• 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

• 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

• 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.

• Diet

• Stress reduction

• Regular aerobic exercise

• Weight reduction (if required)

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

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