• 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

• 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

Cushing's syndrome

Hyperaldosteronism

Pheochromocytoma

• Adrenal hyperplasia:

  • Secondary to excessive pituitary ACTH production

    • Pituitary-hypothalamic dysfunction

    • Pituitary ACTH-producing micro-or macroadenomas

  • Secondary to ACTH or CRH producing nonendocrine tumors

    1. Bronchogenic carcinoma

    2. Thymic carcinoma

    3. Pancreatic carcinoma

    4. Bronchial adenoma

• Adrenal nodular hyperplasia

• Adrenal neoplasia

  • Adenoma

  • Carcinoma

• Exogenous, iatrogenic causes (most common cause)

  • Long-term glucocorticoid use

  • Long-term ACTH use

  • Primary Non-iatrogenic Cause:

    •  bilateral adrenal hyperplasia due to pituitary adenoma (basophilic tumor)

    •  about 20 to 25 percent of Cushing's syndrome patients have adrenal neoplasm

"Adenoma composed of basophilic cells (blue with H&E stain) in Cushing disease."

• (c) 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• *"Stretch marks on the skin with a silvery-white hue. Often the result of stretching the skin in pregnancy. Heavy or long-term
  corticosteroid use (cream or oral forms) can cause striae formation.-on-line medical dictionary"

Primary aldosteronism 

• Overview:

  •   Twice as common in women as in man

  •   Most often presents between 30 in 50 years of age

• Most common cause:

  •  Adrenal adenoma -- excessive aldosterone production

    • unilateral adenoma (usually small; either side)

  •  Conn's syndrome (primary hyperaldosteronism;Two types of abnormalities are noted: (1) benign tumor of one adrenal (adenoma) or (2) hyperplasia., a general enlargement of both adrenals. 

• Other causes:

  • hyperplastic adrenal glands -- abnormal secretion

  • malignant tumor

    • adrenal carcinoma (rare)

• Physiological Effects of aldosterone hypersecretion:

  • increased renal distal tubular exchange of sodium for secreted potassium and hydrogen ions -- body potassium depletion/hypokalemia

• Diagnosis--Criteria:

  1.   diastolic hypertension (no edema)

  2.   renin hyposecretion (low plasma renin activity)

     • renin secretion does not increase with volume depletion

  3.   aldosterone hypersecretion that is not suppressed with volume expansion

Secondary aldosteronism 

• Cause: inappropriate increased aldosterone production due to renin-angiotensin system activation

•    Associated with:

  •   Accelerated hypertension

  •   Edema 

• in pregnancy:

  • normal physiologic response to estrogen-induced increased plasma renin substrate and plasma renin activity and to antialdosterone actions of progestogens

• in hypertension -- cause:

  • overproduction of renin (primary reninism)

  •  renin overproduction secondary to reduced renal blood flow/perfusion pressure

    •   reduced renal artery lumen secondary to atherosclerosis or fiber muscular hyperplasia

  •  severe arteriolar nephrosclerosis (malignant hypertension)

  •  profound renal vasoconstriction (accelerated hypertension)

• may be caused by rare renin-producing tumors (primary reninism)

  • juxtaglomerular cell tumor

• Physiological characteristics:

  • increased plasma renin activity

  • moderate/marked increases in aldosterone levels

  • hypokalemic alkalosis

• Pheochromocytoma 

  • Occurs as:

    •  a singular tumor or as

    •  an element of  multiple endocrine neoplasia {including thyroidal medullary carcinoma and hyperparathyroidism}

  •  Associated with elevated catecholamine levels

  • Surgical manipulation {during tumor removal} is likely to cause a rapid increase in blood-pressure due to releases of catecholamines.

  • Patients with pheochromocytoma may have reduced blood volume-a factor to consider in perioperative management

  • Undiagnosed pheochromocytoma in patients presenting intraoperatively with hypertension is associated with high mortality {50%}

  • Pharmacological management prior to tumor removal

    • alpha & ß-adrenoceptor blockers (a blockers to reduce vasoconstriction; ß-blockers decrease heart and contractility, also reducing blood pressure) -- both groups of adrenergic blocking agents protect against the effects of elevated circulating catecholamines due to tumor.

      • alpha-adrenergic blockade should precede beta-receptor blockade in order to prevent severe hypertension due to unopposed (ß-receptor-mediated) a receptor mediated  vasoconstriction.

      • alpha-adrenergic blockers--Phenoxybenzamine (Dibenzyline) or phentolamine (Regitine): used to control blood pressure prior to definitive surgical treatment

Pheochromocytoma

• "Catecholamine-secreting pheochromocytoma of adrenal medulla gross. Note spherical enlargement of the adrenal medulla in this cross section of adrenal."

  • (c) 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

   

•  Methyldopa (Aldomet) is a prodrug which is metabolized to the active agent, alpha-methylnorepinephrine.

  • Alpha-methylnorepinephrine acts in the brain, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

• Methyldopa (Aldomet) produces no change in cardiac output in younger patients, but in older patients a decline in cardiac output results from reduced heart rate and stroke volume.

  • The reduction in stroke volume occurs due to increased venous pooling (decreased preload).

• Since renal blood flow and function is maintained during methyldopa (Aldomet) treatment, methyldopa maybe valuable in managing hypertensive patients with renal insufficiency.

• Calcium channel blockers are effective in treating hypertension because they reduce peripheral resistance.

• Arteriolar vascular tone depends on free intracellular Ca²⁺ concentration.

  • Calcium channel blockers reduce transmembrane movement of Ca²⁺ , reduce the amount reaching intracellular sites and therefore reduce vascular smooth muscle tone.

• All calcium channel blocks appear similarly effective for management of mild to moderate hypertension.

• For low-renin hypertensive patients (elderly and African-American groups), Ca²⁺ channel blockers appear good choices for monotherapy (single drug) control.

• Interactions with Anesthetics:

  • In anesthetized patients with preexisting left ventricular dysfunction--

    •  verapamil (Isoptin, Calan) administration results in:

      1. myocardial depression

      2. reduced cardiac output

  • In patients with depressed left ventricular function, anesthetized with a volatile anesthetic,and undergoing open-chest surgery:

    •  IV verapamil (Isoptin, Calan) or diltiazem (Cardiazem) further decreases ventricular function

  • In patients with preoperative cardiac conduction anomalies, treated with combined calcium channel blockers and beta-adrenergic receptor blockers: condition not associated with perioperative cardiac conduction abnormalities.

• Interactions with neuromuscular-blocking drugs:

  • Calcium channel blockers potentiate depolarizing and nondepolarizing neuromuscular-blocking drug effects.

  • Similar to effects produced by "mycin" antibiotics in the presence of neuromuscular-blocking drugs (mycins:decrease acetylcholine release, e.g. gentamycin; tetracyclines - chelate calcium and decrease acetylcholine release) 

    •  Note that verapamil (Isoptin, Calan) possesses local anesthetic properties -- due to sodium channel blockade -- in effect which contributes to neuromuscular-blocking drug effect potentiation

    •  Neuromuscular effects of verapamil (Isoptin, Calan): more likely to be evidenced in patients with reduced neuromuscular transmission margin of safety.

  •  Neuromuscular-blockade antagonism: possibly impaired by reduced acetylcholine presynaptic release in the presence of a calcium channel blocker (presynaptic calcium influx is typically required for neurotransmitter release)

• Angiotensin II, a potent vasoconstrictor, is produced by the action of angiotensin converting enzyme (ACE) on the substrate angiotensin I. Angiotensin II activity produces

  • a rapid pressor response

  • a slow pressor response and

  • vascular and cardiac hypertrophy and remodeling.

• Antihypertensive effects of ACE inhibitors are due to the reduction in the amount of angiotensin II produced.

• ACE inhibitors are efficacious in management of hypertension and have a favorable side effect profile.

• ACE inhibitor are advantageous in management of diabetic patients by reducing the development of diabetic neuropathy and glomerulosclerosis.

• ACE inhibitor are probably the antihypertensive drug of choice in treatment of hypertensive patient who have hypertrophic left ventricles.

  • Hypertensive patients who have ischemic heart disease with impaired left ventricular function also benefit from ACE inhibitor treatment.

• ACE inhibitors reduce the normal aldosterone response to sodium loss (normally aldosterone opposes diuretic-induced sodium loss).

  • Therefore, the use of ACE inhibitors enhance the efficacy of diuretic treatment, allowing the use of lower diuretic dosages and improving control of hypertension.

•  If diuretics are administered at higher dosages in combination with ACE inhibitors significant and undesirable hypotensive reactions can occur with attendant excessive sodium loss.

•  Reduction in aldosterone production by ACE inhibitors also affects potassium levels.

  • The tendency is for potassium retention, which may be serious in patients with renal disease or if the patient is also taking potassium sparing diuretics, nonsteroidal anti-inflammatory agents or potassium supplements.

Captopril (Capoten)

• Overview

  • Orally effective, competitive inhibitor of angiotensin I-converting enzyme (peptidyl dipeptidase) [enzyme converts angiotensin I to angiotensin II (active)]

  • Decreases circulating angiotensin II & aldosterone {angiotensin II stimulates aldosterone secretion by the adrenal cortex}

    •  Compensatory response: increase in angiotensin I & increased renin levels {loss of negative feedback control}

  • Decrease in aldosterone cause slight increase in serum potassium

• Pharmacokinetics:captopril

  • well absorbed; 25%-30% protein bound

  • rapid converting enzyme inhibition (within 15 minutes following oral administration)

  • 50% drug excreted unchanged

  • elimination half-life: two hours -- oxidation, real excretion

• Cardiovascular Effects: captopril (Capoten)

  • Decrease systemic vascular resistance (secondary to a decrease in Na⁺ & water retention)

  • Prominent decrease in renal vascular resistance

  • Reduced systemic blood pressure: no change in heart rate & cardiac output

    • Absence of heart rate change despite reduced blood pressure may suggest alteration in baroreceptor sensitivity

  • No orthostatic hypotension (captopril does not interfere with sympathetic nervous system function)

  • captopril may improve vasodilator drug treatment efficacy in management of CHF by blocking vasodilator-induced increases in renin secretion

Adverse Effects

• Angioedema, although rare, may be potentially fatal.

• ACE inhibitiors should not be used during pregnancy.

• Dry cough.

• In renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the post-glomerular arterioles, an effect mediated by angiotensin II. 

  • Use of ACE inhibitors in patients with renovascular hypertension due to bilateral renal artery stenosis can therefore precipitate a significant reduction in GFR and acute renal failure

• Initial dose of an ACE inhibitor may precipitate an excessive hypotensive response.