antihypertensive drugs - part ii

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.


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


SODIUM NITROPRUSSIDE (SNP)

SNPSNPNONO

guanylil cyclaseguanylil cyclase cGMPcGMP

Venules

Arterioles

VSMCsVSMCs

Mechanism of action

Light chain of myosin Light chain of myosin dephosphorylationdephosphorylation

CNCN


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


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.


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


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


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


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


Side Effects


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®

antihypertensive drugs - part ii

Documents

hypertensive patients

hypertensive crisisgiven

hypertensive crisisstevan

hypertensive urgency

heart failure snp

increase intracranial

nitroprusside tolerance

advantages of nitroprusside