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Center for Clinical Pharmacology

Department of Medicine
University of Pittsburgh School of Medicine

Antihypertensive Drugs
PART II
Antihypertensive Drugs for Hypertensive
Crisis
Stevan P. Tofovic MD, PhD, FAHA, FASN
tofovic@dom.pitt.edu
412-648-3363
Antihypertensive Drugs for
Hypertensive Crisis

 Hypertensive Crisis:

Arbitrarily defined as a severe elevation of blood
pressure (i.e., DBP > 120 mmHg) which, if not treated
promptly, will result with high morbidity and mortality.
Antihypertensive Drugs for
Hypertensive Crisis

 Hypertensive Emergency:
Severe elevation in blood pressure in the presence of
acute or ongoing end-organ damage.

 Hypertensive Urgency:
Severe elevation of blood pressure in the absence of
target-organ involvement
Hypertensive Emergencies
Key Points
 The diagnosis of hypertensive emergency is based
more on the clinical state of the patient rather than on
the absolute level of blood pressure per se.

 Sometimes the absolute level of blood pressure (i.e.,
>250/150 mm Hg), or the rate of rise of BP may
constitute an emergency because of the risk of
developing hypertensive encephalopathy, intracerebral
hemorrhage, or acute congestive heart failure
Hypertensive Emergency
Key Points
 CNS Emergencies
• Hypertensive encephalopathy; • Intracerebral or subarachnoidal
hemorrhage; • Thrombotic brain infarction with severe HTN

 Cardiac Emergencies
• Acute CHF; • Acute coronary insufficiency; • Aortic dissection;
• Post vascular surgery HTN

 Renal Emergencies
• Severe HTN with rapidly progressive renal failure
• Rapidly rising BP with rapidly progressive glomerulonephritis
Hypertensive Emergency
Key Points
 Be cautions but aggressive

 Distinguish from situations where rapid BP reduction is
not necessary or may be even hazardous

 Treatment may be necessary based on a presumptive
diagnosis (i.e., before results of laboratory tests are
done)

 Select an agent that allows for “titration” of BP
Antihypertensive Drugs for
Hypertensive Crisis
Given by continuous infusion
 Sodium nitroprusside

 Nitroglycerin

 Nicardipine

 Labetalol

 Esmolol

 Fenoldapam
SODIUM NITROPRUSSIDE (SNP)

Mechanism of action

Venules
Light chain of myosin
guanylil cyclase cGMP
VSMCs dephosphorylation

NO
Arterioles
SNP CN
SODIUM NITROPRUSSIDE (SNP)

 Very short half-life (t1/2 = 2 min)

 Administered by a computerized continuous
infusion device utilizing continuous intra-
arterial blood pressure monitoring

 Onset of action within 30 seconds; maximal
hypotensive effect within 2-3mn; the effect
disappears 3-5 min after infusion is stopped.

 Usually causes moderate increase in heart
rate
SODIUM NITROPRUSSIDE (SNP)

 Decreases pre-load (venodilatation) and
after-load (arteriolar dilatation) to a similar
degree

 In hypertensive patients reduces cardiac
output (CO) and increases heart rate.

 In patients with heart failure SNP increases
CI, CO and SV and reduces heart rate.
SODIUM NITROPRUSSIDE (SNP)

Side Effects
 Conversion to NO generates cyanide which, in
the liver is converted to thiocyanate. Thiocyantes
are eliminated by urine

 Risk of toxicity
 Doses >2µg/kg/min,
 Prolonged administration >24-48h
 Renal insufficiency

 Tachycardia, “Coronary steal”
 Hypoxemia
 Increased velocity of ventricular ejection (in
patients with aortic dissection)
SODIUM NITROPRUSSIDE (SNP)

MAY NOT BE THE DRUG OF CHO
In patients with
 Acute coronary insufficiency

 Aortic dissection

 Severe pre-eclampsia and eclampsia

 Severe liver or kidney disease

 Increased intracranial pressure

 Hyponatremia

 Chronic Obstructive Pulmonary Disease
COPD
INTRAVENOUS NITROGLYCERIN
(NTG)

Lower concentrations
Mechanism of action

NTG NO Venules

Light chain of myosin
guanylil cyclase cGMP
VSMCs dephosphorylation

Arterioles

Higher concentrations
INTRAVENOUS NITROGLYCERIN
(NTG)

 Short half-life (t1/2 ~ 3 min)

 Special plastic tubing needed

 Redistribution of blood flow to subendocardial region
(not typical for other vasodilators)

 Venous pooling first, arteriolar dilation later
INTRAVENOUS NITROGLYCERIN
(NTG)

 Shares many of the advantages of nitroprusside
 Does not affect coronary blood flow (CBF) auto-
regulation, and even produces favorable CBF
redistribution
 No risk of cyanide or thiocyanate toxicity
 Produces less hypoxemia than nitroprusside
 Tolerance develops after prolonged use
INTRAVENOUS NITROGLYCERIN
(NTG)

MAY BE THE DRUG OF CHOICE

 Post coronary bypass hypertension
 Acute coronary insufficiency
 Acute CHF when BP is only slightly increased
INTRAVENOUS NITROGLYCERIN
(NTG)
Side Effects
May not be the drug of choice in patients
 Increased intracranial pressure
 Glaucoma
 Severe anemia (methemoglobin)
 Constrictive pericarditis
 Pregnancy category C drug
NICARDIPINE

 Dihydropyridine CCB
 Used for:
 Postoperative hypertension
 Hypertension with increase intracranial pressure
 Presumably more selective for cerebral and
coronary blood vessels
 Similar pharmacological profile with other CCBs
 Dose: 2mg bolus followed by 10-15 mg/hr
FENOLDOPAM
[CORLOPAM®]

 Agonist of dopamine D1 receptors
 Peripheral arterial dilation and natriuresis
 Reduced BP and vascular resistance, while RBF is
increased
 Hypertensive emergency; Postoperative
hypertension
 Adverse effects dose related: Flushing, headache,
nausea vomiting, tachycardia
 Dose: 0.1-0.3 mcg/kg/min
ESMELOL
[BREVIBLOCK®]

 Selective β1 adrenergic receptor antagonist
 Short half-life (terminal t ½ = 9 minutes)
 Beta-blockade disappears within 20 min after
discontinuation of infusion
 Used for intra or postoperative hypertension and
for control of certain supraventricular arrhythmias.
AGENTS GIVEN BY INTERMITTENT IV
INJECTION

 Labetalol
 Enalaprilat

 Hydralazine

 Diazoxide
LABETALOL

 Combined α1 and β receptor antagonist

 Onset of action - 3 to 5 minutes

 Duration of action variable – 3-6 hours

 20-80mg IV bolus every 10-20 minutes
LABETALOL

 Adverse effects: Vomiting, scalp tingling,
bronchoconstriction, dizziness, heart block

 In pheochromocytoma may induced paradoxical rise in
BP

 Contraindications - same as with other β blockers

 Should not be used in HTN crisis with acute heart failure
ENALAPRILAT

 Active metabolites (“post-drug”) of enalapril

 Primary indication is for prevention or management
of postoperative hypertension in hypertensive
patients previously treated with an ACE inhibitor

 -Dose: 0.625-1.25 mg Q6H
HYDRALAZINE
[APRESOLINE® ]

 Direct vasodilating agent (arterioles)

 Reduces TPVR; Reflex increase in HR and

 Onset of action 3-5 minutes, duration 2-5 h

 For HTN crisis associated with preeclamps
DIAZOXIDE
[HYPERSTAT®; PROGLYCEM®

 Direct vasodilating agent; Activates K+ chan

 Reduces TPVR; Reflex increase in HR and

 Onset of action 3-5 minutes, duration variab

 Increases blood glucose levels

 Rarely used as IV agent for treatment of HT