CHAPTER 41: REVIEW OF HEMODYNAMICS
CHAPTER 41 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Differentiate among arterioles, veins, and arteries.
2. Describe the mechanisms that contribute to venous return.
3. Describe the factors influencing cardiac output.
4. Discuss mechanisms that help regulate arterial blood pressure.
CHAPTER 41 OUTLINE
I. Introduction to Hemodynamics—A study of the movement of blood throughout the circulatory system, including the regulatory factors and driving forces
II. Overview of the Circulatory System—Circulatory system has two primary functions: (1) to deliver oxygen, nutrients, hormones, electrolytes, and other essentials to cells and (2) to remove carbon dioxide, metabolic wastes, and other detritus from cells; plus the function of fighting infection; two divisions: pulmonary and systemic (or peripheral) circulation
A. Components of the Circulatory System—Heart and blood vessels (arteries, arterioles, capillaries, venules, and veins)
B. Distribution of Blood—Five liters of blood: 9% in pulmonary, 7% in heart, and 84% in systemic circulation with most (64%) of systemic in veins, venules, and venous sinuses; venous system serves as a reservoir
C. What Makes Blood Flow—Driving force greater than resistance; from pharmacologic viewpoint, resistance determined by vessel diameter
D. How Does Blood Get Back to the Heart—Small pressure head in venules, negative pressure in right atrium, constriction of smooth muscle in veins to increase venous pressure, combination of venous valves and skeletal muscle contraction to act as “venous pump”
III. Regulation of Cardiac Output (CO)—About 5 liters/min in an adult
A. Determinants of Cardiac Output—CO = HR x SV: HR controlled primarily by ANS; SV largely determined by myocardial contractility, cardiac afterload, and cardiac preload
B. Control of Stroke Volume by Venous Return
1. Starling’s law of the heart
2. Factors that determine venous return—Most important for pharmacology is systemic filling pressure (~7 mm Hg and can increase to about ~17 mm Hg with vasoconstriction and can be lowered with venodilation, a reduction in blood volume and drugs can alter volume and tone); second is auxiliary muscle pump; then resistance to flow between peripheral vessels and right atrium; and also right atrial pressure
C. Starling’s Law and Maintenance of Systemic-Pulmonary Balance
IV. Regulation of Arterial Pressure—Arterial pressure is driving force that moves blood through arterial side of circulation (AP = PR x CO)
A. Overview of Control Systems—ANS, renin-angiotensin system (RAS), and kidneys; ANS is rapid response, RAS next, taking hours or days and kidneys taking days or weeks to adjust AP
B. Steady-State Control by the ANS—Adjusts cardiac output and peripheral resistance; sympathetic tone increases HR and contractility to increase CO while parasympathetic tone slows heart and decreases CO
C. Rapid Control by the ANS—The Baroreceptor Reflex: maintains AP at predetermined level; drugs that lower AP will trigger the baroreceptor reflex
D. The Renin-Angiotensin System—Causes constriction of arterioles and veins, retention of water by kidney
E. Renal Retention of Water—RAS and aldosterone effects
F. Postural Hypotension (orthostatic hypotension)
V. Key Points
CHAPTER 39 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Describe the mechanism of action of selected diuretics.
2. Determine which diuretic is more appropriate for the different pathophysiologies.
3. Describe the adverse effects of selected diuretics.
CHAPTER 39 OUTLINE
I. Introduction—Diuretics are drugs that increase output of urine to treat hypertension, to mobilize edematous fluid, and to prevent renal failure
II. Review of Renal Anatomy and Physiology
A. Anatomy—Basic unit is nephron with four regions (glomerulus, proximal convoluted tubule, loop of Henle, and distal convoluted tubule); see Figure 38-1 in the text
B. Physiology
1. Overview of kidney function—(1) cleansing of extracellular fluid (ECF) with maintenance of ECF volume and composition (Most affected by diuretics), (2) maintenance of acid-base balance, and (3) excretion of metabolic wastes and foreign substances
2. The three basic renal processes to produce net effects on ECF
a. Filtration—At glomerulus, each minute kidney produces 125 ml of filtrate in a nonselective process
b. Reabsorption—More than 99% of water, electrolytes, and nutrients reabsorbed by active transport of solutes
c. Active tubular secretion by two pumps (one is selective for transporting organic acids and the other transports organic bases) in proximal convoluted tubule
3. Processes of reabsorption that occur at specific sites along the nephron—Most diuretics act by disrupting solute reabsorption; sodium and chloride ions are predominant solutes in filtrate (see Figure 39-2 in the text)
a. Proximal convoluted tubule (PCT)—About 65% of filtered sodium and chloride, almost all bicarbonate and potassium reabsorbed at PCT with water following passively (isotonic)
b. Loop of Henle—At descending limb, freely permeable to water, so drawn into interstitial space to decrease urine volume; at thick segment of ascending limb about 20% of filtered sodium and chloride reabsorbed, but not water
c. Distal convoluted tubule (early segment)—10% of filtered sodium and chloride reabsorbed and water follows passively
d. Late distal convoluted tubule and collecting duct—Two important processes: (1) exchange of sodium for potassium under influence of aldosterone and (2) regulation of final concentration of urine by antidiuretic hormone (ADH)
e. Sodium-potassium exchange—Adrenal cortex mineralocorticoid (aldosterone) stimulates reabsorption of sodium from distal nephron, causes potassium to be secreted
f. Regulation of urine concentration by antidiuretic hormone—ADH has little to do with action of diuretics, but it does act on collecting ducts to regulate conservation of water; without ADH develop syndrome called diabetes insipidus
III. Introduction to the Diuretics
A. How Diuretics Work—Most block by blocking sodium and chloride reabsorption to create osmotic pressure within the nephron to prevent passive reabsorption of water to then be excreted; increase of urine flow directly related to amount of sodium and chloride reabsorption blocked; at earliest part of nephron have greatest blockade (increase output by 1.8 L for each 1% of blocked solute reabsorption)
B. Adverse Impact on Extracellular Fluid—Can cause hypovolemia, acid-base imbalance and disturbance of electrolyte levels
C. Classification of Diuretics—Four major categories: (1) high-ceiling or loop, (2) thiazide, (3) osmotic, and (4) potassium-sparing (aldosterone antagonists and nonaldosterone antagonists), and (5) unique drugs to lower intraocular pressure called carbonic anhydrase inhibitors
IV. High-Ceiling (Loop) Diuretics—Most effective
A. Furosemide (Lasix)—Most frequently prescribed
1. Mechanism of action—Acts in thick segment of ascending limb of Henle’s loop to provide profound diuresis
2. Pharmacokinetics—PO, IV, and IM; PO action in 60 minutes, with IV it begins within 5 minutes and last for 2 hours; hepatic metabolism
3. Therapeutic uses—When rapid and massive fluid removal needed: pulmonary edema; edema of hepatic, cardiac, or renal origin unresponsive to other drugs; hypertension (diuresis occurs even when renal blood flow and GFR low)
4. Adverse effects—Hyponatremia, hypochloremia and dehydration; hypotension; hypokalemia; ototoxicity; hyperglycemia; hyperuricemia; danger in pregnancy; reduces HDL cholesterol and raises LDLs and triglycerides, which may increase risk of CAD; increases excretion of magnesium and calcium
5. Drug interactions
a. Digoxin—Risk of toxicity if low potassium from diuretic
b. Ototoxic drugs—Increased chance of hearing loss if combined
c. Potassium-sparing diuretics—Can counterbalance potassium-wasting effects to decrease risk of hypokalemia
d. Lithium—If decreased sodium, can get lithium toxicity
e. Antihypertensive agents—Additive effect; assess carefully
f. Nonsteroidal anti-inflammatory drugs—ASA can alter effects by inhibition of prostaglandin, which will blunt diuretic effects
6. Preparation, dosage, and administration—Tablets, injection (give over 1–2 minutes for 20–40 mg and infusion of 4mg/min)
B. Other High-Ceiling Diuretics—Ethacrynic acid, bumetanide and torsemide similar to Lasix
V. Thiazides (Benzothiadiazides) and Related Diuretics—Increased excretion of sodium, chloride, potassium, and water as well as elevated plasma levels of uric acid and glucose; maximum effect less than high-ceiling agents and are not effective with scant urine flow
A. Hydrochlorothiazide (HCTZ)—Most widely used
1. Mechanism of action—Blocks reabsorption of sodium and chloride in early segment of distal convoluted tubule; ability to promote diuresis dependent on kidney function; does not work well with renal damage
2. Pharmacokinetics—Diuresis 2 hours after oral with peak 4–6 hours, lasting 12 hours
3. Therapeutic uses—Primary hypertension, edema, and diabetes insipidus
4. Adverse effects—Identical to loop except these lack ototoxicity
5. Drug interactions—Similar to loop diuretics except can be combined with other ototoxic drugs without hearing loss
6. Preparations, dosages, and administration—Tablets and oral solution, take early in day to decrease nocturia
B. Other Thiazide-Type Diuretics—Twelve other agents used that are similar
VI. Potassium-Sparing Diuretics—modest increase in urine production and decrease in potassium excretion; two subcategories (aldosterone and nonaldosterone antagonists)
A. Spironolactone (Aldactone)—Only one approved in U.S.
1. Mechanism of Action—Blocks actions of aldosterone in distal nephron to increase retention of potassium and excretion of sodium but may take up to 48 hours to work
2. Therapeutic Uses—For hypertension and edema in combination with loop or thiazide most often and for primary hyperaldosteronism; in 1999 researchers found that spironolactone can benefit patients with heart failure
3. Adverse Effects—Hyperkalemia, endocrine effects of gynecomastia, menstrual irregularities, impotence, hirsutism and deepening voice
4. Drug Interactions—Thiazide and loop diuretics to counteract potassium loss; never give with drugs that increase potassium (ACE inhibitors)
5. Preparations, Dosages, and Administration—Tablets or with HCTZ as Aldactazide
B. Triamterene
1. Mechanism of action—Disrupts sodium-potassium exchange in distal nephron, but difference is triamterene directly inhibits exchange mechanism; acts more quickly than spironolactone
2. Therapeutic uses—Alone or in combination for hypertension and edema
3. Adverse effects—Hyperkalemia, nausea, vomiting, leg cramps, dizziness, and blood dyscrasias (rare)
C. Amiloride-like triamterene care with ACE inhibitors
VII. Osmotic Diuretics
A. Mannitol (Osmitrol)—Six-carbon sugar that is freely filtered at glomerulus, minimal reabsorption, not metabolized significantly, basically inert
1. Mechanism of Diuretic Action—Osmotic force in lumen of nephron
2. Pharmacokinetics—IV works in 30–60 minutes, lasts up to 8 hours
3. Adverse effects—Can leave vascular system at capillary beds except in brain; caution with heart disease, headache, nausea, vomiting, and fluid and electrolyte imbalance
4. Therapeutic uses—(1) prophylaxis of renal failure, (2) reduction of intracranial pressure (ICP), and (3) reduction of intraocular pressure
5. Preparation, dosage, and administration—IV rate to get urine flow of at least 30–50 ml/hour, keep warm or may crystallize, stop if no urine
B. Urea, Glycerin, and Isosorbide—Only for decreasing intraocular and intracranial pressure
VIII. Key Points
IX. Summary of Major Nursing Implications
A. High-Ceiling (Loop) Diuretics
B. Thiazide Diuretics
C. Potassium-Sparing Diuretics
CHAPTER 42: DRUGS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM
CHAPTER 42 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Describe the mechanism of action of the renin-angiotensin system (RAS).
2. Discuss how drugs can affect blood pressure by alterations in the RAS.
3. Describe the effects of angiotensin-converting enzyme inhibitors.
4. Identify the significance of angiotensin II receptor antagonists.
CHAPTER 42 OUTLINE
I. Introduction—Two drug groups for this chapter: RAS inhibitors and angiotensin II receptor antagonists
II. Physiology of the Renin-Angiotensin System—Role in regulation of blood pressure, blood volume, and fluid and electrolyte balance as appears to mediate pathophysiologic changes associated with hypertension, heart failure, and myocardial infarctions
A. Types of Angiotensin—Angiotensin I, II, and III (polypeptides)
B. Action of Angiotensin II—Mediates all effects of RAS, with most prominent effect being vasoconstriction and stimulation of aldosterone release; but can alter morphology of heart and blood vessels
1. Vasoconstriction—Extremely potent vasoconstrictor; acts directly on vascular smooth muscle especially in arterioles and less in veins, by action in the CNS to increase sympathetic outflow, and by acting on adrenal medulla to cause release of epinephrine
2. Release of aldosterone—Acts on adrenal cortex to promote synthesis and secretion of aldosterone, which acts on the kidney to cause retention of sodium (retains water to increase volume) and excretion of potassium and hydrogen; effects lead to increased blood pressure; secretion enhanced with low sodium or high potassium levels
3. Alteration in cardiac and vascular structure—Thought to cause hypertrophy and remodeling; may increase thickness of blood vessel walls in hypertension; thickening of the intimal surface of blood vessels in atherosclerosis; and hypertrophy and fibrosis in heart failure and MIs; however, known effects include increased migration, proliferation, and hypertrophy of vascular smooth muscle (VSM) cells; increased production of extracellular matrix by VSM cells; hypertrophy of cardiac myocytes; and increased production of extracellular matrix by cardiac fibroblasts
C. Formation of Angiotensin II by Renin and Angiotensin-Converting Enzyme
1. Renin—Catalyzes formation of angiotensin I from angiotensinogen, which is rate-limiting step of angiotensin II
2. Regulation of renin release—Increase due to decrease in BP, blood volume, plasma sodium content, or renal perfusion pressure; decrease due to opposites
3. Angiotensin—Converting enzyme (kinase II)—Catalyzes conversion of angiotensin I to angiotensin II; as a hormone ACE known as bradykinin or kinase II
D. Regulation of Blood Pressure by the Renin-Angiotensin System—Major factor in BP control with hemorrhage, dehydration, or sodium depletion; angiotensin II constricts renal blood vessels to decrease renal blood flow, which decreases GFR and secondarily stimulates release of aldosterone from adrenal cortex
E. Tissue (Local) Renin-Angiotensin Systems—Local effects independent of main RAS
III. Angiotensin-Converting Enzyme Inhibitors
A. Captopril (Capoten)
1. Mechanism of action and overview of pharmacologic effects—Benefits from inhibition of ACE, which inhibits production of angiotensin II, resulting in vasodilation (especially of arterioles), decreased blood volume, and reversal or prevention of possible angiotensin II changes in heart and blood vessels; prevents breakdown of bradykinin, a vasodilator
2. Pharmacokinetics—Readily absorbed (~70%) but decreased if taken with food, especially since half-life only 2 hours and 50% unchanged when excreted by kidneys
3. Therapeutic uses
a. Hypertension—Especially malignant hypertension and hypertension secondary to renal artery stenosis; does not interfere with cardiovascular reflexes and safe with asthma
b. Heart failure—Lowers arteriolar tone, improves regional blood flow, thus reducing afterload, increasing CO; venodilation reduces pulmonary congestion and peripheral edema; increases renal blood flow to promote excretion of sodium and water; may suppress growths of myocytes (heart wall thickening)
c. Myocardial infarction—May decrease mortality and decrease chance of developing overt heart failure
d. Diabetic and nondiabetic nephropathy—Slows progression of disease in diabetic nephropathy by decreasing GF pressure
4. Adverse effects—Less than 12% have intolerable reactions and minimize by using low doses with effects including: first-dose hypotension, cough, hyperkalemia, renal failure with bilateral renal artery stenosis, fetal injury, angioedema; dysgeusia and rash; neutropenia; GI disturbances and neurologic effects including headache and insomnia
5. Drug interactions—Diuretics, antihypertensive agents, drugs that raise potassium levels, lithium
6. Preparations, Dosage, and Administration—Tablets or combined with HCTZ as Capozide, take 1 hour before meals, gradually increase dosage to effect (maximum of 450 mg/day)
B. Enalapril (Vasotec) and Enalaprilat—Enalapril is prodrug that is converted into active form (enalaprilat) by liver; enalaprilat is potent ACE inhibitor; action/uses: like captopril for HTN, heart failure and asymptomatic left ventricular dysfunction; pharmacokinetics: rapidly absorbed from GI (~60%) with conversion taking several hours; half-life is 11 hours; adverse effects/interactions: well tolerated, similar to captopril (less rash, dysgeusia)
C. Newer ACE Inhibitors—Benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril—similar to captopril, except for lisinopril all are prodrugs; except for moexipril all can be administered with food unlike captopril; all have prolonged half-lives
IV. Angiotensin II Receptor Blockers—Five drugs currently approved
A. Losartan—Approved only for hypertension; may be useful for heart failure also
1. Mechanism of action and pharmacologic effects—Blocks action of angiotensin II at receptors in blood vessels, adrenals and all other tissues; does not cause significant increases in potassium; does not inhibit kinase II; does not cause cough or angioedema
2. Pharmacokinetics—Rapidly absorbed but significant first-pass effect (~30%), 99% bound to proteins, elimination via bile
3. Therapeutic use—BP reductions equal enalapril
Heart failure—Losartan under investigation with encouraging results
4. Adverse effects—Devoid of significant adverse effects, except dizziness
5. Contraindications—Contraindicated for pregnant women during second and third trimesters and for patients with bilateral renal artery stenosis
IV. Key Points
V. Summary of Nursing Implications
A. Angiotensin-Converting Enzyme Inhibitors
CHAPTER 43: CALCIUM CHANNEL BLOCKERS
CHAPTER 43 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Discuss the mechanism of action for calcium channel blockers.
2. Discuss the role of calcium channel blockers as treatment modality.
3. Describe the adverse effects of calcium channel blockers.
4. Discuss drug interactions with calcium channel blockers.
CHAPTER 43 OUTLINE
I. Introduction—Calcium channel blockers prevent calcium ions from entering cells with greatest effects on heart and blood vessels
II. Calcium Channels: Physiologic Functions and Consequences of Blockade—Calcium channels are gated pores in cytoplasmic membrane that regulate entry of calcium ions into cells
A. Vascular Smooth Muscle—Role in vascular smooth muscle (VSM) is to regulate contraction; action potential travels down surface of smooth muscle cell, channels open and calcium ions flow in beginning contractile process; if blocked, contraction will be prevented à vasodilation; at therapeutic doses, blockers act selectively on peripheral arterioles and arteries and arterioles of the heart
B. Heart—Regulate function of myocardium, SA node and AV node; coupled to beta1-adrenergic receptors
1. Myocardium—Calcium has positive inotropic effect; blockade decreases force of contraction
2. SA node—Regulated by calcium influx and heart rate; blockade slows HR
3. AV node—Excitability of AV node regulated by calcium entry; blockade decreases velocity of conduction
4. Coupling of cardiac calcium channels to beta1-adrenergic receptors—When beta1-adrenergic receptors are activated, calcium influx is enhanced (calcium and beta blockers have identical effects on heart)
III. Calcium Channel Blockers: Classification and Sites of Action—Family names not important
A. Classification—Three chemical families: dihydropyridines, including nifedipine; phenylakylamine, with verapamil the only one; and benzothiazepines, including diltiazem
B. Sites of Action—Dihydropyridines act primarily on arterioles; with verapamil and diltiazem action on arterioles and the heart at therapeutic doses
IV. Verapamil and Diltiazem: Agents That Act on Vascular Smooth Muscle and the Heart
A. Verapamil (Calan, Covera-HS, Verelan, Isoptin)—Indications are angina pectoris, essential HTN, and cardiac dysrhythmias
1. Hemodynamic effects—Direct effect on the heart and blood vessels by blocking at peripheral arterioles, causing dilation and decreasing BP, blocking at arteries and arterioles of heart to increase coronary perfusion, blocking at SA node to decrease HR, blocking at AV node to decrease nodal conduction (most important), and blocking in myocardium to decrease force of contraction; indirect effect by activation of baroreceptor negated by direct effect; therefore, overall effect is vasodilation with decreased BP and increased coronary perfusion
2. Pharmacokinetics—Orally (extensive first-pass effect with only 20% to circulation) or IV; oral begins in 30 minutes, peaks in 5 hours, eliminated by liver
3. Therapeutic uses—Angina pectoris, essential HTN, cardiac dysrhythmias and migraine headaches
4. Adverse effects—Common (constipation most common then dizziness, facial flushing, headache, edema, and gingival hyperplasia); cardiac effects (compromised cardiac function d/t bradycardia, complete heart block, and in myocardium decreased contractility
5. Drug interactions—Increase plasma digoxin levels 60% and, with beta adrenergic blocking agents, have same effects, so increased risk of excessive cardiosuppression
6. Toxicity—For severe hypotension and cardiotoxicity, give IV calcium gluconate to counter vasodilation and negative inotropic effects; treat hypotension with IV norepinephrine, IV fluids and Trendelenburg position; for bradycardia and AV block, treat with isoproterenol and atropine or electronic pacing; treat ventricular tachydysrhythmias with DC cardioversion and may try procainamide or lidocaine
7. Preparation, dosage, and administration—Oral in tablets, sustained-release (administer with food) and IV with monitoring ECG
B. Diltiazem (Cardizem or Dilacor)—Like verapamil with less constipation
V. Dihydropyridines: Agents That Act Mainly on Vascular Smooth Muscle—Minimal effect on heart
A. Nifedipine (Procardia, Adalat)—Different from verapamil by having little effect on heart, so not used for dysrhythmias and does not cause cardiac suppression
1. Hemodynamic effects—Direct effects on VSM; indirect effects on baroreceptor reflex, which will cause cardiac stimulation of increased HR and force of contraction but only with fast-acting form, not the sustained-release form à decreased BP, increased HR and force of contraction
2. Pharmacokinetics—Well absorbed, 50% bioavailability, peaks in 30 minutes
3. Therapeutic uses—Angina pectoris, HTN, and investigational for migraine headaches and to suppress preterm labor
4. Adverse effects—Like those of verapamil except no constipation and cardiac status not affected as much, but can get reflex tachycardia; rapid acting is associated with increased mortality with MI
5. Drug Interactions—Beta-adrenergic blockers prevent reflex tachycardia; with verapamil and diltiazem, would be worse
6. Toxicity—Excessive dosage loses selectivity
7. Preparations, dosage, and administration—Capsules and sustained release tablets
B. Other Dihydropyridines—Similar to nifedipine with greater blockade of VSM
1. Nicardipine (Cardene)
2. Amlodipine (Norvasc)—Long-acting so only once-per-day dosage
3. Isradipine (DynaCirc) in U.S., only approved for HTN
4. Felodipine (Plendil) once-per-day dosing
5. Nimodipine (Nimotop) for cerebral blood vessels only for prophylaxis of neurologic injury following rupture of intracranial aneurysm
6. Nislodipine (Sular) only for HTN
VI. Key Points
VII. Summary of Major Nursing Implications
A. Verapamil and Diltiazem
B. Dihydropyridines
VIII. Special Interest Topics—Are Calcium Channel Blockers Safe?
CHAPTER 44 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Differentiate among vasodilators that are selective for arterioles, veins, and both types of vessels.
2. Describe the differences in preload and afterload as a result of differences in drug selection.
3. Discuss the adverse effects of vasodilators.
CHAPTER 44 OUTLINE
I. Introduction—Vasodilators widely used for hypertension to angina pectoris to heart failure
II. Basic Concepts in Vasodilator Pharmacology
A. Selectivity of Vasodilator Effects—Differ with respect to types of blood vessels they affect; selectivity of vasodilator determines hemodynamic effects; dilators of resistance vessels (arterioles) cause a decrease in cardiac afterload; dilators of capacitance vessels (veins) reduce ventricular filling or preload
B. Overview of Therapeutic Uses—For essential HTN, HTN crisis, angina pectoris heart failure, pheochromocytoma, peripheral vascular disease, and production of controlled hypotension during surgery
C. Adverse Effects Related to Vasodilation
1. Postural hypotension
2. Reflex tachycardia—Produced by dilation of arterioles or veins
3. Expansion of blood volume—Secondary to prolonged reduction of blood pressure by two mechanisms: secretion of aldosterone by adrenal glands and by decreasing filtrate volume from decreased arterial pressure, which increases amount of sodium and water reabsorption
III. Pharmacology of Individual Vasodilators
A. Hydralazine (Apresoline)
1. Cardiovascular effects—Selective direct dilation of arterioles with little or no effect on veins; peripheral resistance and arterial blood pressure falls; heart rate and myocardial contractility increases
2. Pharmacokinetics—Readily absorbed after oral administration, begins within 45 minutes and persists for 6 hours or more; IV effects begin within 10 minutes and last for 2–4 hours; inactivated by metabolic process known as acetylation
3. Therapeutic uses
a. Essential hypertension—Almost always includes beta blocker and maybe a diuretic
b. Hypertensive crisis—Parenteral use for crisis: take care with use
c. Heart failure—For short-term use to reduce afterload in heart failure patients; prolonged use leads to tolerance
4. Adverse effects
a. Reflex tachycardia—Avoid beta blockers because of risk for heart failure
b. Increased blood volume—Causes sodium and water retention
c. Systemic lupus erythematosus-like syndrome (SLE)—Discontinue drug, but it may take 6 months to subside
d. Other adverse effects—Headache, dizziness, weakness, and fatigue
5. Drug interactions—With beta blockers, protect against reflex tachycardia; with diuretics, prevent sodium and water retention and expansion of blood volume; with other antihypertensive agents, can cause excessive hypotension
6. Preparations, dosage, and administration—Tablets, IV for crisis
B. Minoxidil (Loniten)—Produces more intense vasodilation for severe hypertension refractory to less dangerous drugs
1. Cardiovascular effects—Direct dilation of arterioles with little or no venous dilation; decreased peripheral resistance and arterial blood pressure; reflex increased heart rate and myocardial contractility à oxygen demand, which can make angina pectoris worse
2. Pharmacokinetics—Rapidly and completely absorbed with oral, maximum vasodilation within 2–3 hours; effects may persist for 2 or more days; extensively metabolized and eliminated in urine
3. Therapeutic uses—For severe hypertension in those who fail to respond to safer drugs; topical minoxidil (Rogaine) promotes hair growth
4. Adverse effects
a. Reflex tachycardia—Decreased BP triggers reflex tachycardia; use beta blocker to treat
b. Sodium and water retention—Can cause cardiac decompensation; need high-ceiling diuretic
c. Hypertrichosis—80% experience excessive hair growth
d. Pericardial effusion—Usually asymptomatic but could in rare cases cause cardiac tamponade, which may need pericardiocentesis
e. Other adverse effects—Nausea, headache, fatigue, breast tenderness, glucose intolerance, thrombocytopenia, and skin reactions (rashes, Stevens-Johnson syndrome)
5. Preparations, dosage, and administration—Tablets once per day
C. Diazoxide (Hyperstat IV)—Similar to thiazide diuretics but devoid of diuretic actions
1. Cardiovascular effects—Selective direct dilation of arterioles, no effect on veins; IV causes rapid drop in diastolic and systolic pressure, which will trigger reflex tachycardia and increased myocardial contractility to increase cardiac output
2. Pharmacokinetics—IV bolus or infusion; effects begin in minutes and last for hours; drug eliminated unchanged in urine
3. Therapeutic uses—IV for acute emergencies
4. Adverse effects—Reflex tachycardia, salt and water retention, hyperglycemia, hyperuricemia, and other effects (GI effects, headache, flushing hypotension, and interruption of labor)
5. Drug interactions—High-ceiling diuretics counter sodium and water retention; do not use thiazides since they potentiate hyperglycemia and hyperuricemia states; do not combine with other antihypertensives except diuretics
6. Preparations, dosage, and administration—Use minidoses (1–3 mg/kg injected in <30 seconds and repeated every 5–15 minutes), not single bolus
D. Sodium Nitroprusside (Nipride, Nitropress)—A potent and efficacious vasodilator; fastest acting antihypertensive agent available; drug of choice for emergencies
1. Cardiovascular effects—Venous dilation in addition to arteriolar dilation with minimal reflex tachycardia; diluted IV administration with immediate results; adjust infusion to BP; when stopped, BP returns in pretreatment levels in minutes; triggers retention of sodium and water so use furosemide to offset effect
2. Mechanism of Action—Breaks down to release nitric oxide, activates guanylate cyclase, which catalyzes production of cyclic GMP, which causes vasodilation; similar to nitroglycerin’s effects
3. Metabolism—Contains five cyanide groups; nitric oxide released first; cyanide groups convert to thiocyanate in liver eliminated by kidneys
4. Therapeutic uses
a. Hypertensive emergencies
b. Other uses—To control bleeding in surgery by decreasing BP
5. Adverse effects
a. Excessive hypotension—From too rapid administration
b. Cyanide poisoning—Can be lethal amounts, so give no faster than 10 mcg/kg/min and not for prolonged time
c. Thiocyanate toxicity—Seen after several days infusion and symptoms include CNS involvement
6. Preparations, dosage, and administration—Powdered form for dilution for IV infusion; slight brown color; if deeply colored (blue, green, or dark red, discard; protect from light; monitor BP with arterial line if possible; do not mix with other drugs in IV
E. Angiotensin-Converting Enzyme (ACE) Inhibitors—Promote vasodilation by preventing conversion of angiotensin I into angiotensin II; benefit patients with heart failure and diabetes
F. Losartan: Angiotensin II Receptor Antagonist—Similar to ACE inhibitors except blocks receptors for angiotensin II, thus dilates arterioles and veins, drug approved only for HTN
G. Organic Nitrates (nitroglycerin, isosorbide dinitrate)—Selective dilation of veins with minimal dilation of arterioles; use primarily for angina pectoris; also for heart failure and MIs and to control BP in surgery
H. Calcium Channel Blockers—Vasodilation by preventing calcium entry into VSM, selective dilation of arterioles, little venous dilation for HTN and angina pectoris
I. Sympatholytics—Vasodilation by preventing sympathetic nervous system from causing vasoconstriction; some act by direct blockade of adrenergic receptors of blood vessels; others act on ganglia, adrenergic neurons or in CNS
1. Alpha-adrenergic blocking agents—Vasodilation by preventing stimulation of alpha-adrenergic receptors on veins and arterioles, used for essential HTN, peripheral vascular disease, and pheochromocytoma
2. Ganglionic blocking agents—Interrupt impulse transmission through all ganglia of the ANS to prevent sympathetic stimulation of arterioles and veins in HTN emergencies and severe cases of HTN and hypotension during surgery
3. Adrenergic neuron blocking agents—Act within terminals of adrenergic neurons to reduce norepinephrine release
4. Centrally acting agents—Act within CNS to inhibit outflow of impulses along sympathetic nerves for HTN treatment
IV. Key Points
CHAPTER 45: DRUGS FOR HYPERTENSION
CHAPTER 45 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Describe hypertension.
2. Discuss the management of hypertension including lifestyle changes and medication therapy.
3. Describe management for hypertensive emergencies.
4. Discuss hypertension during pregnancy.
CHAPTER 45 OUTLINE
I. Introduction—A common and chronic disorder affecting 50 million Americans; untreated, leads to heart disease, kidney disease, blindness, and stroke; drug therapy does not cure HTN, but only reduces symptoms; chapter discusses drugs already presented for treatment of HTN
II. Hypertension: Definition, Types, and Consequences
A. Definition and Diagnosis—Systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg; if SBP >140 and DBP <90, diagnosis of isolated systolic hypertension is likely; classified as stages based on degree of blood pressure elevations from Sixth Report of Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (1997); base classification on higher category when SBP and DBP in different categories; never base BP on single reading
B. Types of Hypertension
1. Primary (essential) hypertension—Most common; no identifiable cause; a progressive chronic disorder; drugs lower BP but don’t treat underlying cause
2. Secondary hypertension—Has identified primary cause (see Table 45-2 in the text); some people can be cured by treating cause
C. Consequences of Hypertension àheart disease (left ventricular hypertrophy, MI, angina pectoris), kidney disease, blindness and stroke; degree of injury related to degree of elevation; injury can occur during asymptomatic stage
III. Objectives of Antihypertensive Therapy—Reduce BP to 140/90 mm Hg and prevention of long-term complications
IV. Risk Stratification and Selection of Treatment Modality
A. JNC VI introduced new concept in management of HTN (not only BP, but target organ damage, and other risk factors)
B. Evaluate for major CV risks, clinical CV disease, and target organ damage
C. Treatment based on lifestyle modification with or without drug therapy
V. Management of Essential Hypertension I: Lifestyle Modifications—Prevent HTN
A. Weight Reduction—Reduction in BP occurs in 60%–80% of overweight with weight loss; caloric restriction if >110% body weight with fat <30% of diet; keep body mass index (BMI) 27 or less.
B. Sodium Restriction—Can decrease BP and enhance drug therapy; experts disagree on role of salt intake and blood pressure
C. Alcohol Restriction—Excessive intake increases BP; limit to 1 oz/day
D. Exercise—Regular exercise can decrease BP by 10 mm Hg
E. Smoking Cessation—Major risk for cardiovascular disease and may impair ability of antihypertensives to protect against cardiovascular disease; evidence of CV benefit seen in a year
F. Maintenance of Potassium and Calcium Intake—Potassium has beneficial effect on BP; in normotensives, help protect against HTN; take 50–90 mmol of potassium a day (fresh fruits and vegetables); calcium needed for overall good health with only modest effect on BP
VI. Management of Essential Hypertension II: Pharmacologic Therapy—Use drug therapy if BP elevated after implementation of lifestyle changes; try to decrease drugs or dosages after 12 months therapy
A. Review of Blood Pressure Control
1. Principal determinants of blood pressure (see Figure 45-1 in the text)—BP is product of cardiac output and peripheral resistance and influenced by four things (HR, myocardial contractility, blood volume, and venous return)
2. Systems that help regulate blood pressure—Regulatory systems are
sympathetic nervous system, renin-angiotensin system, and kidneys
a. Sympathetic baroreceptor reflex—Reflex circuit (baroreceptor reflex) keeps BP at preset level; reflex opposes attempts to reduce BP with drugs; need beta blocker to block reflex tachycardia
b. Renin-angiotension system (RAS)—Elevates BP, negating hypotensive effects of drugs; suppress renin release with beta blockers; prevent conversion of angiotensin I into II with ACE inhibitor; and block receptors for angiotensin II with losartan
c. Renal regulation of blood pressure—With decreased BP, GFR decreases, promoting retention of sodium, chloride, and water to increase blood volume; increases blood flow to the heart; increases cardiac output and BP; negates renal effects on BP with diuretic
B. Antihypertensive Mechanisms—Sites of Drug Action and Effects Produced
1. Brainstem—Suppresses sympathetic outflow to heart and blood vessels; decreases HR; decreases myocardial contractility and vasodilation; arteriole dilation decreases BP by decreasing vascular resistance; dilation of veins decreases BP by decreasing venous return
2. Sympathetic ganglia—Blockade reduces sympathetic stimulation to heart and blood vessels; used in hypertensive emergencies
3. Terminals of adrenergic nerves—Drugs decrease release of norepinephrine, resulting in decreased sympathetic stimulation of heart and blood vessels
4. Beta1-adrenergic receptors on the heart—Blockade prevents sympathetic stimulation of heart
5. Alpha1-adrenergic receptors on blood vessels—Blockade promotes dilation of arterioles (decrease peripheral resistance) and veins (increases venous return to heart)
6. Vascular smooth muscle—Some act directly on VSM to cause relaxation; most for essential HTN, two for emergencies (sodium nitroprusside and diazoxide)
7. Renal tubules—Diuretics to promote salt and water excretion
8. Beta1 receptors on juxtaglomerular cells—Blockade suppresses release of renin
9. Angiotensin-converting enzyme—Suppresses formation of angiotensin II, which results in peripheral vasodilation, renal vasodilation, and suppression of aldosterone
10. Angiotensin II receptors—Blockade prevents actions at angiotensin II receptors
C. The Antihypertensive Drugs (see Table 45-5 and Table 45-6 in the text)
1. Diuretics—Mainstay of antihypertensive therapy; include thiazides (most commonly used and work by reduction of blood volume and arterial resistance with adverse effect being hypokalemia, dehydration, hyperglycemia, and hyperuricemia); high-ceiling or loop diuretics (reserved for patients requiring greater diuresis than with thiazides, patients with low GFR; most adverse effects are hypokalemia, dehydration, hyperglycemia, and hyperuricemia plus risk of hearing loss); and potassium-sparing diuretics (least effective but balance the potassium loss by thiazides or loop diuretics; most significant adverse effect is hyperkalemia; not to be used with potassium supplements or with ACE inhibitors)
2. Sympatholytics (adrenergic antagonists)—Suppress influence of SNS on heart, blood vessels, and other structures; five categories (beta-adrenergic blockers, centrally acting alpha2 agonists, adrenergic neuron blockers, alpha1-adrenergic antagonists, and alpha1/beta blockers); beta blockers are most widely used
3. Direct-acting vasodilators: hydralazine and minoxidil—Promote decreased blood pressure by promoting dilation of arterioles
4. Calcium channel blockers—Dilate arterioles and cause reflex tachycardia, especially with nifedipine
5. ACE Inhibitors—Examples: captopril and enalapril, which lower BP by preventing conversion of angiotensin I to angiotensin II; adverse effects are persistent cough, first-dose hypotension, and hyperkalemia
6. Angiotensin II receptor antagonists (ARBs) —Work very much like ACE inhibitors, but block action at angiotensin II receptors; devoid of serious adverse effects except for fetal harm
D. Fundamentals of Antihypertensive Therapy
1. The basic strategy (see Figure 45-3 and Table 45-3 in the text)—Base treatment on risk category; lifestyle changes first; begin with single drug (diuretic or beta blocker); add another drug or substitute drug to produce adequate response; then another drug can be added
2. Initial drug selection—Selection based on presence or absence of comorbid conditions (see Table 45-7 and Figure 45-3 in the text)
a. Major categories of drugs for initial therapy and those for supplemental drugs—Initial is usually beta blocker and diuretic or alternative is ACE inhibitor, calcium channel blockers, alpha1-adrenergic blockers and alpha/beta adrenergic blockers, which are less effective; supplemental are centrally acting sympatholytics, adrenergic neuron blockers, and direct-acting vasodilators; selection of drugs should be from different mechanism of action
3. Adding drugs to the regimen
a. Rationale for drug selection—If using two or more drugs, each should come from different class
b. Benefits of multidrug therapy—Increases chance of success, dosage can be lower than if used alone, one agent can offset adverse effects of another
4. Dosing—Start low and gradually increase
5. Step-down therapy—After 1 year, attempt to reduce dosages and number of drugs
E. Individualizing Therapy
1. Patients with comorbid conditions—Take care to select or avoid drugs that make existing diseases worse (see Table 45-7 in the text); drugs to avoid for specific conditions are found in Table 45-8 in the text
a. Renal disease—Secondary to HTN; want BP <130/85 if no proteinuria and 125/75 if proteinuria
b. Diabetes—BP <130/85; ACE inhibitors retard renal damage; those on CCB had higher incidence of MI than if on ACEI
2. Patients in Special Populations
a. African Americans—HTN major health problem for AA adults so they have greater risk for heart disease, end-stage renal disease and stroke; diuretics work well, monotherapy with calcium channel blockers, alpha1 blockers, or labetalol are equally effective in blacks as whites; beta blockers and ACE inhibitors are less effective; lifestyle changes most important, especially with salt sensitivity, obesity and cigarette use
b. Children and Adolescents—Secondary HTN more prevalent than in adults; treat cause; do not give ACEIs or ARBs in sexually active girls
c. Older Adults—65% incidence in over 60 with prevalence of isolated systolic HTN greater than in younger adults; need treatment to decrease stroke and MIs and use beta blockers and diuretics; start lower than in younger adults and watch for orthostatic hypotension and drugs causing cognitive dysfunction
F. Minimizing Adverse Effects—Tailor regimen to patient
G. Promoting Compliance—Lack of compliance is cause of treatment failure
1. Why compliance can be difficult to achieve—HTN is chronic, progressive disease devoid of overt symptoms
2. Ways to promote compliance
a. Educate the patient—Compliance requires motivation, which patient education can help with; teaching consequences of HTN and benefits of treatment and lifelong therapy usually required
b. Teach self-monitoring—Teach goal of therapy and how to monitor and record BP
c. Minimize side effects—Encourage patients to report side effects, discontinue objectionable drugs, and substitute more acceptable ones, avoiding drugs that exacerbate coexisting pathology and using low initial doses and gradually increasing
d. Establish a collaborative relationship—More likely to comply, set goals, follow treatment plan, and evaluate progress
e. Simplify the regimen—Increases compliance
f. Other measures—Give positive reinforcement, involve family members, schedule convenient office visits, and follow up missed appointments
VII. Drugs for Hypertensive Emergencies—When DBP >120 mm Hg, excessive BP associated with papilledema, intracranial hemorrhage, MIs, or acute congestive heart failure; if severe, emergency exists and may need to decrease BP in <1 hour; if no crisis, then decrease BP over 24–48 hours to prevent cerebral ischemia, MIs, or renal failure
A. Sodium Nitroprusside—For acute, severe HTN, demanding rapid, controlled reduction in BP; a direct-acting vasodilator that relaxes smooth muscle of arterioles and veins; begin immediately and effects fade fast when discontinued; do not use longer than 72 hours or toxic effects can occur
B. Nifedipine—Dilates arterioles, get 20% reduction in 20–30 minutes, repeat every 4–6 hours; can cause serious dysrhythmias and cardiac arrest
C. Fenoldopam (Corlopam)—New IV drug for short-term use, half-life 5 min.
D. Labetalol—Blocks alpha and beta receptors
E. Diazoxide—Dilation of arterioles; given by IV bolus or infusion; not for patients with angina; may need beta blocker for HR and diuretic for fluid
VIII. Drugs for Hypertensive Disorders of Pregnancy—HTN most common complication of pregnancy (10% incidence); distinguish between chronic hypertension and preeclampsia (a life-threatening condition)
A. Chronic Hypertension—Present prior to pregnancy or before 20th week of gestation; goal to minimize risk of HTN to mother; use drugs previously used except for ACE inhibitors or ARBs, which are contraindicated during pregnancy because of fetal harm; start with methyldopa, which does not affect fetus or placenta
B. Preeclampsia and Eclampsia—Preeclampsia develops after 20th week of pregnancy; increased BP, proteinuria, and generalized edema; may see liver dysfunction and coagulation abnormalities; preeclampsia can develop to convulsive phase; if close to term, treat with delivery; if can’t deliver infant, use hydralazine (5 mg bolus) and repeat 3 times every 20 minutes; if BP too high, may need nifedipine or labetalol; may need to treat with anticonvulsants such as magnesium sulfate
1. Recent evidence indicates that preeclampsia can be reduced with vitamins C and E (reduction in high risk by 76%)
IX. Key Points
X. Summary of Major Nursing Implications
A. Antihypertensive Drugs