Stevan P. Tofovic MD, PhD, FAHA, FASNStevan P. Tofovic MD, PhD, FAHA, [email protected]
412-648-3363412-648-3363
Center for Clinical Pharmacology Department of Medicine
University of Pittsburgh School of Medicine
Antihypertensive Drugs for Hypertensive Antihypertensive Drugs for Hypertensive CrisisCrisis
Antihypertensive DrugsAntihypertensive DrugsPART II PART II
Antihypertensive Drugs for Antihypertensive Drugs for Hypertensive CrisisHypertensive Crisis
Hypertensive Crisis:
Arbitrarily defined as a severe elevation of blood Arbitrarily defined as a severe elevation of blood pressure (i.e., DBP > 120 mmHg) which, if not treated pressure (i.e., DBP > 120 mmHg) which, if not treated promptly, will result with high morbidity and mortality.promptly, will result with high morbidity and mortality.
Antihypertensive Drugs for Antihypertensive Drugs for Hypertensive CrisisHypertensive Crisis
Hypertensive Emergency: Severe elevation in blood pressure in the presence of Severe elevation in blood pressure in the presence of acute or ongoing end-organ damage.acute or ongoing end-organ damage.
Hypertensive UrgencyHypertensive Urgency:: Severe elevation of blood pressure in the absence of Severe elevation of blood pressure in the absence of target-organ involvementtarget-organ involvement
Hypertensive EmergenciesHypertensive EmergenciesKey PointsKey Points
The diagnosis of hypertensive emergency is based The diagnosis of hypertensive emergency is based more on the clinical state of the patient rather than on more on the clinical state of the patient rather than on the absolute level of blood pressure the absolute level of blood pressure per se.per se.
Sometimes the absolute level of blood pressure (i.e., Sometimes the absolute level of blood pressure (i.e., >250/150 mm Hg), or the rate of rise of BP may >250/150 mm Hg), or the rate of rise of BP may constitute an emergency because of the risk of constitute an emergency because of the risk of developing hypertensive encephalopathy, intracerebral developing hypertensive encephalopathy, intracerebral hemorrhage, or acute congestive heart failurehemorrhage, or acute congestive heart failure
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 EmergenciesRenal Emergencies• Severe HTN with rapidly progressive renal failure Severe HTN with rapidly progressive renal failure • Rapidly rising BP with rapidly progressive glomerulonephritisRapidly rising BP with rapidly progressive glomerulonephritis
Hypertensive EmergencyHypertensive EmergencyKey PointsKey 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 Treatment may be necessary based on a presumptive diagnosis (i.e., before results of laboratory tests are diagnosis (i.e., before results of laboratory tests are done) done)
Select an agent that allows for “titration” of BP
Hypertensive EmergencyHypertensive EmergencyKey PointsKey Points
Given by continuous infusionGiven by continuous infusion Sodium nitroprussideSodium nitroprusside NitroglycerinNitroglycerin Nicardipine Nicardipine LabetalolLabetalol EsmololEsmolol FenoldapamFenoldapam
Antihypertensive Drugs for Antihypertensive Drugs for Hypertensive CrisisHypertensive Crisis
SODIUM NITROPRUSSIDE (SNP)
SNPSNPNONO
guanylil cyclaseguanylil cyclase cGMPcGMP
Venules
Arterioles
VSMCsVSMCs
Mechanism of action
Light chain of myosin Light chain of myosin dephosphorylationdephosphorylation
CNCN
SODIUM NITROPRUSSIDE (SNP)
Very short half-life (tVery short half-life (t1/21/2 = 2 min) = 2 min)
Administered by a computerized continuous Administered by a computerized continuous infusion device utilizing continuous intra-arterial infusion device utilizing continuous intra-arterial blood pressure monitoringblood pressure monitoring
Onset of action within 30 seconds; maximal Onset of action within 30 seconds; maximal hypotensive effect within 2-3mn; the effect hypotensive effect within 2-3mn; the effect disappears 3-5 min after infusion is stopped. disappears 3-5 min after infusion is stopped.
Usually causes moderate increase in heart rate Usually causes moderate increase in heart rate
SODIUM NITROPRUSSIDE (SNP)
Decreases pre-load (venodilatation) and after-load Decreases pre-load (venodilatation) and after-load (arteriolar dilatation) to a similar degree(arteriolar dilatation) to a similar degree
In hypertensive patients reduces cardiac output In hypertensive patients reduces cardiac output (CO) and increases heart rate.(CO) and increases heart rate.
In patients with heart failure SNP increases CI, CO In patients with heart failure SNP increases CI, CO and SV and reduces heart rate.and SV and reduces heart rate.
SODIUM NITROPRUSSIDE (SNP)
Conversion to NO generates cyanide which, in Conversion to NO generates cyanide which, in the liver is converted to thiocyanate. Thiocyantes the liver is converted to thiocyanate. Thiocyantes are eliminated by urineare eliminated by urine
Risk of toxicity Risk of toxicity Doses >2Doses >2g/kg/min, g/kg/min, Prolonged administration >24-48hProlonged administration >24-48h Renal insufficiencyRenal insufficiency
Tachycardia, “Coronary steal” Tachycardia, “Coronary steal” HypoxemiaHypoxemia Increased velocity of ventricular ejection (in Increased velocity of ventricular ejection (in
patients with aortic dissection)patients with aortic dissection)
Side Effects
SODIUM NITROPRUSSIDE (SNP)
MAY MAY NOTNOT BE THE DRUG OF CHOICE BE THE DRUG OF CHOICE
In patients with In patients with Acute coronary insufficiencyAcute coronary insufficiency Aortic dissectionAortic dissection Severe pre-eclampsia and eclampsiaSevere pre-eclampsia and eclampsia Severe liver or kidney diseaseSevere liver or kidney disease Increased intracranial pressureIncreased intracranial pressure Hyponatremia Hyponatremia Chronic Obstructive Pulmonary Disease COPD Chronic Obstructive Pulmonary Disease COPD
NONO Venules
Arterioles
Mechanism of action
INTRAVENOUS NITROGLYCERIN INTRAVENOUS NITROGLYCERIN (NTG)(NTG)
NTGNTG
Lower concentrationsLower concentrations
Higher concentrationsHigher concentrations
guanylil cyclaseguanylil cyclase cGMPcGMPVSMCsVSMCsLight chain of myosin Light chain of myosin
dephosphorylationdephosphorylation
Short half-life (t1/2 ~ 3 min) Short half-life (t1/2 ~ 3 min)
Special plastic tubing neededSpecial plastic tubing needed
Redistribution of blood flow to subendocardial region Redistribution of blood flow to subendocardial region (not typical for other vasodilators) (not typical for other vasodilators)
Venous pooling first, arteriolar dilation later Venous pooling first, arteriolar dilation later
INTRAVENOUS NITROGLYCERIN INTRAVENOUS NITROGLYCERIN (NTG)(NTG)
Shares many of the advantages of nitroprussideShares many of the advantages of nitroprusside
Does not affect coronary blood flow (CBF) auto-Does not affect coronary blood flow (CBF) auto-regulation, and even produces favorable CBF regulation, and even produces favorable CBF redistributionredistribution
No risk of cyanide or thiocyanate toxicityNo risk of cyanide or thiocyanate toxicity
Produces less hypoxemia than nitroprusside Produces less hypoxemia than nitroprusside
Tolerance develops after prolonged use Tolerance develops after prolonged use
INTRAVENOUS NITROGLYCERIN INTRAVENOUS NITROGLYCERIN (NTG)(NTG)
MAY BE THE DRUG OF CHOICEMAY BE THE DRUG OF CHOICE
Post coronary bypass hypertensionPost coronary bypass hypertension Acute coronary insufficiencyAcute coronary insufficiency Acute CHF when BP is only slightly increased Acute CHF when BP is only slightly increased
INTRAVENOUS NITROGLYCERIN INTRAVENOUS NITROGLYCERIN (NTG)(NTG)
Side Effects
INTRAVENOUS NITROGLYCERIN INTRAVENOUS NITROGLYCERIN (NTG)(NTG)
May May not not be the drug of choice in patients withbe the drug of choice in patients with
Increased intracranial pressureIncreased intracranial pressure GlaucomaGlaucoma Severe anemia (methemoglobin)Severe anemia (methemoglobin) Constrictive pericarditisConstrictive pericarditis Pregnancy category C drug Pregnancy category C drug
NICARDIPINE
Dihydropyridine CCBDihydropyridine CCB Used for:Used for:
Postoperative hypertensionPostoperative hypertension Hypertension with increase intracranial pressureHypertension with increase intracranial pressure
Presumably more selective for cerebral and Presumably more selective for cerebral and coronary blood vesselscoronary blood vessels
Similar pharmacological profile with other CCBsSimilar pharmacological profile with other CCBs Dose: 2mg bolus followed by 10-15 mg/hrDose: 2mg bolus followed by 10-15 mg/hr
FENOLDOPAM
Agonist of dopamine DAgonist of dopamine D11 receptors receptors Peripheral arterial dilation and natriuresisPeripheral arterial dilation and natriuresis Reduced BP and vascular resistance, while RBF is Reduced BP and vascular resistance, while RBF is
increased increased Hypertensive emergency; Postoperative hypertensionHypertensive emergency; Postoperative hypertension Adverse effects dose related: Flushing, headache, Adverse effects dose related: Flushing, headache,
nausea vomiting, tachycardianausea vomiting, tachycardia Dose: 0.1-0.3 mcg/kg/minDose: 0.1-0.3 mcg/kg/min
[CORLOPAM®]
ESMELOL
Selective Selective 11 adrenergic receptor antagonist adrenergic receptor antagonist Short half-life (terminal t ½ = 9 minutes)Short half-life (terminal t ½ = 9 minutes) Beta-blockade disappears within 20 min after Beta-blockade disappears within 20 min after
discontinuation of infusiondiscontinuation of infusion Used for intra or postoperative hypertension and Used for intra or postoperative hypertension and
for control of certain supraventricular arrhythmias. for control of certain supraventricular arrhythmias.
[BREVIBLOCK®]
AGENTS GIVEN BY INTERMITTENT IV AGENTS GIVEN BY INTERMITTENT IV INJECTIONINJECTION
LabetalolLabetalol EnalaprilatEnalaprilat HydralazineHydralazine DiazoxideDiazoxide
LABETALOLLABETALOL
Combined Combined 11 and and receptor antagonist receptor antagonist
Onset of action - 3 to 5 minutesOnset of action - 3 to 5 minutes
Duration of action variable – 3-6 hoursDuration of action variable – 3-6 hours
20-80mg IV bolus every 10-20 minutes 20-80mg IV bolus every 10-20 minutes
LABETALOLLABETALOL
Adverse effects: Vomiting, scalp tingling, Adverse effects: Vomiting, scalp tingling, bronchoconstriction, dizziness, heart block bronchoconstriction, dizziness, heart block
In pheochromocytoma may induced paradoxical rise in In pheochromocytoma may induced paradoxical rise in BPBP
Contraindications - same as with other Contraindications - same as with other blockers blockers
Should not be used in HTN crisis with acute heart failureShould not be used in HTN crisis with acute heart failure
ENALAPRILAT ENALAPRILAT
Active metabolites (“post-drug”) of enalaprilActive metabolites (“post-drug”) of enalapril
Primary indication is for prevention or management Primary indication is for prevention or management of postoperative hypertension in hypertensive of postoperative hypertension in hypertensive patients previously treated with an ACE inhibitorpatients previously treated with an ACE inhibitor
-Dose: 0.625-1.25 mg Q6H-Dose: 0.625-1.25 mg Q6H
HYDRALAZINE
Direct vasodilating agent (arterioles)Direct vasodilating agent (arterioles)
Reduces TPVR; Reflex increase in HR and COReduces TPVR; Reflex increase in HR and CO
Onset of action 3-5 minutes, duration 2-5 hoursOnset of action 3-5 minutes, duration 2-5 hours For HTN crisis associated with preeclampsiaFor HTN crisis associated with preeclampsia††
[APRESOLINE® ]
DIAZOXIDE
Direct vasodilating agent; Activates K+ channelsDirect vasodilating agent; Activates K+ channels
Reduces TPVR; Reflex increase in HR and COReduces TPVR; Reflex increase in HR and CO
Onset of action 3-5 minutes, duration variableOnset of action 3-5 minutes, duration variable Increases blood glucose levelsIncreases blood glucose levels
Rarely used as IV agent for treatment of HTN crisisRarely used as IV agent for treatment of HTN crisis
[HYPERSTAT®; PROGLYCEM®