Deja Review Pharmacology, 2nd Edition

CHAPTER 10. Anti-inflammatory Agents and p-Aminophenol Derivatives (Acetaminophen)

 

Eicosanoids (inflammatory mediators) are synthesized from what chemical compound?

Arachidonic acid

Give two examples of eicosanoids:

 

  1. Leukotrienes (LTs)
  2. 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?

 

  1. Montelukast
  2. 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 PGF analogs promote bronchiolar and uterine smooth muscle contraction?

 

  1. Carboprost
  2. Dinoprost

 

Why are nonsteroidal anti-inflammatory drugs (NSAIDs) effective in the treatment of dysmenorrhea?

Inhibition of PGE2 and PGF 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:

 

  1. Celecoxib
  2. Rofecoxib
  3. 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?

 

  1. Asthma
  2. Nasal polyps
  3. 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:

 

  1. APAP
  2. 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

CLINICAL VIGNETTES

 

A 16-year-old adolescent is brought into the emergency room by his parents who say that he tried to kill himself by taking all of the extra-strength Tylenol (acetaminophen) in their medicine cabinet 1 hour ago. Blood tests are ordered which return normal, including normal liver function tests. After 12 hours of observation in the emergency department (ED), the parents insist on taking their son home saying that he is obviously fine since he’s been asymptomatic for so long. The father adds that there were not that many pills left in the bottle anyway, so the boy was just making a dramatic gesture. Besides explaining that their child needs a full psychiatric evaluation to ensure he is not a danger to himself and others, what other reasons should you explain to the parents regarding extended monitoring of the patient?

Acetaminophen toxicity has four phases. In the earliest phase, lasting up to 24 hours, patients may be largely asymptomatic and serum transaminases only begin to rise gradually approximately 12 hours after the toxic dose is taken. This is important to remember in patients who are exhibiting no signs of toxicity, even several hours after ingestion. As serum transaminases rise, right upper quadrant pain, nausea, vomiting, anorexia, jaundice, hepatic and renal failure ensue, ultimately with fatal results if the dose taken is high enough. Therefore, this patient needs to be closely monitored medically and N-acetylcysteine given to decrease mortality. The maximum daily dose of acetaminophen is only 4 g. When you consider that each extra-strength Tylenol Gelcap is 500 mg, even ingestion of a nearly empty bottle can have devastating consequences.

A 26-year-old woman is brought to the emergency room in respiratory distress. She is using accessory muscles to breath and appears tired. Auscultation of her lungs reveals wheezes bilaterally. Her husband relates that she has had a minor viral illness for the past 2 days associated with abdominal discomfort, vomiting, and diarrhea. She took Pepto-Bismol (bismuth subsalicylate) this morning to help her gastrointestinal issues. From what chronic medical condition does this patient likely suffer, and by what mechanism did the Pepto-Bismol cause her current symptoms?

Pepto-Bismol contains a salicylate, the class of medication to which aspirin belongs. Salicylates can cause bronchoconstriction in a small number (3%-5%) of asthmatics due to preferential production of leukotrienes via lipoxygenase from arachidonic acid when the cyclooxygenase enzyme is inhibited by the salicylates. Leukotrienes then contribute to inflammation of the respiratory mucosa leading to edema and respiratory distress. Therefore, asthmatic patients should be made aware of this rare, but potentially lethal side effect of all salicylate containing medications.

A term infant is born to a 29-year-old mother who has diabetes. Despite oxygen therapy, the infant develops increasing cyanosis in the hours following birth. The cyanosis is increased during crying spells. Transposition of the great arteries (TGA) is diagnosed. What medication should the infant be given before definitive surgical correction can take place?

TGA is more common in infants born to diabetic mothers. The great vessels are reversed in these patients so that the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. Oxygenated blood cannot reach the systemic circulation in this fashion. At this point, the infant is being kept alive by the still patent ductus arteriosus, a connection between the aorta and pulmonary artery that allows the pulmonary circulation to be bypassed in utero. The ductus begins to close shortly after birth, normally within 12 to 24 hours. Closure will be fatal in this infant’s case. Patency is maintained by prostaglandins. Therefore, prostaglandin analogs such as alprostadil or misoprostol should be used while awaiting surgery.