antihypertensive drugs - part ii

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Center for Clinical Pharmacology Department of Medicine University of Pittsburgh School of Medicine

Antihypertensive Drugs PART IIAntihypertensive Drugs for Hypertensive CrisisStevan P. Tofovic MD, PhD, FAHA, FASNtofovic@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 Severe HTN with rapidly progressive renal failure Rapidly rising BP with rapidly progressive glomerulonephritis

Renal Emergencies

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 CrisisGiven by continuous infusion Sodium nitroprusside Nitroglycerin Nicardipine Labetalol Esmolol Fenoldapam

SODIUM NITROPRUSSIDE (SNP)

Mechanism of actionVenules VSMCsguanylil cyclase

cGMP

Light chain of myosin dephosphorylation

NO SNP CN

Arterioles

SODIUM NITROPRUSSIDE (SNP) Very short half-life (t1/2 = 2 min) Administered by a computerized continuous infusion device utilizing continuous intraarterial 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 >2g/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 CHOIn 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 actionNOcGMP

NTG VSMCs

VenulesLight chain of myosin dephosphorylation

guanylil cyclase

ArteriolesHigher 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) autoregulation, 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 Increased intracranial pressure Glaucoma Severe anemia (methemoglobin) Constrictive pericarditis Pregnancy category C drug

May not be the drug of choice in patients

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 1 adrenergic receptor antagonist Short half-life (terminal t = 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 1 and 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 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

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