CASE

14: Diuretics CASE 15: Diuretics / Anti-Hypertensive Drugs CASE 16: Anti-Hypertensive Drugs
A 64-year-old woman with a history of A 67-year-old woman was referred to a hypertension specialty clinic for A 50-year-old man presents for follow up of his hypertension. He is
two previous myocardial infarctions refractory hypertension and intermittent hypokalemia. Evaluations for maintaining a low sodium diet, exercising regularly and taking metoprolol
(MIs) comes to the emergency room primary aldosteronism and renal artery stenosis were negative, plasma renin at maximum dosage. He is on no other medications. His blood pressure
with shortness of breath. In the was low. She was hypertensive for 15 years. Most recently she had taken remains elevated at 150/100mmhg. His examination is otherwise
previous 2 weeks, she has developed chlorthalidone 25mg. She was not diabetic and had never smoked. Her blood unremarkable. You decided to add thiazide diuretic to his regimen.
dyspnea with exertion and swelling of pressure was in the range of 160 to 170/95 to 100mmhg. Except for her being
her legs. She sleeps on three pillows mildly overweight (BMI 28), the physical exam was unremarkable, with no
because she coughs and gets short of sign of target organ damage. Voltage criteria for left ventricular enlargement
breath if she tries to lie flat. In the were present on ECG, Adherent to medication. Spironolactone 40mg/d was
emergency department, she is sitting added and her dose of chlorthalidone was reduced to 12.5mg/d. She was
upright, appears to be in moderate given amlodipine 5mgs once daily and metoprolol 50mgs twice a day. Over
respiratory distress, and is tachycardic the next year, her blood pressure fell to the range of 135 to 145/85mmhg and
and hypertensive. She has jugular serum potassium was consistently normal.
venous distention to the angle of her
jaw. On auscultation of her lungs, wet
rales are heard bilaterally. She has
pitting edema of both lower legs up to
her knees. A chest X-ray confirms the
diagnosis of pulmonary edema. She is
placed on oxygen therapy and
immediately given an IV injection of
furosemide. *NOTE: Clorthalidone is a thiazide (diuretic)
DIAGNOSIS: DIAGNOSIS: DIAGNOSIS:
Myocardial Infarction Refractory Hypertension and Intermittent Hypokalemia Hypertension
Drug: Drug Added: Drug Added: Maintenance Drug: Drug Added:
FUROSEMIDE SPIRONOLACTONE AMLODIPINE METOPROLOL THIAZIDE (Diuretic)
(Cardioselective and most widely used)
CLASSIFICATION: CLASSIFICATION: CLASSIFICATION: CLASSIFICATION: CLASSIFICATION:
Loop Diuretic Potassium Sparing Diuretics Calcium Channel Blocker Beta-Blockers Thiazides
(OTHERS: Bumetanide, Torsemide, (OTHERS: Amiloride, Triamterene) (OTHERS: Dihydropyridine Family= (OTHERS: Atenolol, Bisoprolol, Propanolol) (EX: Hydrochlorothiazide,
Ethacrynic Acid) Felodipine, Isradipine, Nicardipine, Chlorthalidone)
Nifedipine, Nisoldipine)
MOA: MOA: MOA: MOA: MOA:
Inhibits the Na-K-Cl transporter Stops the entry of aldosterone into Block vascular calcium channels > Block β1 receptors Block Na/Cl transporter
protein present in the walls of the the PRINCIPAL CELLS of the cardiac calcium channels in renal distal convoluted
ASCENDING LOOP OF HENLE. COLLECTING DUCT and LATE DISTAL ü Reduce vascular Approximately equipotent to propranolol in tubule
ü Causes reduction in the TUBULE of the nephron resistance inhibiting stimulation of B1 adrenoceptors
reabsorption of the NaCl ü Increase diuresis but but 50-100-fold less potent than propranolol Acts by inhibiting NaCl
(salt) which significantly without causing potassium Amlodipine is a peripheral arterial in blocking B2 receptors reabsorption in the
increases diuresis. to be lost from the body vasodilator that acts directly on DISTAL CONVOLUTED
Blocks aldosterone receptor in renal vascular smooth muscle to cause a In contrast to propranolol, the cardioselective TUBULE of the kidney
collecting tubule reduction in peripheral vascular β-blockers have fewer effects on pulmonary
ü Increases Na excretion and resistance and reduction in blood function, peripheral resistance, and ↑ urinary excretion of Na
decrease K excretion (given pressure. carbohydrate metabolism. Nevertheless, and water = ↓ Blood
or added to this patient to asthma patients treated with these agents Volume, ↓BP
correct intermittent Amlodipine is a dihydropyridine must be carefully monitored to make certain
hypokalemia brought about calcium antagonist (calcium ion that respiratory activity is not compromised
 by Chlorthalidone, a antagonist or slow- channel
thiazide diuretic) blocker) that inhibits the Advantageous in treating hypertensive
transmembrane influx of calcium patients who also suffer from BA, DM or
ions into vascular smooth muscle peripheral vascular disease
and cardiac muscle.
They relax the blood vessels and decrease HR
The contractile processes of to improve blood flow and ↓ BP
cardiac muscle and vascular
smooth muscle are dependent
upon the movement of
extracellular calcium ions into
these cells through specific ion
channels.

Amlodipine inhibits calcium ion
influx across cell membranes
selectively, with a greater effect on
vascular smooth muscle cells than
on cardiac muscle cells.
FUROSEMIDE ADVERSE EFFECTS: SPIRONOLACTONE ADVERSE AMLODIPINE ADVERSE EFFECTS: METOPROLOL ADVERSE EFFECTS: THIAZIDE ADVERSE
ü Hypokalemic Metabolic Alkalosis EFFECTS: ü Excessive Hypotension, ü Bronchospasm EFFECTS:
o By inhibiting salt reabsorption in ü Hyperkalemia ü Baroreceptor Reflex ü Bradycardia Electrolyte Imbalance:
the thick ascending limb, loop o Risk increased in those with Tachycardia ü Obstructive Airway Disease (HYPO KaNatMag,
diuretics increase Na+ delivery renal disease, or use of drugs HyperCal)
to the collecting duct. that reduce or inhibit renin - Hypokalemia,
o Increased Na+ delivery leads to (BB, NSAIDs, aliskerin) or Hyponatremia,
increased secretion of K+ and H+ angiotensin II activity (ACEI, Hypomagnesemia,
by the duct, causing ARBs) Hypercalcemia
hypokalemic metabolic alkalosis ü Hyperchloremic Metabolic
ü Ototoxicity (Dose-related, Acidosis BOOK:
reversible) o By inhibiting H+ secretion in Toxicity=
ü Hyperuricemia parallel with K+ secretion, the Hypokalemic metabolic
o Caused by hypovolemia- K+ - sparing diuretics can cause alkalosis,
associated enhancement of uric acidosis hyperuricemia,
acid reabsorption in the ü Gynecomastia hyperglycemia,
proximal tubule o Synthetic steroids may cause hyponatremia
ü Hypomagnesemia endocrine abnormalities by
ü Allergic reactions actions on other steroid
receptors.
o Gynecomastia, impotence, and
benign prostatic hyperplasia
(very rare) have been reported
with spironolactone
ü Kidney Stones
o Triamterene is only slightly
soluble and may precipitate in
the urine, causing kidney
stones
ü Acute Renal Failure
FUROSEMIDE INDICATIONS: SPIRONOLACTONE INDICATIONS: AMLODIPINE INDICATIONS: METOPROLOL INDICATIONS: THIAZIDE INDICATIONS:
Acute pulmonary edema and Aldosteronism Hypertension, Angina Hypertension, Heart Failure, Coronary Hypertension
other edematous conditions Heart Failure CONTRAINDICATIONS: Disease Mild Heart Failure
– most important indication Hypertension (an inhibitor in the INTERNET SOURCE!!! CONTRAINDICATIONS: CONTRAINDICATIONS:
Hyperkalemia mineralocorticoid receptor can Hypersensitivity to INTERNET SOURCE!!! INTERNET SOURCE!!!
Acute renal failure be highly effective in patients Dihydropyridines Sick Sinus Syndrome, Second or Third- Hypotension
Anion overdose with refractory hypertension in Severe Hypotension Degree Heart Block , Decompensated Heart Allergy to sulfa
CONTRAINDICATIONS: combination with thiazide type Shock (Including Cardiogenic Failure, Hypotension, Hypersensitivity to drugs
Sulfonamide hypersensitivity, thiazide diuretic) Shock) Metoprolol Gout
diuretic hypersensitivity, electrolyte CONTRAINDICATIONS: Obstruction of The Outflow Hypokalemia
imbalance, hypocalcemia, Adrenal insufficiency, anuria, Tract of The Left Ventricle Renal failure
hypochloremia, hypokalemia, diabetes mellitus, hyperkalemia, (E.G., High Grade Aortic Lithium treatment
hypomagnesemia, hyponatremia, renal disease, renal failure, renal Stenosis). Pregnancy (because
metabolic alkalosis, DM, HF, impairment, pregnancy, and Hemodynamically Unstable of a decrease in
pregnancy, and lactation lactation Heart Failure After Acute placental perfusion)
Myocardial Infarction
NOTES: NOTES: NOTES:
FUROSEMIDE is the most efficacious REFRACTORY HYPERTENSION: BP that remained uncontrolled after ≥ 3 visits NORMAL REGULATION OF BP
diuretic agents available to a hypertension clinic within a minimum 6-month follow-up period. Physiologically, in both normal and hypertensive individuals, blood pressure
ü Diuretics reduce intravascular is maintained by moment-to-moment regulation of cardiac output and
volume, leading to a decrease in RATIONALE FOR USING 2 OR MORE ANTIHTN IN THIS CASE: peripheral vascular resistance, exerted at three anatomic site: arterioles,
central venous pressure, right ü most drugs evoke compensatory regulatory mechanisms for postcapillary venules (capacitance vessels), and heart. A fourth anatomic
and left heart filling pressures, maintaining blood pressure which may markedly limit their effect control site, the kidney, contributes to maintenance of blood pressure by
and pulmonary vascular ü Vasodilators such as amlodipine cause a significant decrease in regulating the volume of intravascular fluid. Baroreflexes, mediated by
pressures. peripheral vascular resistance but evoke a strong compensatory autonomic nerves, act in combination with humoral mechanisms, including
ü Venous capacitance increases, tachycardia and salt and water retention capable of almost completely the renin-angiotensin-aldosterone system, to coordinate function at these
and intrapulmonary fluid returns reversing their effect four control sites and to maintain normal blood pressure. Finally, local
to the circulation. The left ü Addition of Beta Blocker (Metoprolol) prevents the tachycardia release of vasoactive substances from vascular endothelium may also be
ventricular volume is smaller, ü All the drugs increase the sensitivity of the CV system to each other’s involved in the regulation of vascular resistance. For example, endothelin-1
and cardiac output typically actions constricts and nitric oxide dilates blood vessels. Blood pressure in a
increases. In the setting of mitral hypertensive patient is controlled by the same mechanisms that are
regurgitation, the reduced left operative in normotensive subjects. Regulation of blood pressure in
ventricular volume improves hypertensive patients differs from healthy patients in that the
mitral leaflet coaptation baroreceptors and the renal blood volume-pressure control systems appear
Selectively inhibit NaCl reabsorption in to be “set” at a higher level of blood pressure.
the thick ascending limb
ü Because of the large NaCl (A)Postural Baroreflex
absorptive capacity of this Baroreflexes are responsible for rapid, moment-to-moment adjustments in
segment and the fact that the blood pressure, such as in transition from a reclining to an upright posture.
diuretic action of these drugs is Central sympathetic neurons arising from the vasomotor area of the
not limited by development of medulla are tonically active. Carotid baroreceptors are stimulated by the
acidosis, as is the case with the stretch of the vessel walls brought about by the internal pressure (arterial
carbonic anhydrase inhibitors, blood pressure). Baroreceptor activation inhibits central sympathetic
loop diuretics are the most discharge.
efficacious diuretic agents Conversely, reduction in stretch results in a reduction in baroreceptor
currently available activity. T
hus, in the case of a transition to upright posture, baroreceptors sense the
reduction in arterial pressure that results from pooling of blood in the veins
below the level of the heart as reduced wall stretch, and sympathetic
 discharge is disinhibited. The reflex increase in sympathetic outflow acts
through nerve endings to increase peripheral vascular resistance
(constriction of arterioles) and cardiac output (direct stimulation of the
heart and constriction of capacitance vessels, which increases venous
return to the heart), thereby restoring normal blood pressure. The same
baroreflex acts in response to any event that lowers arterial pressure,
including a primary reduction in peripheral vascular resistance (eg, caused
by a vasodilating agent) or a reduction in intravascular volume (eg, due to
hemorrhage or to loss of salt and water via the kidney).

(B)Renal Response to Decreased Blood Pressure
By controlling blood volume, the kidney is primarily responsible for long-
term blood pressure control. A reduction in renal perfusion pressure causes
intrarenal redistribution of blood flow and increased reabsorption of salt
and water. In addition, decreased pressure in renal arterioles as well as
sympathetic neural activity (via β adrenoceptors) stimulates production of
renin, which increases production of angiotensin II. Angiotensin II causes (1)
direct constriction of resistance vessels and (2) stimulation of aldosterone
synthesis in the adrenal cortex, which increases renal sodium absorption
and intravascular blood volume. Vasopressin released from the posterior
pituitary gland also plays a role in maintenance of blood pressure through
its ability to regulate water reabsorption by the kidney.


DIURETICS
GENERAL THERAPEUTIC USE OF DIURETICS
(1) Antihypertensive Therapy
- Reduces blood volume, cardiac output and with long term therapy reduces systemic vascular resistance
(2) Heart Failure
- To reduce pulmonary systemic congestion and edema
- Long term treatment reduces afterload on the heart by promoting systemic vasodilation leading to improve ventricular ejection
(3) Pulmonary and Systemic Edema

DIFFERENT DIURETICS:
THIAZIDE DIURETICS (Hydrochlorothiazide, Indapamide, Metolazone) – Case 16
- acts by inhibiting NaCl reabsorption in the DISTAL CONVOLUTED TUBULE of the kidney
- Action is mediated through suppression of the sodium chloride co-transporter.
CARBONIC ANHYDRASE (Acetazolamide, Dorzolamide)
- Inhibits the enzyme carbonic anhydrase which has an effect of decreasing the reabsorption of bicarbonate in the PROXIMAL TUBULE
- This leads to retention of potassium in urine and decrease sodium reabsorption leading to decrease water reabsorption
OSMOTIC DIURETICS (Mannitol, Glycerol)
- Inhibit the reabsorption of sodium and water by increasing osmolarity of the blood and the renal filtrate
POTASSIUM SPARING DIURETICS (Spironolactone, Amiloride, Triamterene) – Case 15
- Increase diuresis but without causing potassium to be lost from the body
- Spironolactone: stops the entry of aldosterone into the PRINCIPAL CELLS of the COLLECTING DUCT and LATE DISTAL TUBULE of the nephron
LOOPS DIURETICS (Furosemide, Bumetanide, Torsemide, Ethacrynic Acid) – Case 14
- Inhibits the Na-K-Cl transporter protein present in the walls of the ASCENDING LOOP OF HENLE


CLASSIFICATION OF ANTIHYPERTENSIVES
BRAIN Centrally Acting Alpha Agonists Stimulate alpha-2 receptors in the brainstem,
reducing sympathetic outflow
HEART Beta Adrenergic Blocking Agents Block cardiac Beta-1 adrenergic receptors, reducing
heart rate and cardiac contractility
VEINS/ARTERIES Angiotensin Converting Enzyme Block conversion of angiotensin I to angiotensin II, a
Inhibitors potent vasoconstrictor
Angiotensin II Receptor Blockers Competitively block angiotensin II receptors
Dihydropyridine Calcium Bind alpha-1 subunit of L-type calcium channel in
Channel Blockers muscle membrane, reducing vascular smooth
muscle contractility
Director Vasodilators Hydralazine reduces intracellular calcium in vascular
smooth muscle cells and minoxidil causes potassium
efflux with smooth muscle relaxation; both drugs
cause arteriolar dilation
KIDNEY Thiazide Diuretics Inhibit Na-Cl co-transporter in distal convoluted
tubule of nephron, causing natriuresis
Loop Diuretics Inhibit Na-K-Cl co-transporter in the loop of Henle of
the nephron, causing natriuresis
Mineralocorticoid Receptor Competitively inhibits aldosterone binding to the
Blockers mineralocorticoid receptor, ultimately reducing
sodium reabsorption in the collecting duct of the
nephron
COMMON SIDE EFFECTS: Bronchospasm, Bradycardia, Obstructive Airway Disease
























 CASE 17: Drugs Active on Renin-Angiotensin System CASE 18: Antihypertensive Agents
A 72-year-old man presents to the office for routine follow-up. He is under treatment for hypertension and congestive Mr. R is a 45-year-old African-American, No history of hypertension. At
heart failure with enalapril and a diuretic. His blood pressure is under acceptable control, and he has no symptoms of screening clinic his BP was found to be180/120 mm Hg.
heart failure at present. He does complain that he has been coughing frequently in the past few months. History and
examination reveal no other cause of a chronic cough, so you decide to discontinue his enalapril and start him on losartan. Family and Social Data:
- Father died of stroke (60 years old)
- Mother is alive but has hypertension
- States that he feels fine and is not a “hyper” person
- Smokes one pack of cigarettes daily
- Drinks six-pack of beer (Friday and Saturday nights)

PE:
- Grade I/IV Keith-Wagener retinopathy
- Sustained apical impulse palpable in the fourth intercostal
space (lateral to the midclavicular line)

Laboratory work - up:
- ECG: left ventricular hypertrophy
- Urinalysis: protein 31 mg/dL.
- Serum creatinine level: 1.6 mg/dL
DIAGNOSIS: Hypertension and Congestive Heart Failure DIAGNOSIS: Stage 2 Hypertension
Maintenance Drug: Alternative Drug: Drug:
ENALAPRIL LOSARTAN 2 Drug Combination:
(Enalapril and Lisinopril are recommended as first-line treatment) (Alternatives to ACE Inhibitors) v Thiazide Type Diuretic and
v ACE Inhibitors or ARB (Angiotensin Receptor Blockers) or
BB (Beta Blockers) or CCB (Calcium Channel Blockers)
CLASSIFICATION: CLASSIFICATION: CLASSIFICATION:
Angiotensin-converting enzyme (ACE) inhibitors Angiotensin-Receptor Blockers (Angiotensin Thiazides: SEE CASE # 16
(OTHERS: Captopril, benazepril, fosinopril, moexipril, perindopril, II; Type 1) ACE Inhibitors: SEE CASE # 17
quinapril, ramipril, and trandolapril) (OTHERS: Azilsartan, candesartan, ARB: SEE CASE # 17
eprosartan, irbesartan, olmesartan, and BB: SEE CASE # 16
telmisartan) CCB: SEE CASE # 15
MOA: MOA: MOA:
Ø Inhibits the converting enzyme peptidyl dipeptidase that Ø Blocks AT1 receptors, decreasing the Thiazides: SEE CASE # 16
hydrolyzes angiotensin I to angiotensin II and inactivates activation of AT1 receptors by ACE Inhibitors: SEE CASE # 17
bradykinin/ plasma kininase, which is a potent vasodilator that angiotensin II ARB: SEE CASE # 17
works at least in part by stimulating release of nitric oxide and - The same with ACE inhibitors BB: SEE CASE # 16
prostacyclin. - Arteriolar and venous dilation CCB: SEE CASE # 15
Ø Lowers BP by reducing peripheral vascular resistance without - Block aldosterone secretion → lowers BP
reflexively increasing CO, heart rate or contractility and decrease salt and water retention
Ø Decrease angiotensin II and increase bradykinin levels - Do not increase bradykinin levels
(enhanced vasodilation)
- Decrease secretion of aldosterone → decreased water retention
- Reduce cardiac preload and afterload → decrease cardiac work

The hypotensive activity results both from an inhibitory action on the
renin-angiotensin system and a stimulating action on the kallikrein-kinin
system
ENALAPRIL ADVERSE EFFECTS: LOSARTAN ADVERSE EFFECTS: ADVERSE EFFECTS:
ü Dry cough Same with ACE inhibitors but risk of cough Thiazides: SEE CASE # 16
(Common when taking ACE inhibitors; about 10% occurs in patients and angioedema are significantly decreased ACE Inhibitors: SEE CASE # 17
due to an ↑ levels of Bradykinin and Substance P (causes ARB: SEE CASE # 17
Bronchoconstriction) in the Pulmonary tree activating the mast BB: SEE CASE # 16
cells CCB: SEE CASE # 15
ü Rash
ü Fever
ü Altered Taste
ü Hypotension
ü Hyperkalemia
ENALAPRIL INDICATIONS: LOSARTAN INDICATIONS: CONTRAINDICATIONS:
Chronic heart failure, hypertension, diabetic renal disease, may reduce CHF, HTN, Diabetic renal disease, may Thiazides: SEE CASE # 16
morality reduce morality, used in px intolerant to ACE Inhibitors: SEE CASE # 17
ENALAPRIL CONTRAINDICATIONS: ACE inhibitors ARB: SEE CASE # 17
Idiopathic Angioedema, Hereditary Angioedema, Previous History of LOSARTAN CONTRAINDICATIONS: BB: SEE CASE # 16
Angioedema Associated with Ace Inhibitors, History of Use of aliskiren in diabetes mellitus, CCB: SEE CASE # 15
Hypersensitivity Reaction with the Use of Ace Inhibitors, Pregnancy Hypersensitivity to losartan, Pregnancy &
and Lactation lactation
(losartan acts on the renin-angiotensin
system, it causes oligohydramnios, thus
resulting in fetal lung hypoplasia and skeletal
deformities. Potential neonatal adverse
effects are skull hypoplasia, hypotension,
anuria, renal failure, and death. Therefore
therapy with the drug should immediately
stop when pregnancy is detected)
NOTES: NOTES:
Enalpril – an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalprilat with the same JNC 8 CLASSIFICATION:
effects to captopril Normal = <120 / <80
Prehypertension= 120-139 / 80-89
Captopril – inhibit converting enzymes peptidyl dipeptidase; inactivates bradykinin Hypertension= ≥140/90
Stage 1 HTN= 140-159 / 90-99
RAAS ACTIVATION Stage 2 HTN= ≥160 / 100
BOOK:
The renin-angiotensin system is an important control system involved in the regulation of blood pressure, fluid and PATIENT RISK FACTORS:
electrolyte balance, and other functions. Overactivity of this system has been implicated in hypertension, heart failure, - Age: 45 years old
and other diseases. Drugs that block the formation or actions of ANG II are used extensively in the treatment of these - Race: African American
diseases. More recent observations suggest that the system is even more complex than originally envisioned. Specifically, - Family History: Father died of stroke at age 60, mother (+) for
there is evidence for roles of ANG 1-7, possibly acting via the Mas receptor, and the (pro)renin receptor, which may act hypertension)
via angiotensin-independent pathways. - Precipitating Factors
o Sedentary Lifestyle: Not a "hyper" person
JOURNAL: o Smoking: Smokes one pack of cigarettes daily
The renin–angiotensin–aldosterone system (RAAS) is a critical regulator of blood volume and systemic vascular resistance. o Alcohol: Drinks six-pack of beer on Friday and Saturday nights
While the baroreceptor reflex responds in a short-term manner to decreased arterial pressure, the RAAS is responsible for
more chronic alterations. It is composed of three major compounds: renin, angiotensin II, and aldosterone. These three TREATMENT
act to elevate arterial pressure in response to decreased renal blood pressure, decreased salt delivery to the distal (1) PHARMACOLOGIC TREATMENT
2 Drug Combination:
 convoluted tubule, and/or beta-agonism. Through these mechanisms, the body can elevate the blood pressure in a v Thiazide Type Diuretic and
prolonged manner. v ACE or ARB (Angiotensin Receptor Blockers) or BB (Beta
Blockers) or CCB (Calcium Channel Blockers)
The RAAS involves the kidneys, lungs, systemic vasculature, and the brain. The RAAS functions to elevate blood volume (2) LIFESTYLE MODIFICATIONS
and arterial tone in a prolonged manner. It does this by increasing sodium reabsorption, water reabsorption, and vascular v Weight reduction
tone. v DASH eating plan (diet rich in fruits, veggies, low-fat dairy,
reduced content of saturated and total fats)
MECHANISM v Reduce dietary sodium intake
Within the afferent arterioles of the kidney, specialized cells called juxtaglomerular (JG) cells contain prorenin. While v Engage in Physical Activity (aerobic exercises at least 30
prorenin is secreted constitutively in its inactive form, activation of JG cells causes the cleavage of prorenin to renin. min/day)
Activation of these cells occurs in response to decreased blood pressure, beta-activation, or activation by macula densa v Moderate consumption of alcohol
cells in response to a decreased sodium load in the distal convoluted tubule. Once renin has been released into the blood,
it can act on its target, angiotensinogen. Angiotensinogen is produced in the liver and is found continuously circulating in
the plasma. Renin then acts to cleave angiotensinogen into angiotensin I. Angiotensin I is physiologically inactive, but acts
as a precursor for angiotensin II.

The conversion of angiotensin I to angiotensin II is catalyzed by an enzyme called angiotensin converting enzyme (ACE).
ACE is found primarily in the vascular endothelium of the lungs and kidneys. After angiotensin I is converted to angiotensin
II, it has effects on the kidney, adrenal cortex, arterioles, and brain by binding to angiotensin II type I (AT) and type II (AT)
receptors. The effects discussed below are a result of binding to AT receptors. The role of AT receptors is still being
investigated, but pertinently, they have been shown to cause vasodilation by nitric oxide generation. In the plasma,
angiotensin II has a half-life of 1-2 minutes, at which point peptidases degrade it into angiotensin III and IV. Angiotensin III
has been shown to have 100% of the aldosterone stimulating effect of angiotensin II, but 40% of the pressor effects, while
angiotensin IV has further decreased the systemic effect.

In the proximal convoluted tubule of the kidney, angiotensin II acts to increase Na-H exchange, increasing sodium
reabsorption. Increased levels of Na in the body acts to increase the osmolarity of the blood, leading to a shift of fluid into
the blood volume and extracellular space (ECF). This increases the arterial pressure of the patient.

Angiotensin II also acts on the adrenal cortex, specifically the zona glomerulosa. Here, it stimulates the release of
aldosterone. Aldosterone is a steroid hormone that causes an increase in sodium reabsorption and potassium excretion
at the distal tubule and collecting duct of the nephron. Aldosterone works by stimulating the insertion of luminal Na
channels and basolateral Na-K ATPase proteins. The net effect is an increased level of sodium reabsorption. This has the
same effect as mentioned previously: the increased total body sodium leads to an increase in osmolarity and subsequent
increase in blood and ECF volume. In contrast to angiotensin II, aldosterone is a steroid hormone. As a result, it enacts
change by binding to nuclear receptors and altering gene transcription. Thus, the effects of aldosterone may take hours
to days to begin, while the effects of angiotensin II are rapid.
The effect of angiotensin II on vasoconstriction takes place in systemic arterioles. Here, angiotensin II binds to G protein-
coupled receptors, leading to a secondary messenger cascade that results in potent arteriolar vasoconstriction. This acts
to increase total peripheral resistance, causing an increase in blood pressure.

Finally, angiotensin II acts on the brain. Here, it has three effects. First, it binds to the hypothalamus, stimulating thirst and
increased water intake. Second, it stimulates the release of antidiuretic hormone (ADH) by the posterior pituitary. ADH,
or vasopressin, acts to increase water reabsorption in the kidney by inserting aquaporin channels at the collecting duct.
Finally, angiotensin II decreases the sensitivity of the baroreceptor reflex. This diminishes baroreceptor response to an
increase in blood pressure, which would be counterproductive to the goal of the RAAS.
The net effect of these interactions is an increase in total body sodium, total body water, and vascular tone.


 CASE 19: CHF Drugs CASE 20: Heart Failure Drugs CASE 21: Antiarrhythmic Drugs
A 69-year-old man sees you in the office for the follow up of his chronic Mr. S. L. is a 63-year old who has been treated for a variety A 62-year-old man is being managed in the intensive
congestive heart failure. He has a marked reduction in his ejection fraction of medical problems during the past 5 years. He has been care unit following a large anterior wall MI. He has
following a series of myocardial infarctions. He also has hypertension and treated for two myocardial infarctions and hypertension. been appropriately managed with oxygen, aspirin,
type 2 diabetes mellitus. His symptoms include dyspnea on exertion, He had an aorto-coronary bypass one year ago. Today, he nitrates and B-adrenergic receptor blockers but has
orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema. He has presents in the office with shortness of breath which has developed recurrent episodes of ventricular
normal renal function. He has a normal renal function. He is on appropriate been progressive over the past five days. He has, however, tachycardia. During these episodes he remains
treatment of his diabetes, along with ACE inhibitor and a loop diuretic. You experienced episode of shortness of breath during the past conscious but feels dizzy and he becomes diaphoretic
decide to add digoxin to his regimen. four months, especially when exerting himself. He fatigues and hypotensive. He is given in IV bolus of lidocaine
easily and has lost “all my energy to do anything.” He also and started on an IV
complains of anorexia. Last night he awoke suddenly from lidocaine infusion.
sleep because “I couldn’t catch my breath” and developed
a dry cough. The breathing problem improved when he sat
on the edge of his bed for an hour. He generally sleeps with
two, sometimes three, pillows. He has not experienced
chest pain, leg pain or fainting spells. Examination in the
office reveals an undernourished man who appears
depressed and older than his stated age. His breathing is
labored and his lips have a blue tinge.
DIAGNOSIS: DIAGNOSIS: DIAGNOSIS:
Chronic Congestive Heart Failure Congestive Heart Failure Ventricular Tachycardia
Drug: Drug: Drug:
Captopril, Carvedilol, Digoxin Carvedilol, Metoprolol, Losartan, Spironolactone Lidocaine (Tocainide, Encainide, Propofenone,
Moricizine)
CLASSIFICATION: CLASSIFICATION: CLASSIFICATION:
ACE Inhibitors, Diuretics, Digitalis Glycosides Potassium Sparing Diuretics, Beta blockers, ACE Class IB Antiarrhythmic
inhibitors/ARBS
MOA: MOA: MOA:
ACE INHIBITORS Beta Blockers (Bisoprolol, Carvedilol, It works by blocking sodium channels and thus
Decrease vascular resistance (afterload) and venous tone (preload) → Metoprolol) decreasing the rate of contractions of the heart.
increased CO. -decrease heart rate and inhibit release of renin in the
DIURETICS kidneys. In addition, β-blockers prevent the deleterious
-Relieve pulmonary congestion and peripheral edema effects of norepinephrine on the cardiac muscle fibers,
- Decrease plasma volume and decrease venous return to the heart decreasing remodeling, hypertrophy, and cell death.
(preload) →decreases cardiac workload and oxygen demand ACE INHIBITORS (Captopril)
- Decrease plasma volume → decrease BP → decrease afterload. Decrease vascular resistance (afterload) and venous tone
DIGITALIS GLYCOSIDES (preload) → increased CO.
DIGOXIN – most widely used agent ARBS (Losartan)
-Na+/K+-ATPase inhibition results in reduced Ca2+ expulsion and increased Blocks AT1 receptors, decreasing the activation of AT1
Ca2+ stored in sarcoplasmic reticulum receptors by
-Inhibit Na+/K+ ATPase enzyme, digoxin reduces the ability of the myocyte angiotensin II
to actively pump Na+ from the cell → intracellular NA+ increases and the Spironolactone (Potassium Sparing Diuretics)
concentrating gradient decreases → increased Na+ decreases the driving Blocks aldosterone receptor in renal collecting tubule
force for the Na+/Ca2+ exchanger so there is a decrease extrusion of Ca2+ - Increases Na excretion and decrease K excretion.
into the
extracellular space → increasing cardiac contractility
-Digoxin inhibit Na+/K+ ATPase increasing resting membrane potential (-70
mV instead of -90 mV) which makes the membrane more excitable,
increasing the risk of arrhythmias (toxicity)

EFFECT ON CARDIAC CONTRACTILITY
-increases the force of myocardial infarction. (most beneficial effect) à
increase CO
EFFECT ON ELECTRO-PHYSIOLOGIC PROPERTIES OF THE HEART:
-Increase the vagal tone of the heart indirectly
-Prolong the refractory period of the AV node
-Decrease the conduction velocity through the AV node
EFFECTS OF DIGOXIN ON THE FAILING HEART:
- It increases contractility of the heart muscle. It increases the
cardiac output
- Regulation of cytosolic calcium concentration:
o Inhibits Na+/K+ ATPase enzyme
o Reduces ability of myocyte to actively pump Na+ from
the cell
o Na+ concentration gradient is decreased
NEURAL EFFECTS OF DIGOXIN:
- include vagal and chemoreceptor trigger zone stimulation
- Less often, disorientation and hallucinations – especially in
elderly – and visual disturbances are noted
- Latter effect may include aberrations of color perception
- Gynecomastia is a rare effect reported in men taking digitalis

DRUG INTERACTIONS OF DIGOXIN: Amiodarone, Anticholinergic Drugs,
Captopril, Clarithromycin, Diltiazem

ADVERSE EFFECTS: ADVERSE EFFECTS: Bronchospasm, Bradycardia, ADVERSE EFFECTS: Neurologic: paresthesias,
ACE INHIBITORS: postural hypotension, renal insufficiency, hyperkalemia, Atrioventricular block, Renal insufficiency, Hyperkalemia, tremor, nausea of central origin, Lightheadedness,
persistent dry cough, and angioedema Dry cough, Angioedema hearing disturbances, slurred speech, and
DIURETICS: Profound hypovolemia convulsions.
DIGITAL GLYCOSIDES: Blurred vision, Yellowish vision, Cardiac arrhythmias,
Tachycardia, Diarrhea, Confusion
INDICATIONS: Hypertension, Diabetic renal disease, Has been shown to INDICATIONS: Edematous conditions, Hypertension, INDICATIONS: Polymorphic Ventricular tachycardia,
reduce mortality, Severe hypertension, Edematous conditions, Rapid Diabetic renal disease, Has been shown to reduce Ventricular arrhythmias
nd rd
ventricular rate in atrial fibrillation mortality, Edematous conditions CONTRAINDICATIONS: Sinus bradycardia, 2 /3
CONTRAINDICATIONS: Patients with known hypersensitivity and electrolyte
• CONTRAINDICATIONS: Angioedema, Hypersensitivity degree AV block, heart failure, hypersensitivity
imbalance.


ANTIDOTE: DIGOXIN
NOTES: NOTES: NOTES:
DIGOXIN Predisposing Factors to Adverse effects: PATHOPHYSIOLOGY An arrhythmia is described as an irregular
- General - Old age - The Frank-Starling mechanism: an increased preload heartbeat.
- Cardiac - Myocardial ischemia helps to sustain cardiac performance.
- Respiratory - Acute hypoxia - Alterations in myocyte regeneration and death
- Hepatobiliary - Reduced hepatic clearance - Myocardial hypertrophy with or without cardiac. - It may beat to fast (tachycardia), too slow
- Metabolic - Electrolyte disturbance, Hypokalemia, Hypercalcemia - chamber dilatation, in which the mass of contractile (bradycardia), too early (premature contraction) or
- Endocrine - Hypothyroidism tissue is augmented activation of neurohumoral systems. irregularly (fibrillation).
- Renal - Reduced renal clearance, Renal insufficiency - Any interruption to the electrical impulses that
causes the heart to contract and pathology that
affects the pacemaker and other nodes of the heart
can result in arrhythmia.

Mechanisms of the Causes of Arrhythmia
●Disturbances of Impulse Formation
- Pacemaking activity is regulated by both
sympathetic and parasympathetic. Therefore, the
factors that antagonize or enhance these effects can
alter normal impulse formation, producing wither
bradycardia or tachycardia.
- Genetic mutations have also been found to alter
normal pacemaking activity.
●Disturbances of Impulse Conduction
- The most common form of conduction disturbance
affects the AV node, causing various degrees of heart
block. The result can be a simple slowing of impulse
propagation through AV node, which is reflected by
increase in PR interval of the ECG.

NORMAL CARDIAC RHYTHM
The electrical impulse that triggers a normal cardiac
contraction originates at regular intervals in the
sinoatrial (SA) node, usually at a frequency of 60–100
bpm. This impulse spreads rapidly through the atria
and enters the atrioventricular (AV) node, which is
normally the only conduction pathway between the
atria and ventricles. Conduction through the AV node
is slow, requiring about 0.15 seconds. (This delay
provides time for atrial contraction to propel blood
into the ventricles.) The impulse then propagates
down the His-Purkinje system and invades all parts of
the ventricles, beginning with the endocardial
surface near the apex and ending with the epicardial
surface at the base of the heart. Activation of the
entire ventricular myocardium is complete in less
than 0.1 second. As a result, ventricular contraction
is synchronous and hemodynamically effective.
Arrhythmias represent electrical activity that
deviates from the above description as a result of an
abnormality in impulse initiation and/or impulse
propagation.







































CASE #22: Antiarrhythmic Drugs CASE #23: Angina Pectoris Treatment
A 75 year old-patient calls your office complaining of fatigue and dizziness during his weekly A 74-year-old man present with a history of anterior chest pressure whenever he walks more
doubles’ tennis game. He noticed these symptoms twice during his game this morning, thought than one block. The chest discomfort is diffuse, and he cannot localize it. The discomfort is
they were due to dehydration, and resumed play after drinking water after each episode. He has more severe when he walks after meals but is relieved within 5-10 minutes when he stops
had excellent functional tolerance to this point, enjoying running and tennis. He has no history walking.
of heart or cerebrovascular disease, although he has well controlled hypertension and well
controlled diabetes (A1c=7). But in light of the symptoms he has experience this morning and his
risk factors for acute coronary syndrome, you ask him to meet you at the emergency
department. Upon arrival in the ED, the patient looks anxious but is speaking in full sentences,
does not look dyspneic, and is complaining of mild chest fluttering.
DIAGNOSIS: DIAGNOSIS:
Atrial Fibrillation Angina Pectoris
Drug: Drug:
Diltiazem, Verapamil, Esmolol, Metoprolol, Digoxin, BETA BLOCKER(Propranolol, metoprolol, atenolol)
Ca2++ CHANNEL BLOCKERS (Amlodipine, felodipine, other dihydropyridine)
ORGANIC NITRATES (Nitroglycerin)
CLASSIFICATION: CLASSIFICATION:
Class 2 (Propranolol, Esmolol) Beta-Adrenergic Blockers, Ca2++ Channel Blockers, Organic Nitrates
Class 4 (Verapamil, Diltiazem)
Cardiac Glycosides (Digoxin)
MOA: MOA:
CLASS 2 BETA-ADRENERGIC BLOCKERS
-β-adrenergic antagonists, or β-blockers. These drugs diminish phase 4 depolarization and, -↓O2 demands of myocardium by blocking B1 receptors,resulting in a ↓HR contractility, CO and
thus, depress automaticity, prolong AV conduction, and decrease heart rate and contractility BP
Ca2++ CHANNEL BLOCKERS
CLASS 4 Protects the tissue by inhibiting the entrance of Ca2++ into cardiac and smooth muscle cells of
-nondihydropyridine calcium channel blockers the coronary and systemic arterial beds.
-Slows SA node automaticity and AV nodal conduction velocity -They are arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular
• decreases cardiac contractility resistance
• reduces blood pressure - CCBs reduce the amount of Ca2++ that goes into these muscle cells causing it to relax
o ↓BP, helps ease angina by widening the coronary arteries
CARDIAC GLYCOSIDES o Ease raynaud’s phenomenon
- Na+/K+-ATPase inhibition results in reduced Ca2+ expulsion and increased Ca2+ stored in o ↓ force and rate of heartbeat and prevent angina pains
sarcoplasmic reticulum ORGANIC NITRATES
- ↑ cGMP ( Cyclic guanosine monophosphate)
↑ dephosphorylation of myosin light chain – vascular, smooth muscle relaxation
ADVERSE EFFECTS: Asthma, AV blockade, acute, Heart failure, Atrioventricular block, acute ADVERSE EFFECTS:
heart failure; Constipation, Edema ORGANIC NITRATES
BAD EFFECTS: Postural HTN, facial flushing, tachycardia
BENEFICIAL EFFECTS: dilation of large veins, reduce preload, reduce workload of the heart
INDICATIONS: Atrial arrhythmias and prevention of recurrent infarction and sudden death. INDICATIONS: Asthma, Atrioventricular block, Acute heart failure, edema, Orthostatic
CONTRAINDICATIONS: Patients with second- or third-degree AV block except in the presence hypotension, Tachycardia
of a functioning ventricular pacemaker, Hypotension, Sick sinus syndrome, Acute myocardial CONTRAINDICATIONS: Peripheral vascular diseases, Diabetes mellitus, Chronic obstructive
infarction pulmonary disease (COPD), Asthma
NOTES: CARDIAC AND NON-CARDIAC CAUSES OF ATRIAL FIBRILLATION: NOTES:
DETERMINANTS OF MYOCARDIAL OXYGEN
-Wall Stress
PRIMARY ARRHYTHMIA in the absence of structural heart disease or other precipitating causes. ● Intraventricular Pressure
As a primary arrhythmia, atrial fibrillation can develop in isolation (no known precipitating ● Ventricular radius (volume)
cause) also known as "lone atrial fibrillation “. This type of atrial fibrillation has been found to ● Wall thickness
occur in the presence of documented normal left ventricular function. It is most commonly seen -Heart Rate
in the younger population. It is characterized by a paroxysmal onset and termination, and it -Contractility
frequently recurs.
PATHOPHYSIOLOGY:
SECONDARY ARRHYTHMIA

TREATMENT Beta-Adrenergic Blockers, Ca2++ Channel Blockers,Organic Nitrates
ACUTE INTERVENTION
-For acute rate control, the administration route of choice is intravenous.
-Antiarrhythmic drugs commonly prescribed for acute rate control include diltiazem, verapamil,
esmolol, metoprolol, and digoxin
- Diltiazem acts by blocking calcium transport into the myocardial
and vascular smooth muscle cells. As a result, conduction through
the SA and AV nodes is slowed, and the refractory period of the
AV node is prolonged. Ventricular rate is slowed, but the
underlying atrial arrhythmia is not corrected.
- Verapamil, another calcium channel blocker, also slows
ventricular rate by slowing conduction through the AV node and
prolonging the refractory period of the AV node.
- Esmolol is a short-acting beta-adrenergic blocker that slows
ventricular rate in atrial fibrillation by slowing conduction
through the AV node.
- Metoprolol is a longer acting beta adrenergic blocking agent that
decreases conduction through the AV node. Although metoprolol
is not labeled for use in the management of atrial arrhythmias, it
is used by some clinicians to control/slow ventricular rate in atrial
fibrillation with a rapid ventricular response.
- Digoxin is an older agent that may be used to control ventricular
rate in some patients. Once considered a leading treatment for
rate control in atrial fibrillation, digoxin is primarily recommended for persons with atrial
fibrillation who also have congestive heart failure caused by systolic dysfunction. Digoxin acts by
prolonging the refractory period of the AV node as well as slowing conduction through SA and
AV nodes.
CHRONIC RATE CONTROL
- Oral diltiazem preparations provide chronic rate control in atrial
fibrillation and are a drug of choice for persons who have a
physically active lifestyle; however, their use for rate control is
unlabeled
- Oral verapamil preparations may also be prescribed for chronic
rate control. Available in short-acting and extended- release
forms, oral verapamil can control ventricular rate at rest and with
activity. In addition, research has shown that verapamil may have
the responsible for frequent recurrence of atrial fibrillation and
resistance to successful cardioversion).
- Oral digoxin may be the first drug of choice for patients with
atrial fibrillation and congestive heart failure caused by systolic
dysfunction. Digoxin does not provide adequate rate control
during exercise or activity.
- Oral metoprolol is not labeled for management of atrial
fibrillation; however, in patients with coronary artery disease,
hypertension, and angina, it may be prescribed for rate control
plus its other therapeutic effects
- Oral propranolol, another beta-adrenergic blocking agent, may
also be prescribed for long-term rate control in atrial fibrillation.
Unlike metoprolol, propranolol is approved for use in atrial
fibrillation addition






CASE 24: Lipid Lowering Agents CASE 25: Lipid Lowering Agents CASE 26: Lipid Lowering Agents
A 65- year old man with HPN and Type II diabetes comes in A 52-year-old man presented to the emergency room with chest pain. A 55-year old man presented with polyuria, polydipsia and
for a follow up visit. Along with making appropriate diet and The chest pain lasted approximately 15 minutes then subsided on its “feeling dry” during the past 2 months. His medical history
lifestyle changes, he is taking ACE inhibitor-thiazide diuretic own. He had no medical problems and had not seen any physician for was remarkable for a 3-year history of poorly controlled
combination for his HPN and metformin for his diabetes. His several years. On examination he was in no acute distress with normal hypertriglyceridemia. His initial fasting serum cholesterol
blood pressure and diabetes are under acceptable control. vital signs. Both lungs were clear to auscultation bilaterally and heart was 299 mg/dl. Patient drinks 2-3 cans of beer per day and
Routine blood work revealed normal electrolytes, renal had a regular rate and rhythm with no murmurs. smokes 3 to 5 sticks of cigarettes per day.
function, and liver enzymes. He is noted to have elevated Laboratory:
total cholesterol and low-density lipoprotein (LDL) levels, ECG: Slight Ischemic change
which have remained high in spite of his lifestyle changes. Lipid Profile: Total Cholesterol: 320 mgs / dl
LDL: 280 mgs/ dl
HDL : 30 mgs/dl
DIAGNOSIS: DIAGNOSIS: DIAGNOSIS:
Hypercholesterolemia secondary to Hypertension and Hypercholesterolemia Hypertriglyceridemia
Type 2 Diabetes
BASIS OF DIAGNOSIS: BASIS OF DIAGNOSIS: BASIS OF DIAGNOSIS:
a. Elevated total cholesterol & LDL a. Chest pain a. Polyuria (urinates excessively >3L/day)
b. Taking ACE inhibitor-thiazide diuretic (for b. Elevated Total cholesterol & LDL b. Polydipsia (extreme thirst)
hypertension) and Metformin (for diabetes) c. History of poorly controlled hypertriglyceridemia
d. Fasting serum cholesterol: 299 mg/dl
e. Drinks 2-3 cans of beer/day
f. Smokes 3-5 sticks of cigarettes/day

ABOUT THE DISEASE: ABOUT THE DISEASE: ABOUT THE DISEASE:
Hypercholesterolemia Hypercholesterolemia Hypertriglyceridemia
- presence of high levels of cholesterol in the - presence of high levels of cholesterol in the blood - elevated level of triglycerides (a type of lipid) in
blood - form of hyperlipidemia, high blood lipids, and the bloodstream
- form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia CONSEQUENCES/COMPLICATIONS:
hyperlipoproteinemia Hyperlipidemia a. increases the risk of coronary artery disease
- caused by Atherosclerosis - abnormally high levels of fats (lipids) in the blood
CONSEQUENCES/COMPLICATIONS: CONSEQUENCES/COMPLICATIONS:
a. increases the risk of developing heart disease and heart a. increases the risk of developing heart disease and heart attack
attack b. increases the risk of stroke and death
b. increases the risk of stroke and death
Drug: Drug: Drug:
Lovastatin, Atorvastatin, Fluvastatin, Pravastatin, Lovastatin, Atorvastatin, Fluvastatin, Pravastatin, Simvastatin, Fenofibrate, Gemfibrozil, Atorvastatin, Lovastatin,
Simvastatin, Rosuvastatin, and Pitavastatin Rosuvastatin, and Pitavastatin Simvastatin, Rosuvastatin, Pitavastatin, Colestipol,
Ezetimibe
 CLASSIFICATION: CLASSIFICATION: CLASSIFICATION:
Statins (HMG-CoA Reductase Inhibitors) Statins (HMG-CoA Reductase Inhibitors) Fibrates, Statins, Bile Acid-Binding Resins, Sterol Absorption
Inhibitors
MOA: MOA: FIBRATES MOA:
- Competitively binds to the catalytic domain of HMG- - Competitively binds to the catalytic domain of HMG-CoA - PPAR-alpha agonists
CoA reductase thus blocks the conversion of HMG- reductase thus blocks the conversion of HMG-CoA to mevalonate, - Stimulate cellular fatty acid uptake, conversion to acyl-
CoA to mevalonate, which is the rate-limiting step of which is the rate-limiting step of cholesterol biosynthesis. CoA derivatives, and catabolism by the β-oxidation
cholesterol biosynthesis. - Reduce cholesterol synthesis and upregulate low-density pathways, which, combined with a reduction in fatty
- Reduce cholesterol synthesis and upregulate low- lipoprotein (LDL) receptors on hepatocytes, modest reduction in acid and triglyceride synthesis, results in a decrease in
density lipoprotein (LDL) receptors on hepatocytes, triglycerides VLDL production
modest reduction in triglycerides STATINS MOA:
**See Cases 24-25
BILE ACID-BINDING RESINS MOA:
- prevents reabsorption, increases cholesterol
catabolism, and upregulates LDL receptors
STEROL ABSORPTION INHIBITORS
- inhibits intestinal cholesterol absorption by
selectively blocking the NPC1L1 protein in the
jejunal brush border, integral to the uptake of
intestinal lumen micelles into the enterocyte, thus
reduces the entry of cholesterol into both
enterocytes and hepatocytes.
INDICATIONS INDICATIONS INDICATIONS
- Asymptomatic adults aged 40 to 75 years who have an - Asymptomatic adults aged 40 to 75 years who have an LDL-C level - Hypertriglyceridemia, low HDL
LDL-C level of 70 to 189 mg/dL and if they also of 70 to 189 mg/dL and if they also have diabetes - Hyperlipidemia
have diabetes - Patients with Primary hypercholesterolaemia - Elevated LDL, digitalis toxicity, pruritus
- Patients with Primary hypercholesterolaemia - Atherosclerotic vascular disease (primary and
secondary prevention)
- Acute coronary syndromes
CONTRAINDICATIONS CONTRAINDICATIONS CONTRAINDICATIONS
- Hypersensitivity to medication - Hypersensitivity to medication - anemia
- Pregnancy - Pregnancy - myopathy
- Lactation (breastfeeding mothers) - Lactation (breastfeeding mothers) - obstruction of a blood vessel by a blood clot
- Acute liver failure or decompensated cirrhosis - Acute liver failure or decompensated cirrhosis - liver problems
- disease of the gallbladder
- acute inflammation of the pancreas
- rhabdomyolysis
- pregnancy and lactation
- primary biliary cholangitis
- chronic kidney diseases
ADVERSE EFFECTS: headache, dizziness, feeling sick, ADVERSE EFFECTS: headache, dizziness, feeling sick, feeling unusually ADVERSE EFFECTS: Gastrointestinal discomfort, Myopathy,
feeling unusually tired or physically weak, digestive system tired or physically weak, digestive system problems, such as Gallstone formation, Hepatotoxicity, Dizziness, Muscle pain,
problems, such as constipation, diarrhea, indigestion or constipation, diarrhea, indigestion or farting, muscle pain, sleep Sleep problems
farting, muscle pain, sleep problems, low blood platelet problems, low blood platelet count
count
NO ANTIDOTE (immediate discontinuation) NO ANTIDOTE (immediate discontinuation) NO ANTIDOTE (immediate discontinuation)
TREATMENT & DOSAGE: TREATMENT & DOSAGE: TREATMENT & DOSAGE:
 PHARMACOLOGIC: PHARMACOLOGIC: PHARMACOLOGIC:
ACC/AHA LIPID GUIDELINES (ORAL): ACC/AHA LIPID GUIDELINES (ORAL): Fenofibrate 50-150 mg orally once/day
a. High-intensity a. High-intensity Omega-3 fatty acids (fish oils) 3–4 g/day
Atorvastatin 40–80 mg daily Atorvastatin 40–80 mg daily Statins (**See Cases 24-25 for dosages)
Rosuvastatin 20–40 mg daily Rosuvastatin 20–40 mg daily NON-PHARMACOLOGIC:
b. Moderate-intensity b. Moderate-intensity ü Appropriate diet and lifestyle changes
Atorvastatin 10–20 mg daily Atorvastatin 10–20 mg daily ü Exercise
Fluvastatin 80 mg daily Fluvastatin 80 mg daily ü Weight control
Lovastatin 40–80 mg daily Lovastatin 40–80 mg daily ü No smoking & alcohol
Pitavastatin 1–4 mg daily Pitavastatin 1–4 mg daily ü Blood pressure and glucose level control
Pravastatin 40–80 mg daily Pravastatin 40–80 mg daily ü Stress management
Rosuvastatin 5–10 mg daily Rosuvastatin 5–10 mg daily
Simvastatin 20–40 mg daily Simvastatin 20–40 mg daily
c. Low-intensity c. Low-intensity
Fluvastatin 20–40 mg daily Fluvastatin 20–40 mg daily
Lovastatin 20 mg daily Lovastatin 20 mg daily
NON-PHARMACOLOGIC: NON-PHARMACOLOGIC:
ü Appropriate diet and lifestyle changes ü Appropriate diet and lifestyle changes
ü Exercise ü Exercise
ü Weight control ü Weight control
ü No smoking & alcohol ü No smoking & alcohol
ü Blood pressure and glucose level control ü Blood pressure and glucose level control
ü Stress management ü Stress management
























 CASE 27: Anticoagulants CASE 28: Anticoagulants
BB, a 65-year-old man with atrial fibrillation. Bob reports that the most recent INR, A 42-year-old former semi-professional soccer player sustained a right lower
measured this morning, was 4.6. Up until now, his INR results (which have been extremity popliteal contusion during a soccer game. He was clinically diagnosed
measured every 15 days) have been stable and in the range of 2.0-3.0. BB also has with a possible traumatic deep vein thrombosis (DVT) and sent for confirmatory
hypertension and osteoarthritis (for which he had a left total hip replacement 6 test. A duplex Doppler ultrasound was positive for DVT and the patient was
months ago). Current medications: Atenolol 50 mg once daily, Ramipril 10 mg once admitted to hospital for anticoagulation (unfractionated heparin, warfarin). He
daily and Warfarin 6 mg at night. He is also taking celecoxib for his arthritic pains. was then discharge and was given oral anti-coagulant.
He also claimed to be taking herbal supplements that contains gingko and garlic.
DIAGNOSIS: DIAGNOSIS:
Atrial Fibrillation with Hypertension and Osteoarthritis Deep Vein Thrombosis (DVT)
BASIS OF DIAGNOSIS: BASIS OF DIAGNOSIS:
**Stated in the case a. Right lower extremity popliteal contusion
b. Positive in duplex doppler ultrasound for DVT
ABOUT THE DISEASE: ABOUT THE DISEASE:
Atrial Fibrillation Deep Vein Thrombosis (DVT)
- Irregular and often rapid heart rate that occurs when the two upper - occurs when a blood clot forms in a deep vein.
chambers of your heart experience chaotic electrical signals. - can cause leg pain or swelling but also can occur with no symptoms.
- The result is a fast and irregular heart rhythm. - main causes of DVT are damage to a vein from surgery or trauma and
- The heart rate may range from 100 to 175 bpm. inflammation due to infection or injury.
CONSEQUENCES/COMPLICATIONS: CONSEQUENCES/COMPLICATIONS:
a. Heart failure a. Pulmonary embolism (PE)
b. Stroke b. Chronic venous insufficiency
c. Post-thrombotic syndrome
Drug: Drug:
Warfarin Heparin
CLASSIFICATION: CLASSIFICATION:
Anticoagulants (Blood thinners) Anticoagulants (Blood thinners)
MOA: MOA:
- Competitively inhibits and blocks the reduction oxidized vitamin K (vitamin K - Binds to antithrombin causing a surface change and inactivates thrombin,
epoxide), thereby prevent vitamin K- dependent post-translational thus blocks thrombin Factor IIa and Factor Xa. By inactivating thrombin, it
carboxylation of clotting factors blocks the conversion of fibrinogen to fibrin; this prevents the formation of
- Inhibit synthesis of proteins C and S which are endogenous anticoagulants clots and prolongs the clotting time of blood.
that inactivate factors V and VIII and promote fibrinolysis
- Vitamin K – essential for effective production of clotting factors II, VII, IX, X
and anticoagulant proteins C and S
INDICATIONS INDICATIONS
- Atrial fibrillation (AF) - Atrial fibrillation with embolization;
- Deep vein thrombosis (DVT) - Treatment of acute and chronic consumptive coagulopathies (disseminated
- Venous thromboembolism (VTE) intravascular coagulation);
- Prosthetic heart valves - Prevention of clotting in arterial and cardiac surgery;
- Prophylaxis and treatment of peripheral arterial embolism;
- Anticoagulant use in blood transfusions, extracorporeal circulation, and
dialysis procedures.
CONTRAINDICATIONS CONTRAINDICATIONS
- Hypersensitivity to warfarin - The platelet count is 100,000/mm or lower
- Hemorrhagic tendencies - The patient cannot have routine monitoring tests performed to monitor
therapeutic heparin
- Recent or contemplated surgery of the eye, central nervous system, or - The patient has an active, uncontrollable bleed except for disseminated
traumatic surgery resulting in large open surfaces intravascular coagulation (DIC)
- Bleeding tendencies associated with Active ulceration or overt bleeding of - Patients with a history of heparin-induced thrombocytopenia should also
the gastrointestinal, genitourinary, or respiratory tract, Central nervous avoid heparin use
system hemorrhage, Cerebral aneurysms, dissecting aorta, Pericarditis and
pericardial effusions, and Bacterial endocarditis
- Threatened abortion, eclampsia, or preeclampsia
- Unsupervised patients with conditions associated with a high potential of
non-adherence
- Spinal puncture and other diagnostic or therapeutic procedures with the
potential for uncontrollable bleeding
- Major regional or lumbar block anesthesia
- Malignant hypertension
- Pregnancy (exception: women with mechanical heart valves at high risk for
thromboembolism)
ADVERSE EFFECTS: ADVERSE EFFECTS:
ü Severe bleeding, including heavier than normal menstrual bleeding ü Easy bleeding and bruising;
ü Red or brown urine; Black or bloody stool ü Pain, redness, warmth, irritation, or skin changes where the medicine was
ü Severe headache or stomach pain, Joint pain, discomfort or swelling, injected;
especially after an injury ü Itching of your feet; or.
ü Vomiting of blood or material that looks like coffee grounds; Coughing up ü Bluish-colored skin.
blood
ü Bruising that develops without an injury you remember
ü Dizziness or weakness, Vision changes
ANTIDOTE: ANTIDOTE:
Vitamin K (Phytonadione, Aquamephyton) = ≤1 mg IV (may repeat in 12-24 hrs if Protamine sulfate= For every 100 units of heparin remaining in the patient, 1 mg
necessary) INR of protamine sulfate is given intravenously; the rate of infusion should not
exceed 50 mg in any 10-minute period.
TREATMENT & DOSAGE: TREATMENT & DOSAGE:
PHARMACOLOGIC: PHARMACOLOGIC:
a. Anticoagulation Drugs Initial bolus injection of 80–100 units/kg, a continuous infusion of about 15–22
Warfarin 1-10 mg once/day units/kg per hour is required to maintain the anti-Xa activity in the range of 0.3–
Celecoxib 200 mg once/day 0.7 units/mL. Low-dose prophylaxis is achieved with subcutaneous
b. Cardio-conversion administration of heparin, 5000 units every 8–12 hours.
c. Heart Rate Control NON-PHARMACOLOGIC:
Beta blocker: Atenolol 25-50 mg ü Appropriate diet and lifestyle changes
once/day ü Exercise
ACE inhibitor: Ramipril 10-20 mg ü Weight control
once/day ü No smoking & alcohol
d. NSAIDs for arthritic pains: Celecoxib 200 mg once/day ü Blood pressure control
NON-PHARMACOLOGIC: ü Stress management
ü Appropriate diet and lifestyle changes
ü Exercise
ü Weight control
ü No smoking & alcohol
ü Blood pressure control
ü Stress management

 CHAPTER 11 Antihypertensive Agents 191

and brain injury. Rather, blood pressure should be lowered by
about 25%, maintaining diastolic blood pressure at no less than
100–110 mm Hg. Subsequently, blood pressure can be reduced to
normal levels using oral medications over several weeks. The paren-
teral drugs used to treat hypertensive emergencies include sodium
nitroprusside, nitroglycerin, labetalol, calcium channel blockers,
fenoldopam, and hydralazine. Esmolol is often used to manage
intraoperative and postoperative hypertension. Diuretics such as
furosemide are administered to prevent the volume expansion that
typically occurs during administration of powerful vasodilators.

SUMMARY Drugs Used in Hypertension

Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Clinical Applications Toxicities, Interactions

DIURETICS
Block Na/Cl transporter in
Hydrochlorothiazide, renal distal convoluted tubule
chlorthalidone
Block Na/K/2Cl transporter in
Furosemide renal loop of Henle
Block aldosterone receptor in
eplerenone renal collecting tubule
Reduce blood volume and
poorly understood vascular
effects
Increase Na and decrease K
reduction in heart failure
mortality
Hypertension, mild heart  
failure
Severe hypertension, heart See Chapter 15
failure
Aldosteronism, heart  
failure, hypertension

SYMPATHOPLEGICS, CENTRALLY ACTING

Activate α2 adrenoceptors Reduce central sympathetic
methyldopa also used in withdrawal Toxicity:
release from noradrenergic from abused drugs hemolytic anemia
nerve endings

SYMPATHETIC NERVE TERMINAL BLOCKERS

Blocks vesicular amine Reduces all sympathetic effects, Hypertension but rarely
transporter in noradrenergic especially cardiovascular, and used Toxicity: psychiatric depression,
nerves and depletes reduce blood pressure gastrointestinal disturbances
transmitter stores
Interferes with amine release Same as reserpine Same as reserpine Severe orthostatic
guanadrel and replaces norepinephrine
in vesicles
limited

` BLOCKERS
Selectively block α1 Prevent sympathetic Toxicity: Orthostatic
adrenoceptors prostatic hyperplasia hypotension
prostatic smooth muscle tone

a BLOCKERS
Block β1 receptors; carvedilol Prevent sympathetic cardiac See Chapter 10
also blocks α receptors;
nebivolol also releases nitric secretion
oxide
Propranolol: Nonselective prototype β blocker
Metoprolol and atenolol: Very widely used β1-selective blockers

VASODILATORS
Nonselective block of L-type
calcium channels
Block vascular calcium
amlodipine, other channels > cardiac calcium
dihydropyridines channels
Causes nitric oxide release
Metabolite opens K channels
in vascular smooth muscle
Reduce cardiac rate and output
Reduce vascular resistance
tachycardia
Hypertension, angina,
arrhythmias
Hypertension, angina
also used to treat hair loss
See Chapter 12
See Chapter 12
Toxicity: Angina,
Minoxidil: Hypertrichosis

(continued)
192 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Clinical Applications Toxicities, Interactions

PARENTERAL AGENTS
Releases nitric oxide Powerful vasodilation Hypertensive emergencies
Activates D1 receptors Toxicity: Excessive
Opens K channels in hypoglycemia hypotension, shock
α, β blocker

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

Inhibit angiotensin-converting Reduce angiotensin II levels Toxicity: Cough,
others enzyme diabetes

bradykinin

ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)

Block AT1 angiotensin Same as ACE inhibitors but no Toxicity: Same as ACE
others receptors increase in bradykinin inhibitors but less cough

RENIN INHIBITOR
Inhibits enzyme activity Reduces angiotensin I and II and Hypertension Toxicity: Hyperkalemia,
of renin aldosterone
teratogen

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Thompson AM et al: Antihypertensive treatment and secondary prevention of
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Weber MA et al: Clinical practice guidelines for the management of hypertension
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Whelton PK et al: Sodium, blood pressure, and cardiovascular disease: Further
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 CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 209

TABLE 12–7 Effects of nitrates alone and with a blockers or calcium channel blockers in angina pectoris.
Beta Blockers or Calcium Combined Nitrates with Beta Blockers
Nitrates Alone Channel Blockers or Calcium Channel Blockers

Heart rate Reflex1 increase Decrease Decrease

Arterial pressure Decrease Decrease Decrease
End-diastolic volume Decrease Increase None or decrease
1
Contractility Reflex increase Decrease None
Ejection time Decrease1 Increase None
1
Baroreceptor reflex.
Note: Undesirable effects are shown in italics.

with stenting), glycoprotein IIb/IIIa inhibitors such as abciximab
should be added. In addition, therapy with nitroglycerin and β
blockers should be considered; calcium channel blockers should be
added in refractory cases for relief of myocardial ischemia. Primary
lipid-lowering and ACE-inhibitor therapy should also be initiated.
TREATMENT OF PERIPHERAL
ARTERY DISEASE & INTERMITTENT
CLAUDICATION
Atherosclerosis can result in ischemia of peripheral muscles just
as coronary artery disease causes cardiac ischemia. Pain (claudi-
cation) occurs in skeletal muscles, especially in the legs, during
exercise and disappears with rest. Although claudication is not
immediately life-threatening, peripheral artery disease (PAD) is
associated with increased mortality, can severely limit exercise
tolerance, and may be associated with chronic ischemic ulcers,
susceptibility to infection, and the need for amputation.
Intermittent claudication results from obstruction of blood
flow by atheromas in large and medium arteries. Insertion of
stents in the obstructed vessels is becoming more common. Super-
vised exercise therapy is of benefit in reducing claudication and
increasing pain-free walking distance. Medical treatment directed
at reversal or control of atherosclerosis requires measurement and
control of hyperlipidemia (see Chapter 35), hypertension (see
Chapter 11), and obesity; cessation of smoking; and control of
diabetes, if present. Physical therapy and exercise training are
of proven benefit. Conventional vasodilators are of no benefit
because vessels distal to the obstructive lesions are usually already
dilated at rest. Antiplatelet drugs such as aspirin or clopidogrel
(see Chapter 34) are often used to prevent clotting in the region
of plaques and have documented benefit in reducing the risk of
myocardial infarction, stroke, and vascular death even though
they have little or no effect on claudication. Two drugs are used
almost exclusively for PAD. Cilostazol, a phosphodiesterase type
3 (PDE3) inhibitor, may have selective antiplatelet and vaso-
dilating effects. This drug has been shown to increase exercise
tolerance in patients with severe claudication. Pentoxifylline, a
xanthine derivative, is widely promoted for use in this condition
but is not recommended. It is thought to act by reducing the
viscosity of blood and perhaps increasing the deformability of red
blood cells, allowing blood to flow more easily through partially
obstructed areas. Naftidrofuryl, a 5-HT2 antagonist, is available
outside the USA and appears to have benefits similar to those of
cilostazol. Percutaneous angioplasty with stenting may be effec-
tive in patients with medically intractable signs and symptoms of
lower limb ischemia.

SUMMARY Drugs Used in Angina Pectoris

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

NITRATES  
Releases nitric oxide in
smooth muscle, which
activates guanylyl cyclase
and increases cGMP
Smooth muscle relaxation,
smooth muscle is relaxed
but not as markedly
venous return and heart size
in some areas and in variant
angina
Angina: Sublingual form for
transdermal forms for
acute coronary syndrome
High first-pass effect, so sublingual dose
solubility ensures rapid absorption
Toxicity: Orthostatic hypotension,
Interactions:
Synergistic hypotension with
phosphodiesterase type 5 inhibitors
(sildenafil, etc)

Isosorbide dinitrate: Very similar to nitroglycerin, slightly longer duration of action; no transdermal form
Isosorbide mononitrate: Active metabolite of the dinitrate; used orally for prophylaxis

(continued)
210 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

BETA BLOCKERS        
Nonselective competitive Decreased heart rate, Oral and parenteral, 4–6 h duration of
antagonist at β cardiac output, and blood other applications, see Toxicity: Asthma, atrioventricular
adrenoceptors Chapters 10, 11, and 13 block, acute heart failure, sedation
myocardial oxygen demand Interactions: Additive with all cardiac
depressants

Atenolol, metoprolol, others: β 1-selective blockers, less risk of bronchospasm, but still significant
See Chapters 10 and 11 for other β blockers and their applications

CALCIUM CHANNEL BLOCKERS      

Nonselective block of
diltiazem L-type calcium channels in
vessels and heart
Block of vascular L-type
dihydropyridine) calcium channels > cardiac
channels
Reduced vascular resistance,
cardiac rate, and cardiac
force results in decreased
oxygen demand
Like verapamil and
diltiazem; less cardiac effect
Prophylaxis of angina,
hypertension, others
Prophylaxis of angina and
treatment of hypertension
but prompt release
nifedipine is
contraindicated
Toxicity:
Atrioventricular block, acute heart failure;
Interactions: Additive
with other cardiac depressants and
hypotensive drugs
Toxicity: Excessive
hypotension, baroreceptor reflex
Interactions: Additive with
other vasodilators

Amlodipine, felodipine, other dihydropyridines: Like nifedipine but slower onset and longer duration (up to 12 h or more)

MISCELLANEOUS  
Inhibits late sodium current
fatty acid oxidation at
much higher doses
Reduces cardiac oxygen
oxidation modification
could improve efficiency of
cardiac oxygen utilization
Prophylaxis of angina Toxicity: QT interval
prolongation (but no increase of torsades
de pointes), nausea, constipation, dizziness
Interactions: Inhibitors of CYP3A increase
ranolazine concentration and duration of
action

Ivabradine: Inhibitor of sinoatrial pacemaker; reduction of heart rate reduces oxygen demand
Trimetazidine, allopurinol, perhexiline, fasudil: See text

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224 SECTION III Cardiovascular-Renal Drugs

pulmonary capillary wedge pressure are particularly useful in patients
with acute myocardial infarction and acute heart failure. Patients
with acute myocardial infarction are often treated with emergency
revascularization using either coronary angioplasty and a stent, or a
thrombolytic agent. Even with revascularization, acute failure may
develop in such patients.
Intravenous treatment is the rule in drug therapy of acute
heart failure. Among diuretics, furosemide is the most commonly
used. Dopamine or dobutamine are positive inotropic drugs with
prompt onset and short durations of action; they are most useful
in patients with failure complicated by severe hypotension. Levo-
simendan has been approved for use in acute failure in Europe,
and noninferiority has been demonstrated against dobutamine.
Vasodilators in use in patients with acute decompensation include
nitroprusside, nitroglycerine, and nesiritide. Reduction in after-
load often improves ejection fraction, but improved survival has
not been documented. A small subset of patients in acute heart
failure will have dilutional hyponatremia, presumably due to
increased vasopressin activity. A V1a and V2 receptor antagonist,
conivaptan, is approved for parenteral treatment of euvolemic
hyponatremia. Some clinical trials have indicated that this drug
and related V2 antagonists (tolvaptan) may have a beneficial
effect in some patients with acute heart failure and hyponatremia.
However, vasopressin antagonists do not seem to reduce mortality.
Clinical trials are under way with the myosin activator, omecamtiv
mecarbil.

SUMMARY Drugs Used in Heart Failure

Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Clinical Applications Toxicities, Interactions

DIURETICS  
Loop diuretic: Decreases NaCl
and KCl reabsorption in thick
ascending limb of the loop of
Henle in the nephron (see
Chapter 15)
Increased excretion of salt
preload and afterload
peripheral edema
Acute and chronic heart
Toxicity: Hypovolemia,
hypokalemia, orthostatic
hypotension, ototoxicity,
sulfonamide allergy

Decreases NaCl reabsorption in Same as furosemide, but

the distal convoluted tubule much less efficacious Toxicity: Hyponatremia,
hypokalemia, hyperglycemia,
shown to reduce mortality hyperuricemia, hyperlipidemia,
sulfonamide allergy

Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a sulfonamide
Many other thiazides: All basically similar to hydrochlorothiazide, differing only in pharmacokinetics

ALDOSTERONE ANTAGONISTS
Blocks cytoplasmic aldosterone Increased salt and water Chronic heart failure
receptors in collecting tubules Toxicity:
remodeling adrenal tumor) Hyperkalemia, antiandrogen
membrane effect actions
shown to reduce mortality

Eplerenone: Similar to spironolactone; more selective antimineralocorticoid effect; no significant antiandrogen action; has been shown to reduce mortality

ANGIOTENSIN ANTAGONISTS
Angiotensin-converting Arteriolar and venous Chronic heart failure
enzyme (ACE) inhibitors: formation by inhibiting in large doses so duration
conversion of AI to AII aldosterone secretion Toxicity: Cough,
shown to reduce mortality hyperkalemia, angioneurotic
Interactions: Additive
with other angiotensin
antagonists

Angiotensin receptor
blockers (ARBs):
Antagonize AII effects at AT1 Like ACE inhibitors Toxicity:
receptors patients intolerant to ACE Hyperkalemia; angioneurotic
Interactions: Additive
to reduce mortality with other angiotensin
antagonists

Enalapril, many other ACE inhibitors: Like captopril

Candesartan, valsartan, many other ARBs: Like losartan

(continued)

Subclass, Drug
BETA BLOCKERS
Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality
CARDIAC GLYCOSIDE
glycosides are used
outside the USA)
VASODILATORS
Venodilators:
Arteriolar dilators:
Combined arteriolar
and venodilator:
BETA-ADRENOCEPTOR AGONISTS
BIPYRIDINES
NATRIURETIC PEPTIDE
NEPRILYSIN INHIBITOR
in combination with
valsartan [ARNI])
Mechanism of Action
Competitively blocks β1
Na+/K+-ATPase inhibition results
in reduced Ca2+ expulsion and
increased Ca2+ stored in
sarcoplasmic reticulum
Releases nitric oxide (NO)
(see Chapter 12)
Probably increases NO
synthesis in endothelium
(see Chapter 11)
Releases NO spontaneously
Beta1-selective agonist
Dopamine receptor agonist
β and
α adrenoceptors
Phosphodiesterase type 3
breakdown
Activates BNP receptors,
increases cGMP
Inhibits neprilysin, thus
reducing breakdown of ANP
and BNP; valsartan inhibits
action of angiotensin on its
receptors
Effects
understood other effects
Increases cardiac contractility
effect (slowed sinus heart rate,
slowed atrioventricular
conduction)
preload and ventricular
stretch
Reduces blood pressure
increased cardiac output
Marked vasodilation
afterload
Increases cardiac
contractility, output
Increases renal blood flow
cardiac force and blood
pressure
Vasodilator; lower peripheral
increases cardiac
contractility
Vasodilator
CHAPTER 13 Drugs Used in Heart Failure
Clinical Applications
Chronic heart failure: To slow
in moderate and severe heart
Chronic symptomatic heart
been shown to reduce
mortality but does reduce
rehospitalization
Acute and chronic heart
Hydralazine plus nitrates may
reduce mortality in African-
Americans
Acute cardiac
decompensation
(malignant hypertension)
Acute decompensated
heart failure
Acute decompensated heart
Acute decompensated heart
increases mortality in
chronic failure
Acute decompensated failure
reduce mortality
reduces mortality and
rehospitalizations
225
Pharmacokinetics,
Toxicities, Interactions
Toxicity:
Bronchospasm, bradycardia,
atrioventricular block, acute
and interactions
Toxicity: Nausea,
arrhythmias
Toxicity:
Postural hypotension,
Interactions: Additive with other
vasodilators and synergistic
with phosphodiesterase type 5
inhibitors
Toxicity:
Tachycardia, fluid retention,
lupus-like syndrome
Toxicity: Excessive hypotension,
thiocyanate and cyanide
Interactions: Additive
with other vasodilators
Toxicity: Arrhythmias
Interactions: Additive with
other sympathomimetics
Toxicity: Arrhythmias
Interactions: Additive with
sympathomimetics
Toxicity: Arrhythmias
Interactions: Additive with
other arrhythmogenic agents
Toxicity: Renal damage,
hypotension, may increase
mortality
in combination with ARB
Toxicity: Hypotension,
angioedema
250 SECTION III Cardiovascular-Renal Drugs

Relevant structural heart disease No or minimal heart disease including

ESC: Heart failure, CAD, valvular heart disease, LVH hypertension without LVH
ACCF/AHA/HRS: heart failure, CAD, valvular heart disease, LVH ESC: Includes LVH with preserved LV function
CCS only considers heart failure or LVEF < 35% CCS: Including CAD, LVH, and HFpEF

Heart failure Coronary artery Hypertension Paroxysmal Persistent

disease with LVH AF AF

Dronedarone Dronedarone ESC: Ablation possible Dronedarone

Sotalol Amiodarone as first-line therapy Flecainide
US: Only Amiodarone Propafenone
Sotalol
Catheter
ablation for AF

Amiodarone Catheter Amiodarone

Dofetilide ablation for AF
CCS: Sotalol when LVEF > 35%

FIGURE 14–11 Selection of rhythm control therapies depends on presence and nature of any underlying heart disease. Patients
may be divided into two broad categories: those with and those without underlying heart disease. Patient with heart failure, left ventricular
ejection fraction (LVEF) less than 35%, coronary artery disease (CAD), valvular heart disease, and left ventricular hypertrophy (LVH) fall into the
first category. The second category includes patients with mild LVH and with heart failure but a preserved ejection fraction (HFpEF). The
recommendations are based on the guidelines of the American College of Cardiology Foundation (ACCF), the American Heart Association
(AHA), the Heart Rhythm Society (HRS), and the Canadian Cardiology Society (CCS). AF, atrial fibrillation; ESC, European Society of Cardiology;
LV, left ventricle.

SUMMARY Antiarrhythmic Drugs

Mechanism Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Clinical Applications Interactions

CLASS 1A    
INa (primary) and IKr Slows conduction velocity and
(secondary) blockade
potential duration and dissociates
from INa channel with intermediate
on sinoatrial (SA) and atrioventricular
(AV) nodes
Most atrial and ventricular
choice for most sustained
ventricular arrhythmias
associated with acute
myocardial infarction
metabolism to N-acetylprocainamide
(NAPA; see text) and renal elimination
Toxicity:
produces reversible lupus-related
symptoms

Quinidine: Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias; see Chapter 52 for malaria
Disopyramide: Similar to procainamide but significant antimuscarinic effects; may precipitate heart failure; not commonly used

CLASS 1B        
Sodium channel (INa) Blocks activated and inactivated Terminates ventricular
blockade tachycardias and prevents
not prolong and may shorten action ventricular fibrillation after Toxicity:
potential cardioversion Neurologic symptoms

Mexiletine: Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain syndromes

(continued)
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 251

Mechanism Pharmacokinetics, Toxicities,

Subclass, Drug of Action Effects Clinical Applications Interactions

CLASS 1C        
Sodium channel (INa) Dissociates from channel with slow Supraventricular arrhythmias
blockade in patients with normal heart ∼ Toxicity: Proarrhythmic
potential duration
conditions (post-myocardial
infarction)

Propafenone: Orally active, weak β-blocking activity; supraventricular arrhythmias; hepatic metabolism
Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA.

CLASS 2        
β-Adrenoceptor Direct membrane effects (sodium Atrial arrhythmias and
blockade channel block) and prolongation of prevention of recurrent Toxicity: Asthma, AV blockade, acute
infarction and sudden death Interactions: With other
node automaticity and AV nodal cardiac depressants and hypotensive
conduction velocity drugs

Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias

CLASS 3        
Blocks IKr, INa, ICa-L Prolongs action potential duration Serious ventricular
channels, β arrhythmias and
adrenoceptors supraventricular Toxicity:
incidence of torsades de pointes arrhythmias Bradycardia and heart block in diseased
heart, peripheral vasodilation,

Interactions: Many,
based on CYP metabolism

IKr block Prolongs action potential, effective Maintenance or restoration Toxicity: Torsades
refractory period of sinus rhythm in atrial de pointes (initiate in hospital with
fibrillation Interactions: Additive with
other QT-prolonging drugs

Sotalol: β-Adrenergic and IKr blocker, direct action potential prolongation properties, use for ventricular arrhythmias, atrial fibrillation
Ibutilide: Potassium channel blocker, may activate inward current; IV use for conversion in atrial flutter and fibrillation
Dronedarone: Amiodarone derivative; multichannel actions, reduces mortality in patients with atrial fibrillation
Vernakalant: Investigational in the USA, multichannel actions in atria, prolongs atrial refractoriness, effective in atrial fibrillation

CLASS 4  
Calcium channel
(ICa-L type) blockade
     
Slows SA node automaticity and AV Supraventricular tachycardias,
hypertension, angina Toxicity
& Interactions: See Chapter 12
pressure

Diltiazem: Equivalent to verapamil

MISCELLANEOUS        
Activates inward Very brief, usually complete AV Paroxysmal supraventricular Toxicity:
rectifier IK Ca blockade tachycardias Flushing, chest tightness, dizziness
Interactions: Minimal

Normalizes or increases
interacts with Na+/K+- plasma Mg2+ induced arrhythmias Toxicity: Muscle weakness in overdose
ATPase, K+, and Ca2+
channels

Increases K+ Digitalis-induced arrhythmias Toxicity: Reentrant arrhythmias,

permeability, K+ conduction velocity in heart fibrillation or arrest in overdose
currents hypokalemia
272 SECTION III Cardiovascular-Renal Drugs
be idiopathic. In these situations, thiazides are also effective but
should be used as adjunctive therapy with other measures.
HYPERCALCEMIA
Hypercalcemia can be a medical emergency (see Chapter 42). Because
loop diuretics reduce Ca2+ reabsorption significantly, they can be
quite effective in promoting Ca2+ diuresis. However, loop diuretics
alone can cause marked volume contraction. If this occurs, loop
diuretics are ineffective (and potentially counterproductive) because
Ca2+ reabsorption in the proximal tubule would be enhanced. Thus,
saline must be administered simultaneously with loop diuretics if
an effective Ca2+ diuresis is to be maintained. The usual approach is
to infuse normal saline and furosemide (80–120 mg) intravenously.
Once the diuresis begins, the rate of saline infusion can be matched
with the urine flow rate to avoid volume depletion. Potassium
chloride may be added to the saline infusion as needed.
DIABETES INSIPIDUS
Diabetes insipidus is due to either deficient production of
ADH (neurogenic or central diabetes insipidus) or inadequate
responsiveness to ADH (nephrogenic diabetes insipidus [NDI]).
Administration of supplementary ADH or one of its analogs
is effective only in central diabetes insipidus. Thiazide diuret-
ics can reduce polyuria and polydipsia in nephrogenic diabetes
insipidus, which is not responsive to ADH supplementation.
Lithium, used in the treatment of manic-depressive disorder, is a
common cause of NDI, and thiazide diuretics have been found
to be helpful in treating it. This seemingly paradoxical beneficial
effect of thiazides was previously thought to be mediated through
SUMMARY Diuretic Agents
Subclass, Drug Mechanism of Action Effects
CARBONIC ANHYDRASE INHIBITORS
Inhibition of the enzyme Reduce reabsorption of HCO3−, causing
others prevents dehydration of
H2CO3 and hydration of CO2
in the proximal convoluted
tubule
Brinzolamide, dorzolamide: Topical for glaucoma
SGLT2 INHIBITORS    
Inhibition of sodium/glucose Inhibition of glucose reabsorption lowers
cotransporter (SGLT2) in the serum glucose concentration, and
PCT results in decreased Na+ reduced Na+ reabsorption causes mild
and glucose reabsorption diuresis
Dapagliflozin, empagliflozin: similar to canagliflozin
plasma volume reduction, with an associated fall in GFR, lead-
ing to enhanced proximal reabsorption of NaCl and water and
decreased delivery of fluid to the downstream diluting segments.
However, in the case of Li+-induced NDI, it is now known
that HCTZ causes increased osmolality in the inner medulla
(papilla) and a partial correction of the Li+-induced reduction in
aquaporin-2 expression. HCTZ also leads to increased expres-
sion of Na+ transporters in the DCT and CCT segments of
the nephron. Thus, the maximum volume of dilute urine that
can be produced is significantly reduced by thiazides in NDI.
Dietary sodium restriction can potentiate the beneficial effects of
thiazides on urine volume in this setting. Serum Li+ levels must
be carefully monitored in these patients, because diuretics may
reduce renal clearance of Li+ and raise plasma Li+ levels into the
toxic range (see Chapter 29). Lithium-induced polyuria can also
be partially reversed by amiloride, which blocks Li+ entry into
collecting duct cells, much as it blocks Na+ entry. As mentioned
above, thiazides are also beneficial in other forms of nephrogenic
diabetes insipidus. It is not yet clear whether this is via the same
mechanism that has been found in Li+-induced NDI. Acetazol-
amide has also shown efficacy in treating polyuria in nephrogenic
diabetes insipidus with fewer adverse events.
RENAL & CARDIAC PROTECTION
Aldosterone antagonists have been shown to be cardioprotective in
patients with heart disease. In addition, they may exert an addi-
tional benefit in lowering albuminuria in patients with diabetes
and microalbuminuria. Their use has been limited in patients
with renal dysfunction because of the increased risk of inducing
hyperkalemia. Finerenone may afford similar cardiac and renal
protection with a lower risk for hyperkalemia.
Clinical Pharmacokinetics,
Applications Toxicities, Interactions
Glaucoma, mountain Oral and topical preparations
sickness, edema with
alkalosis ∼ Toxicity: Metabolic
acidosis, renal stones,
hyperammonemia in
cirrhotics
   
Diabetes mellitus; Available orally. Half-life
approved for the
treatment of in severe renal or liver
hyperglycemia, not as disease
a diuretic
(continued)

Subclass, Drug Mechanism of Action
LOOP DIURETICS  
Inhibition of the Na/K/2Cl
transporter in the ascending
limb of Henle’s loop
Bumetanide, torsemide: Sulfonamide loop agents like furosemide
Ethacrynic acid: Not a sulfonamide but has typical loop activity and some uricosuric action
THIAZIDES  
Inhibition of the Na/Cl
transporter in the distal
convoluted tubule
Metolazone: Popular for use with loop agents for synergistic effects
Chlorothiazide: Only parenteral thiazide available (IV)
Chlorthalidone: Long half-life (50–60 h) due to binding to red blood cells
POTASSIUM-SPARING DIURETICS
Pharmacologic antagonist
of aldosterone in collecting
of androgen receptors
Blocks epithelial sodium
channels in collecting tubules
Eplerenone: Like spironolactone, more selective for aldosterone receptor
Triamterene: Mechanism like amiloride, much less potent, more toxic
OSMOTIC DIURETICS
Physical osmotic effect on
tissue water distribution
because it is retained in the
vascular compartment
VASOPRESSIN (ADH) ANTAGONISTS
Antagonist at V1a and V2 ADH
receptors
Selective antagonist at
V2 ADH receptors
CHAPTER 15 Diuretic Agents 273
Clinical Pharmacokinetics,
Effects Applications Toxicities, Interactions
     
Marked increase in NaCl excretion, some K Pulmonary edema, Oral and parenteral
wasting, hypokalemic metabolic alkalosis, peripheral edema,
increased urine Ca and Mg heart failure, Toxicity:
hypertension, acute Ototoxicity, hypovolemia,
hypercalcemia, anion K wasting, hyperuricemia,
overdose hypomagnesemia
     
Hypertension, mild
heart failure, Toxicity: Hypokalemic
nephrolithiasis, metabolic alkalosis,
nephrogenic diabetes hyperuricemia,
insipidus hyperglycemia,
hyponatremia
Reduces Na retention and K wasting in Aldosteronism from Slow onset and offset of
any cause
aldosterone in heart and vessels Toxicity: Hyperkalemia,
other diuretics gynecomastia
(spironolactone, not
infarction
interaction with other
K-retaining drugs
Reduces Na retention and K wasting Hypokalemia from
other diuretics Toxicity: Hyperkalemic
metabolic acidosis
induced polyuria
Marked increase in urine flow, reduced Renal failure due to Toxicity:
brain volume, decreased intraocular increased solute load Nausea, vomiting, headache
pressure, initial hyponatremia, then (rhabdomyolysis,
hypernatremia chemotherapy),
increased intracranial
pressure, glaucoma
Reduces water reabsorption, increases Hyponatremia, IV only, usually continuous
plasma Na concentration, vasodilation congestive heart Toxicity: Infusion site
failure reactions, thirst, polyuria,
hypernatremia
Reduces water reabsorption, increases Hyponatremia, SIADH
plasma Na concentration Toxicity: Polyuria (frequency),
thirst, hypernatremia
 CHAPTER 35 Agents Used in Dyslipidemia 639

HMG-CoA REDUCTASE INHIBITORS & REDUCTASE INHIBITORS &

BILE ACID-BINDING RESINS
This synergistic combination is useful in the treatment of familial
hypercholesterolemia but may not control levels of VLDL in some
patients with familial combined hyperlipoproteinemia.
NIACIN & BILE ACID-BINDING RESINS
This combination effectively controls VLDL levels during resin
therapy of familial combined hyperlipoproteinemia or other
disorders involving both increased VLDL and LDL levels. When
VLDL and LDL levels are both initially increased, doses of niacin
as low as 1–3 g/d may be sufficient in combination with a resin.
The niacin-resin combination is effective for treating heterozygous
familial hypercholesterolemia.
NIACIN & REDUCTASE INHIBITORS
If the maximum tolerated statin dose fails to achieve the LDL
cholesterol goal in a patient with hypercholesterolemia, niacin
may be helpful. This combination may be useful in the treatment
of familial combined hyperlipoproteinemia.
REDUCTASE INHIBITORS & EZETIMIBE
This combination is synergistic in treating primary hypercho-
lesterolemia and may be of use in the treatment of patients
with homozygous familial hypercholesterolemia who have some
receptor function.
FENOFIBRATE
Fenofibrate appears to be complementary with most statins in
the treatment of familial combined hyperlipoproteinemia and
other conditions involving elevations of both LDL and VLDL.
The combination of fenofibrate with rosuvastatin appears to
be especially well tolerated. Some other statins may interact
unfavorably owing to effects on cytochrome P450 metabolism.
In any case, particular vigilance for liver and muscle toxicity is
indicated.
COMBINATIONS OF RESINS, EZETIMIBE,
NIACIN, & REDUCTASE INHIBITORS
These agents act in a complementary fashion to normalize cho-
lesterol in patients with severe disorders involving elevated LDL.
The effects are sustained, and little compound toxicity has been
observed. Effective doses of the individual drugs may be lower
than when each is used alone; for example, as little as 1–2 g of
niacin may substantially increase the effects of the other agents.
COMBINATIONS OF PCSK9 ANTIBODY
WITH STATIN AND EZETIMIBE
These agents can be used together to achieve maximal reduction of
LDL. Because of the need for parenteral administration of PCSK9
antibody and its expense, this therapy is reserved for patients with
familial hypercholesterolemia or atherosclerotic vascular disease
who do not respond adequately to other regimens.

SUMMARY Drugs Used in Dyslipidemia

Subclass, Pharmacokinetics, Toxicities,
Drug Mechanism of Action Effects Clinical Applications Interactions

STATINS        
Inhibit HMG-CoA reductase Reduce cholesterol synthesis and Atherosclerotic vascular Toxicity: Myopathy,
simvastatin, upregulate low-density disease (primary and Interactions:
rosuvastatin, lipoprotein (LDL) receptors on secondary prevention)
pitavastatin interacts with CYP inhibitors/competitors
in triglycerides syndromes

Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious

FIBRATES        
Peroxisome proliferator- Decrease secretion of Hypertriglyceridemia, Toxicity: Myopathy,
gemfibrozil activated receptor-alpha very-low-density lipoproteins low HDL hepatic dysfunction
(PPAR-α) agonists

high-density lipoproteins (HDL)

(continued)
640 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Subclass, Pharmacokinetics, Toxicities,

Drug Mechanism of Action Effects Clinical Applications Interactions

BILE ACID SEQUESTRANTS

Binds bile acids in gut Decreases LDL Elevated LDL, digitalis
toxicity, pruritus Toxicity:
with absorption of some drugs and vitamins

receptors

Cholestyramine, colesevelam: Similar to colestipol

STEROL ABSORPTION INHIBITOR

Blocks sterol transporter Inhibits reabsorption of Elevated LDL, Toxicity: Low incidence
NPC1L1 in intestine brush cholesterol excreted in bile phytosterolemia of hepatic dysfunction, myositis
border

NIACIN
  Decreases catabolism of Toxicity: Gastric irritation,
lipoprotein(a) [Lp(a)], LDL Lp(a); elevated LDL in flushing, low incidence of hepatic toxicity
secretion from liver statin-unresponsive or
intolerant patients

Extended-release niacin: Similar to regular niacin

Sustained-release niacin (not the same as extended-release product): Should be avoided

PCSK9 HUMANIZED MONOCLONAL ANTIBODIES

Evolocumab Complexes PCSK9 Inhibits catabolism of LDL Familial Toxicity:
receptor hypercholesterolemia not injection site reactions, nasopharyngitis,
responsive to oral therapy flu-like symptoms, rarely myalgia,
neurocognitive and ophthalmologic events

Alirocumab Similar to evolucumab

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