1. HYPERTENSION Emergencies & Urgencies Stephen S. Levin, D.O.

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

3. Begin Treatment! This is a Hypertensive Emergency Begin to look for other causes of symptoms

5. Principles of Therapy Lower B.P. over hours Lower B.P. over hours Initial goal B.P. Initial goal B.P.  160’s/90’s Too rapid lowering may cause dire consequences (CVA, MI) Too rapid lowering may cause dire consequences (CVA, MI) May take several days to get to reasonable levels May take several days to get to reasonable levels Avoid medications that cannot be controlled (sublingual nifedipine) Avoid medications that cannot be controlled (sublingual nifedipine) Lower B.P. over hours Lower B.P. over hours Initial goal B.P. Initial goal B.P.  160’s/90’s Too rapid lowering may cause dire consequences (CVA, MI) Too rapid lowering may cause dire consequences (CVA, MI) May take several days to get to reasonable levels May take several days to get to reasonable levels Avoid medications that cannot be controlled (sublingual nifedipine) 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. 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. Treat with short acting, easily titratable, I.V. drug. For most patients the greatest risk of treating a hypertensive emergency is the risk of accompanying hypotension. 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. Treat with short acting, easily titratable, I.V. drug.

7. Parenteral Drugs for Treatment of Hypertensive Emergencies DrugDosageOnsetDurationAdverseEffectsIndic.(I)Contrain.(C) Vasodilators Nitroprus- side 0.3-10 mcg/kg/min IV infusion 1-2 min. N/V,mus. twitch., cyanide, thiocyan. tox. intracran. intracran.pressure I: CHF, aortic dissect., catechol. catechol. C: hepatic, renal insuff. Nitrogly- cerin (IV ) 5-100mcg/kg/min 2-5 min. 3-5 min. HA, dizziness, vomit.,methemglo.tolerance I: coronary dis., CHF C: CVA intracran. pressure intracran. pressure

8. Parenteral Drugs for Treatment of Hypertensive Emergencies Diazoxide ( Hyperstat IV) IV) 1-3 mg/kg (up to 150 mg) IV bolus, q5- 15 min; repeat q4- 24 hr as needed 2-4 min 3-12 hr Nausea, hypotension, flushing, tachycardia, hypergly- cemia, aggravation of angina, fluid retention C: Syndromes of coronary insufficiency, (unless used with beta- blocking agent), cerebrovascul ar accident, hypersensi- tivity to sulfonamides

9. Parenteral Drugs for Treatment of Hypertensive Emergencies Fenoldopam mesylate ( Corlopam ) 0.1-1.7 micrograms/kg/min IV infusion 5-15 min 1-4 hr Headache, dizziness, flushing, increased intraocular pressure, hypokalemia, dose-related tachycardia I: Severe hyperten- sion with renal insuffi- ciency C: Glaucoma Hydralazine HCl (Apresoline) 10-20 mg IV or IM bolus, repeat q4-6 hr as needed (maximum dose, 40 mg) 10-20 min 3-8 hr Tachycardia, flushing, headache, vomiting, aggravation of angina I: CHF C: Coronary insufficiency, aortic dissection, cerebrovas- cular accident (may increase intracranial pressure)

10. Parenteral Drugs for Treatment of Hypertensive Emergencies Enalaprilat (Vasotec I.V.) 1.25-5 mg q6 hr IV 15min 6 hr Precipitous drop in blood pressure in high-renin states, variable response I: CHF C: Use with caution in patients with severe renal insufficiency (not receiving dialysis ) Nicardipine HCl (Cardene) 5-15 mg/hr IV infusion 5-20 min 1-2 hr Tachycardia, headache, flushing, local phlebitis C: Greater than first- degree heart block, CHF

11. Parenteral Drugs for Treatment of Hypertensive Emergencies Adrenergic Inhibitors Phentol- amine (Regitine)  -blocker 5-20 mg IV, repeat as necessary 1-2 min 10-30 min Tachycardia, nausea, flushing, abdominal pain, aggravation of angina I: Catecholamine excess C: Syndromes of coronary insufficiency Esmolol HCl (Brevibloc) 200-500 micrograms/kg/ min over 1-4 min, then 50-300 micrograms/kg/ min IV infusion 1-2min10-20min Hypotension, nausea, bradycardia or heart block, dizziness I: Syndromes of coronary insufficiency C: Greater than first-degree heart block, CHF

12. Parenteral Drugs for Treatment of Hypertensive Emergencies Labetalol HCl (Normo- dyne, Trandate)  -  blocker 20-80 mg IV bolus, repeat as needed (maximu m dose, 300 mg); or 2 mg/min IV infusion 2-10 min 2-4 hr Hypoten- sion, nausea, itching, scalp tingling, dizziness I: Synd- romes of coronary insuffi- ciency, catechol- amine excess C: > first- degree heart block, CHF, bronchial asthma

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. 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.

14. Physiologic Effects Fenoldopam Systemic Vasodilation Does not cross BBB Coronary Vasodilation Coronary Vasodilation without “steal” without “steal” (in animals) (in animals) Reflex tachycardia Reflex tachycardia Metabolized by conjugation Metabolized by conjugation No P450 interaction No P450 interaction  RBF  RBF  Na excretion  Na excretion  H 2 O excretion  H 2 O excretion Maintains GFR during BP lowering Maintains GFR during BP lowering Mesenteric vasodilation Mesenteric vasodilation  Mucosal PO 2  Mucosal PO 2 (in animals) (in animals)

15. Fenoldopam Receptor Activity Selective peripheral dopamine-1 (DA 1 ) receptor agonism Systemic vasodilation Regional vasodilation (especially renal) Renal proximal and distal tubular effects No binding to DA 2 or beta-adrenergic receptors No binding to DA 2 or beta-adrenergic receptors No alpha-adrenergic agonism, but is an alpha 1 antagonist No alpha-adrenergic agonism, but is an alpha 1 antagonist Does not cross blood brain barrier Does not cross blood brain barrier Selective peripheral dopamine-1 (DA 1 ) receptor agonism Systemic vasodilation Regional vasodilation (especially renal) Renal proximal and distal tubular effects No binding to DA 2 or beta-adrenergic receptors No binding to DA 2 or beta-adrenergic receptors No alpha-adrenergic agonism, but is an alpha 1 antagonist No alpha-adrenergic agonism, but is an alpha 1 antagonist Does not cross blood brain barrier Does not cross blood brain barrier

16. Mechanism of Action of Fenoldopam Fenoldopam infusion Selective stimulation of D 1 -dopamine receptors Adenylyl cyclase activation Increase in intracellular concentration of cAMP Vascular smooth muscle relaxation Vasodilation of renal arteries Vasodilation of coronary arteries Vasodilation of mesenteric arteries Vasodilation of systemic arteries Maintenance of blood flow to vital organs Decrease in systemic vascular resistance Decrease in blood pressure Direct increase in sodium excretion

17. Fenoldopam Metabolism Metabolism via conjugation Metabolism via conjugation Metabolites pharmacologically inactive Metabolites pharmacologically inactive No cytochrome P 450 interactions No cytochrome P 450 interactions No known metabolic drug interactions No known metabolic drug interactions 88% albumin bound 88% albumin bound Elimination: 90% urine, 10% feces Elimination: 90% urine, 10% feces No dose adjustment for renal or hepatic impairment No dose adjustment for renal or hepatic impairment Metabolism via conjugation Metabolism via conjugation Metabolites pharmacologically inactive Metabolites pharmacologically inactive No cytochrome P 450 interactions No cytochrome P 450 interactions No known metabolic drug interactions No known metabolic drug interactions 88% albumin bound 88% albumin bound Elimination: 90% urine, 10% feces Elimination: 90% urine, 10% feces No dose adjustment for renal or hepatic impairment No dose adjustment for renal or hepatic impairment

18. t ½ (~ 5 min)  t ½ (~ 5 min)  Small volume of distribution  Rapid attainment of steady state (~ 30 min)  Plasma concentrations proportional to dose  No alteration in pharmacokinetics over 48 hr infusion 48 hr infusion  Rapid elimination upon discontinuation Fenoldopam: Pharmacokinetics

19. Predictable hemodynamic effect Predictable hemodynamic effect  Rapid onset of effect  Predictable dose response for lowering BP  No rebound hypertension Fenoldopam: Pharmacodynamics

20. Rapid, predictable, dose-dependent blood pressure decrease (without overshoot)  Rapid, predictable, dose-dependent blood pressure decrease (without overshoot)  Short t ½, rapid attainment of steady state titration  Linear pharmacokinetics  No cytochrome P 450 interactions  Dose-response curves well defined  No dosing adjustment for pre-existing renal or hepatic impairment  Increases renal blood flow and maintains GFR  Ease of use Fenoldopam: Potential Benefits

21. Fenoldopam: Adverse Events HeadacheFlushingNauseaHypotensionHypokalemiaHeadacheFlushingNauseaHypotensionHypokalemia EKG Abnormalities TachycardiaVomitingDizzinessExtrasystolesDyspnea

22. Nicardipine: Characteristics Dihydropyridine Reflex tachycardia Useful when β-Blockers contraindicated Water soluble and light stable (allows for IV infusion) (allows for IV infusion)Dihydropyridine Reflex tachycardia Useful when β-Blockers contraindicated Water soluble and light stable (allows for IV infusion) (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

23. NitroprussideNitroprusside Onset 1-4 min., half-life 1-2 min. Onset 1-4 min., half-life 1-2 min. Metabolized by RBC to cyanide then by liver to thiocyanate, cleared by kidneys Metabolized by RBC to cyanide then by liver to thiocyanate, cleared by kidneys Caution with hepatic &/or renal disease Caution with hepatic &/or renal disease Onset 1-4 min., half-life 1-2 min. Onset 1-4 min., half-life 1-2 min. Metabolized by RBC to cyanide then by liver to thiocyanate, cleared by kidneys Metabolized by RBC to cyanide then by liver to thiocyanate, cleared by kidneys Caution with hepatic &/or renal disease Caution with hepatic &/or renal disease Toxicity related to total dose 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 Oral meds. Preferred Close monitoring Close monitoring Fast follow-up Fast follow-up Start with short acting forms Start with short acting forms (not Ca +2 channel blockers) Oral meds. Preferred Oral meds. Preferred Close monitoring Close monitoring Fast follow-up Fast follow-up Start with short acting forms Start with short acting forms (not Ca +2 channel blockers)

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

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