cyclooxygenase (COX) enzymes.

COX-1 catalyzes the production of several cytoprotective prostaglandins that coat the stomach lining with mucus and aid platelet aggregation, among other functions.

COX-2 catalyzes the conversion of arachidonic acid into the inflammatory prostaglandins that are involved in three key biological functions: sensitizing skin pain receptors, elevating body temperature through the hypothalamus, and recruiting inflammatory cells toward injured body parts

Prostaglandins are made of unsatured fatty acid derivatives containing 20 carbons that include a cyclic ring structure. These compounds are referred to as eicosanoids where "eicosa" refers to the 20 carbons atoms.

There are four families of eicosanoids- prostaglandins, protacyclins, thromboxanes and leukotrienes.

Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inflammatory drugs, the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers.  

Arachinoid acid, a 20 carbon fatty acid, is the primary precursor of the prostaglandins.It is present as a component of the phospholipids of cell membranes. It is released from tissue phospholipids by the action of phospholipase A2 and other acyl hydrolases via a process controlled by hormones and other stimuli. Two major pathways exist by which eicosanoids are synthetized from arachidonic acid: 1. cyclooxygenase pathway, 2. lipoxygenase pathway.

Arachidonic acid is freed from a phospolipid molecule by the enzyme phospholipase A2, which cleaves off the fatty acid, but can also be generated from DAG by Diacylglycerol lipase.

Arachidonic acid is a precursor in the production of eicosanoids. The enzymes cyclooxygenase and peroxidase lead to Prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes.

The production of these derivatives and their action in the body are collectively known as the arachidonic acid cascade.

Prostaglandins are produced in minute quantities by virtually all tissues and generally act locally on the tissues in which they are synthesized (that’s why they are called autacoids). They are rapidly metabolized to inactive products at their site of action. Therefore, PGs do not circulate in blood in significant quantities and are difficult to detect in blood.

Arachidonic acid has a short half-life and can be metabolized by two major routes, the cyclo-oxygenase and lipoxygenase pathways. The cyclo-oxygenase pathway produces prostaglandins, prostacyclin, and thromboxanes; the lipoxygenase pathway produces in one branch leukotrienes and in the second branch lipoxins.

N-acetylcysteine, perhaps more recognizable by one of its trade names, Mucomyst, is a mucolytic and antidote to acetaminophen overdose.

It is indicated for management of excessive mucous production, prevention of contrast induced nephropathy, and treatment of acetaminophen overdose.

The textbook focused on its use in acetaminophen overdoses.  When acetaminophen is taken in excess, glutathione stores are depleted and excess N-acetylbenzoiminoquinone is free to react with sulfhydryl groups of hepatic proteins, leading to hepatic necrosis. N-acetylcysteine contains a sulfhydryl group that will directly bind to the excess N-acetylbenzoiminoquinone, protecting the liver from potential necrosis.

Note that mucus is a noun and mucous is an adjective. Mucus is produced by mucous glands.

Prostaglandins, are like hormones in that they act as chemical messengers, but do not move to other sites, but work right within the cells where they are synthesized. They are mediators and have a variety of strong physiological effects such as regulating the contraction and relaxation of smooth muscle tissue.
Prostaglandins are mediated by their binding to a variety of distinct cell membrane receptors.

• cause constriction or dilation in vascular smooth muscle cells
• cause aggregation or disaggregation of platelets
• sensitize spinal neurons to pain
• decrease intraocular pressure
• regulate inflammatory mediation
• regulate calcium movement
• control hormone regulation
• control cell growth
• acts on thermoregulatory center of hypothalamus to produce fever
• acts on mesangial cells in the glomerulus of the kidney to increase Glomerular filtration rate

Give 4 physiological effects of prostaglandins:

1. Activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result.

2. Blood clots form when a blood vessel is damaged. A prostanoid called thromboxane stimulates constriction and clotting of platelets. Conversely, PGI2 (prostacyclin), is produced to have the opposite effect on the walls of blood vessels where clots should not be forming.

3. Certain prostaglandins are involved with the induction of labor and other reproductive processes. PGE2 causes uterine contractions and has been used to induce labor. (PGFalpha also does this)

4. Prostaglandins are involved in several other organs such as the gastrointestinal tract (inhibit acid synthesis and increase secretion of protective mucus), increase blood flow in kidneys, and leukotrienes promote constriction of bronchi associated with asthma.

In marginally functioning kidneys and hypovolemia, prostaglandins derived from renal cortical COX-2 maintain renal blood flow and GFR through their local vasodilating effects. These prostanglandins also modulate systemic blood pressure through regulation of sodium and water excretion.

NSAIDs inhibits cyclooxygenase and as a cyclooxygenase inhibitor, it prevents the synthesis of certain prostaglandins. The major prostanoids synthesized in the kidney include PGI2 (prostacyclin), PGE2, thromboxane A2 (TXA2), and PGF2-alpha.

These prostaglandins are produced to preserve renal function when pathologic states supervene and compromise physiologic kidney processes such as:

 
Glomerular filtration rate (GFR) is preserved through the antagonism of arteriolar vasoconstriction.Renal prostaglandins also have an important role in modulating salt and water homeostasis. Ultimately, intravascular volume status is controlled, and hypotension and dehydration--as well as hypertension and edema formation--are avoided.

Patients with high-renin states (such as CHF, volume depletion, and cirrhosis) and chronic renal insufficiency rely on renal prostaglandin synthesis to ensure sufficient renal blood flow and to maintain an adequate GFR. In the absence of these prostaglandin effects, unopposed vasoconstriction leads to a decrease in renal blood flow and a decline in GFR.

This is why you should not give drugs like ketorolac (toradol) to these patients.

Thus, NSAID therapy in patients with prostaglandin-dependent disease states often precipitates renal ischemia and acute renal failure. Fortunately, discontinuation of the NSAID leads to reversal of renal failure within 2 to 5 days. In some cases, short-term dialysis may be required for severe uremia or extreme metabolic perturbations.

Edema formation and volume overload may also complicate NSAID therapy. In elderly patients with underlying heart disease, NSAID use can double the risk of CHF.

Diabetic resistance can develop, especially in patients with underlying salt-retentive states, such as CHF and cirrhosis. 

Note: loop diuretics, like furosemide, produce some of their effects by stimulating COX activity. This is one reason diuretic resistance may occur during NSAID therapy.

Aspirin, ethanol and phenytoin are metabolized by zero-order kinetics.

With zero-order kinetics, the metabolizing enzymes are operating at full capacity. They can not metabolize more drug. So for instance, if you increase or decrease liver blood flow then the same amount of drug is being metabolized. Zero-order drugs have erratic half-lifes and are dose dependent. Zero-order processes have units of mg/time.

With first-order processes, the enzymes can metabolize all the drug they encounter. So if you double liver blood flow, then you will double the volume of plasma cleared of drug per unit time. First order processes have units of volume of plasma cleared per time.

Aspirin inhibits cyclooxygenase and thus the prostaglandin synthesis. The drug has analgesic, anti-inflammatory and antipyretic effects. Through its effect on the thrombocyte-cyclooxygenase it inhibits the formation of a highly effective platelet (thrombocyte) aggregator and a vasoconstrictor (thromboxane A2). Since the platelets do not synthesize proteins, the effect remains demonstrable as long as the affected thrombocytes live (7-10 days).

ASA is a weak organic acid that irreversibly inactivates cyclooxygenase. ASA exhibits three major therapeutic functions: anti-inflammatory, analgesic, and antipyretic. All of these effects are related to the inhibition of prostaglandins. In the GI tract, ASA inhibition of prostaglandins results in increased gastric acid and decreased mucus production. This process can lead to irritation, ulceration, and potentially hemorrhage. ASA also inhibits thromboxane (TXA2) production and therefore decreases platelet aggregation. ASA is to be avoided in children and teenagers with concomitant viral infections such as varicella or influenza due to the risk of Reye’s syndrome (often fatal fulminating hepatitis with cerebral edema). Absorption does additionally occur through the BBB, placenta, and skin. ASA is 90-95% protein bound and can be displaced from the protein (increasing its concentration in the blood) or displace other protein bound drugs such as warfarin, phenytoin, or valproic acid which results in higher free concentrations of these drugs.

Mild ASA toxicity is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus.

Severe toxicity progresses to restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure.

ASA is not used in patients with gout because it is a weak organic acid that interferes with the kidneys' ability to eliminate uric acid.

Note that all these drugs are reversible nonselective COX inhibitors (ie, they inhibit COX-1 and COX-2). They all have anti-inflammatory, analgesic and antipyretic effects. They all inhibit platelet function and increase bleeding time (by inhibiting TXA2 production). They all are highly bound to albumin and may cause drug interactions. Like aspirin, high doses may cause headaches, dizziness and tinnitus. Unlike aspirin but not unlike COX-2 inhibitors, they all have risk of precipitating life-threatening thrombotic cardiovascular events.

Propionic acid (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiporfen, oxaprozin) posess anti-inflammatory, analgesic, and antipyretic activity and can alter platelet function and prolong bleeding time. Used in treatment of RA and osteoarthritis due to their less intense GI effects than aspirin. These are reversible inhibitors of cyclooxygenases and inhibit the synthesis of prostaglandins but not leukotrienes. Well absorbed on oral administration an dare almost totally bound to serum albumin. Hepatic metabolism and renal excretion.

Acetic acid (indomethacin, sulindac, etodolac) posess anti-inflammatory, analgesic, and antipyretic activity. Reversibly inhibit cyclooxygenase. Generally not used to lower fever. Toxicity of indomethacin limits its use to treat acute gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip; therefore, sulindac which is closely related to indomethacin although less potent is used instead. GI problems are less common than other NSAIDs.

Oxicam derivatives (piroxicam, meloxicam) are used to treat RA, ankylosing spondylitis, and osteoarthritis. They have long halflives, which permit once daily administration and metabolites are excreted in the urine. Note: piroxicam = feldene, meloxicam = mobic

Fenamates (mefenamic acid, meclofenamate) have no advantatges over other NSAIDs as anti-inflammatory agents. Side effects, such as diarrhea, can be severe, and are associated with inflammation of the bowel.

 Briefly describe the pharmacology of methotrexate.

 If a patient taking methotrexate presents for surgery (eg, knee arthroscopy), what lab tests would you order and why?

When used in oncology patients, the drug acts by folic acid antagonist by inhibiting the enzyme that converts folic acid to its active form. Folic acid is essential for cell replication. Actively proliferating cells, such as malignant cancer cells, are more sensitive than non-proliferating cells to this action of methotrexate.

Cytopenias, liver cirrhosis, and acute pneumonia-like syndrome may occur with chronic methotrexate administration. Accordingly, labs for this patient should include a CBC, hepatic function panel, and pancultures if the patient presents with signs and symptoms of infection.

MTX is the disease modifying antirheumatic drug of choice for patients with rheumatoid arthritis. MTX doses in RA are much lower than those used in cancer chemotherapy. At high doses MTX inhibits folic acid synthesis as Matt mentioned. At low doses MTX works by inhibiting proliferation and stimulating apoptosis in immune-inflammatory cells.

For the Test:

Know the difference between COX-1 and COX-2.

Know that steroids (glucocorticoids) block PLA2 and the expression of COX-2.

Know that COX-1 enzymes are responsible for the physiologic production of prostanoids, whereas COX-2 enzymes cause the elevated production of prostanoids that occurs in sites of disease and inflammation.

Know that if you block COX-1 you will affect TXA2, prostacyclin (PGI2) and prostaglandin production.

Know the pros and cons of COX-2 therapy.

COX-1 regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function.

COX-2 is normally expressed in tissues such as the brain, kidney, and bone. Its expression at other sites is increased during states of inflammation. COX-2 has a larger and more flexible substrate channel and a larger space at the site where inhibitors bind than COX-1. These structural differences allowed for the development of selective COX-2 inhibitors. COX-2 expression is inhibited by glucocorticoids, which may contribute to the significant anti-inflammatory effects of those drugs.

Note that glucocorticoids block inflammation by (1) inhibiting PLA2 and (2) by inhibiting COX-2 expression.

Celecoxib inhibits prostaglandin synthesis through inhibition of COX-2. At therapeutic levels it does not inhibit COX-1. It may cause sodium and water retention. In comparison to aspirin and other NSAIDs, it does not inhibit platelet aggregation or increase bleeding time. It has a similar risk of negative cardiovascular events when compared with other NSAIDs.

Celecoxib is indicated for osteoarthritis, RA, acute pain, menstrual symptoms, and to prevent colon polyps in patients at risk of colon CA (eg, strong family history or familial polyposis). Celecoxib has lower risk of causing GI problems than nonselective COX inhibitors. It can inhibit cytochrome 2D6 (CYP2D6, the same enzyme that converts codeine to morphine) which can increase levels of some B-blockers, antidepressants, and antipsychotic drugs.

Pros:
No effects on bleeding time
Less GI disturbances
Safe for use in children (when specifically compared with aspirin)
Safer for use in renally impaired patients
Not a risk for negative cardiovascular events
Cheaper and does not require a prescription (when compaired with COX-2 inhibitors)

Cons:
Lacks significant anti-inflammatory action
Potential for life threatening hepatic insult at higher than therapeutic levels

TXA2 can cause these two conditions: 

You do not need to know anything specific about the actions of any of the following prostaglandins (E2, F-alpha, D2 or I2 which is prostacylcin).

The general actions that you should know are that prostaglandins are pyrogenic (raise the temperature set point in the hypothalamus), mediate inflammation, produce hyperalgesia, protect the GI tract (decrease acid production and increase mucus production), cause uterine contraction, lower intra-ocular pressure, and may be used to treat pulmonary hypertension.