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Medical Pharmacology Lectures:  Cardiovascular Pharmacology, Antihypertensive Agents Slide 3


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Table of Contents

  • Essential Hypertension

  • Classification of Arterial Hypertension

  • Control of Blood Pressure

  • Antihypertensive Drug Mechanisms

  • Baroreceptor Reflexes

  • Antihypertensive Drugs and Anesthesia

  • Hypertension:  Organ Systems Effects:

    • Cardiovascular Effects

    • Pathogenesis

    • Secondary Hypertension

    • Effects on Cardiac Function

    • CNS Effects-stroke

    • Renal Effects

    • Chronic Hypertension: Perioperative Issues

  • Hypertension and Anesthesia Management

  • Pharmacological Management of Hypertension

    • Hypertensive Crisis

  • Diuretics

  • Sympatholytics

  • Vasodilators

    • Hydralazine (Apresoline)

    • Minoxidil (Loniten)

    • Management of Hypertensive Crisis

    • Adverse Effects

    • Nitroprusside (Nipride)

      • Overview

      • Mechanism of Action

      • Metabolism

      • Organ System Effects

        • Cardiovascular

      • Clinical Uses

  • Calcium Channel Blockers

  • Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)

  • Drug Classes




Chronic Hypertension: Perioperative Issues

  • Increased intraoperative blood-pressure lability in patients not receiving their antihypertensive medication: Recommendation -- administer medications on the day of surgery

    •  -- Exception: possibly diuretics

  • Concerning elective surgery in patients with uncontrolled hypertension:

    •  Surgery not associated with elevated incidence of perioperative cardiac morbidity if preoperative diastolic pressures were less than 110 mm Hg with careful perioperative blood-pressure monitoring

  • Preoperative approaches to the hypertensive patients:

    • Factors that increased risk of myocardial ischemia intraoperatively

      • uncontrolled hypertension or hypertension control solely with diuretics {compared to patients treated with atenolol (Tenormin)}

      • myocardial ischemia --most likely occurs during:

        • intubation

        • emergence from anesthesia

    • Intraoperative ischemia: primary association = tachycardia

  • Special considerations:

    •  Diabetic patients with hypertension (noncardiac surgical procedures)

      •  Predictors of postoperative ischemia/infarction

        1. Preoperative cardiomegaly (demonstrate radiographically)

        2. Previous myocardial infarction

      •  Intraoperatively events predictive of postoperative  for cardiovascular complications {renal/cardiac morbidity}

        • intraoperative hypotension (> 20 mm Hg decrease in mean arterial pressure (duration >  1 hour))

        • intraoperative hypertension (> 20 mm Hg increased in mean arterial pressure (duration >  15 minutes )) alternating with hypotension 

    •  Hypertension & organ transplantation

      • Occurs only in some patients

      • Hypertension increases the likelihood of renal failure in the transplanted kidney

      • Antihypertensive drug treatment: no improvement in graft survival

      • Post-organ transplantation hypertension probably due to immunosuppressive drugs:

        • Glucocorticoids -- Na+/H2O retention

        • Cyclosporine (Sandimmune, Neoral): increased sympathetic nervous system activity (suggested factor)


  • Perioperative issues in managing patients with cerebrovascular disease/hypertension:

    •  Aneurysmal subarachnoid hemorrhage patients

      • Hypertension management may reduce re-bleeding

      • Hypertension management, however may increase cerebral infarction risk

      • Surgical intervention for aneurysmal subarachnoid hemorrhage in patients who have had hypertension is associated with increased seizure risk.

        •  Diastolic pressures: best maintained in a range of 95-105 mm Hg

        •  Post-operative control of BP & vasospasm-- nimodipine (Nimotop)

Nimodipine (Nimotop)

  • Overview

    • Highly lipid-soluble nefedipine analog

    • Lipid solubility promotes CNS access where the drug reduces large cerebral arterial contraction

  • Clinical Use:

    • Cerebral Vasospasm:

      • Useful in preventing/reducing cerebral vasospasm associated with subarachnoid hemorrhage

      • Vasospasm -- mediated by calcium ion influx

      • Nimodipine (Nimotop) administered over a three week course (oral administration) results and decreased frequency of neurologic effects secondary to cerebral vasospasm in subarachnoid hemorrhage patients.

        • For comatose patients: deliver through nasogastric tube

      •  Side effects/Concerns:

        • Systemic hypotension (with excess nimodipine (Nimotop) effect)

        • Possible increase in intracranial pressure -- especially in patients with decreased intracranial compliance


Hypertension & Anesthetic management

  • Elective surgery issues:

    • Elective surgery if diastolic pressure > 115 mm Hg {reschedule until evaluation & treatment result  in controlled pressure}

  • Emergency surgery issues:

    • Intraoperative management of BP with--

      • Short-acting parenteral drugs, e.g. nitroprusside sodium (Nipride), nitroglycerin, esmolol (Brevibloc)

  • Nitroprusside (Nipride)

    • Overview:nitroprusside (Nipride)

      • Direct-acting, nonselective peripheral vasodilator--NO mediated

      • Relaxation of arterial and venous vascular smooth muscle

      • Structure:

        • ferrous iron center complex with five cyanide moieties and a nitrosyl group (44% cyanide by weight)

      • Immediate onset of action

      • Short duration (requires continuous IV administration to maintain effect)

      • High-potency:

        •  requires careful dosage titration

        •  frequent systemic blood pressure monitoring -- often by intra-arterial catheter

    • Mechanism of Action: nitroprusside

      • nitroprusside interacts with oxyhemoglobin, forming methemoglobin with cyanide ion and nitric oxide (NO) release

      • NO activates guanylyl cyclase (in vascular smooth muscle);resulting in increased intracellular cGMP

      • cGMP inhibits calcium entry into vascular smooth muscle (may also increase calcium uptake by smooth endoplasmic reticulum): producing vasodilation

        • Mechanisms by which cGMP relaxes vascular smooth muscle remain to be elucidated. cGMP does, however,activate K+ channels (hyperpolarizing effect),  activate a cGMP-dependent protein kinase, , decrease IP3, and inhibit calcium entry into the smooth muscle cells.

      • NO: active mediator responsible for direct nitroprusside vasodilating effect.

        • Note that organic nitrates (e.g. nitroglycerin) require thio-containing agents to generate NO

    • Metabolism:nitroprusside

      • The reaction: nitroprusside interacts with oxyhemoglobin, leading to methemoglobin formation with cyanide ion and nitric oxide (NO) release produces an unstable nitroprusside radical

      • nitroprusside radicals decomposes releasing five cyanide ions (one cyanide reacts with methemoglobin to form cyanomethemoglobin)

      • remaining free cyanide ions (following reaction with hepatic & renal rhodanase) are converted to thiocyanate {thiosulfate donor: body sulfur stores are sufficient detoxifying about 50 milligrams nitroprusside})

    • Organ System Effects: Nitroprusside

      • Overview: Principal effects referable to:

        • Cardiovascular system

        • Cerebral blood flow

        • Hypoxic pulmonary vasoconstriction

        • Platelet aggregation

      • Cardiovascular Effects: Nitroprusside

        • Direct venous/arterial vasodilation; rapid decrease in systemic blood-pressure

        • Reduced systemic vascular resistance (arterial vasodilation; venous capacitance vessel vasodilation)

        • Positive inotropic & chronotropic responses: reflex-mediated secondary to hypotensive response

        • Net increase in cardiac output due to:

          •  increase contractility

          •  decreased left ventricular ejection impedance

        • Hypotensive response: associated with reduced renal function; renin release occurs (explains over shoot upon nitroprusside discontinuation {ACE inhibitor-sensitive, i.e. an ACE inhibitor will prevent this overshoot effect})

        • Nitroprusside: may worsen myocardial infarction damage due to "coronary steal", blood flow directed away from ischemic areas by arteriolar vasodilation

      • Cerebrovascular Effects:

        • Increased cerebral blood flow, volume.

          • with decreased intracranial compliance,  increased intracranial pressure results

          • Generally, increases in intracranial pressure are most apparent when systemic mean arterial pressure decreases by less than 30%

          • if systemic mean arterial pressure decreases by > 30%, intracranial pressure decreases below the awake level.

        • Nitroprusside contraindicated in patients with known inadequate cerebral blood flow (e.g. high intracranial pressure; carotid artery stenosis)

      • Hypoxic Pulmonary Vasoconstriction

        • Nitroprusside infusion (and other vasodilators) causes decrease in PaO2

        • Mechanism: vasodilator-mediated reduction in hypoxic pulmonary vasoconstriction

    • Clinical Uses: -- nitroprusside (Nipride)

      1. Control hypotension during anesthesia and surgery

        • Rapid, predictable vasodilation & decrease in BP allows a nearly bloodless surgical field, required in some operations: spine surgery, neurosurgery (also reduces transfusions)

        • Other drugs that might be chosen to produce controlled hypotension, nitroprusside is most likely to ensure adequate cerebral perfusion (mean arterial pressure's of 50-60 mm Hg can be maintained without apparent complications {in healthy patients})

        • The potential for cyanide toxicity can be diminished by:

          1. Use of other cardiovascular depressant drugs which reduce nitroprusside requirements

          2. These drugs include: volatile anesthetics, beta-adrenergic antagonists, calcium channel blockers; note that beta adrenergic antagonists may cause a decreased cardiac output-- a potential problem in patients with diminished the ventricular reserve.

      2. Treatment of hypertensive emergencies

      3. Acute & chronic heart failure

        • Reduction of afterload may be important for patients with CHF, mitral or aortic regurgitation, acute myocardial infarction with left ventricular failure

        • Role of nitroprusside in chronic, congestive heart failure -- advantageous because:

          1. reduced ventricular ejection impedance (injection at lower end-diastolic volumes

          2. preload reduction (secondary to blood pooling in venous capacitance vessels -- reflected in decreased ventricular and-diastolic volume)

      4. Surgical indications:

        • Aortic surgery

          • reduction of proximal hypertension associated with aortic cross-clamping (thoracic aortic aneurysm, dissections, coarctations)

          • distal hypotension may occur (relative to clamp location)

        • Cardiac surgery necessitating cardiopulmonary bypass

          • Activation of renin-angiotensin system may cause systemic hypertension during cardiac surgery

          • Nitroprusside is effective in reducing such increases in BP

          • Following cardiopulmonary bypass {re-warming phase}, nitroprusside-mediated vasodilation facilitates heat delivery to tissues {reduces nasopharyngeal temperature decline after bypass}

          • Nitroprusside is effective in managing pulmonary hypertension after valve replacement

        • Pheochromocytoma resection

Hypertensive Crisis

  • Vasodilators used for acute management of hypertensive crisis or malignant hypertension include sodium nitroprusside and diazoxide.

    • Nitroprusside sodium (Nipride) is the agent of choice-- advantages

      • Rapid onset

      • Effect diminishes rapidly upon drug discontinuation

      • May also be used (rapid injection) to reduce systemic blood-pressure associated with direct laryngoscopic tracheal intubation

    • Administered by a continuously variable rate i.v. infusion pump, precise blood pressure control can be obtained.

    • Nitroprusside sodium (Nipride), a nitrovasodilator, is metabolized by smooth muscle cells to nitric oxide which dilates both arterioles and venules.


  • If patients have controlled hypertension, anxiolytics may be appropriate {preoperative medication}

    •  diazepam (Valium); oral 

    •  midazolam (Versed); intramuscular

  • Patients managed with diuretic drugs for hypertension:

    • Diuretics not given on same day of surgery

    • Patients may be volume depleted

    • Patients whose hypertension is managed with diuretics may have to be dehydrated prior to the surgical procedure {remaining     antihypertensive medications, i.e. non-diuretics should be  administered on the surgical day.}

  • Management of hemodynamic variability during  anesthetic induction/emergence:

    • Reduction of variability

      • Esmolol (Brevibloc) {short-acting -receptor blockers}

        • Effective in management of sinus tachyarrhythmias & hypertension in cardiac & noncardiac surgical patients

      • Lidocaine (Xylocaine)

      • Nicardipine (Cardene)-management of perioperative hypertension

  • Choice of anesthetic for maintenance:

    • Any agent reasonable except for ketamine (Ketalar)

      • Ketamine (Ketalar) associated with hypertension, increased intracranial pressure & tachycardia

  •  Intraoperative management of acute blood pressure increases:

    • Prior to antihypertensive drug administration, rule out:

      • hypoxemia

      • hypercarbia

      • inadequate anesthetic depth

  • Hulyalkar, A. R., and Miller, E.D., Evaluation of the Hypertensive Patient in Principles and Practice of Anesthesiology (Longnecker, D.E., Tinker, J.H. Morgan, Jr., G. E., eds)  Mosby, St. Louis, Mo., pp. 157-165, 1998.

  • Stoelting, R.K., "Calcium Channel Blockers", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 350.

  • Stoelting, R.K., "Antihypertensive Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 302-312;and "Peripheral Vasodilators", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 315-322.



Pharmacological Management of Hypertension

Non-pharmacological interventions

  • Diet

  • Stress reduction

  • Regular aerobic exercise

  • Weight reduction (if required)

  • Control of other risk factors (blood lipids, smoking)

  • Diet involves several aspects that may include:

    • reduction of sodium intake

    • caloric restriction for obese patients

    • restriction of cholesterol and saturated fat intake.

  • Pharmacological Management

    • Pharmacological interventions in essential hypertension management is based on selecting often a single initial agent and evaluation of patient response. Unless clinical conditions require immediate reduction in blood pressure as in hypertensive crisis, the first step may involve the use of :

      • a calcium channel blocker or beta-blocker, or angiotensin converting enzyme inhibitor (ACE inhibitor). The specific clinical presentation may favor one choice over another.

  1. For example, in patients with asthma or chronic obstructive pulmonary disease (COPD) the use of a beta-adrenoceptor antagonist may be contraindicated since agents belonging to this drug class may cause bronchoconstriction.

  1. Alternatively, a patient with marginal left ventricular function, predisposed to congestive heart failure, may not tolerate beta-blockers or calcium channel blockers because both mediate a negative inotropic effect (reduced myocardial contractility). At this step, beginning with a low dosage first is usually appropriate.

  • Thiazide diuretics has been often used in the past as the first drug given.

    1. Thiazides may be added if adequate blood pressure control by a calcium-channel blocker, a beta-blocker, or an ACE inhibitor has not been achieved.

    2. Thiazides promote potassium loss and increases in serum lipids.


  • If control has not been achieve with the above drugs at optimal dosages, a antiadrenergic drug may be added (such as a central or peripheral-acting sympatholyic). Peripheral vasodilators may also be used at this stage.

  • The general idea is to use a single agent before progressing to multiple agents and then stronger multiple drugs. Often the side-effect profile becomes less favorable as more and stronger drugs are added.


Antihypertensive Medication Sequence

Note the progression of antihypertensive medication 

  1. beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker

  2. and proceeding, if needed to add a diuretic

  3. and ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination.

At each step dosages are reviewed and if the patient's hypertension is controlled then therapy may be continued with review for possible removal of medication.

Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128


  • For hypertensive emergencies/crises sodium nitroprusside is the agent of first choice.

Hypertensive Crisis

  • Definition: diastolic pressure > 130 mm Hg

  • Malignant hypertension (evidence of  end-organ damage): Medical emergency-requires immediate treatment

    • Malignant hypertension requires the use of parenteral agents with intra-arterial BP monitoring

  • Without end-organ damage present, oral or sublingual antihypertensive drugs might be used

  • Factors causing a rapid increase in BP:

    • Elevation of intracranial pressure (increased blood pressure allows maintenance of cerebral perfusion)

    • Neurological causes of hypertensive crisis:

      1. intracranial hemorrhage

      2. head trauma

      3. CNS tumor

      4. thromboembolic stroke

      5. subarachnoid hemorrhage

    • Cautious management for patients with hypertensive crisis -- and hypertensive drugs given in severe hypertension (> 200/130 mm Hg)

      • Nitroprusside sodium (Nipride) -- careful administration {may increase intracranial pressure and patients with reduced intracranial compliance)

      • Beta adrenergic receptor blocking drugs: Not recommended; may cause cerebral vasospasm

      • Centrally acting drugs {e.g., clonidine (Catapres); methyldopa (Aldomet)}: not recommended for hypertensive crisis as a result  of neurological cause


Hemorrhage, Subarachnoid, Hypertensive Vessels (left); Hemorrhage, Intraventricular Medulla, Extension into Lateral Recess and Subarachnoid Space (right): Courtesy of Digital Slice of Life (

  •  Cardiovascular causes of hypertensive crisis:

    • Myocardial infarction

    • Dissecting aortic aneurysm

    • Therapeutic Objectives:

      •  20%-25% reduction in diastolic or pressure (100 mm Hg)

      • For dissecting aortic aneurysm cases, reducing the arterial pressure rate of rise may prevent aneurysmal rupture-{nitroprusside sodium (Nipride) + -adrenoceptor blocker is a useful combination}

      •  In myocardial infarction, maintenance of coronary perfusion is critical as systemic pressure is reduced-Useful drugs include:

        • nitroglycerin

        • calcium channel blockers

        • adrenoceptor blockers


  • Renal causes of hypertensive crisis:

    • Renal artery stenosis

    • Parenchymal renal disease

    • Therapeutic objectives: 

      • maintain renal perfusion while decreasing BP to prevent fibrinoid necrosis

    • Useful drugs:

      • Nitroprusside sodium (Nipride)

      • Calcium channel blockers

    • Other interventions:

      • the combination of renal failure & malignant hypertension may require dialysis

    •  Special cautions:

      • Thiocyanate levels must be monitored when nitroprusside sodium (Nipride) is used at high doses for extended periods of time

      • ACE inhibitors should not be used if bilateral renal artery stenosis suspected/confirmed:

        • Mechanism -- glomerular filtration is dependent on post-glomerular arteriolar constriction, which is maintained by angiotensin II. Renal failure can be induced if post-glomerular arterial constriction is lost.

  • Other causes of hypertensive crisis:

    •  Ingestion of tyramine-rich foods in patients taking MAO inhibitors

    •  Preeclampsia

    •  Recreational drug use

    •  Hyperautonomic syndromes {chronic smoke or dysfunction}

    •  Pheochromocytoma-massive release of endogenous catecholamines by tumor.


CT imaging: Right Renal Artery Stenosis (left); bilateral Renal Artery Stenosis (right)-( used with permission


  • Hulyalkar, A. R., and Miller, E.D., Evaluation of the Hypertensive Patient in Principles and Practice of Anesthesiology (Longnecker, D.E., Tinker, J.H. Morgan, Jr., G. E., eds)  Mosby, St. Louis, Mo., pp. 157-165, 1998.


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