HYPERTENSION Emergencies Urgencies

1. HYPERTENSIONEmergencies & Urgencies Stephen S. Levin, D.O.

2. Definitions Emergencies Symptomatic Acute End-Organ Damage Diastolic B.P. usually >130 mmHg Urgencies Asymptomatic NO Acute End-Organ Damage Diastolic B.P. usually >110 mmHg; Systolic B.P. usually >180 mmHg

5. Principles of Therapy Lower B.P. over hours Initial goal B.P. ? 160’s/90’s Too rapid lowering may cause dire consequences (CVA, MI) May take several days to get to reasonable levels Avoid medications that cannot be controlled (sublingual nifedipine)

6. Hypertensive Emergencies: Treatment For most patients the greatest risk of treating a hypertensive emergency is the risk of accompanying hypotension. Treat with short acting, easily titratable, I.V. drug.

7. Parenteral Drugs for Treatment of Hypertensive Emergencies

8. Parenteral Drugs for Treatment of Hypertensive Emergencies

9. Parenteral Drugs for Treatment of Hypertensive Emergencies

10. Parenteral Drugs for Treatment of Hypertensive Emergencies

11. Parenteral Drugs for Treatment of Hypertensive Emergencies

12. Parenteral Drugs for Treatment of Hypertensive Emergencies

13. Fenoldopam: Indications In-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end organ function. Transition to oral therapy with another agent can begin at any time after blood pressure is stable during fenoldopam infusion. SLIDE H2 The next several slides present essential information from the Corlopam package insert.SLIDE H2 The next several slides present essential information from the Corlopam package insert.

14. Physiologic Effects Fenoldopam SLIDE D6 Fenoldopam’s activation of dopaminergic receptors on the proximal and distal renal tubules inhibits sodium reabsorption and results in diuresis and natriuresis, whereas activation of the renal vascular receptors in both afferent and efferent glomerular arterioles results in an increase in renal blood flow. In general, glomerular filtration rate increases in hypertensive patients and is maintained in normotensive patients. Animal studies indicate that fenoldopam also causes vasodilation in the splanchnic and coronary vascular beds. A study in dogs with experimental occlusion of the left anterior descending coronary artery demonstrated that fenoldopam improved the perfusion of normal and ischemic borderline myocardium. A study in pigs demonstrated a dose-dependent increase in gut mucosal oxygenation with fenoldopam. References Shi Y, Zalewski A, Bravette B, et al. Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine. Am Heart J 1992;124:418-423. Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993;95:161-168. Germann R, Hasibeder W, Haisjackl M, et al. Dopamine-1-receptor stimulation and mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 1995;23:1560-1566.SLIDE D6 Fenoldopam’s activation of dopaminergic receptors on the proximal and distal renal tubules inhibits sodium reabsorption and results in diuresis and natriuresis, whereas activation of the renal vascular receptors in both afferent and efferent glomerular arterioles results in an increase in renal blood flow. In general, glomerular filtration rate increases in hypertensive patients and is maintained in normotensive patients. Animal studies indicate that fenoldopam also causes vasodilation in the splanchnic and coronary vascular beds. A study in dogs with experimental occlusion of the left anterior descending coronary artery demonstrated that fenoldopam improved the perfusion of normal and ischemic borderline myocardium. A study in pigs demonstrated a dose-dependent increase in gut mucosal oxygenation with fenoldopam. References Shi Y, Zalewski A, Bravette B, et al. Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine. Am Heart J 1992;124:418-423. Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993;95:161-168. Germann R, Hasibeder W, Haisjackl M, et al. Dopamine-1-receptor stimulation and mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 1995;23:1560-1566.

15. Fenoldopam Receptor Activity Selective peripheral dopamine-1 (DA1) receptor agonism Systemic vasodilation Regional vasodilation (especially renal) Renal proximal and distal tubular effects No binding to DA2 or beta-adrenergic receptors No alpha-adrenergic agonism, but is an alpha1 antagonist Does not cross blood brain barrier SLIDE E2 Fenoldopam is the product of an extensive search for a specific, peripherally acting dopamine-1 agonist. Dopamine is the parent compound, and by appropriate molecular modification, many of the undesirable properties—such as lack of receptor specificity of dopamine—were eliminated. Over 500 compounds were synthesized and phamacologically screened for activity as systemic and renal vasodilators. Fenoldopam was identified as having the optimal mix of potency, receptor specificity, and lack of effects on the central nervous system. The primary phamacological actions of fenoldopam are cardiovascular and renal. The drug does not inhibit or induce platelet aggregation and has no effect on the coagulation system. There are no data on the effects of fenoldopam on cerebral blood flow, but in the clinical trial experience, there is no evidence for a steal phenomenon in the cerebral or coronary circulation. Reference Weinstock J, Wilson JW, Ladd DL, Brenner M. Dopaminergic benzazepines with divergent cardiovascular profiles. Am Chem Soc Symp Ser 1996;224:L157-L167.SLIDE E2 Fenoldopam is the product of an extensive search for a specific, peripherally acting dopamine-1 agonist. Dopamine is the parent compound, and by appropriate molecular modification, many of the undesirable properties—such as lack of receptor specificity of dopamine—were eliminated. Over 500 compounds were synthesized and phamacologically screened for activity as systemic and renal vasodilators. Fenoldopam was identified as having the optimal mix of potency, receptor specificity, and lack of effects on the central nervous system. The primary phamacological actions of fenoldopam are cardiovascular and renal. The drug does not inhibit or induce platelet aggregation and has no effect on the coagulation system. There are no data on the effects of fenoldopam on cerebral blood flow, but in the clinical trial experience, there is no evidence for a steal phenomenon in the cerebral or coronary circulation. Reference Weinstock J, Wilson JW, Ladd DL, Brenner M. Dopaminergic benzazepines with divergent cardiovascular profiles. Am Chem Soc Symp Ser 1996;224:L157-L167.

16. Mechanism of Action of Fenoldopam SLIDE E3 When D1 receptors are stimulated, adenyl cyclase is activated, which in turn raises the intracellular concentration of cyclic adenosine monophosphate (cAMP). This biochemical signal leads to vascular smooth muscle relaxation, resulting in vasodilation. Vasodilation of systemic arteries lowers systemic vascular resistance, thus decreasing blood pressure. Localized vasodilation, most prominent in the cardiovascular and renal systems, may preserve blood flow in the face of reduced systemic blood pressure. References Brogden RN, Markham A. Fenoldopam: a review of its pharmacodymic and pharmacokinetic properties and intravenous clinical potential in the management of hypertensive urgencies and emergencies. Drugs 1997;54:634-650. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): The Pharmacological Basis of Therapeutics (9th ed). New York, McGraw-Hill, 1996:199-248. Mathur VS, Ellis D, Fellman J, Luther RR. Therapeutics for hypertensive urgencies and emergencies: fenoldopam, a novel systemic and renal vasodilator. Cardiovasc Rev Rep 1998, in press.SLIDE E3 When D1 receptors are stimulated, adenyl cyclase is activated, which in turn raises the intracellular concentration of cyclic adenosine monophosphate (cAMP). This biochemical signal leads to vascular smooth muscle relaxation, resulting in vasodilation. Vasodilation of systemic arteries lowers systemic vascular resistance, thus decreasing blood pressure. Localized vasodilation, most prominent in the cardiovascular and renal systems, may preserve blood flow in the face of reduced systemic blood pressure. References Brogden RN, Markham A. Fenoldopam: a review of its pharmacodymic and pharmacokinetic properties and intravenous clinical potential in the management of hypertensive urgencies and emergencies. Drugs 1997;54:634-650. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): The Pharmacological Basis of Therapeutics (9th ed). New York, McGraw-Hill, 1996:199-248. Mathur VS, Ellis D, Fellman J, Luther RR. Therapeutics for hypertensive urgencies and emergencies: fenoldopam, a novel systemic and renal vasodilator. Cardiovasc Rev Rep 1998, in press.

17. Fenoldopam Metabolism Metabolism via conjugation Metabolites pharmacologically inactive No cytochrome P450 interactions No known metabolic drug interactions 88% albumin bound Elimination: 90% urine, 10% feces No dose adjustment for renal or hepatic impairment SLIDE E5 Fenoldopam has excellent metabolic and safety profiles. Because metabolism is via hepatic conjugation, no dosage adjustment is necessary in hepatic failure. Fenoldopam is unusual because it has been demonstrated to maintain or improve renal blood flow and function while lowering blood pressure.SLIDE E5 Fenoldopam has excellent metabolic and safety profiles. Because metabolism is via hepatic conjugation, no dosage adjustment is necessary in hepatic failure. Fenoldopam is unusual because it has been demonstrated to maintain or improve renal blood flow and function while lowering blood pressure.

18. SLIDE E9 A number of studies have examined the pharmacokinetics of fenoldopam. It can be concluded that this agent has a very short half-life and a fairly rapid attainment of steady-state plasma levels (about 20 minutes or four half-lives). The steady state plasma concentrations attained when fenoldopam was infused at 0.1 µg/kg/min were similar in diverse patient populations. Plasma levels are predictable relative to dose, and there is no alteration in these kinetics over 48 hours of infusion. These kinetics are fairly similar to those seen with nitroprusside. Pharmacokinetics were not influenced by age, gender, or race in hypertensive emergency patients. Clearance of parent (active) drug is not altered in patients with end-stage renal disease on continuous ambulatory peritoneal dialysis, and is not affected, on average, in severe hepatic failure. The effects of hemodialysis on drug clearance have not been evaluated. SLIDE E9 A number of studies have examined the pharmacokinetics of fenoldopam. It can be concluded that this agent has a very short half-life and a fairly rapid attainment of steady-state plasma levels (about 20 minutes or four half-lives). The steady state plasma concentrations attained when fenoldopam was infused at 0.1 µg/kg/min were similar in diverse patient populations. Plasma levels are predictable relative to dose, and there is no alteration in these kinetics over 48 hours of infusion. These kinetics are fairly similar to those seen with nitroprusside. Pharmacokinetics were not influenced by age, gender, or race in hypertensive emergency patients. Clearance of parent (active) drug is not altered in patients with end-stage renal disease on continuous ambulatory peritoneal dialysis, and is not affected, on average, in severe hepatic failure. The effects of hemodialysis on drug clearance have not been evaluated.

19. SLIDE E10 Multiple studies have also examined the pharmcodynamics of fenoldopam. It has been demonstrated that the medication has a highly predictable hemodynamic effect based upon dose. The onset of that effect is quite rapid. With time, there is partial tolerance to its antihypertensive effects, similar to what is observed with nitroprusside. When fenoldopam is discontinued, no blood pressure rebound effect is observed.SLIDE E10 Multiple studies have also examined the pharmcodynamics of fenoldopam. It has been demonstrated that the medication has a highly predictable hemodynamic effect based upon dose. The onset of that effect is quite rapid. With time, there is partial tolerance to its antihypertensive effects, similar to what is observed with nitroprusside. When fenoldopam is discontinued, no blood pressure rebound effect is observed.

20. SLIDE E11 In summary, fenoldopam has a number of benefits such that it approaches an “ideal” agent for the treatment of hypertensive emergencies. Fenoldopam also has some advantages over nitroprusside, particularly in selected subsets of patients. Its use in patients with congestive heart failure or preexisting renal disease is particularly attractive.SLIDE E11 In summary, fenoldopam has a number of benefits such that it approaches an “ideal” agent for the treatment of hypertensive emergencies. Fenoldopam also has some advantages over nitroprusside, particularly in selected subsets of patients. Its use in patients with congestive heart failure or preexisting renal disease is particularly attractive.

21. Fenoldopam:Adverse Events Headache Flushing Nausea Hypotension Hypokalemia EKG Abnormalities Tachycardia Vomiting Dizziness Extrasystoles Dyspnea

22. Nicardipine: Characteristics Dihydropyridine Reflex tachycardia Useful when ß-Blockers contraindicated Water soluble and light stable (allows for IV infusion) Slow onset and offset Arterial catheter not mandatory May accumulate Variable duration of hypertensive effect Good in patients with renal disease SLIDE C15 Nicardipine is the first dihydropyridine calcium channel blocker to be available commercially in intravenous form. The half-life of the agent is relatively long (approximately 40 minutes). A potential disadvantage is the persistence of the arterial vasodilatory effect after discontinuation of the drug. Reference Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995;35:747-762. Kikura M, Levy JH. New cardiac drugs. Int Anesthesiol Clin 1995;33:21-37. SLIDE C15 Nicardipine is the first dihydropyridine calcium channel blocker to be available commercially in intravenous form. The half-life of the agent is relatively long (approximately 40 minutes). A potential disadvantage is the persistence of the arterial vasodilatory effect after discontinuation of the drug. Reference Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995;35:747-762. Kikura M, Levy JH. New cardiac drugs. Int Anesthesiol Clin 1995;33:21-37.

23. Nitroprusside Onset 1-4 min., half-life 1-2 min. Metabolized by RBC to cyanide then by liver to thiocyanate, cleared by kidneys Caution with hepatic &/or renal disease Toxicity related to total dose S&S: met. acidosis, confusion, air hunger, hyper-reflexia, confusion, and seizures. Reversible by hydroxycobalamine, sodium nitrate, (?) methylene blue

24. Therapy Hypertensive Urgencies Oral meds. Preferred Close monitoring Fast follow-up Start with short acting forms (not Ca+2 channel blockers)

25. Drugs for Urgencies Clonidine ?-Blockers, ??-? Blockers Captopril, Enalapril Minoxidil (if already on ?-blocker & diuretic) Hydralazine

26. Drug Related Malignant Hypertension MAO Inhibitors “Cold Preparations” Withdrawal Antihypertensive Meds Clonidine, ?-Blockers “Street Drugs” Cocaine, PCP