Anti-inflammatory Agents and p-Aminophenol Derivatives (Acetaminophen)
Eicosanoids (inflammatory mediators) are synthesized from what chemical compound?
Arachidonic acid
Give two examples of eicosanoids:
- Leukotrienes (LTs)
- Prostaglandins (PGs)
How is arachidonic acid formed?
Phospholipase A2 acting on cell membrane phospholipids
Corticosteroids block what part of the inflammatory pathway?
Inhibition of phospholipase A2
Angiotensin and bradykinin have what effect on the inflammatory pathway?
Stimulation of phospholipase A2
What enzyme acts on arachidonic acid to form LTs?
5-Lipoxygenase
Which LT is involved in neutrophil chemotaxis?
LTB4
Which LTs are involved in anaphylaxis and bronchoconstriction?
LTA4; LTC4; LTD4
What drug inhibits 5-lipoxygenase, thereby inhibiting LT synthesis?
Zileuton
What is zileuton used for?
Asthma; allergies
What two drugs act as LT receptor antagonists and are used in the treatment of asthma and allergy?
- Montelukast
- Zafirlukast
What are the adverse effects of zileuton and the LT receptor antagonists?
Increased liver function tests (LFTs); headache; Churg-Strauss syndrome
5-Lipoxygenase is found in which cell types?
Neutrophils; eosinophils; basophils; mast cells
Which LTs are considered the slow-releasing substances of anaphylaxis (SRS-A)?
LTA4; LTC4; LTD4
What enzyme acts on arachidonic acid to form PGs and thromboxanes (TXAs)?
Cyclooxygenase (COX)
Where is COX 1 found?
Platelets; gastrointestinal (GI) mucosa; vasculature
Where is COX 2 found?
Sites of inflammation; brain; kidney; GI tract (low amounts vs COX 1)
Is COX 1 a constitutive or inducible enzyme?
It is a constitutive enzyme, meaning that its concentration is not influenced by the concentration of substrate in the cell.
Is COX 2 a constitutive or inducible enzyme?
It is an inducible enzyme, meaning that in resting conditions the enzyme is present in only trace quantities in the cell. Upon entry of the enzyme’s substrate, the concentration of the enzyme increases exponentially.
Prostaglandin E1 (PGE1) does what to the following?
Patent ductus arteriosus
Maintains patency
Uterine smooth muscle
Increases contraction; used as an abortifacient during pregnancy
Blood vessels
Vasodilation
Gastric mucosa
Cytoprotective effect (inhibition of HC1 secretion and stimulation of mucus and bicarbonate secretion)
What two PGF2α analogs promote bronchiolar and uterine smooth muscle contraction?
- Carboprost
- Dinoprost
Why are nonsteroidal anti-inflammatory drugs (NSAIDs) effective in the treatment of dysmenorrhea?
Inhibition of PGE2 and PGF2α synthesis
What PGE1 analog is used for impotence due to its vasodilatory effects?
Alprostadil
What is another name for PGI2?
Prostacyclin
What are the actions of prostacyclin?
Inhibits platelet aggregation; vasodilation
What is the name of a prostacyclin analog and what is it used for?
Epoprostenol; pulmonary hypertension (HTN)
What are the actions of TXA2?
Promotes platelet aggregation; bronchoconstriction; vasoconstriction
Increasing cyclic adenosine monophosphate (cAMP) will do what to platelet aggregation?
Decrease platelet aggregation (mechanism of action of PGI2)
What is the mechanism of action of the nonselective NSAIDs?
Inhibit both COX 1 and COX 2, thereby inhibiting synthesis of PGs and TXAs
Name the three COX 2-specific inhibitors:
- Celecoxib
- Rofecoxib
- Valdecoxib
Do COX 2 inhibitors inhibit platelet aggregation?
No
Which adverse effects of celecoxib have sparked debates about whether it should be pulled from the market or not?
Increased risk of cardiovascular events (myocardial infarction, stroke, and worsening of preexisting HTN)
What are the main therapeutic effects of NSAIDs?
Anti-inflammatory; analgesic; antipyretic; antiplatelet
What is the prototype NSAID?
Acetylsalicylic acid
What is acetylsalicylic acid also known as?
Aspirin; ASA
Does ASA act as a reversible or irreversible inhibitor of COX 1?
Irreversible
How does ASA irreversibly inhibit COX?
Acetylates serine hydroxyl group near active site of COX, thereby forming an irreversible covalent bond
What is the half-life of a platelet?
5 to 7 days
Why can’t platelets produce more COX after ASA therapy?
Nonnucleated cells, therefore, lacking the capability of protein synthesis
What laboratory test is prolonged after ASA therapy?
Bleeding time
How does ASA work as an antipyretic?
Inhibits IL-1 stimulated synthesis of PGE2 in the hypothalamus, thereby inhibiting alteration of the temperature “set-point”
Low-dose ASA does what to uric acid elimination?
Decreases tubular secretion (increases serum uric acid levels)
High-dose ASA does what to uric acid elimination?
Decreases tubular reabsorption (decreases serum uric acid levels)
What type of acid-base disturbance is seen in ASA overdose?
Mixed respiratory alkalosis with metabolic acidosis
Does ASA overdose cause an anion gap or nonanion gap metabolic acidosis?
Anion gap metabolic acidosis
What are the signs/symptoms of salicylism?
Decreased hearing; tinnitus; vertigo; nausea; vomiting; headache; hyperventilation; confusion; dizziness
Why is ASA not given to children especially during times of viral (varicella and influenza) infections?
Reye syndrome
What characterizes Reye syndrome?
Encephalopathy; hepatotoxicity
How can excretion of ASA from the urine be expedited?
Alkalinization of urine with NaHCO3
What should be given instead of ASA to children with fever?
Acetaminophen (or acetyl-para-aminophenol, APAP)
What is the mechanism of action of APAP?
The direct fashion in which acetaminophen produces analgesia is unknown. The drug inhibits synthesis of PGs (via COX 3 inhibition) in the central nervous system (CNS), the only place in the body COX 3 is found. It also blocks pain impulse generation peripherally. Antipyresis is achieved via inhibition of the hypothalamic heat regulating center.
ASA can do what to asthmatics?
Exacerbate symptoms via bronchoconstriction due to unopposed production of leukotrienes
What is the “triad” of ASA hypersensitivity?
- Asthma
- Nasal polyps
- Rhinitis
What is the mechanism of ASA-induced hyperthermia at toxic doses?
Uncoupling of oxidative phosphorylation
What are the GI adverse effects of NSAIDs?
Ulcers; gastritis; GI bleeding (via decreased PGs which act as GI mucosal protectants); nausea; abdominal cramping
If a patient is taking ASA and warfarin concomitantly, what should the dose of ASA be?
81 mg daily
ASA can do what to blood glucose?
Decrease blood glucose
What type of kinetics does ASA follow?
Zero order
Antiplatelet and analgesic effects of ASA occur at lower or higher doses than those required for anti-inflammatory effects?
Lower
What is the drug of choice for closing a patent ductus arteriosus?
Indomethacin
What is the mechanism of NSAID-induced renal failure?
Inhibition of PGE2 and PGI2 synthesis which are responsible for maintaining renal blood flow
Give examples of nonselective NSAIDs other than ASA:
Ibuprofen; naproxen; diclofenac; indomethacin; ketorolac; piroxicam; oxaprozin; nabumetone; sulindac
What are the major differences between nonselective NSAIDs and selective COX-2 inhibitors?
COX-2 inhibitors have less antiplatelet action and less GI adverse effects.
Which COX-2 inhibitors are potentially cross-reactive in patients with sulfonamide allergy?
Celecoxib; valdecoxib
Name two drugs that have antipyretic and analgesic effects yet lack anti-inflammatory and antiplatelet effects:
- APAP
- Phenacetin
APAP inhibits COX centrally, peripherally, or both?
Centrally (inhibits PG synthesis in the CNS)
Overdose of APAP can potentially cause what life-threatening condition?
Hepatic necrosis
How is APAP predominantly metabolized?
Glucuronidation; sulfation
Cytochrome P-450 2E1 metabolizes APAP to which compound (this is a minor metabolic pathway)?
N-acetyl-benzoquinoneimine (NAPQI)
Which metabolite of APAP is hepatotoxic?
NAPQI
Which compound binds to NAPQI and ultimately leads to its excretion?
Glutathione
What happens to patients taking APAP when glutathione stores run out?
Accumulation of NAPQI with subsequent hepatotoxicity
What drug is used to replenish reduced glutathione during times of APAP overdose?
N-acetylcysteine
What is the maximum daily dose of APAP in patients with normal hepatic function?
4 g per 24 hours
What is the maximum daily dose of APAP in patients with abnormal hepatic function?
2 g per 24 hours
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