What are some properties of prostaglandins?

1. TXA2 causes vasoconstriction and plt aggregation.

2. Prostaglandins are pyrogenic (raise temp set point in the hypothalamus)

3. Mediate inflammation

4. Produce hyperalgesia

5. Protect the GI tract (dec. acid and inc. mucus production)

6. Cause uterine contraction

7. Lower intra-ocular pressure

8. Used to treat pulmonary HTN

9. If COX-1 is blocked: TXA2, prostacyclin (PGI2), prostaglandin production will be blocked too

10. Steroids (glucocorticoids) block PLA2 and the EXPRESSION of COX-2

11. COX-2 use is reserved for only: Rheumatoid arthritis and prevention of colon polyps.

12. Misoprostol is used to protect the stomach in patients requiring NSAIDS

What is the difference between COX-1 and COX-2?

What is the mechanism of action of NSAIDs?

1. NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic properties.

2. 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.

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

4. 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.

Why are prostalgandins (PG) also known as eicosanoids?

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

2. Prostaglandins and leukotrienes are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid that are involved in numerous homeostatic biological functions and inflammation.

3. 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.

4. 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.

Outline the role of arachadonic acid in prostaglandin biosynthesis

1. 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.

2. Arachidonic acid is a precursor in the production of eicosanoids.

3. The enzymes cyclooxygenase and peroxidase lead to Prostaglandin H2

4. This is used to produce the prostaglandins, prostacyclin and thromboxanes.

5. The enzyme lipoxygenase leads to 5-HPETE and is used to produce the leukotrienes.

6. The production of these derivatives and action are known as the arachidonic acid cascade.
7. Arachinoid acid, a 20 carbon fatty acid, is the primary precursor of the prostaglandins.

8. It is present as a component of the phospholipids of cell membranes.

9. 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.

10. Two major pathways exist by which eicosanoids are synthetized from arachidonic acid:

                cyclooxygenase pathway and lipoxygenase pathway

Is it difficult to detect PG in blood? Why?

1. 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).

2. They are rapidly metabolized to inactive products at their site of action.

3. PGs do not circulate in blood in significant quantities and are difficult to detect in blood.

Briefly compare cyclo-oxygenase and lipoxygenase pathways of Prostaglandin synthesis.

Arachidonic acid has a short half-life and can be metabolized by two major routes:

           1. The cyclo-oxygenase pathway produces prostaglandins, prostacyclin, and thromboxanes

           2. The lipoxygenase pathway produces in one branch leukotrienes and in the second branch lipoxins.

What is N-acetylcysteine and what are its indications and mechanism of action?

1. N-acetylcysteine (Mucomyst) is a mucolytic and antidote to acetaminophen overdose.

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

3. 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.

4. N-acetylcysteine contains a sulfhydryl group that will protect the liver from potential necrosis.

What are prostaglandins.

1. Prostaglandins (like hormones) act as chemical messengers

2. They do not move to other sites, but work right within the cells where they are synthesized.

3. They are mediators and have a variety of strong physiological effects such as regulating the contraction and relaxation of smooth muscle tissue.

4. Prostaglandins are mediated by their binding to a variety of distinct cell membrane receptors

Prostaglandins act on an array of cells and have a wide variety of effects such as:

Physiological effects of prostaglandins include:

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.

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.

Explain the mechanism of nephrotoxicity of NSAIDs

1. NSAIDs inhibits cyclooxygenase preventing the synthesis of certain prostaglandins.

2. Prostanoids synthesized in the kidney include: PGI2 (prostacyclin), PGE2, thromboxane A2 (TXA2), and PGF2-alpha (Table 1).
3. These prostaglandins preserve renal function when pathologic states supervene and compromise physiologic kidney processes.
4. In marginally functioning kidneys and hypovolemia, prostaglandins derived from renal cortical COX-2 maintain renal blood flow/GFR through local vasodilating effects.

5. These prostanglandins also modulate systemic blood pressure through regulation of sodium and water excretion.

NSAIDs and neprotoxicity part 2

1. Intravascular volume depletion (associated with vomiting, diarrhea, and diuretics) stimulates COX enzyme activity and prostaglandin synthesis to optimize renal blood flow.

2. Other causes of decrease renal blood flow include: CHF, cirrhosis and nephrotic syndrome.

3. Prostaglandin production is increased in chronic renal insufficiency to maintain perfusion of remnant nephrons.

4. GFR is preserved through the antagonism of arteriolar vasoconstriction
5. Renal prostaglandins also have an important role in modulating salt and water homeostasis.

6. Intravascular volume status is controlled (hypotension/dehydration) and (hypertension/edema) and avoided.
7. Patients with high-renin states (CHF, volume depletion, and cirrhosis) and chronic renal insufficiency rely on renal prostaglandin synthesis to ensure sufficient renal blood flow 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.
8. NSAID therapy in pts with prostaglandin-dependent disease often precipitates renal ischemia/acute renal failure.

9. Discontinuation of the NSAID leads to reversal of renal failure within 2 to 5 days.

10. Short-term dialysis may be required for severe uremia or extreme metabolic perturbations.
11. 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.
12. Diuretic resistance can develop during NSAID therapy, in those w/ salt-retentive states (CHF and cirrhosis)

Is aspirin metabolism zero-order, first-order or both? Explain

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

2. With zero-order kinetics, the metabolizing enzymes are operating at full capacity (can not metabolize more drug)

3. If you increase or decrease liver blood flow then the same amount of drug is being metabolized.

4. Zero-order drugs have erratic half-lifes and are dose dependent

5. For 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.

6. Zero-order processes have units of mg/time, first order processes have units of volume of plasma cleared per time.

Summarize the pharmacology of ASA.

1. Aspirin inhibits COX and thus prostaglandin synthesis.

2. Through its effect on the thrombocyte-COX it inhibits the formation of a highly effective platelet (thrombocyte) aggregator and a vasoconstrictor (thromboxane A2).

3. Since plts do not synthesize proteins, effects remain as long as the affected thrombocytes live (7-10 days).
4. ASA is a weak organic acid that irreversibly inactivates COX

5. ASA exhibits 3 major functions: anti-inflammatory, analgesic, antipyretic are d/t the inhibition of prostaglandins.

5. GI: ASA inhibition of prostaglandins results in inc. gastric acid/dec mucus production leading to irritation, ulceration, and potentially hemorrhage.

6. ASA also inhibits thromboxane (TXA2) production and therefore decreases platelet aggregation.

7. 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 (fatal fulminating hepatitis w/ cerebral edema).

8. Absorption does occur through the BBB, placenta, and skin.

9. ASA is 90-95% protein bound and can be displaced from the protein (increasing its concentration in the blood) or displaces other protein bound drugs: warfarin, phenytoin, or valproic acid -->higher free concentrations of these drugs.

ASA toxicity:

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

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

3. 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.

Compare and contrast the pharmacology of:

1. proprionic acid

2. acetic acid

3. oxicam derivatives

4. fenamates

1. Note that all these drugs are reversible nonselective COX inhibitors (ie, they inhibit COX-1 and COX-2).

2. Have anti-inflammatory, analgesic and antipyretic effects.

3. Inhibit platelet function and increase bleeding time (by inhibiting TXA2 production).

4. Highly bound to albumin and may cause drug interactions. Like aspirin, high doses may cause headaches, dizziness and tinnitus.

5. Unlike aspirin but not unlike COX-2 inhibitors, they all have risk of precipitating life-threatening thrombotic cardiovascular events.

Compare and contrast the pharmacology of:

1. proprionic acid

2. acetic acid

3. oxicam derivatives

4. fenamates

Propionic acid (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiporfen, oxaprozin)

1. Posess anti-inflammatory, analgesic, and antipyretic activity and can alter platelet function and prolong bleeding time.

2. Used in treatment of RA and osteoarthritis due to their less intense GI effects than aspirin.

3. These are reversible inhibitors of cyclooxygenases and inhibit the synthesis of prostaglandins but not leukotrienes.

4. Well absorbed w/oral administration and are almost bound to serum albumin. Hepatic metabolism/renal excretion.

Compare and contrast the pharmacology of:

1. proprionic acid

2. acetic acid

3. oxicam derivatives

4. fenamates

Acetic acid (indomethacin, sulindac, etodolac)

1. Posess anti-inflammatory, analgesic, and antipyretic activity.

2. Reversibly inhibit cyclooxygenase.

3. Generally not used to lower fever.

4. 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.

5. GI problems are less common than other NSAIDs.

Compare and contrast the pharmacology of:

1. proprionic acid

2. acetic acid

3. oxicam derivatives

4. fenamates

Oxicam derivatives (piroxicam, meloxicam)

1. Used to treat RA, ankylosing spondylitis, and osteoarthritis.

2. They have long halflives, which permit once daily administration and metabolites are excreted in the urine

1. Briefly describe the pharmacology of methotrexate.

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

3. Why?

1. When used in oncology patients, the drug acts as a folic acid antagonist by inhibiting the enzyme that converts folic acid to its active form (folic acid is essential for cell replication)

2. Actively proliferating cells are more sensitive than non-proliferating cells to this action of MTX
3. Cytopenias, liver cirrhosis, and acute pneumonia-like syndrome may occur with chronic MTX admin.

4. Labs for this patient should include a CBC, hepatic function panel, and pancultures if the patient presents with signs and symptoms of infection.
5. MTX is the disease modifying antirheumatic drug of choice for patients with rheumatoid arthritis.

6. MTX doses in RA are much lower than those used in chemotherapy.

7. At high doses MTX inhibits folic acid synthesis

8. At low doses MTX inhibits proliferation and stimulating apoptosis in immune-inflammatory cells 

Describe COX-1 and COX-2 enzymes

COX-1 enzymes are responsible for the physiologic production of prostanoids. COX-1 regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function.

COX-2: enzymes cause the elevated production of prostanoids that occurs in sites of disease and inflammation. It 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 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.

Summarize the pharmacology of celecoxib.

Celecoxib

1. Inhibits prostaglandin synthesis through inhibition of COX-2.

2. At therapeutic levels it does not inhibit COX-1.

3. It may cause sodium and water retention.  

4. In comparison to aspirin and other NSAIDs, it does not inhibit platelet aggregation or increase bleeding time.

5. It has a similar risk of negative cardiovascular events when compared with other NSAIDs.
6. 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).

7. Lower risk of causing GI problems than nonselective COX inhibitors.

8. 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.

What are the pros and cons of acetaminaphen vs. NSAIDs?

Pros:
1. No effects on bleeding time
2. Less GI disturbances
3. Safe for use in children (when specifically compared with aspirin)
4. Safer for use in renally impaired patients
5. Not a risk for negative cardiovascular events
6. 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