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

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In summary, hypertensive emergencies require prompt IV antihypertensive therapy with agents like nicardipine and labetalol that allow predictable titration. Clevidipine is emerging as an efficacious option for rapid BP reduction. Sodium nitroprusside can overcome nitrate tolerance but has risks with prolonged use. A transition to oral therapy can occur once the crisis is controlled.