ch04.qxd 336 8/13/2001 1:46 PM Page 336 C ARDIOVASCULAR D RUGS congestion, and flushing occur A syndrome similar to SLE with joint pain and skin rash (only rarely with cerebritis and nephritis) has been reported at an overall frequency of 6.7% in 281 patients over 51 months; daily dosage affects the frequency, with none at 50 mg/day, 5.4% at 100 mg/day, and 10.4% at 200 mg/day Women had a higher overall frequency than men (11.6 and 2.8%, respectively), and women taking 200 mg/day had a 19.4% rate; slow acetylator phenotype also can increase the risk; the syndrome is reversible with drug discontinuation, although residual effects can be detected years later.187 An immune complex glomerulonephritis has been reported in patients with hydralazine-induced SLE.188 Contraindications Coronary artery disease, mitral valvular rheumatic disease Precautions Reflex tachycardia can precipitate anginal attacks or ECG evidence of myocardial ischemia Drug Interactions NSAIDs can antagonize the hypotensive effect of hydralazine Parameters to Monitor Blood pressure and heart rate regularly Baseline and periodic CBC ANA titers can become positive after several months of therapy; routine monitoring is generally not warranted because the symptoms of hydralazineinduced SLE are characteristic and reversible with drug discontinuation Notes Reflex increases in heart rate, cardiac output, and stroke volume and increases in plasma renin activity and retention of sodium and water can attenuate the antihypertensive action of hydralazine; therefore, long-term regimens for hypertension should include a diuretic and a sympatholytic drug When hydralazine is used as an afterload-reducing drug in the treatment of CHF in patients on maintenance diuretics, the increase in cardiac output usually prevents the development of reflex tachycardia; likewise, hypotension is usually prevented by the increased cardiac output but can occur if myocardial reserves are inadequate or if the heart cannot respond by increasing output (eg, severe cardiomyopathy or aortic stenosis).185 LABETALOL HYDROCHLORIDE Normodyne, Trandate, Various Pharmacology Labetalol is an adrenergic receptor blocking drug that has selective ␣1- and nonselective ␤-adrenergic receptor blocking actions Although its pharmacologic profile resembles that of other ␤-blockers and the postsynaptic ␣1-adrenergic blocking action of prazosin, its ␤-blocking activity is approximately times greater than the ␣-blocking activity after oral administration and times greater after IV administration During long-term treatment, ␣-blocking activity is reduced even more.189,190 Administration and Adult Dosage PO for hypertension 100 mg bid initially, increasing at 2- to 3-day intervals in 100 mg bid increments until blood pressure is controlled Usual maintenance dosage is 200–400 mg bid, to a maximum of 1.2–2.4 g/day for severe hypertension IV for hypertension 20 mg by slow (2 min) injection, followed by 40–80 mg at 10-min intervals until blood pressure is controlled or to a total of 300 mg Alternatively, administer a dilute solution by continuous infusion at a rate of mg/min, to a maximum total dosage of 300 mg; the usual effective cumulative dosage is 50–200 mg; the infusion can be repeated q 6–8 hr.173,189,190 ch04.qxd 8/13/2001 1:46 PM Page 337 A NTIHYPERTENSIVE D RUGS 337 Special Populations Pediatric Dosage Safety and efficacy not established, but the following has been used: IV for hypertension 0.2–1 (average 0.55) mg/kg initially, followed by a continuous infusion of 0.25–1.5 (average 0.8) mg/kg/hr.191 Geriatric Dosage PO Initiate therapy with 50 mg bid.189 Other Conditions Titrate dosage to blood pressure control No dosage adjustment is required in renal impairment Patients with hepatic dysfunction might require lower than usual dosages Dosage Forms Tab 100, 200, 300 mg; Inj mg/mL Patient Instructions (See Antihypertensives Class Instructions.) Do not discontinue medication abruptly except under medical supervision Do not sit up or stand for hours after intravenous administration Pharmacokinetics Onset and Duration PO onset is within hr, peak in hr, and duration of 8–12 hr; can be longer with higher dosages IV injection onset 48 hr) or high-dosage (>10 ␮g/kg/min) infusions, when cyanide elimination is increased by the administration of thiosulfate, or in the presence of renal dysfunction To limit the risk of thiocyanate toxicity, infuse at 10 ␮g/kg/min) are infused rapidly or for longer than hr An early manifestation of cyanide toxicity can be apparent nitroprusside resistance, so increasing dosage requirements to achieve the same level of blood pressure control is an indication to look for metabolic acidosis, an indicator of cyanide toxicity, that might not be evident for more than hr after accumulation of dangerous cyanide levels Other symptoms of cyanide toxicity include dyspnea, vomiting, dizziness, loss of consciousness, weak pulse, distant heart sounds, areflexia, dilated pupils, shallow breathing, convulsions, and the occasional smell of bitter almonds on the breath Hydroxocobalamin (25 mg/hr by continuous infusion) can facilitate the conversion of cyanide to cyanocobalamin,209 but an appropriate hydroxocobalamin dosage form is unavailable Concurrent sodium thiosulfate administration also can prevent cyanide toxicity, but thiocyanate levels can increase.210 Management of cyanide toxicity includes immediate discontinuation of nitroprusside and the administration of sodium nitrite (0.2 mL/kg of a 3% solution IV over 2–4 min), followed by 12.5 g of sodium thiosulfate infused over 10 Methemoglobinemia can develop in patients congenitally unable to convert nitroprusside-induced methemoglobin back to hemoglobin Management consists of IV administration of methylene blue 1–2 mg/kg over several minutes Contraindications Compensatory hypertension (eg, arteriovenous shunt or coarctation of the aorta); controlled hypotension during surgery in patients with ch04.qxd 8/13/2001 1:46 PM Page 345 A NTIHYPERTENSIVE D RUGS 345 inadequate cerebral circulation; congenital (Leber’s) optic atrophy; use of sildenafil (See Drug Interactions.) Precautions If an adequate hypotensive response is not achieved after the maximum recommended infusion rate of 10 ␮g/kg/min for a maximum of 10 min, stop the infusion because these dosages increase the risk of toxicity Use with caution in renal, hepatic, or thyroid disease, and in vitamin B12 deficiency or elevated intracranial pressure Drug Interactions Use during general anesthesia can impair the capacity to compensate for hypovolemia and anemia and cause abnormal perfusion:ventilation ratio Use in patients taking sildenafil can result in profound hypotension with serious consequences, including death Parameters to Monitor Monitor blood pressure frequently (ie, every few minutes) because of the rapid onset and offset of effects Monitor thiocyanate levels after 24–48 hr in patients with normal renal function and daily in patients with impaired renal function or receiving large dosages However, these levels are of no value in detecting cyanide toxicity Monitoring of serum cyanide concentrations has been recommended, but the assay is technically difficult and not readily interpretable if fluids other than packed RBCs are analyzed Frequent monitoring of acid–base balance, particularly in patients with hepatic dysfunction, is considered adequate by most clinicians Notes Protect from light and discard solution after 24 hr or if the color changes from the usual faint brownish tint to blue, green, or dark red Do not administer IV push medications through the same line or use the solution for the simultaneous administration of any other drug OMAPATRILAT (Investigational—Bristol-Myers Squibb) Vanlev Pharmacology Omapatrilat is the first of a new class of drugs called vasopeptidase inhibitors Omapatrilat inhibits ACE and neutral endopeptidase, leading to blockades of the formation of angiotensin II and the breakdown of vasodilatory hormones such as natriuretic peptides, bradykinin, and adrenomedullin This results in vasodilation, natriuresis, and diuresis.211 Adult Dosage Not established Pharmacokinetics Oral absorption is rapid, with peak plasma concentrations occurring 0.5–2 hr postdose Biotransformation of the thiol group produces inactive metabolites; half-life is 14–19 hr; dosage adjustments are not necessary in renal dysfunction.211 Adverse Reactions Omapatrilat is well tolerated, with an adverse event profile similar to that of placebo The most commonly reported adverse reactions are hypotension (11%) and cough (about 10%) Flushing and syncope (about 1%) also have been reported, and angioedema is rare.211 Notes Omapatrilat produces greater blood pressure reductions than lisinopril in hypertensive patients and in one study reduced morbidity and mortality (not the primary endpoint) to a greater extent than lisinopril in patients with CHF.212,213 ch05.qxd 438 8/13/2001 2:00 PM Page 438 C ENTRAL N ERVOUS S YSTEM D RUGS Pharmacokinetics Onset and Duration Steady-state serum concentrations are attained in days in patients with normal renal function Serum Levels A therapeutic range has not been established.91 Fate The bioavailability of oral tablets is 80% compared with oral solution and peak concentrations occur 3.5 ± 0.6 hr after 400 mg.2 Administration with food delays absorption (by approximately hr) but does not affect extent of absorption.2 Topiramate is 13–17% bound to plasma proteins and binds to a saturable, low-capacity binding site on or in erythrocytes.85 Vd is 0.6–0.8 L/kg in healthy volunteers.2 Cl is 0.021 ± 0.004 L/kg/hr in adults on topiramate monotherapy after tapering of valproic acid.91 Approximately 70% is eliminated unchanged in urine Six metabolites (each 100–150 mg/L.2 Fate The bioavailability of the oral capsule is 93 ± 13%, with peak levels occurring 1–2 hr after the dose The bioavailability of the EC divalproex tablet is ch05.qxd 440 8/13/2001 2:00 PM Page 440 C ENTRAL N ERVOUS S YSTEM D RUGS 90 ± 14%, with peak levels in hr.2,96 The peak time of both is delayed by food: (Cap) 5.2 ± 1.7 hr; (EC divalproex tab) 8.1 ± 3.6 hr.97 Bioavailability of the SR tab is 80–90% of the EC product Bioavailability is 80 ± 7% after a 250 mg suppository.98 Peak serum levels of 40–50 mg/L (280–350 ␮mol/L) occur 2–4 hr after a 15–20 mg/kg dose of syrup diluted 1:1 with water as a retention enema.11 Vd is 0.19 ± 0.05 L/kg in adults and 0.26 ± 0.09 L/kg in children.2 Plasma protein binding is about 90%.96 Increasing serum concentrations, hypoalbuminemia, severe liver disease, renal disease, or pregnancy reportedly increases the unbound fraction and might alter clearance Cl is (healthy adults) 0.0066 ± 0.0005 L/hr/kg; (epileptic adults) 0.018 ± 0.011 L/hr/kg; (children) 0.027 ± 0.015 L/hr/kg.2 Over 96% is metabolized to at least 10 metabolites Only 1.8–3.2% of drug is excreted unchanged in urine.2 t¹⁄₂ (Healthy adults) 13.9 ± 3.4 hr; (epileptic adults) 8.5 ± 3.3 hr; (children) 7.2 ± 2.3 hr.2 Adverse Reactions (See Serum Levels.) Nausea, vomiting, diarrhea, and abdominal cramps occur frequently during initiation of therapy and are minimized by slow titration of valproic acid or substitution of EC divalproex for valproic acid Transient elevations in liver function tests occur frequently The risk of valproateexposed women having children with spina bifida is approximately 1–2% Drowsiness, ataxia, tremor, behavioral disturbances, transient hair loss, asymptomatic hyperammonemia, or weight gain occurs occasionally Drowsiness and ataxia are more prominent in patients taking valproic acid with other anticonvulsants.2 Rarely, thrombocytopenia, acute pancreatitis, abnormal coagulation parameters, or hyperglycinemia occurs Liver failure occurs rarely; the greatest risk is during the first months of therapy and in children 90% of patients when asked directly rather than relying on self-reporting.114 Seizures occur in 0.5% of patients receiving 250 mg/day or less, and 2% of patients experience seizures with dosages above 250 mg/day Clomipramine is contraindicated in patients who have received MAOIs within the past 14 days Use with caution in patients with cardiovascular disease (eg, arrhythmias, angina, MI) Drug Interactions Drug interactions are the same as other tricyclic antidepressants (TCAs) (See Heterocyclic Antidepressants.) FLUOXETINE Prozac, Sarafem Pharmacology Fluoxetine is a bicyclic antidepressant that is a selective and potent inhibitor of presynaptic reuptake of serotonin (an SSRI) It does not affect reuptake of norepinephrine or dopamine and has a relative lack of affinity for muscarinic, histamine, ␣1- and ␣2-adrenergic, and serotonin receptors.115 Administration and Adult Dosage (See Antidepressants Comparison Chart.) PO for depression or OCD 20 mg/day initially, administered in the morning Increase dosage no more frequently than q 3–5 weeks Divide higher dosages, with the last dose given in early afternoon Although the maximum labeled dosage is 80 mg/day, 20 mg is equal in efficacy for major depression to higher dosages with the benefit of fewer adverse effects.115,116 For depression maintenance, Prozac Weekly 90 mg once/week can be started one week after the last 20 mg/day dose PO for bulimia 60 mg/day in the morning PO for premenstrual dysphoric disorder 20 mg/day; higher dosages appear to have no increased efficacy Administration for the 14 days before menses can be as effective as continuous use.117 Special Populations Pediatric Dosage (