Nursing Pharmacology: Management of Hypertension

Hypertension Treatment:

ß-receptor antagonists:²⁷²

Use of ß-adrenergic antagonists (a.k.a. beta blockers) are effective in reducing blood pressure.²⁷²
- The primary mechanism is by antagonism at ß₁-adrenergic receptors.
- Reduced adrenergic receptor activity manifests, in part, as a reduction in both heart rate and myocardial contractility.
  - Moreover, ß-adrenergic receptor blockade also decreases renin release and angiotensin II levels.²⁹⁴
    - Additional actions of ß-antagonists include downregulation (reduction in number) of adrenergic receptors, increased prostacyclin synthesis and changes in baroreceptor sensitivity.
  - In black and elderly patients ß-adrenergic receptor blockers may be less efficacious as monotherapy.
    - However, effectiveness improves if ß-adrenergic antagonists are administered in combination with diuretics or Ca²⁺ channel antagonists.
  - As described earlier, some ß-adrenergic antagonists also possess intrinsic sympathomimetic properties and as such may be useful in those patients who require ß-adrenergic blockade but exhibit bradycardia or vasoconstriction.
    - Agents which exhibit both α- and ß-adrenergic antagonism show faster onset of antihypertensive effects with reduced actions on blood lipids and glucose levels.²⁹⁵
    - Most ß-adrenergic antagonists exhibit comparable clinical antihypertensive effectiveness.²⁷²

Treatment of Hypertension²⁷⁶

Abbreviations:²⁷⁶ ACEI: Angiotensin Converting Enzyme Inhibitor ARB: Angiotensin Receptor Blocker BB: Beta Blocker CCB: Calcium Channel Blocker

**ß-antagonists: Antihypertensive Agents**²⁹⁶
ß-antagonists	Trade Name
atenolol	Tenormin
betaxolol	Kerlone
bisoprolol	Zebeta
metoprolol	Lopressor
metoprolol extended-release	Toprol XL
nadolol	Corgard
propranolol	Inderal
propranolol long-acting	Inderal LA
timolol	Blocadren

α- & ß-antagonists: Antihypertensive Agents²⁹⁶
ß-antagonists with sympathomimetic activity	Trade Name
acebutalol	Sectral
penbutolol	Levatol
pindolol	(generic)

**α- & ß-antagonists: Antihypertensive Agents**²⁹⁶
Combined α- and ß-adrenergic receptor antagonism	Trade Name
carvedilol	Coreg
labetalol	Normodyne, Trandate

**ß-antagonist + Diuretic: Combination Antihypertensive Agents**²⁹⁶
Combined ß-adrenergic receptor antagonism and diuretic	Trade Name
atenolol-chlorothalidone	Tenoretic
bisoprolol-hydrochlorothiazide	Ziac
metoprolol-hydrochlorothiazide	Lopressor HCT
nadolol-bendroflumethiazide	Corzide
propranolol LA-hydrochlorothiazide	Inderide LA
timolol-hydrochlorothiazide	Timolide

Adverse effects associated with β-adrenergic receptor agonists:¹⁵²
- Adverse effects associated with β₂-adrenergic receptor agonists are directly related to β-receptor activation. Patients with cardiovascular disease perhaps especially myocardial disease may be particularly sensitive to adrenergic activation.
- Administration of adrenergic receptor agonist by inhalation reduces systemic absorption and accordingly decreases systemic toxicities.β₂-adrenergic agonist administration may induce tremor, which, over time, often diminishes.
- The likelihood of tremor following oral administration is reduced if a lower drug dose is administered at first, followed by increasing drug dosages as tolerance to tremor develops.
- Anxiety, apprehension, and restlessness, sometimes therapy limiting, are also noted with these drugs.
- Tachycardia is commonly observed with administration of β-adrenergic receptor agonists, possibly a consequence of direct receptor activation (β₁-adrenergic receptor subtype).
  - Another possibility is that agents with β₂-adrenergic agonist activity may produce peripheral vasodilation which, by autonomic reflex mechanisms, cause tachycardia.
  - Tachycardia associated with an ongoing severe asthma attack may be reduced following administration of a β-receptor agonist, because of improved pulmonary function on one hand and resultant reduced anxiety, which reduces circulating catecholamines, on the other.
  - If tachycardia is considered a relatively benign arrhythmia, more serious arrhythmias may develop associated with β-adrenergic stimulation in patients with pre-existing coronary vascular disease or pre-existing arrhythmia.
- Adverse cardiovascular incidents are more likely in patients receiving monoamine oxidase inhibitors (MAO inhibitors), presumably administered as part of management of endogenous depression.

Thiazide diuretics:²⁷²

Diuretic action: Renal Physiology²⁹⁸

Thiazide diuretics inhibit the distal tubular Na⁺-Cl^- renal cotransporter and therefore decrease extracellular volume in reduced cardiac output.²⁷²

Diuresis is central to the antihypertensive effect of thiazide agents, although diuresis by itself is inadequate to fully account for thiazide-mediated long-term antihypertensive effects.
Thiazide-type agents result in some vasodilation.
- Possible other pharmacological mechanisms which may explain more completely thiazide-antihypertensive effects include effects on the Ca²⁺-activated K⁺ channels and actions at vascular smooth muscle.
  - The most commonly prescribed thiazide drugs are hydrochlorothiazide (HydroDIURIL) and chlorthalidone (Hygroton), the latter being about 1.5-2 times more potent.²⁷²
    - Indapamide (Lozol) is less likely to produce hypokalemia, an effect of thiazide-type diuretics.
  - Hydrochlorothiazide (HydroDIURIL)
  - Chlorthalidone (Hygroton)
  - Indapamide (Lozol)
Thiazide diuretics tend to be less effective as antihypertensive drugs when glomerular filtration rate (GFR) becomes <30-40 mL/min; metolazone and indapamide represents an exception to this finding.²⁷²
Diuretics have been found essentially unsurpassed in limiting cardiovascular complications associated with hypertension.²⁹⁶
- The ALLHAT study involved following 40,000 hypertensive patients.²⁹⁶
  - Analysis of the ALLHAT study, when considering the primary coronary heart disease (CHD) outcome or mortality, no difference was found between a thiazide-type diuretic, chlorthalidone (Hygroton), and angiotensin-converting enzyme inhibitor, lisinopril (Prinivil) or a calcium channel blocker, amlodipine (Norvasc) .
    - Elevation of stroke incidence was greater with lisinopril compared to chlorthalidone; however, this difference was localized mainly in African-American patients who exhibited reduced blood pressure response to lisinopril, compared to diuretics.
  - The likelihood of heart failure was found greater in calcium channel blocker-treated and ACE inhibitor-treated patients compared to patients receiving the diuretic in both white and African-American groups.²⁹⁶
  - Most clinical trial results suggest that diuretics are typically well-tolerated and appear efficacious at "low-dose" levels [equivalent of 25-50 mg hydrochlorothiazide or 12.5-25 mg chlorthalidone].²⁹⁶
    - Higher thiazide doses appear to confer limited additional antihypertensive effect but are more likely to cause hypokalemia along with other undesirable effects.
      - Uric acid levels tend to increase in patients on a diuretic although gout is unlikely at dosages = <50 mg/day of hydrochlorothiazide or = <25 mg chlorthalidone.
      - High dose thiazide administration may cause hypokalemia, a predisposing factor for ventricular ectopy and even possible sudden death.
        
        Use of the potassium-sparing agent along with a thiazide may be considered.²⁹⁶

Antihypertensive: Thiazide Diuretics²⁹⁶
Thiazide Diuretic	Trade Name
chlorothiazide	Diuril
chlorthalidone	(generic)
hydrochlorothiazide	Microzide, HydroDIURIL
polythiazide	Renese
indapamide	Lozol
metolazone	Mykrox
metolazone	Zaroxolyn

Loop Diuretics:²⁷²

Loop diuretics inhibit Na⁺-K⁺-2Cl^- at the thick ascending limb of the loop of Henle.
- Nephron Anatomy²⁹⁷
  Loop of Henle: Ascending Limb, site of action of "loop" diuretics.
- These agents are usually highly effective in inducing profound diuresis.
Prominent "loop" diuretics include furosemide (Lasix), bumetanide (Bumex), ethacrynic acid (Edecrin) and torsemide (Demadex).²⁷²
- Due to their limited half-life, loop diuretics are less effective compared to thiazides in reducing blood pressure in patients with normal renal function, when prescribed once or twice per day.²⁷²
  - However, in patients with reduced GFR (glomerular filtration rate) <30-40 mL/min/1.73m², loop diuretics are important for blood pressure reduction.
  - Loop diuretics also may be used to achieve volume control in patients receiving vasodilators, particularly minoxidil which promotes fluid retention.
    - Adverse effects are related to electrolyte abnormalities and include:
      - Hypokalemia
      - Hyponatremic
      - Hypochloremic alkalosis
      - Hyperuricemia, and
      - Hyperglycemia.
    - Hypomagnesemia and hypokalemia occur as a result of enhanced Mg²⁺ and Ca²⁺ excretion.
    - Thiazide diuretics and loop diuretics act in a synergistic manner; however, nonsteroidal anti-inflammatory drugs (NSAIDS) and probenecid attenuate loop diuretic activity.²⁷²
Loop Diuretics Trade Name

Furosemide Lasix

Bumetanide Bumex

Torsemide Demadex

Thiazide Diuretics: Pharmacological Actions
Reduction in blood pressure is initially due to a reduction in extracellular volume and cardiac output. Long-term antihypertensive effects of thiazides appear due to reduced vascular resistance. The exact mechanism responsible for the reduction in vascular resistance is not known. Thiazides, due to their inhibition of the Na⁺-Cl^- symport system, increase sodium and chloride excretion.(renal synport diagram) Distal Convoluted Tubule: From: Goodman and Gilman's "The Pharmacological Basis of Therapeutics, Ninth Edition

Potassium-Sparing Diuretics:²⁷²

Potassium-sparing diuretics act by inhibiting renal epithelial Na⁺, promoting an increase in NaCl excretion.
- These agents are not suitable as monotherapy in management of peripheral edema or hypertension; however, potassium-sparing agents are helpful in preventing or limiting diuretic-caused hypokalemia.
- Accordingly, potassium-sparing drugs may be prescribed along with other diuretics.
- Hyperkalemia is a serious adverse effect associated with these agents.
  - The risk of hyperkalemia is increased when potassium-sparing drugs are used with:
    - Nonsteroidal anti-inflammatory agents (NSAIDs)
    - Angiotensin-converting enzyme (ACE) inhibitors
    - Angiotensin receptor antagonist
Triamterine (Dyrenium) and amiloride (Midamor) are classical potassium-sparing diuretics.²⁷²

**Amiloride and Triamterine: Pharmacological Actions**
Note that amiloride (Midamor) and probably triamterene (Dyrenium) blocks sodium channels in the luminal membrane in the late distal tubule and collecting duct. Such action inhibits the normal movement of Na⁺ into the cell. Normally, Na⁺ entry create the net negative luminal charge that results in K⁺ efflux. By reducing the net negative luminal charge, amiloride (Midamor)/triamterene (Dyrenium) administration help conserve potassium. Therefore, they are called "potassium sparing". Figure adapted from "Goodman and Gillman's The Pharmacological Basis of Therapeutics" Ninth Edition, p. 705

Mineralocorticoid Receptor Antagonists:²⁷²

Mineralocorticoid antagonists represent another group of potassium-sparing diuretics.
- Mineralcorticoids bind to the mineralcorticoid receptors, causing both water and salt retention and K⁺ and H⁺ excretion.
- Antagonism of this process reduces K⁺ excretion.
- Mineralcorticoid antagonists include spirolactone (Aldactone) and eplerenone (Inspra).
Mineralcorticoid antagonists are typically combined with thiazide diuretics for hypertension management.
- Also, these agents are helpful in treating primary aldosteronism.
- Prominent adverse effects include:
  - Hyperkalemia
  - Anti-androgen effects (breast pain, gynecomastia, sexual dysfunction in males) and
  - Hypertriglyceridemia.
- Anti-androgenic effects are less likely observed with eplerenone which is more selective for mineralcorticoid receptors compared to spirolactone.²⁷²

**Spironolactone and Eplerenone: Pharmacological Actions**
Spironolactone is an antagonist of mineralocorticoid receptors (aldosterone-antagonist) . Normally, aldosterone interactions with mineralocoricoid receptors result in synthesis of aldosterone-induced proteins (AIPs). These proteins appear to increase the number or activity of Na⁺ channels and cause an increase in Na⁺ conductance. Increased Na⁺ conductance (with inward movement of Na⁺⁾results in a net negative luminal charge favoring K⁺ loss. Antagonism of the interaction between aldosterone and its receptor by spironolactone conserves K⁺ (potassium sparing). Figure from Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Ninth Edition, p. 708

Calcium Channel Antagonists:²⁷²
- Calcium channel antagonists limit Ca²⁺ entry into vascular smooth muscle through voltage-sensitive L-type Ca²⁺ channels.
  - "Ion-Channel Coupled Receptors"²⁹⁹
  - Reduced Ca²⁺ entry results in coronary and peripheral arterial vasodilation.
  - Calcium channel blockers may be classified as dihydropyridines and non-dihydropyridines.
    - An example of a dihydropyridine calcium channel antagonist is nifedipine (Procardia); whereas, examples of non-dihydropyridines include diltiazem (Cardizem) and verapamil (Calan).
    - Agents belonging to these classes exhibit comparable antihypertensive effectiveness but differ in terms of actions on AV (atrioventricular) impulse conduction, vasodilation, and myocardial contractility.
      - For example, non-dihydropyridines decrease myocardial contractility and AV nodal conduction.
        
        Because they may reduce cardiac contractility, non-dihydropyridine-type calcium channel blockers are relatively contraindicated in patients with substantial left ventricular dysfunction (poor contractility) or AV block.
      - Dihydropyridine calcium channel antagonists are effective arteriolar vasodilators while exhibiting limited suppression of cardiac impulse conduction or contractility.
        
        Examples of dihydropyridine calcium channel antagonists with demonstrated relative safety in hypertensive patients with heart failure include amlodipine and felodipine.
        
        Common side effects of dihydropyridine-calcium channel antagonists include flushing, headache, and a dose-dependent peripheral edema caused by precapillary arteriolar dilatation with fluid moving from vascular compartments into tissue.
        
        This type of edema may be less readily managed by diuretics.²⁷²

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Loop Diuretics	Trade Name
Furosemide	Lasix
Bumetanide	Bumex
Torsemide	Demadex

Nephron Anatomy²⁹⁷

Loop of Henle: Ascending Limb, site of action of "loop" diuretics.