An estimated 30% of adults in the United States have hypertension; thus, antihypertensives are medications commonly found in patient homes.¹ Several classes of drugs used to treat hypertension are discussed in this chapter: diuretics, sympatholytic agents, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and vasodilators (Table 196-1). Calcium channel blockers and β-blockers, also used in the treatment of hypertension, are discussed elsewhere (see chapters 195, “Calcium Channel Blockers,” and 194, “Beta-Blockers”).

For most of these agents, life-threatening toxicity is not expected in acute overdose.² In nearly all cases, good supportive care is adequate. The initial approach to the patient with potential overdose of an antihypertensive drug is fairly uniform. Secure the airway as necessary, establish IV access, provide continuous cardiac monitoring, and obtain an ECG. A bolus of crystalloid solution is first-line treatment for hypotension. If a vasopressor is required, a direct-acting drug such as norepinephrine is preferred. If pulmonary aspiration is not a concern, activated charcoal can be given within the first hour. Although there is usually no specific therapy for initial management of these drugs in overdose, the different classes of antihypertensives are distinct in their potential for causing metabolic derangements and adverse effects.

Acetazolamide, a carbonic anhydrase inhibitor diuretic, is not used for management of hypertension. Acetazolamide may be indicated for management of high-altitude disease or glaucoma (in oral or topical preparations). Carbonic anhydrase plays a role in the renal proximal tubule sodium-hydrogen exchange. In the proximal tubule, [Na⁺] is reabsorbed from the tubule in exchange for [H⁺]. Carbonic anhydrase in the proximal tubule brush border catalyzes the conversion of H₂CO₃ (formed from [H⁺] and [HCO₃^–] present within the tubular lumen) to H₂O and CO₂. The CO₂ is then reabsorbed. Inhibition of carbonic anhydrase reduces the amount of [H⁺] available for exchange, so that more [Na⁺] and [HCO₃^–] stays within the tubular lumen and is eliminated. Because sodium can be reabsorbed distally, the most clinically significant effect of carbonic anhydrase inhibition is loss of urinary bicarbonate with the development of a non–anion gap metabolic acidosis. Overdose experience is limited, and treatment is supportive.

Diuretics initially control hypertension by increasing elimination of salts, but their mechanism of action in long-term blood pressure control is not clear. All diuretics cause increased sodium elimination, which results in the potential for hyponatremia, hypokalemia, hypomagnesaemia, and hypovolemia.

Thiazides, like hydrochlorothiazide, inhibit sodium chloride reabsorption in the renal distal convoluted tubule. Decreased sodium reabsorption leads to increased excretion of potassium and the possibility of hypokalemia. Calcium regulation is also affected by thiazide diuretics via two separate mechanisms: (1) inhibition of vitamin D synthesis and thus decreased calcium absorption from the GI tract, and (2) increased renal absorption of calcium. The net result, however, is calcium retention and potentially hypercalcemia.³ Glucose intolerance is noted at higher doses.

Loop diuretics, such as furosemide and bumetanide, are used more frequently for control of edema and pulmonary congestion than for management of high blood pressure. Loop diuretics inhibit the activity of the sodium-potassium-chloride symporter (a type of cotransporter that facilitates transport across a plasma membrane) in the renal loop of Henle, where 25% of the filtered sodium load is typically reabsorbed. A secondary effect of the inhibition of this symporter is decreased calcium and magnesium reabsorption, which results in hypocalcemia, hypokalemia, and hypomagnesemia.

Triamterene, amiloride, spironolactone, and eplerenone are referred to as potassium-sparing diuretics for their ability to cause a sodium chloride diuresis without increased potassium secretion. Triamterene and amiloride inhibit sodium channels in the distal renal tubule and collecting duct, which play a role in both reabsorbing sodium and secreting potassium. These drugs may be used in conjunction with other stronger diuretics for management of hypertension. Triamterene has been associated with rare cases of crystalline nephropathy.⁴

Spironolactone and eplerenone are antagonists of mineralocorticoids, such as aldosterone. Mineralocorticoid antagonists increase elimination of sodium and retention of hydrogen and potassium. Spironolactone is typically used to treat heart failure and hepatic cirrhosis. In the acute overdose setting, hyperkalemia and hypotension are the most serious clinical manifestations of these drugs.

Clinical manifestations of excessive diuresis include tachycardia, hypotension (orthostatic or supine), electrolyte abnormalities, and generalized weakness. The ECG may show changes caused by these electrolyte abnormalities (see chapter 17, “Fluids and Electrolytes”). A widened QRS interval or peaked T waves may suggest hyperkalemia, such as from a potassium-sparing diuretic. A prolonged QT interval may indicate hypokalemia, hypomagnesemia, or hypocalcemia, which may be caused by a loop diuretic.

The first priority of therapy is restoration of plasma volume. Administer an isotonic crystalloid solution bolus, such as 0.9% saline. If life-threatening hyperkalemia is encountered, provide standard management and fluid resuscitation.

In addition to causing direct toxicity, diuretics may potentiate toxicity from other medications. Mechanisms include decreased renal clearance of drugs or creation of a metabolic state that changes a particular drug’s effect. Diuretics and ACEIs can increase the risk of lithium toxicity by reducing lithium elimination (see chapter 181, “Lithium”).⁵ Because hypokalemia exacerbates digoxin toxicity, non–potassium-sparing diuretics may exacerbate arrhythmias seen in chronic digoxin poisoning or other antiarrhythmics (see chapter 193, “Digitalis Glycosides”).

Catecholamines produced by the sympathetic nervous system play a key role in maintaining blood pressure. Drugs with action at α-adrenergic receptors are used to diminish peripheral sympathetic tone in order to decrease blood pressure. There are two subtypes of α-adrenergic receptors. Stimulation of the α₁-adrenergic receptors causes vasoconstriction of arterioles and veins, increasing peripheral vascular resistance and elevating blood pressure. Stimulation of the α₂-adrenergic receptors produces different effects in the peripheral and central nervous systems. In the peripheral nervous system, stimulation of the α₂-receptors produces vasoconstriction and increases blood pressure. In the CNS, stimulation of the α₂-receptors at presynaptic sympathetic terminals inhibits the release of catecholamines, thereby decreasing sympathetic tone, promoting peripheral vasodilation, and decreasing blood pressure.

Doxazosin, prazosin, and terazosin antagonize α₁-adrenergic receptors, reducing peripheral vascular resistance. Although the aforementioned drugs are used for the treatment of hypertension, other members of this class, such as tamsulosin, are used exclusively for management of benign prostatic hyperplasia and as an adjunct in nephrolithiasis management. Because an increase in peripheral vascular resistance is required to maintain blood pressure when changing from a supine to an upright position, it is not surprising that the most typical adverse effect observed with α₁-adrenergic antagonists is orthostatic hypotension, particularly within 30 to 90 minutes after ingestion, and is most prominent after taking the first dose.⁶