Hypertensive Emergency Pharmacotherapy

• Non-pharmacologic management:
  • Close hemodynamic monitoring in ICU
  • Procedures to treat organ damage (e.g., revascularization for MI, ICP monitor for stroke)
  • Identify and discontinue causative agents if applicable
• Initial antihypertensive therapy:
  • Parenteral agents are preferred for predictable effects and easy titration
  • Continuous IV infusions ideal for tight BP control
  • Oral agents can be used if there is no IV access, but they are less predictable
  • IV labetalol, nicardipine, and nitroprusside are the most commonly used
  • Clevidipine emerging as an efficacious option

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Goals of Hypertensive Emergency

Definition and Goals

A hypertensive emergency is defined as severely elevated blood pressure (≥180/120 mmHg) associated with acute end-organ damage.

• In the first 1-2 hours, the goal is to reduce mean arterial pressure by about 10-15%.
• Over the next 24 hours, further gradual reduction targeting a total 25% reduction from baseline.
• For most patients, this results in a goal of <180/120 mmHg in the first hour and <160/110 mmHg over the next 24 hour

Goals for Specific Indications

• Aortic dissection: Rapidly lower SBP to 100-120 mmHg and heart rate less than 60-80 with IV beta blocker ± vasodilator to reduce shear stress.
• Preeclampsia/eclampsia: Lower BP by 25% over 2-6 hours using IV labetalol or hydralazine. Prevent seizures and other end-organ damage.
• Acute ischemic stroke: Avoid rapidly lowering BP unless >185/110 mmHg and candidate for thrombolysis. Goal is to maintain penumbra perfusion.
• Acute pulmonary edema: Goal is improvement in CHF and edema. Reduce BP by 10-15% using IV nitroglycerin and loop diuretic.
• Hypertensive encephalopathy: Lower BP by 10-25% over 24 hours. Use IV nicardipine, clevidipine, or nitroprusside
• Hemorrhagic Stroke: Goal is SBP 130-150

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Intravenous Antihypertensive Agents in Hypertensive Emergencies

1. Sodium Nitroprusside

• Direct vasodilator that provides smooth, titratable blood pressure reduction.
• Dose: Start at 0.25-0.5 mcg/kg/min, increase by 0.5 mcg/kg/min every 5 minutes, usual max 8-10 mcg/kg/min.
• Onset: Within seconds, peak effect in 1-2 minutes.
• Duration: 1-2 minutes after stopping infusion.
• Pharmacokinetics: Metabolized to cyanide which requires detoxification. Prolonged infusions or higher doses can lead to cyanide toxicity. Use lowest dose for shortest duration.
• Adverse Effects: Reflex tachycardia, nausea/vomiting, cyanide toxicity, thiocyanate toxicity with renal insufficiency.
• Avoid in: Cerebral edema/increased ICP as may increase ICP. Hepatic dysfunction and renal dysfunction increase risk of metabolite accumulation.
• Favored in: Rapid blood pressure control needed (except in setting of acute stroke). Widely available.

2. Nicardipine

• Dihydropyridine calcium channel blocker that blocks influx of calcium into vascular smooth muscle.
• Dose: Start at 5 mg/hour, increase by 2.5 mg/hour every 5 minutes, usual max 15 mg/hour.
• Onset: 5-15 minutes, peak effect in 15-30 minutes.
• Duration: 4-6 hours.
• Pharmacokinetics: Hepatic metabolism via CYP3A4.
• Adverse Effects: Reflex tachycardia, headache, flushing. High volumes of infusion fluid administered.
• Avoid in: Hepatic dysfunction.
• Favored in: Cerebral edema/increased ICP as doesn’t increase ICP like nitroprusside. Preferred agent in acute ischemic and hemorrhagic stroke.

3. Clevidipine

• Ultra-short acting dihydropyridine CCB, metabolized by esterases.
• Dose: Start at 1-2 mg/hour, double every 90 seconds until desired effect, max 32 mg/hour.
• Onset: 2-4 minutes.
• Duration: 5-15 minutes after stopping infusion.
• Pharmacokinetics: Esterase metabolism so no dose adjustments needed.
• Adverse Effects: Reflex tachycardia. Lipid emulsion can become contaminated.
• Avoid in: Egg or soy allergy.
• Favored in: Requires very rapid titration. Excellent for procedures requiring tight blood pressure control.

4. Nitroglycerin

• Venodilator that reduces preload. Higher doses cause arterial dilation.
• Dose: Start at 5 mcg/min, increase by 5-10 mcg/min every 5 minutes, usual max 100 mcg/min.
• Onset: 1-3 minutes.
• Duration: 5-10 minutes after stopping infusion.
• Pharmacokinetics: Degraded by glutathione. Tolerance develops within 24-48 hours.
• Adverse Effects: Hypotension, headache, reflex tachycardia.
• Avoid in: Inferior MI as venodilator effect can worsen ischemia.
• Favored in: Pulmonary edema/heart failure exacerbation. Helpful in ischemic chest pain.

5. Labetalol

• Combined alpha/beta blocker. Mostly beta blockade at low doses.
• Dose: 20-80 mg boluses every 10 minutes (max 300 mg), or continuous infusion starting at 1-2 mg/min.
• Onset: 5 minutes after bolus, peak at 5-15 minutes.
• Duration: 2-6 hours.
• Pharmacokinetics: Hepatic metabolism.
• Adverse Effects: Bradycardia, heart block, bronchospasm. Prolonged hypotension with overdose.
• Avoid in: Reactive airway disease, heart block, decompensated heart failure.
• Favored in: Aortic dissection when combined with vasodilator. Pregnancy-related hypertension.

6. Esmolol

• Short-acting beta-1 selective blocker.
• Dose: Loading dose optional. Infusion starting at 25-50 mcg/kg/min.
• Onset: 1-2 minutes.
• Duration: 10-20 minutes after stopping infusion.
• Pharmacokinetics: Rapid hydrolysis by red blood cell esterases.
• Adverse Effects: Hypotension, bradycardia.
• Avoid in: Heart block, decompensated heart failure.
• Favored in: Aortic dissection when combined with vasodilator. Very rapid blood pressure control needed.

7. Hydralazine

• Direct vasodilator – dilates arterioles and venous system.
• Dose: 10-20 mg IV bolus every 4-6 hours.
• Onset: 10-30 minutes.
• Duration: 4-8 hours.
• Pharmacokinetics: Hepatic acetylation, half-life highly variable.
• Adverse Effects: Reflex tachycardia, hypotension, headache, lupus-like syndrome.
• Avoid in: Coronary artery disease – can cause tachycardia and imbalance between myocardial oxygen supply and demand.
• Favored in: Limited mainly to pregnancy-related hypertension currently. Not ideal agent.

8. Fenoldopam

• Peripheral dopamine D1 receptor agonist. Vasodilates renal and other peripheral arteries.
• Dose: Start at 0.1 mcg/kg/min, titrate up to max 1.6 mcg/kg/min.
• Onset: 5 minutes, peak 15 minutes.
• Duration: 10-15 minutes after stopping infusion.
• Pharmacokinetics: Hepatic metabolism.
• Adverse effects: Headache, reflex tachycardia.
• Avoid in: Glaucoma.
• Favored in: Preserves renal blood flow. Not commonly used..

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Pharmacologic Agents in Hypertensive Emergency

Pharmacologic Agent	Dose	Onset	Duration	Adverse Effects	Avoid in	Favored in
Sodium Nitroprusside	Start at 0.25-0.5 mcg/kg/min, increase by 0.5 mcg/kg/min every 5 minutes, usual max 8-10 mcg/kg/min	Within seconds, peak effect in 1-2 minutes	1-2 minutes after stopping infusion	Reflex tachycardia, nausea/vomiting, cyanide toxicity, thiocyanate toxicity with renal insufficiency	Cerebral edema/increased ICP, hepatic dysfunction, renal dysfunction	Rapid blood pressure control needed (except in setting of acute stroke), widely available
Nicardipine	Start at 5 mg/hour, increase by 2.5 mg/hour every 5 minutes, usual max 15 mg/hour	5-15 minutes, peak effect in 15-30 minutes	4-6 hours	Reflex tachycardia, headache, flushing, high volumes of infusion fluid administered	Hepatic dysfunction	Cerebral edema/increased ICP, acute ischemic and hemorrhagic stroke
Clevidipine	Start at 1-2 mg/hour, double every 90 seconds until desired effect, max 32 mg/hour	2-4 minutes	5-15 minutes after stopping infusion	Reflex tachycardia, lipid emulsion can become contaminated	Egg or soy allergy	Requires very rapid titration, excellent for procedures requiring tight blood pressure control
Nitroglycerin	Start at 5 mcg/min, increase by 5-10 mcg/min every 5 minutes, usual max 100 mcg/min	1-3 minutes	5-10 minutes after stopping infusion	Hypotension, headache, reflex tachycardia	Inferior MI	Pulmonary edema/heart failure exacerbation, ischemic chest pain
Labetalol	20-80 mg boluses every 10 minutes (max 300 mg), or continuous infusion starting at 1-2 mg/min	5 minutes after bolus, peak at 5-15 minutes	2-6 hours	Bradycardia, heart block, bronchospasm, prolonged hypotension with overdose	Reactive airway disease, heart block, decompensated heart failure	Aortic dissection when combined with vasodilator, pregnancy-related hypertension
Esmolol	Loading dose optional. Infusion starting at 25-50 mcg/kg/min	1-2 minutes	10-20 minutes after stopping infusion	Hypotension, bradycardia	Heart block, decompensated heart failure	Aortic dissection when combined with vasodilator, very rapid blood pressure control needed
Hydralazine	10-20 mg IV bolus every 4-6 hours	10-30 minutes	4-8 hours	Reflex tachycardia, hypotension, headache, lupus-like syndrome	Coronary artery disease	Limited mainly to pregnancy-related hypertension currently
Fenoldopam	Start at 0.1 mcg/kg/min, titrate up to max 1.6 mcg/kg/min	5 minutes, peak 15 minutes	10-15 minutes after stopping infusion	Headache, reflex tachycardia	Glaucoma	Preserves renal blood flow, not commonly used

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• Transition to oral agent when hypertensive emergency is controlled
  • Re-initiate pre-admission oral regimen if applicable
  • Start new oral agent that can be continued outpatient
  • Overlap IV and oral agents, withdraw IV once stable on oral