Eicosanoids (inflammatory me diators) are synthe siz e d from what che mical compound?
Arachidonic acid
Give two e xample s of e icosanoids:
1. Leukotrienes (LT s) 2. Prostaglandins (PGs)
How is arachidonic acid forme d?
Phospholipase A2 acting on cell membrane phospholipids C orticoste roids block what part of the inflammatory pathway?
Inhibition of phospholipase A2
Angiote nsin and bradykinin have what e ffe ct on the inflammatory pathway?
Stimulation of phospholipase A2
W hat e nz yme acts on arachidonic acid to form LTs?
5-Lipoxygenase
W hich LT is involve d in ne utrophil che motaxis?
LT B4
W hich LTs are involve d in anaphylaxis and bronchoconstriction?
LT A4; LT C4; LT D4
W hat drug inhibits 5-lipoxyge nase , the re by inhibiting LT synthe sis?
Zileuton
W hat is z ile uton use d for?
Asthma; allergies
W hat two drugs act as LT re ce ptor antagonists and are use d in the tre atme nt of asthma and alle rgy?
1. Montelukast 2. Zafirlukast
W hat are the adve rse e ffe cts of z ile uton and the LT re ce ptor antagonists?
Increased liver function tests (LFT s); headache; Churg-Strauss syndrome 5-Lipoxyge nase is found in which ce ll type s?
Neutrophils; eosinophils; basophils; mast cells
W hich LTs are conside re d the slow-re le asing substance s of anaphylaxis (SRS-A)?
LT A4; LT C4; LT D4
W hat e nz yme acts on arachidonic acid to form PGs and thromboxane s (TXAs)?
Cyclooxygenase (COX) W he re is C O X 1 found?
Platelets; gastrointestinal (GI) mucosa; vasculature W he re is C O X 2 found?
Sites of inflammation; brain; kidney; GI tract (low amounts vs COX 1) Is C O X 1 a constitutive or inducible e nz yme ?
It is a constitutive enzyme, meaning that its concentration is not influenced by the concentration of substrate in the cell.
Is C O X 2 a constitutive or inducible e nz yme ?
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) doe s what to the following?
Pate nt ductus arte riosus Maintains patency Ute rine smooth muscle
Increases contraction; used as an abortifacient during pregnancy Blood ve sse ls
Vasodilation Gastric mucosa
Cytoprotective effect (inhibition of HC1 secretion and stimulation of mucus and bicarbonate secretion) W hat two PGF2α analogs promote bronchiolar and ute rine smooth muscle contraction?
1. Carboprost 2. Dinoprost
W hy are nonste roidal anti-inflammatory drugs (NSAIDs) e ffe ctive in the tre atme nt of dysme norrhe a?
Inhibition of PGE2 and PGF2α synthesis
W hat PGE1 analog is use d for impote nce due to its vasodilatory e ffe cts?
Alprostadil
W hat is anothe r name for PGI2? Prostacyclin
W hat are the actions of prostacyclin?
Inhibits platelet aggregation; vasodilation
W hat is the name of a prostacyclin analog and what is it use d for?
Epoprostenol; pulmonary hypertension (HT N) W hat are the actions of TXA2?
Promotes platelet aggregation; bronchoconstriction; vasoconstriction
Incre asing cyclic ade nosine monophosphate (cAMP) will do what to plate le t aggre gation?
Decrease platelet aggregation (mechanism of action of PGI2) W hat is the me chanism of action of the nonse le ctive NSAIDs?
Inhibit both COX 1 and COX 2, thereby inhibiting synthesis of PGs and T XAs Name the thre e C O X 2-spe cific inhibitors:
1. Celecoxib 2. Rofecoxib 3. Valdecoxib
Do C O X 2 inhibitors inhibit plate le t aggre gation?
No
W hich adve rse e ffe cts of ce le coxib have sparke d de bate s about whe the r it should be pulle d from the marke t or not?
Increased risk of cardiovascular events (myocardial infarction, stroke, and worsening of preexisting HT N) W hat are the main the rape utic e ffe cts of NSAIDs?
Anti-inflammatory; analgesic; antipyretic; antiplatelet W hat is the prototype NSAID?
Acetylsalicylic acid
W hat is ace tylsalicylic acid also known as?
Aspirin; ASA
Doe s ASA act as a re ve rsible or irre ve rsible inhibitor of C O X 1?
Irreversible
How doe s ASA irre ve rsibly inhibit C O X?
Acetylates serine hydroxyl group near active site of COX, thereby forming an irreversible covalent bond W hat is the half-life of a plate le t?
5 to 7 days
W hy can’t plate le ts produce more C O X afte r ASA the rapy?
Nonnucleated cells, therefore, lacking the capability of protein synthesis W hat laboratory te st is prolonge d afte r ASA the rapy?
Bleeding time
How doe s ASA work as an antipyre tic?
Inhibits IL-1 stimulated synthesis of PGE2 in the hypothalamus, thereby inhibiting alteration of the temperature “ set-point”
Low-dose ASA doe s what to uric acid e limination?
Decreases tubular secretion (increases serum uric acid levels) High-dose ASA doe s what to uric acid e limination?
Decreases tubular reabsorption (decreases serum uric acid levels) W hat type of acid-base disturbance is se e n in ASA ove rdose ?
Mixed respiratory alkalosis with metabolic acidosis
Doe s ASA ove rdose cause an anion gap or nonanion gap me tabolic acidosis?
Anion gap metabolic acidosis
W hat are the signs/symptoms of salicylism?
Decreased hearing; tinnitus; vertigo; nausea; vomiting; headache; hyperventilation; confusion; dizziness W hy is ASA not give n to childre n e spe cially during time s of viral (varice lla and influe nz a) infe ctions?
Reye syndrome
W hat characte riz e s Re ye syndrome ? Encephalopathy; hepatotoxicity
How can e xcre tion of ASA from the urine be e xpe dite d?
Alkalinization of urine with NaHCO3
W hat should be give n inste ad of ASA to childre n with fe ve r?
Acetaminophen (or acetyl-para-aminophenol, APAP) W hat is the me chanism of action of APAP?
T he direct fashion in which acetaminophen produces analgesia is unknown. T he 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 W hat is the “triad” of ASA hype rse nsitivity?
1. Asthma 2. Nasal polyps 3. Rhinitis
W hat is the me chanism of ASA-induce d hype rthe rmia at toxic dose s?
Uncoupling of oxidative phosphorylation W hat are the GI adve rse e ffe cts of NSAIDs?
Ulcers; gastritis; GI bleeding (via decreased PGs which act as GI mucosal protectants); nausea; abdominal cramping If a patie nt 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
W hat type of kine tics doe s ASA follow?
Zero order
Antiplate le t and analge sic e ffe cts of ASA occur at lowe r or highe r dose s than those re quire d for anti-inflammatory e ffe cts?
Lower
W hat is the drug of choice for closing a pate nt ductus arte riosus?
Indomethacin
W hat is the me chanism of NSAID-induce d re nal failure ?
Inhibition of PGE2 and PGI2 synthesis which are responsible for maintaining renal blood flow Give e xample s of nonse le ctive NSAIDs othe r than ASA:
Ibuprofen; naproxen; diclofenac; indomethacin; ketorolac; piroxicam; oxaprozin; nabumetone; sulindac W hat are the major diffe re nce s be twe e n nonse le ctive NSAIDs and se le ctive C O X-2 inhibitors?
COX-2 inhibitors have less antiplatelet action and less GI adverse effects.
W hich C O X-2 inhibitors are pote ntially cross-re active in patie nts with sulfonamide alle rgy?
Celecoxib; valdecoxib
Name two drugs that have antipyre tic and analge sic e ffe cts ye t lack anti-inflammatory and antiplate le t e ffe cts:
1. APAP 2. Phenacetin
APAP inhibits C O X ce ntrally, pe riphe rally, or both?
Centrally (inhibits PG synthesis in the CNS)
O ve rdose of APAP can pote ntially cause what life -thre ate ning condition?
Hepatic necrosis
How is APAP pre dominantly me taboliz e d?
Glucuronidation; sulfation
C ytochrome P-450 2E1 me taboliz e s APAP to which compound (this is a minor me tabolic pathway)?
N-acetyl-benzoquinoneimine (NAPQI) W hich me tabolite of APAP is he patotoxic?
NAPQI
W hich compound binds to NAPQ I and ultimate ly le ads to its e xcre tion?
Glutathione
W hat happe ns to patie nts taking APAP whe n glutathione store s run out?
Accumulation of NAPQI with subsequent hepatotoxicity
W hat drug is use d to re ple nish re duce d glutathione during time s of APAP ove rdose ? N-acetylcysteine
W hat is the maximum daily dose of APAP in patie nts with normal he patic function?
4 g per 24 hours
W hat is the maximum daily dose of APAP in patie nts with abnormal he patic function?
2 g per 24 hours CLINICAL VIGNETTES
A 16-ye ar-old adole sce nt is brought into the e me rge ncy room by his pare nts who say that he trie d to kill himse lf by taking all of the e xtra-stre ngth Tyle nol (ace taminophe n) in the ir me dicine cabine t 1 hour ago. Blood te sts are orde re d which re turn normal, including normal live r function te sts.
Afte r 12 hours of obse rvation in the e me rge ncy de partme nt (ED), the pare nts insist on taking the ir son home saying that he is obviously fine since he ’s be e n asymptomatic for so long. The fathe r adds that the re we re not that many pills le ft in the bottle anyway, so the boy was just making a dramatic ge sture . Be side s e xplaining that the ir child ne e ds a full psychiatric e valuation to e nsure he is not a dange r to himse lf and othe rs, what othe r re asons should you e xplain to the pare nts re garding e xte nde d monitoring of the patie nt?
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. T his 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. T herefore, this patient needs to be closely monitored medically and N-acetylcysteine given to decrease mortality.
T he 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-ye ar-old woman is brought to the e me rge ncy room in re spiratory distre ss. She is using acce ssory muscle s to bre ath and appe ars tire d.
Auscultation of he r lungs re ve als whe e z e s bilate rally. He r husband re late s that she has had a minor viral illne ss for the past 2 days associate d with abdominal discomfort, vomiting, and diarrhe a. She took Pe pto-Bismol (bismuth subsalicylate ) this morning to he lp he r gastrointe stinal issue s. From what chronic me dical condition doe s this patie nt like ly suffe r, and by what me chanism did the Pe pto-Bismol cause he r curre nt 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. T herefore, asthmatic patients should be made aware of this rare, but potentially lethal side effect of all salicylate containing medications.
A te rm infant is born to a 29-ye ar-old mothe r who has diabe te s. De spite oxyge n the rapy, the infant de ve lops incre asing cyanosis in the hours following birth. The cyanosis is incre ase d during crying spe lls. Transposition of the gre at arte rie s (TGA) is diagnose d. W hat me dication should the infant be give n be fore de finitive surgical corre ction can take place ?
T GA is more common in infants born to diabetic mothers. T he 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. T he 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.
T herefore, prostaglandin analogs such as alprostadil or misoprostol should be used while awaiting surgery.