Autocoids and Eicosanoids

Question 1

Diphenhydramine (Benadryl, Sominex)

Answer 1

• Description
  
  • 1st generation antihistamine
  • TX for allergic rhinitis, sneezing, itching, urticaria, motion sickness, insomnia
• Mechanism of action
  
  • H1 receptor inverse agonist, stabilizes the inactive conformation of H1 receptors; blocks the effects of histamine on H1 receptors in the GI tract, large blood vessels, bronchial muscle, uterus and suppresses the formation of edema, flare, and pruritus
  • Produces sedation via antagonism of CNS H1 receptors, effective as a hypnotic
  • Has significant antimuscarinic activity
    
    • Effective in the relief of nausea, vomiting, and vertigo associated with motion sickness; effective as an antiparkinsonian agent
• Pharmacokinetics
  
  • Administered PO, topically, IV, or IM; PO onset in 15-30 min, duration 4-6 hr
  • Hepatic metabolism mostly by CYP2D6
• Adverse reactions lCNS: confusion, dizziness, sedation
  
  • Antimuscarinic effects: mydriasis, xerostomia, reduced bronchial secretions, tachycardia, constipation, urinary retention
• Precautions
  
  • Asthma
  • Heart disease
  • Hepatic disease
  • Glaucoma
  • Bladder obstruction, urinary retention
  • Infants (sleep apnea and SIDS can occur via unknown mechanism)

Question 2

Cetirizine (Zyrtec)

Answer 2

• Description
  
  • 2nd generation antihistamine; active metabolite of 1st generation hydroxyzine
  • TX for allergic conditions (rhinitis, sneezing, itching, urticaria)
  • Less sedating than older H1 antagonists
  • Formulated with pseudoephedrine as Zyrtec-D® (additive effect)
• Mechanism of action
  
  • H1 receptor inverse agonist, stabilizes the inactive conformation of H1 receptors; blocks the effects of histamine on H1 receptors in the GI tract, uterus, large blood vessels, and bronchial muscle and suppresses the formation of edema, flare, and pruritus
  • Minimal antimuscarinic activity
• Pharmacokinetics
  
  • Administered PO as tabs, chewable tabs, or syrup, usually 5-10 mg QD; duration up to 24 hr
  • Low CNS accumulation; effluxed from the CNS via the P-glycoprotein pump system (aka less sedative)
  • 50% metabolized in liver by CYP3A4
• Adverse reactions
  
  • Few adverse reactions
  • CNS (higher doses): sedation (10-14%), fatigue (6%)
  • Xerostomia (5%)
• Precautions
  
  • If CrCL < 31 mL/min, do not exceed 5 mg QD

Question 3

Fexofenadine (Allegra)

Answer 3

• Description
  
  • 2nd generation antihistamine; active metabolite terfenadine
  • TX for allergic conditions (rhinitis, sneezing, itching, urticaria)
• Mechanism of action
  
  • H1 receptor inverse agonist, stabilizes the inactive conformation of H1 receptors; blocks the effects of histamine on H1 receptors in the GI tract, uterus, large blood vessels, and bronchial muscle and suppresses the formation of edema, flare, and pruritus
  • Virtually no antimuscarinic activity at therapeutic doses
• Pharmacokinetics
  
  • Administered PO as tabs, disintegrating tabs, or suspension, usually 30-60 mg BID or 180 mg QD; duration < 24 hr
  • Low CNS accumulation; effluxed from the CNS via the P-glycoprotein pump system
  • Low (< 5%) metabolism, 80% excreted in feces (less concern w/ renal function)
• Adverse reactions
  
  • Few adverse reactions
  • GI: nausea, dyspepsia (1.5%)
  • CNS: drowsiness, sedation (1.3%)
• Precautions
  
  • Decrease dose in patients with decreased renal function
  • Avoid taking with fruit juices, get decreased absorption

Question 4

Loratadine (Claritin, Tavist ND)

Answer 4

• Description
  
  • 2nd generation antihistamine
  • TX for allergic conditions (rhinitis, sneezing, itching, urticaria)
  • Formulated with pseudoephedrine as Claritin-D®
  • Desloratidine (Clarinex®) is active metabolite of loratidine
• Mechanism of action
  
  • H1 receptor inverse agonist, stabilizes the inactive conformation of H1 receptors; blocks the effects of histamine on H1 receptors in the GI tract, uterus, large blood vessels, and bronchial muscle and suppresses the formation of edema, flare, and pruritus
  • Little or no antimuscarinic activity at therapeutic doses
• Pharmacokinetics
  
  • Administered PO as tabs, disintegrating tabs, or syrup, usually 10 mg QD; duration > 24 hr
  • Low CNS accumulation; effluxed from the CNS via the P-glycoprotein pump system
  • Extensive CYP3A4 metabolism in liver → drug interactions
• Adverse reactions
  
  • Few adverse reactions
  • CNS: headache, sedation
  • Xerostomia (3%)
• Precautions
  
  • Hepatic disease
  • If CrCL < 30 mL/min, give 10 mg Q 48 hr

Question 5

Cimetidine (Tagamet)

Answer 5

• Description
  
  • First commercially available drug for peptic ulcer disease
  • Indicated for GERD, peptic ulcer disease, intermittent dyspepsia (not as effective as proton pump inhibitors)
• Mechanism of action
  
  • Inverse agonist, reduces constitutive activation of H2 receptors on parietal cells
  • Decreases acid secretion by 60-70%
• Pharmacokinetics
  
  • Available for PO or IV dosing, usually 100-400 mg BID-QID or 800 mg HS
  • Nonselective inhibitor of CYP enzymes → many drug interactions possible
    
    • Newer H2 blockers (ranitidine, nizatidine, famotidine) have little or no CYP inhibition
  • ~ 48% is excreted unchanged in the urine
• Adverse reactions
  
  • Moderate-to-severe headaches (3%)
  • Rare blood dyscrasias: neutropenia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia
• Precautions
  
  • Hepatic disease
  • Renal insufficiency

Question 6

Ergotamine (Ergomar)

Answer 6

Description

• Ergot alkaloid used to relieve migraines; ~ 70% effective in controlling acute attacks

Mechanism of action

• MOA is complex; some of the pharmacologic actions are unrelated to each other and some actions are even mutually antagonistic
• Partial agonist or antagonist activity at 5-HT, DA, and a-adrenergic receptors; causes vasoconstriction of arteries and veins and ↓ blood flow to the extremities
• Oxytocic agent: ↑ force and frequency of uterine contractions, ↓ postpartum bleeding by constricting the placental vascular bed

Pharmacokinetics

• Formulated alone or with caffeine, atropine, and/or pentobarbital; administered PO or SL; absorption is incomplete and erratic
• Migraine relief is obtained in 30-120 min; vasoconstricting effects last ~ 48 hr
• Ergotamine is primarily metabolized via CYP3A4

Adverse reactions

• GI: NVD (10%), xerostomia
• Ergotism: angina, asthenia, coronary vasospasm, cramps, myalgia, paresthesias, changes in HR; vasoconstriction may result in hypothermia or tissue necrosis

Precautions

• CV: angina, arteriosclerosis, coronary artery disease, hypertension, peripheral vascular disease, Raynaud’s disease, thrombophlebitis, MI, stroke
• Hepatic disease, biliary tract disease, cholestasis
• Renal failure or impairment
• FDA Pregnancy Risk Category X

Question 7

Sumatriptan (Imitrex)

Answer 7

Description

• Approved for the TX of acute migraine with or without aura; give ASAP after onset
• Not for long-term migraine prophylaxis

Mechanism of action

• Agonist at presynaptic 5-HT1D autoreceptors and at vascular 5-HT1B receptors → vasoconstriction

Pharmacokinetics

• Available PO, SC, or as nasal spray; PO dose of 25-100 mg give ~ 70% pt response rate after 60 min
• SC gives most consistent peak blood levels; onset of pain relief after SC injection within ~ 10 min, and as many as 80% of patients experience relief within 60 min
• Approximately 80% of a dose undergoes hepatic metabolism, mostly by MAO-A
• Excretion of metabolites is via feces and urine

Adverse reactions

• Potentially fatal CV events: coronary artery vasospasm, arrhythmias, MI, cardiac arrest
• GI: NVD, vasospastic effects leading to bowel ischemia, abdominal pain, bloody diarrhea, and cramping
• Injection site reaction (50%): pain, burning

Precautions

• CV: angina, arteriosclerosis, arrhythmias, coronary artery disease, hypertension, peripheral vascular disease, Raynaud’s disease, thrombophlebitis, MI, stroke
• • Ischemic bowel disease*
• Hepatic disease
• Renal insufficiency

Question 8

Hydrocortisone (Cortizone-10)

Answer 8

Description

• Natural steroid hormone secreted by the adrenal cortex
• Main uses are antiinflammatory: anaphylaxis, asthma, COPD, inflammatory bowel disease, rheumatic disorders, dermatoses (pruritus, psoriasis, contact dermatitis, urticaria, insect stings)
• DOC for glucocorticoid replacement therapy in patients with adrenal insufficiency (Addison’s disease)
• Low potency topical corticosteroids are the safest for chronic use and may be used in infants and young children

Mechanism of action

• Acts via nuclear receptors to modulate gene expression
• Anti-inflammatory: represses COX-2 expression; ↓ cytokine production, decreased formation and release of endogenous inflammatory mediators; causes apoptosis of eosinophils

Pharmacokinetics

• Available in various forms for IV, IM, PO, or topical administration
• Biological half-life of hydrocortisone is 8-12 hr

Adverse reactions

• Essentially none, even with large doses, if given for < 1 week
• Systemic corticosteroids administered for prolonged periods can result in physiological dependence due to HPA suppression and exaggerated normal effects such as hyperglycemia, immunosuppression, CNS effects, etc.
• Prolonged therapy will cause cataracts, exacerbate glaucoma, and thinning of skin

Precautions

• Abrupt DC of prolonged systemic therapy
• Cushing’s syndrome
• Preexisting bacterial, viral, fungal infections
• Patients receiving corticosteroids chronically should be periodically assessed for cataracts

Question 9

Prednisone (Sterapred, generic)

Answer 9

Description

• Immunosuppressive oral corticosteroid; most-prescribed oral corticosteroid
• TX for autoimmune disorders, allograft rejection, asthma, inflammatory bowel disease, rheumatoid arthritis, and other inflammatory states
• more potent than hydrocortisone

Mechanism of action

• Prodrug of prednisolone, must be metabolized in vivo to prednisolone
• Acts via nuclear receptors to modulate gene expression
• Anti-inflammatory: represses COX-2 expression; ↓ cytokine production, decreased formation and release of endogenous inflammatory mediators; causes apoptosis of eosinophils

Pharmacokinetics

• Given PO, doses range from 5-100 mg QD depending on disease
• Metabolized in the liver to prednisolone
• t1/2 ~ 18-36 hr

Adverse reactions (more common with high doses or prolonged therapy)

• CNS: headache, insomnia, vertigo, depression, anxiety, euphoria, personality changes, psychosis
• GI: NVD, anorexia, gastritis
• Cataracts
• Opportunistic infections

Precautions (same as hydrocortisone)

• Cushing’s syndrome
• High doses and long-term therapy can suppress hypothalamic-pituitary-adrenal system; avoid abrupt DC of prolonged therapy
• Preexisting bacterial, viral, fungal infections
• Patients receiving corticosteroids chronically should be periodically assessed for cataracts

Question 10

Fluticasone (Cutivate, Flovent)

Answer 10

Description

• Medium-potency steroid used topically to relieve the symptoms of dermatoses and psoriasis and intranasally for allergic and nonallergic rhinitis; used in the TX of asthma, but for prophylaxis only

Mechanism of action

• Acts via nuclear receptors to modulate gene expression
• Anti-inflammatory: represses COX-2 expression; ↓ cytokine production, decreased formation and release of endogenous inflammatory mediators; causes apoptosis of eosinophils

Pharmacokinetics

• Formulated as an ointment, lotion, and cream for topical use. A thin film is applied to the affected skin areas BID. Formulated with salmeterol (Advair®)
• For asthma, administered by metered-dose inhaler, usually BID
• Metabolism occurs via hepatic CYP3A4

Adverse reactions

• Pruritus, burning, hypertrichosis (4%) (excessive hair growth); mild and self-limiting
• Hoarseness, irritation, 2° infections, e.g. oropharyngeal candidiasis with inhaled form (thrush)

Precautions

• Cushing’s syndrome
• High doses and long-term therapy can suppress hypothalamic-pituitary-adrenal system; avoid abrupt DC of prolonged therapy
• Not a bronchodilator, not for acute bronchospasm
• Preexisting bacterial, viral, fungal infections
• Patients receiving corticosteroids chronically should be periodically assessed for cataracts

Question 11

Betamethasone diproprionate (Celestone)

Answer 11

• Ultra-potent steroid
  
  • 25-40x anti-inflammatory potency of Hydrocortisone
  • no minerlocorticoid potency
• Longer lasting (>36 hrs)

Question 12

Dexamethasone (Decadron)

Answer 12

• High-potency steroid
  
  • 30x anti-inflammatory potency of Hydrocortisone
  • no minerlocorticoid potency
• Longer lasting (>36 hrs)

Question 13

Aspirin (ASA, Bayer, generic)

Answer 13

Description

• The first NSAID, synthesized in 1853 and marketed in the late 1890s
• NSAID of the salicylate chemical class
• Used for thrombosis prevention; prevents or reduces the risk of MI in patients with a history of MI, coronary bypass, angioplasty, angina, stroke, transient ischemic attacks (TIAs)

Mechanism of action

• Irreversible inhibitor of COX enzymes, ~ 5-fold selective for COX-1 vs. COX-2
• reason why can be used for prophylatic thrombosis

Pharmacokinetics

• Dosing is usually 325-650 mg PO QID PRN for inflammation, pain, fever
• For thrombosis prevention, dosing is usually 80-325 mg QD
• Antiplatelet effect lasts 8-10 days; in other tissues, synthesis of new COX replaces inactivated COX so that ordinary doses have a duration of action of 6-12 hr
• Metabolized in the liver to salicylic acid and related compounds which are excreted in the urine

Adverse reactions

• GI disturbances (2-30%; dose-dependent): NVD, mucosal damage, bleeding, pain
• Tinnitus or hearing loss with high doses
• Hypersensitivity and anaphylactic reactions
• Incidence: patients with chronic urticaria (20%), asthma (4%), or chronic rhinitis (1.5%)
• Sensitivity manifests as bronchospasm in asthmatics and is commonly associated with nasal polyps; the correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad

Precautions

• Children < 15 years old with viral infections → Reye’s syndrome (fever, vomiting, fatty liver and elevated LFTs, disorientation, coma)
• Renal disease
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 14

Ketorolac (Toradol)

Answer 14

Description

• Promoted mainly as a strong analgesic, not as an anti-inflammatory drug
• Used short term (≤ 5 days) for postsurgical pain that requires analgesia at the opioid level
• mainly analgesic, potent, used short-term

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 100-fold selective for COX-1 vs. COX-2

Pharmacokinetics

• Formulated as tables, parenteral solution, and ophthalmic solution
• Usual regimen is a single IV (30 mg) or IM (60 mg) dose
• Parenteral dosing followed by 10 mg PO QID (administered in hospital)
• Well-absorbed, oral F = 1
• > 90% excreted in the urine, 40% as hepatic metabolites and 60% unchanged

Adverse reactions

• CNS: headaches, dizziness, drowsiness
• GI (1-10%): NVD, damage to mucosa, gastric bleeding, abdominal pain

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• • CrCL < 30 ml/min*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 15

Indomethacin (Indocin)

Answer 15

Description

• NSAID of the indole and indene acetic acid class
• In premature infants, indomethacin is used to accelerate closure of patent ductus arteriosus (PDA) (remains patent due to PGs from placenta)

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 3-5-fold selective for COX-1 vs. COX-2

Pharmacokinetics

• Administered PO, rectally, or IV (for PDA closure; 3 doses 12 hr apart)
• Usual anti-inflammatory dose is 50–70 mg TID
• Metabolized in the liver and undergoes enterohepatic recirculation
• About 60% is recovered in the urine as drug and metabolites and 33% is recovered in the feces

Adverse reactions

• CNS: dizziness (3-9%), headache (> 10%), fatigue/malaise (1-3%), depression, tremor, ataxia
• GI disturbances (1-9%): NVD, damage to mucosa, gastric bleeding, abdominal pain

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency
• CNS: seizure disorder, Parkinson’s disease, major depression or other psychiatric disturbance (only NSAIDs w/ CNS precautions)
• Pregnancy Risk Category D if in 3rd trimester, otherwise Category B

Question 16

Naproxen (Aleve, Anaprox)

Answer 16

Description

• Naphthylpropionic acid class NSAID
• Marketed as S-enantiomer

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 3-5-fold selective for COX-1 vs. COX-2

Pharmacokinetics

• Available as tablets, gel caps, enteric-coated tablets, oral suspension; usual dose for RA is 250-500 mg BID
• F = 0.95, t1/2 = 12-17 hr, steady state reached in 3-5 days
• Extensive hepatic metabolism and conjugation, ~ 95% excreted in urine, < 1% unchanged

Adverse reactions (1-10%)

• GI: NVD, damage to mucosa, gastric bleeding, abdominal pain; risk of upper GI bleeding is double that of OTC ibuprofen
• DERM: rashes, urticaria, alopecia

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 17

Ibuprofen (Advil)

Answer 17

Description

• NSAID of the phenylpropionic acid class (as needed for pain, fever)

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 2-fold selective for COX-1 vs. COX-2

Pharmacokinetics

• Administered PO, 200-800 mg TID-QID PRN (shorter duration only real difference compared to Naproxen)
• Excreted in the urine, 50-60% as metabolites

Adverse reactions

• CNS (< 9%): dizziness, headache, nervousness
• GI disturbances (4-16%): NVD, damage to mucosa, gastric bleeding, abdominal pain
• Rash (1-3%)
• Tinnitus (< 3%) or hearing loss (< 1%)
• Blurred vision (< 1%)

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 18

Meloxicam (Mobic)

Answer 18

Description

• Potent enolcarboxamide NSAID
• Indicated for rheumatoid arthritis or osteoarthritis

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 10-fold selective for COX-2 vs. COX-1 (GI effects less since targets COX-2)

Pharmacokinetics

• Available as tablets or oral suspension, usual dose is 7.5-15 mg QD
• Highly bound to serum albumin, Vd ~ 10L
• About 70% metabolized in the liver by CYP2C9 and CYP3A4, another 20% by peroxidases
• Excretion of metabolites occurs equally through urine and feces

Adverse reactions

• GI: pain, dyspepsia, nausea

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 19

Celecoxib (Celebrex)

Answer 19

Description

• First FDA-approved selective COX-2 inhibitor

Mechanism of action

• Competitive inhibitor of COX enzymes, 10-20-fold selective for COX-2 vs. COX-1

Pharmacokinetics

• Administered PO, usually 100-200 mg BID
• > 97% is metabolized in the liver by CYP2C9

Adverse reactions

• GI disturbances: dyspepsia (9%), NVD (3-6%), abdominal pain (4%)
• Dizziness
• Rash (2%)

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 20

Diclofenac (generic)

Answer 20

Description

• NSAID of the phenylacetic acid class

Mechanism of action

• Competitive inhibitor of COX enzymes, ~ 10-20 fold selective for COX-2 vs. COX-1

Pharmacokinetics

• Formulated as tablets, solution, and gel (topical); PO dosing is usually 50-75 mg BID; ER form available for 100 mg QD dosing
• Metabolized in the liver mainly by CYP2C9 followed by glucuronidation or sulfation
• Excretion is ~65% renal and ~35% biliary

Adverse reactions (1-10%)

• GI disturbances: upset stomach, heartburn, bleeding, ulceration, perforation, elevated LFTs (2-4%)
• Renal: ↓ blood flow, ↓ GFR - drug interactions

Precautions

• • Salicylate sensitivity*
• • Aspirin triad*
• Heart disease
• Hepatic disease
• Prior history of GI bleeding or perforation
• Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency

Question 21

Acetaminophen (Tylenol, APAP)

Answer 21

Description

• Has analgesic and antipyretic activity but no anti-inflammatory activity and no platelet effects (anti-thrombotic effects)
• Preferred analgesic/antipyretic for patients in whom aspirin is contraindicated (exhibit aspirin triad)

Mechanism of action

• Competitive inhibitor of COX-1 and COX-2 enzymes within the CNS but not the periphery
• Binds to cannabinoid receptors in spinal cord

Pharmacokinetics

• Administered PO, PR, IV, usually 325-500 mg QID, not to exceed 4 g QD
• In the liver, 85-90% is harmlessly metabolized but 10-15% is converted via CYP2E1, 1A2, or 3A4 to a chemically reactive, potentially hepatotoxic metabolite
• 85% of a dose is renally excreted

Adverse reactions

• Rash, pruritus, urticaria
• GI disturbances (high dose): NV, anorexia, and abdominal pain usually occur within 2-3 hr after ingestion of toxic doses
• Hepatotoxicity; in acute overdose, 2-3 days pass before maximum liver damage becomes apparent; antidote is IV N-acetyl cysteine
• Renal tubule necrosis with high or chronic doses

Precautions

• Alcoholism
• Hepatic disease
• Renal disease; if CrCL < 30 mL/min consider reducing dose or extending dosing interval
• Tobacco smoking
• Salicylate sensitivity

Question 22

N-acetylcysteine

Answer 22

• administration after overdose of acetaminophen decreases cytotoxic effects
• it shunts APAP metabolites down a different pathway so that the reactive metabolite NAPQI cannot react w/ intracellular proteins, rendering them non-functional and signaling for apoptosis

Question 23

Alprostadil (Caverject)

Answer 23

Description

• Synthetic PGE1 used for the treatment of erectile dysfunction (ED) in males and to temporarily maintain the patency of the ductus arteriosus in newborns until corrective or palliative surgery can be performed

Mechanism of action

• Agonist at EP receptors → ↑ cAMP production → vasodilation
• Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries; blood is entrapped by compression of venules (corporal veno-occlusive mechanism)
• In neonates, prevents or reverses the functional closure that occurs shortly after birth, resulting in increased pulmonary or systemic blood flow in infants

Pharmacokinetics

• For ED, supplied as sterile lyophilized powder for intracavernosal use in 5, 10, 20 and 40 mg sizes; reconstituted with water for injection directly into penis
• For pediatric use, supplied as solution in alcohol which is diluted and administered by constant IV infusion, usually 0.05-0.1 mg/kg/min; t1/2 5-10 min
• 81% albumin-bound
• Metabolized by one pass through the lungs, duration of action in ED is 12-70 min

Adverse reactions

• ED: most common adverse effect is mild-to-moderate penile pain (37%); prolonged erection (4%) is a potential medical emergency; penile fibrosis (3%)
• PEDS: fever (14%), apnea (12%), flushing (10%)

Precautions

• ED: regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis
• PEDS: infuse for the shortest time and at the lowest dose that will produce the desired effects

Question 24

Latanoprost (Xalatan)

Answer 24

Description

• Synthetic PGF_2a analog prodrug that is used to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension

Mechanism of action

• Selective FP receptor agonist, believed to reduce the IOP by increasing the outflow of aqueous humor
• Produces 6-9 mm Hg reduction in IOP

Pharmacokinetics

• Formulated as a 0.005% ophthalmic solution, usual dose 1 gtt QV
• Reduction of IOP begins 3-4 hr after administration and maximum effect is reached in 8-12 hr
• Hydrolyzed by esterases in the cornea to the biologically active acid

Adverse reactions

• OPT (5-15%): blurred vision, burning, itching, increased iris pigmentation (↑ melanin), eyelash changes (eyelash growth)

Precautions

• • Active intraocular inflammation*
• Remove contact lenses for 15 min

Question 25

Misoprostol (Cytotec)

Answer 25

Description - Very **potent synthetic prostaglandin** analog used for the **prevention of gastric ulcers**, but slightly **less effective than H₂ antagonists** - PO following mifepristone for early (\< 50 days) PG termination; off-label uses: **intravaginally for labor induction** at term or following 3rd trimester fetal death; as 2nd trimester abortifacient Mechanism of action - **Agonist at EP receptors** on parietal cells in stomach → ↓cAMP → **decreases acid secretion**, promotes mucous and bicarbonate ion secretion, enhances mucosal gel protection - Agonist at EP receptors in uterus, stimulates and **increases amplitude and frequency of uterine contractions**, dilates cervix Pharmacokinetics - Formulated as 100 mg and 200 mg tablets for PO administration - To decrease stomach acidity, 100-200 mg given QID with food - In medical abortions, 48 hr following mifepristone, given as 2 x 200 mg for labor induction - Rapidly absorbed, peak levels are reached in 9-15 min and t_1/2 = 20-40 min - Activity is apparent 30 min after PO administration and persists for at least 3 hr Adverse reactions - CNS: headache (2%) - GI: diarrhea (14-40%), pain (7-20%), NV (3%) Precautions - **Pregnancy Risk Category X**; discontinue immediately if pregnancy occurs - ♀ of childbearing potential should 1) exhibit a negative serum pregnancy test within 2 weeks of initiating therapy, 2) use effective and reliable means of contraception, 3) receive both oral and written warnings on potential hazards, and 4) should initiate therapy only on the 2nd or 3rd day of the next normal menstrual period

Question 26

Zileuton (Zyflow)

Answer 26

Description - Benzothiophene derivative of N-hydroxyurea - Indicated for the **prophylaxis and chronic treatment of asthma**. Mechanism of action - Specific **5-LOX inhibitor** → ↓ leukotriene (LTB4, LTC4, LTD4, and LTE4) formation - Clinical response is inhibition of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, decreased capillary permeability, decreased leukotriene-induced smooth muscle contractions Pharmacokinetics - Formulated as 600 mg tablets for QID dosing - Rapidly absorbed, mean time to peak plasma concentration ~1.7 hr, t1/2 ~2.5 h - Apparent Vd = 1.2 L/kg, 93% bound to plasma proteins - Substrate for CYP1A2, CYP2C9 and CYP3A4 *(1A2 affected by smoking)* Adverse reactions - GI: dyspepsia (8%), elevated LFTs (2-5%) Precautions * - Active liver disease* - **LFTs before treatment begins**, monthly for the first 3 months, every 2-3 months for the remainder of the first year, and periodically thereafter - **Not a bronchodilator, not used for acute episodes of asthma**

Question 27

Zafirlukast (Accolate)

Answer 27

Description - Synthetic, selective peptide leukotriene receptor antagonist indicated for the **prophylaxis and chronic treatment of asthma** in adults and children 5 years of age and older; prophylaxis only - First example of the leukotriene receptor antagonists, FDA approved in 1996 Mechanism of action - **Antagonist at G protein-coupled cysteinyl leukotriene receptors (cysLT1)** in airway smooth muscles, mast cells, and neutrophils - Inhibits bronchoconstriction, edema, mucous secretion Pharmacokinetics - Supplied as 10 and 20 mg tablets for PO administration, usual adult dose is 20 mg BID. Rapidly absorbed, peak plasma concentrations are achieved in ~ 3 hr - **Food can reduce the bioavailability**; dosing should be with an empty stomach - Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin - Extensively metabolized by CYP3A4 and **CYP2C9**, mean plasma half-life is 8-16 hr - **Most excretion of metabolites is via the feces** with 10% excreted in the urine. Adverse reactions - Well-tolerated, adverse effects are rare; most common effects include headache, nausea, diarrhea; rare elevated LFTs. Precautions - **Hepatic status**: cirrhosis, acute hepatitis, cholestasis, alcoholism, smoking, age - **Not a bronchodilator, not used for acute episodes of asthma**

Question 28

Montelukast (Singulair)

Answer 28

Description - Used for **asthma maintenance therapy, prophylaxis only** - Also used for TX of allergic rhinitis Mechanism of action - **Antagonist at G protein-coupled cysteinyl leukotriene receptors (cysLT1)** in airway smooth muscles, mast cells, and neutrophils *(same action as zafirlukast)* - Inhibits bronchoconstriction, edema, mucous secretion Pharmacokinetics - Given PO, usual adult dose is 10 mg QD ***(better adherence because more potent and QD; convenience of dosing)*** - Rapidly absorbed; peak plasma concentration is achieved in 3-4 hr - Greater than 99% bound to plasma proteins resulting in a Vd of 8-11 L - Extensive hepatic metabolism via CYP3A4 and **CYP2C9** - Excreted almost exclusively in the bile with less than 0.2% excreted renally Adverse reactions - Rare: fever, indigestion, gastritis, cough Precautions - **Hepatic status**: cirrhosis, acute hepatitis, cholestasis, alcoholism, smoking, age - **Not a bronchodilator, not used for acute episodes of asthma**