Chapter 11 ANTIHYPERTENSIVE AGENTS

What is Hypertension?
Hypertension is defined conventionally as a
sustained increase in blood pressure 140/90
mm Hg, a criterion that characterizes a group of
patients whose risk of hypertension-related
cardiovascular disease is high enough to merit
medical attention.
Hypertension (HTN) or high blood pressure,
sometimes called arterial hypertension, is a chronic
medical condition in which the blood pressure in
the arteries is elevated.
CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS

The first (or top) number is systolic pressure, the
maximum pressure in the artery as the heart
contracts.
The second (or bottom) number is diastolic
pressure, the lowest pressure in the artery when
the heart is between contractions.
ETIOLOGY
1. Primary, Essential or Idiopathic hypertension
E No specific cause can be identified.
E The average age of onset is about 35 years.
2. Secondary hypertension
E identifiable cause such as:
renal disease
adrenal hyperfunction
E usually develops between the ages of 30 and
50
CAUSES: renal artery constriction, coarctation of the
aorta, pheochromocytoma, Cushing's disease, and
primary aldosteronism.
PHYSIOLOGY
Determinants of Blood Pressure
BP= TPR x CO
where:
BP = blood pressure
TPR = total peripheral resistance
CO = cardiac output
According to the hydraulic equation, arterial blood
pressure (BP) is directly proportionate to the
product of the blood flow (cardiac output, CO) and
the resistance to passage of blood through pre-
capillary arterioles (peripheral vascular resistance,
PVR):
TOTAL PERIPHERAL RESISTANCE
resistance as the heart pumps out blood
Factors:
+ Tone of arterioles (1
0
resistance vessels)
*when dilated downward resistance
*when constricted upward resistance
Total peripheral resistance (TPR) is the sum of
the resistance of all peripheralvasculature in the
systemic circulation.
total peripheral resistance, the
overall resistance to blood flow through the
systemic blood vessels
PHYSIOLOGY
Formula of Cardiac Output
CO = SV x HR
where: CO = Cardiac Output
HR = Heart Rate
SV = Stroke Volume
Cardiac output (Q or or CO) is the volume of blood
being pumped by the heart, in particular by a left or
right ventricle in the time interval of one minute.
Cardiac output is the volume of blood pumped by
the heart per minute (mL blood/min). Cardiac
output is a function of heart rate and stroke
volume. The heart rate is simply the number of
heart beats per minute. The stroke volume is the
volume of blood, in milliliters (mL), pumped out of
the heart with each beat. Increasing either heart
rate or stroke volume increases cardiac output.
Control of Heart Rate
The SA node of the heart is enervated by both
sympathetic and parasympathetic nerve fibers.
Factors of Stroke Volume
Inotropic Activity of the Heart
> Strength of cardiac contraction (inotropism)
> To decrease blood pressure, cardiac
contraction and rate of cardiac contraction should be
lowered
Inotropic-affecting the force of muscular
contractions.
Stroke volume is increased by 2 mechanisms:
increase in end-diastolic volume
increase in sympathetic system activity
Starling's Law describes the relationship between
end-diastolic volume and stroke volume. It states
that the heart will pump out whatever volume is
delivered to it. If the end-diastolic volume doubles
then stroke volume will double.
Preload / Venous Return
> tone of veins / capacitance vessels
-contain highly elastic blood
*when dilated downward venous return
*when constricted upward venous return
preload is the end volumetric pressure that
stretches the right or left ventricle of the heart to its
greatest geometric dimensions under variable
physiologic demand. In other words, it is the initial
stretching of the cardiac myocytes prior to
contraction; therefore, it is related to the
sarcomere length at the end of diastole.
preload the mechanical state of the heart at the
end of diastole, the magnitude of the maximal (end-
diastolic) ventricular volume or the end-diastolic
pressure stretching the ventricles.
Anatomic sites of BP control

arterioles, postcapillary venules (capacitance
vessels), and heart. A fourth anatomic control site,
the kidney, contributes to maintenance of blood
pressure by regulating the volume of intravascular
fluid. Baroreflexes, mediated by autonomic nerves,
act in combination with humoral mechanisms,
including the renin-angiotensin-aldosterone system,
to coordinate function at these four control sites
and to maintain normal blood pressure. Finally,
local release of vasoactive substances from vascular
endothelium may also be involved in the regulation
of vascular resistance. For example, endothelin-1
constricts and nitric oxide dilates blood vessels.
Mechanism of Blood Pressure Regulation
1. SYMPATHETIC NERVOUS SYSTEM.
Baroreceptors Reflex Arc/Postural Mechanism
Important in the moment-moment
Control of BP
2. RAAS
For long term control of BP
Blood pressure is contolled on a minute-to-minute
basis by baroreceptor reflexes. Baroreceptors are
specialized stretch receptors that detect changes in
blood pressure. Baroreceptors are located in the
walls of arteries, veins and the heart. The most
important baroreceptors being those found in the
carotid sinus and the aorta. Baroreceptors, which
constantly monitor blood pressure, communicate
with the Cardiovascular Control Center (CCC) found
in the brain stem.
Baroreflexes are responsible for rapid, moment-to-
moment adjustments in blood pressure, such as in
transition from a reclining to an upright posture .
Baroreflexes, mediated by autonomic nerves, act in
combination with humoral mechanisms, including
the renin-angiotensin-aldosterone system, to
coordinate function at these four control sites and
to maintain normal blood pressure.
Baroreceptor activation inhibits central sympathetic
discharge. Conversely, reduction in stretch results in
a reduction in baroreceptor activity. Thus, 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.
3. Mosaic Theory
OTHER VASOACTIVE SUBSTANCES INVOLVED IN
THE NORMAL MAINTENANCE OF NORMAL
BLOOD PRESSURE:
THESE INCLUDE:
E NITRIC OXIDE (Vasodilating factor)
E ENDOTHELIN (Vasoconstrictor peptide)
E BRADYKININ
Potent vasodilator
Inactivated by ACE
E ATRIAL NATRIURETIC PEPTIDE
Naturally occuring diuretic
4. Fluid Volume Regulation
Increased Fluid Volume
Increases venous system distention thereby
affecting cardiac output and tissue perfusion.
These changes alter vascular resistance therefore
increasing blood pressure
ANTI HYPERTENSIVE AGENTS
O Diuretics
O Vasodilators
- Direct Vasodilators
- Calcium Channel Blockers
O Peripheral Sympatholytics
- Beta blockers
- Alpha blockers
O Angiotensin Modifiers
O Sympathoplegic agents
w DIURETICS
It lowers blood pressure by reducing the blood
volume and reduction in body sodium.
They are the first agents tried in mild
hypertension and affect blood sodium level and
blood volume.
However, they do cause electrolyte and acid-
base disturbances.
it was not until 1957 that a practical and powerful
diuretic agent (chlorothiazide) became available for
widespread use.
a "diuretic" is an agent that increases urine volume,
whereas a "natriuretic" causes an increase in renal
sodium excretion.
TYPES OF DIURETICS:
+ Thiazides
o Bendroflumethiazide (Naturetin)
o Benzthiazide
o Chlorothiazide (Diuril)
o Polythiazide (Renese)
o Trichlormethiazide (Diurese, Naqua)
o Hydrochlorothiazide (Hydrodiuril)
o Hydroflumethiazide ( Saluron)
The prototypical thiazide is hydrochlorothiazide.
Chlorothiazide, the parent of the group, is not very
lipid-soluble and must be given in relatively large
doses.
all of the thiazides have an unsubstituted
sulfonamide group
Major site of action: Distal convoluted tubule
Modest increase in NaCl excretion some K wasting
hypokalemic metabolic alkalosis decreased urine Ca
Thiazide-like diuretics
Chlorthalidone (Hygroton, Thalitone)
Indapamide(Lozol)
With vasodilating activity
Metolazone (Mykrox, Zaroxolyn)
Quinethazone (Hydromox)
Mechanism of action: (THIAZIDES)
E inhibit NaCl reabsorption from the luminal side
of epithelial cells in the distal convoluted tubule
by blocking the Na+/Cl- transporter
E thiazides actually enhance Ca
2+
reabsorption
Clinical Uses:
E Mild or moderate HPN and normal renal and
cardiac function
E CHF
E Nephrolithiasis due to Hypercalciuria(excessive
urinary calcium excretion.)
E Nephrogenic Diabetes Insipidus( is
a condition characterized by excessive
thirst and excretion of large amounts of
severely diluted urine, with reduction of fluid
intake having no effect on the concentration of
the urine. The most common type in humans is
central DI, caused by a deficiency of
arginine vasopressin (AVP), also known as
antidiuretic hormone (ADH). The second
common type of DI is nephrogenic diabetes
insipidus, which is caused by an insensitivity of
the kidneys to ADH.)
Increase excretion of :
water , sodium, chloride, potassium, and
bicarbonate
Decrease excretion of:
calcium and uric acid
Adverse effects:
E Hypokalemia
contraindicated to patients under
digitalis therapy.
E Hyponatremia
E Hypercalcemia
E Hyperuricemia
E Hyperglycemia
E Hyperlipidemia
E Allergic Reactions
Hypokalemic Metabolic Alkalosis
Impaired Carbohydrate Tolerance
Hyperglycemia may occur in patients who are overtly
diabetic or who have even mildly abnormal glucose
tolerance tests. The effect is due to both impaired
pancreatic release of insulin and diminished tissue
utilization of glucose. Hyperglycemia may be
partially reversible with correction of hypokalemia.
Hyperlipidemia
Thiazides cause a 515% increase in total serum
cholesterol and low-density lipoproteins (LDL).
Hyponatremia is an important adverse effect of
thiazide diuretics. It is due to a combination of
hypovolemia-induced elevation of ADH, reduction
in the diluting capacity of the kidney, and increased
thirst. It can be prevented by reducing the dose of
the drug or limiting water intake.
+ Loop diuretics
o a.k.a. high ceiling diuretics
Furosemide (prototype) - Lasix
Bumetanide (Bumex)
Ethacrynic acid (Edecrin)
Torsemide(Demadex)
In addition to furosemide, bumetanide and
torsemide are sulfonamide loop diuretics.
Ethacrynic acidnot a sulfonamide derivativeis a
phenoxyacetic acid derivative.
Organic mercurial diuretics also inhibit salt
transport in the TAL but are no longer used because
of their toxicity.
Major site of action: Thick ascending Loop of Henle
Mechanism of action:
E inhibit the luminal Na+/K+/2Cl- transporter
E inhibit the cotransport of sodium, potassium,
and chloride from the luminal filtrate.
Clinical Uses:
- Drug of choice when rapid and extensive
diuresis is needed
- Reserve drugs for hypertensive emergency or
crisis
- Also used in CHF
- Acute pulmonary edema
- Acute hypercalcemia
- Hyperkalemia
- Acute Renal Failure
- Anion Overdose (halide poisoning)
Acute Renal Failure
Loop agents can increase the rate of urine flow and
enhance K
+
excretion in acute renal failure.
However, they do not shorten the duration of renal
failure. If a large pigment load has precipitated
acute renal failure (or threatens to), loop agents
may help flush out intratubular casts and
ameliorate intratubular obstruction. On the other
hand, loop agents can theoretically worsen cast
formation in myeloma and light chain nephropathy.
Anion Overdose
Loop diuretics are useful in treating toxic ingestions
of bromide, fluoride, and iodide, which are
reabsorbed in the TAL. Saline solution must be
administered to replace urinary losses of Na
+
and to
provide Cl

, so as to avoid extracellular fluid volume

depletion.
Adverse effects:
E Hypokalemic metabolic alkalosis - By inhibiting
salt reabsorption in the TAL, loop diuretics
increase delivery to the collecting duct.
Increased delivery leads to increased secretion
of K
+
and H
+
by the duct, causing hypokalemic
metabolic alkalosis
E Ototoxicity - Loop diuretics occasionally cause
dose-related hearing loss that is usually
reversible. It is most common in patients who
have diminished renal function or who are also
receiving other ototoxic agents such as
aminoglycoside antibiotics.
E Hyperuricemia - Loop diuretics can cause
hyperuricemia and precipitate attacks of gout.
This is caused by hypovolemia-associated
enhancement of uric acid reabsorption in the
proximal tubule. It may be prevented by using
lower doses to avoid development of
hypovolemia.
E Hypomagnesemia - Magnesium depletion is a
predictable consequence of the chronic use of
loop agents and occurs most often in patients
with dietary magnesium deficiency. It can be
reversed by administration of oral magnesium
preparations.
E Allergic Reactions - All loop diuretics, with the
exception of ethacrynic acid, are sulfonamides.
Therefore, skin rash, eosinophilia, and less
often, interstitial nephritis are occasional
adverse effects of these drugs.

+ Potassium-sparing diuretics
Spironolactone (Aldactone)
synthetic steroid that acts as a competitive
antagonist to aldosterone.

Eplerenone (Inspra)
spironolactone analog with much greater selectivity
for the mineralocorticoid receptor. It is several
hundred-fold less active on androgen and
progesterone receptors than spironolactone

Amiloride (Midamor)

Triamterene (Dyrenium)
Amiloride and triamterene are direct inhibitors of
Na
+
influx in the CCT (cortical collecting tubule)
They are not potent when used alone
Major site of action: Late distal & Cortical collecting
tubule
Mechanism of Action:
It prevents the K
+
secretion by antagonizing the
effects of aldosterone at the late distal and
cortical collecting tubules.
Potassium-sparing diuretics prevent K
+
secretion by
antagonizing the effects of aldosterone at the late
distal and cortical collecting tubules. Inhibition may
occur by direct pharmacologic antagonism of
mineralocorticoid receptors ( spironolactone,
eplerenone ) or by inhibition of Na
+
influx through
ion channels in the luminal membrane ( amiloride,
triamterene ).
A.Spironolactone
Structural analog of aldosterone
Active metabolite: canrenone
Clinical Uses:
- Adjunct drug in the managementt of CHF
- Used in Conns syndrome
- CHF and edema (combined with thiazide or
loop diuretic
Site of action:Late distal tubule and cortical
collecting tubule.
Conn's syndrome is a disease of the adrenal glands
involving excess production of a hormone, called
aldosterone.
Conns syndrome is another name for primary
hyperaldosteronism
Potassium-sparing diuretics are most useful in
states of mineralocorticoid excess or
hyperaldosteronism (also called aldosteronism),
due either to primary hypersecretion (Conn's
syndrome, ectopic adrenocorticotropic hormone
production) or secondary hyperaldosteronism
(evoked by heart failure, hepatic cirrhosis, nephrotic
syndrome, or other conditions associated with
diminished effective intravascular volume). Use of
diuretics such as thiazides or loop agents can cause
or exacerbate volume contraction and may cause
secondary hyperaldosteronism.
Hyperaldosteronism, also aldosteronism,
[1]
is
a medical condition where too much aldosterone is
produced by the adrenal glands, which can lead to
lowered levels of potassium in the blood also
known as hypokalemia.
Primary aldosteronism (hyporeninemic
hyperaldosteronism) was previously thought to be
most commonly caused by an adrenal adenoma,
termed Conn's syndrome.
Secondary hyperaldosteronism (also hyperreninism,
or hyperreninemic hyperaldosteronism) is due to
overactivity of the renin-angiotensin system.
Adverse Effects:
Hyperkalemia - Unlike most other
diuretics, K
+
-sparing diuretics reduce
urinary excretion of K
+
(Table 152) and
can cause mild, moderate, or even life-
threatening hyperkalemia.
Hyperchloremic metabolic acidosis - By
inhibiting H
+
secretion in parallel with K
+

secretion, the K
+
-sparing diuretics can
cause acidosis similar to that seen with
type IV renal tubular acidosis.
Menstrual abnormalities in women.
Gynecomastia, impotence, and benign
prostatic hyperplasia
Synthetic steroids may cause endocrine
abnormalities by actions on other steroid receptors.
Gynecomastia, impotence, and benign prostatic
hyperplasia all have been reported with
spironolactone
B. Eplerenone
Spironolactone analog with greater selectivity for the
aldosterone receptor
It is several hundred-fold less active on androgen
and progesterone receptors than spironolactone,
and therefore eplerenone has considerably fewer
adverse effects.
Eplerenone is currently approved for use only in
hypertension.
C. Amiloride and Triamterene
Onset of action is from 2-4 hour


Clinical Uses:
CHF, cirrhosis and edema (secondary to
Hyperladosteronism)
Mechanism of action
Decrease membrane permeability and inhibit
electrogenic absorption of sodium and excretion of
potassium in the collecting tubule which is
independent of the presence of mineralocorticoid.
Adverse Effects: (K sparing diuretics)
Hyperkalemia
nausea and vomiting.
Triamterene : kidney stones.
Kidney Stones
Triamterene is only slightly soluble and may
precipitate in the urine, causing kidney stones.
*Contraindicated in diminished renal function
+ Osmotic diuretics
Mannitol(Osmitrol)
Glycerin
Isosorbide
Urea
Osmotic Diuretics
The proximal tubule and descending limb of Henle's
loop are freely permeable to water. Any osmotically
active agent that is filtered by the glomerulus but
not reabsorbed causes water to be retained in these
segments and promotes a water diuresis. Such
agents can be used to reduce intracranial pressure
and to promote prompt removal of renal toxins. The
prototypic osmotic diuretic is mannitol.
They are easily filtered and poorly reabsorbable
solutes that alter the diffusion of water relative to
sodium by binding with water.
They pull water into the renal tubule without
sodium loss.
Clinical Uses:
E To increase urine volume
Osmotic diuretics are used to increase water
excretion in preference to sodium excretion. This
effect can be useful when avid Na
+
retention limits
the response to conventional agents. It can be used
to maintain urine volume and to prevent anuria that
might otherwise result from presentation of large
pigment loads to the kidney (eg, from hemolysis or
rhabdomyolysis)

E To reduce intracranial and intraocular pressure
Osmotic diuretics alter Starling forces so that water
leaves cells and reduces intracellular volume. This
effect is used to reduce intracranial pressure in
neurologic conditions and to reduce intraocular
pressure before ophthalmologic procedures

A. Mannitol (Osmitol)
E given intravenously for prophylaxis of acute
renal failure resulting from trauma or surgery.
E It increases blood volume and causes nausea
and vomiting.
B. Isosorbide and Glycerin
O Used for ophthalmic procedures.
Adverse Effects:
expansion of the extracellular volume
Mannitol is rapidly distributed in the extracellular
compartment and extracts water from cells. Prior to
the diuresis, this leads to expansion of the
extracellular volume and hyponatremia
Dehydration and Hypernatremia
Excessive use of mannitol without adequate water
replacement can ultimately lead to severe
dehydration, free water losses, and hypernatremia.
As water is extracted from cells, intracellular K
+

concentration rises, leading to cellular losses and
hyperkalemia. These complications can be avoided
by careful attention to serum ion composition and
fluid balance.
+ Carbonic Anhydrase Inhibitors
Acetazolamide (Diamox)
Methazolamide (Neptazane)
Dichlorphenamide (Daranide)
Carbonic anhydrase inhibitors were the forerunners
of modern diuretics. They were discovered when it
was found that bacteriostatic sulfonamides caused
an alkaline diuresis and hyperchloremic metabolic
acidosis. With the development of newer agents,
carbonic anhydrase inhibitors are now rarely used
as diuretics, but they still have several specific
applications that are discussed below. The
prototypical carbonic anhydrase inhibitor is
acetazolamide.
Pharmacodynamics:
Inhibition of carbonic anhydrase activity profoundly
depresses HCO
3

reabsorption in the PCT. At its

maximal safe dosage, 85% of the HCO
3

reabsorptive capacity of the superficial PCT is
inhibited.
Mechanism of action:
E Slows down the movement of hydrogen ions
thereby blocking the effect of carbonic
anhydrase resulting to more sodium and
bicarbonate loss.
Carbonic anhydrase is present in many nephron
sites, but the predominant location of this enzyme
is the luminal membrane of the PCT where it
catalyzes the dehydration of H
2
CO
3
as previously
described. By blocking carbonic anhydrase,
inhibitors block NaHCO3 reabsorption and cause
diuresis
Cinical Uses:
- Relatively mild diuretic
- Used in glaucoma- The reduction of aqueous
humor formation by carbonic anhydrase
inhibitors decreases the intraocular pressure.
Topically active carbonic anhydrase inhibitors
(dorzolamide, brinzolamide) are available and
reduce intraocular pressure without producing
detectable plasma levels
- Used in urinary alkalinization- Uric acid, cystine,
and other weak acids are most easily
reabsorbed from acidic urine. Therefore, renal
excretion of cystine (in cystinuria) and other
weak acids can be enhanced by increasing
urinary pH with carbonic anhydrase inhibitors
- Used in metabolic alkalosis - Acetazolamide can
also be used to rapidly correct the metabolic
alkalosis that may develop in the setting of
respiratory acidosis.
- prophylaxis in acute mountain sickness-
Weakness, dizziness, insomnia, headache, and
nausea can occur in mountain travelers who
rapidly ascend above 3000 m.
- adjuvants for the treatment of epilepsy
Others:hypokalemic periodic paralysis and to
increase urinary phosphate excretion during severe
hyperphosphatemia.
Adverse Effects:
GI upset
urinary infrequency
metabolic acidosis
renal calculi formation
potassium wasting
drowsiness and paresthesias
Hyperchloremic Metabolic Acidosis
Acidosis predictably results from chronic reduction
of body HCO
3

stores by carbonic anhydrase

inhibitors (Table 152) and limits the diuretic
efficacy of these drugs to 2 or 3 days. Unlike the
diuretic effect, acidosis persists as long as the drug
is continued.
Renal Stones
Phosphaturia and hypercalciuria occur during the
bicarbonaturic response to inhibitors of carbonic
anhydrase. Renal excretion of solubilizing factors
(eg, citrate) may also decline with chronic use.
Calcium salts are relatively insoluble at alkaline pH,
which means that the potential for renal stone
formation from these salts is enhanced.
Renal Potassium Wasting
Potassium wasting can occur because the increased
Na
+
presented to the collecting tubule (with HCO
3

)
is partially reabsorbed, increasing the lumen-
negative electrical potential in that segment and
enhancing K
+
secretion. This effect can be
counteracted by simultaneous administration of
potassium chloride. This K
+
wasting is theoretically a
problem with any proximal tubule diuretic that
presents increased Na
+
to the collecting tubule.
However, the new adenosine A1 receptor
antagonists (see under Heart Failure) avoid this
toxicity by blunting Na
+
reabsorption in both the
proximal and collecting tubules.
Other Toxicities
Drowsiness and paresthesias are common following
large doses of acetazolamide. Carbonic anhydrase
inhibitors may accumulate in patients with renal
failure, leading to nervous system toxicity.
Hypersensitivity reactions (fever, rashes, bone
marrow suppression, and interstitial nephritis) may
also occur.
VASODILATORS
E Relax the smooth muscles and lower total
peripheral resistance
E Do not cause orthostatic hypotension or sexual
dysfunction
E Produce reflex stimulation of the heart
E Can increase plasma renin
E Commonly used with a diuretic or beta blocker












ORAL
Hydralazine -Apresoline
Minoxidil-Loniten
E Used for long term out patient therapy of
hypertension

HYDRALAZINE
Mechanism of Action:
E relaxes the arteriolar muscle
E may stimulate EDRF formation
Use/s:
E Used in chronic hypertension and in
hypertensive crises accompanying acute
glomerular nephritis or eclampsia.
Hydralazine, a hydrazine derivative, dilates
arterioles but not veins.
T1/2: 2 4 hours
Hydralazine is well absorbed and rapidly
metabolized by the liver during the first pass, so
that bioavailability is low (averaging 25%) and
variable among individuals. It is metabolized in part
by acetylation at a rate that appears to be
bimodally distributed in the population.
The combination of hydralazine with nitrates is
effective in heart failure and should be considered
in patients with both hypertension and heart
failure, especially in African-American patients.
Usual dosage ranges from 40 mg/d to 200 mg/d.
The higher dosage was selected as the dose at
which there is a small possibility of developing the
lupus erythematosus-like syndrome described in
the next section
Toxicity: The most common adverse effects of
hydralazine are headache, nausea, anorexia,
palpitations, sweating, and flushing. In patients with
ischemic heart disease, reflex tachycardia and
sympathetic stimulation may provoke angina or
ischemic arrhythmias
MINOXIDIL
Description:
E Arteriolar vasodilator
E Used to replace hydralazine when maximal
doses of hydralazine are not effective
E Also used in patients with renal failure and
severe hypertension who do not respond to
hydralazine
E Oral treatment used in severe to malignant
hypertension.
Minoxidil is a very efficacious orally active
vasodilator. The effect results from the opening of
potassium channels in smooth muscle membranes
by minoxidil sulfate, the active metabolite.
T1/2 : 4 hrs
Mechanism of Action:
Minoxidil sulfate, the active metabolite, opens the
K+ channels in smooth muscle membranes causes
the stabilization of the membrane at its resting
potential and makes contractions less likely.
Even more than with hydralazine, the use of
minoxidil is associated with reflex sympathetic
stimulation and sodium and fluid retention.
Minoxidil must be used in combination with a B-
blocker and a loop diuretic.
Started on 5 or 10 mg/d in two doses, then
gradually increase to 40 mg/d
Higher dose >80mg/d - severe HPN
Toxicity
Tachycardia, palpitations, angina, and edema are
observed when doses of B-blockers and diuretics
are inadequate. Headache, sweating, and
hypertrichosis, which is particularly bothersome in
women, are relatively common. Minoxidil illustrates
how one person's toxicity may become another
person's therapy. Topical minoxidil (as Rogaine) is
used as a stimulant to hair growth for correction of
baldness.
PARENTERAL
Nitroprusside-Nitropress
Diazoxide-Hyperstat IV
Fenoldopam -Corlopam
O Used to treat hypertensive emergencies

SODIUM NITROPRUSSIDE
Description:
E Complex of iron, cyanide and nitroso moiety.
E Aqueous solution sensitive to light-made up
fresh before administration and covered with
opaque foil
E A mixed vasodilator
E Drug of choice for all hypertensive emergencies
and crises
Sodium nitroprusside is a powerful parenterally
administered vasodilator that is used in treating
hypertensive emergencies as well as severe heart
failure.
Dosage:0.5 ug/kg/min and may be increased to 10
ug/kg/min, if continued for more than an hour
results to toxicity
It is administered with furosemide
Uses: Used in severe cardiac failure, Maintain
controlled hypotension during surgery
MOA: Nitroprusside dilates both arterial and
venous vessels, resulting in reduced peripheral
vascular resistance and venous return. The action
occurs as a result of activation of guanylyl cyclase,
either via release of nitric oxide or by direct
stimulation of the enzyme. The result is increased
intracellular cGMP, which relaxes vascular smooth
muscle
Sodium nitroprusside slowly breaks down to release
5 cyanide ions, especially upon exposure to UV
light.
Administration of sodium thiosulfate as a sulfur
donor facilitates metabolism of cyanide.
Hydroxocobalamin combines with cyanide to form
the nontoxic cyanocobalamin.
Adverse Drug Reactions:
Accumulation of cyanide results to:
- Metabolic acidosis
- Arrhythmia
- Excessive hypotension
- Methemoglobinemia - infusion
Accumulation of thiocyanate results to:
- weakness
- Disorientation
- Psychosis
- Muscle spasms
- Convulsions
- Delayed hypothyroidism
DIAZOXIDE
Description:
E Chemically related to thiazide diuretics but has
no diuretic activity
E Furosemide is given with diazoxide to prevent
fluid overload
E Long acting parenterally administered arteriolar
dilator
E Given with a beta blocker
Mechanism of Action: An arteriolar vasodilator
opens K
+
channel and stabilizes the membrane
potential at the resting level
Blood pressure lowering effect within 5 minutes and
lasts for 4 -12 hrs
T1/2 : 24 hrs
Dosage: 50 150 mg
Clinical Uses:
E Used intravenously to reduce blood pressure
rapidly in emergency situation
E Hypertensive emergencies
E Hypertensive encephalopathy - is a neurological
dysfunction induced by malignant
hypertension.
E And eclampsia
Adverse drug reaction/s: Hypotension that results
to stroke and MI
Hyperglycemia inhibition of insulin release
Cause renal and salt retention (rare bec it is used
for short period of time only)
Used in caution in patients with renal failure
FENOLDOPAM
E A peripheral arteriolar dilator used for
hypertensive emergencies and postoperative
hypertension.
E It acts primarily as an agonist of dopamine D
1

receptors, resulting in dilation of peripheral
arteries and natriuresis.
T1/2 : 10 mins.
As with otherFenoldopam is initiated at a low
dosage (0.1 mcg/kg/min), and the dose is then
titrated upward every 15 or 20 minutes to a
maximum dose of 1.6 mcg/kg/min direct
vasodilators, the major toxicities are reflex
tachycardia, headache, and flushing. Fenoldopam
also increases intraocular pressure and should be
avoided in patients with glaucoma.
TOLAZOLINE
Mechanism of Action:
E Direct acting vasodilator that produces
transient alpha adrenoceptor blockade.
ClinicalUses:
E Used in treating persistent pulmonary
hypertension of the newborn
Tolazoline is a non-selective competitive -
adrenergic receptor antagonist. It is
a vasodilator that is used to treat spasms of
peripheral blood vessels (as in acrocyanosis). It has
also been used successfully as an antidote to
reverse the severe peripheral
vasoconstriction which can occur as a result
of overdose with certain 5-HT
2A
agonist drugs such
as LSD, DOB and Bromodragonfly (prolonged severe
vasoconstriction can lead to gangrene if untreated)
Adverse drug reaction/s: produces hypotension;
dopamine may be required to counteract this
effect, and may produce erectile dysfunction
Chemical Classes:
1. Phenylalkylamines - are relatively selective for
myocardium, reduce myocardial oxygen
demand and reverse coronary vasospasm, and
are often used to treat angina.
Verapamil (Calan, Isoptin)
2. Benzothiazepines- are an intermediate class
between phenylalkylamine and
dihydropyridines in their selectivity for vascular
calcium channels. By having both cardiac
depressant and vasodilator actions,
benzothiazepines are able to reduce arterial
pressure without producing the same degree of
reflex cardiac stimulation caused by
dihydropyridines.
Diltiazem (Cardizem)
3. 1,4-dihydropyridines
Dihydropyridine calcium channel blockers are
often used to reduce systemic vascular resistance
and arterial pressure, but are not used to
treat angina (with the exception of amlodipine,
nicardipine, and nifedipine, which carry an
indication to treat chronic stable angina as well
as vasospastic angina) because the vasodilation and
hypotension can lead to reflex tachycardia.
Dihydropiridine calcium channel blockers can
worsen proteinuria in patients with nephropathy.
CALCIUM CHANNEL BLOCKERS













Clevidipine is a newer member of this group that is
formulated for intravenous use only.
Nifedipine and the other dihydropyridine agents
are more selective as vasodilators and have less
cardiac depressant effect than verapamil and
diltiazem.
Sympathetic activation with slight tachycardia
maintains or increases cardiac output in most
patients given dihydropyridines.
Verapamil has the greatest depressant effect on the
heart and may decrease heart rate and cardiac
output.
Diltiazem has intermediate actions.
MOA: Calcium channel blockers work by
blocking voltage-gated L-calcium channels (VGCCs)
in cardiac muscle and blood vessels.
USES:Hypertension
Stable angina is chest pain or discomfort that
usually occurs with activity or stress.(Effort Angina)
Dysrhythmias
Migraine headaches
Raynaud phenomenon
Subarachnoid hemorrhage.
ADR: Constipation
Hyperglycemia
Proteinuria
(ACE) Inhibitors
Sulfhydryl-containing agents
E Captopril (trade name Capoten)
E Zofenopril
Dicarboxylate-containing agents
Enalapril (Vasotec/Renitec)
Ramipril (Altace/Prilace/Ramace/Ramiwin/Triat
ec/Tritace)
Quinapril (Accupril)
Perindopril (Coversyl/Aceon)
Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril)
Benazepril (Lotensin)
Imidapril (Tanatril)
Zofenopril (Zofecard)
Trandolapril (Mavik/Odrik/Gopten)
Phosphonate-containing agents
Fosinopril (Fositen/Monopril)
Used as monotherapy in step 2 management of
HPN or in combination with diuretics
Drugs in this class inhibit the converting enzyme
peptidyl dipeptidase that hydrolyzes angiotensin I
to angiotensin II and (under the name plasma
kininase) inactivates bradykinin, a potent
vasodilator, which works at least in part by
stimulating release of nitric oxide and prostacyclin.
Renin, angiotensin, and aldosterone play important
roles in at least some people with essential
hypertension.
Bioavailability of 70% after fasting
bioavailability if taken with food EXCEPT Captopril
unaffected
Enalapril is an oral prodrug that is converted by
hydrolysis to a converting enzyme inhibitor,
enalaprilat, with effects similar to those of
captopril. Enalaprilat itself is available only for
intravenous use, primarily for hypertensive
emergencies.
Lisinopril is a lysine derivative of enalaprilat.
Benazepril, fosinopril, moexipril, perindopril,
quinapril, ramipril, and trandolapril are other long-
acting members of the class.
ACE Use/s:
- Used to treat mild to moderate hypertension
- Treats patients with diabetic nephropathy
because they diminish proteinuria and stabilize
renal function
- Also used in CHF
Adverse Drug Reactions:
E Cholestatic jaundice
E Angioedema
E Acute renal failure
E Hypotension
E Syncope
E Neutropenia
E Anorexia
E Polyuria
E Oliguria
E Idiosyncratic dry cough
E Hyperkalemia
Minor toxic effects:
altered sense of taste
allergic skin rashes
drug fever



Angiotensin II Receptor Antagonists
Description:
E They have no effects on bradykinin metabolism
and are therefore more selective blockers of
angiotensin effects than ACE inhibitors.
E Angiotensin receptor blockers provide benefits
similar to those of ACE inhibitors in patients
with heart failure and chronic kidney disease
Losartan and valsartan were the first marketed
blockers of the angiotensin II type 1 (AT
1
) receptor.
USE:Their main uses are in the treatment
of hypertension (high blood pressure),diabetic
nephropathy (kidney damage due to diabetes)
and congestive heart failure.
ADR:Common adverse drug reactions (ADRs)
include: dizziness, headache, and/or hyperkalemia. I
Cough and angioedema can occur but are less
common with angiotensin receptor blockers than
with ACE inhibitors.
1.Candesartan (Atacand)
- contraindicated in pregnancy because of
associated fetal abnormalities
2. Irbesartan (Avapro)
- with associated fetal abnormalities & death
3. Losartan (Cozaar)
4. Telmisartan (Micardis)
5. Eprosartan-(Teveten)
6. Olmesartan- (Benicar)
7. Valsartan-(Diovan)
SYMPATHOPLEGIC AGENTS
Centrally Acting Sympathomimetic
Methyldopa (L - a-methyl-3,4-
dihydroxyphenylalanine)
-Analog of L-dopa and is converted to alpha-
methyldopamine and alpha -
methylnorepinephrine
-False neurotransmitter
-Useful in the treatment of mild to moderately
severe hypertension
Side effects:Dry mouth and sedation are
common.
Over Sedation (frequent), Persistent mental
lassitude and impaired mental concentration
(long-term)
Lactation (prolactin secretion), (+) Coombs
test (>12 mths)
Clonidine- Binds to alpha2-receptors on
presynaptic adrenergic neurons
a 2-imidazoline derivative, was discovered in
the course of testing the drug for use as a nasal
decongestant.
bindsthe imidazoline receptor, which may also
mediate antihypertensive effects.
Withdrawal of Clonidne is associated with
REBOUND hypertension, S/Sx: nervousness,
tachycardia, headache, and sweating
Antidote: Naloxone
Guanabenz
Guanfacine
Sympathoplegic agents, which lower blood
pressure by reducing peripheral vascular resistance,
inhibiting cardiac function, and increasing venous
pooling in capacitance vessels.
Reduces the sympathetic outflow from vasopressor
centers in the brainstem
Antihypertensive action: stimulation of central
alpha2-adrenoceptors
Guanabenz and guanfacine are centrally active
antihypertensive drugs that share the central -
adrenoceptor-stimulating effects of clonidine. They
do not appear to offer any advantages over
clonidine and are rarely used.
Ganglion-Blocking Agents
Mecamylamine
E Oral
E w/CNS effects
Trimethaphan
E Short-acting
E Parenteral (IV infusion)
E Lacks central effects (4 amine)
MOA: competitively block nicotinic cholinoceptors
on postganglionic neurons in both sympathetic and
parasympathetic ganglia
ADR: These effects include both sympathoplegia
(excessive orthostatic hypotension and sexual
dysfunction) and parasympathoplegia (constipation,
urinary retention, precipitation of glaucoma,
blurred vision, dry mouth, etc).
Adrenergic Neuron-Blockers
Guanethidine- In high enough doses,
guanethidine can produce profound
sympathoplegia. Guanethidine is too polar to
enter the central nervous system.The resulting
high maximal efficacy of this agent made it the
mainstay of outpatient therapy of severe
hypertension for many years. For the same
reason, guanethidine can produce all of the
toxicities expected from "pharmacologic
sympathectomy," including marked postural
hypotension, diarrhea, and impaired
ejaculation. long half-life (5 days)
Guanadrel- is a guanethidine-like drug that is
available in the USA. Bethanidine and
debrisoquin, antihypertensive agents not
available for clinical use in the USA

Bethanidine
Debrisoquin- is a derivative of guanidine. It is an
antihypertensive drug similar to guanethidine.
MOA:lower blood pressure by preventing normal
physiologic release of norepinephrine from
postganglionic sympathetic neurons.
(w/ local anesthetic activity)
USE: For severe hypertension
RESERPINE
E readily enters the brain
E depletion of cerebral amine stores causes:
- sedation
- mental depression
- parkinsonism symptoms
E produces mild diarrhea and gastrointestinal
cramps and increases gastric acid secretion
Used for treating mild to moderate hypertension
Reserpine, an alkaloid extracted from the roots of
an Indian plant, Rauwolfia serpentina, was one of
the first effective drugs used on a large scale in the
treatment of hypertension.
BETA-BLOCKERS
Pharmacological Effects:
E Cardiovascular
hypotension and bradycardia
E Pulmonary
Respiratory depression and apnea
E CNS
Delirium, coma, and seizures
E Metabolic
A. Propranolol
the first -blocker shown to be effective in
hypertension and ischemic heart disease.
very useful for lowering blood pressure in mild
to moderate hypertension.
Propranolol has now been largely replaced by
cardioselective blockers such as metoprolol and
atenolol
The most important of these predictable extensions
of the -blocking action occur in patients with
bradycardia or cardiac conduction disease, asthma,
peripheral vascular insufficiency, and diabetes.
When propranolol is discontinued after prolonged
regular use, some patients experience a withdrawal
syndrome, manifested by nervousness, tachycardia,
increased intensity of angina, and increase of blood
pressure
B. Metoprolol & Atenolol
Metoprolol and Atenolol, which are
cardioselective, are the most widely used
blockers in the treatment of hypertension.
Metoprolol is approximately equipotent to
propranolol in inhibiting stimulation of
1

adrenoceptors such as those in the heart but
50- to 100-fold less potent than propranolol in
blocking
2
receptors.
Relative cardioselectivity may be advantageous in
treating hypertensive patients who also suffer from
asthma, diabetes, or peripheral vascular disease.
Although cardioselectivity is not complete,
metoprolol causes less bronchial constriction than
propranolol at doses that produce equal inhibition
of
1
adrenoceptor responses. Metoprolol is
extensively metabolized by CYP2D6 with high first-
pass metabolism. The drug has a relatively short
half-life of 46 hours
Atenolol is not extensively metabolized and is
excreted primarily in the urine with a half-life of 6
hours; it is usually dosed once daily. Recent studies
have found atenolol less effective than metoprolol
in preventing the complications of hypertension. A
possible reason for this difference is that once-daily
dosing does not maintain adequate blood levels of
atenolol. The usual dosage is 50100 mg/d.
+ Beta-Blockers with long half-lives
Nadolol, Carteolol, Atenolol, Betaxolol, &
Bisoprolol
+ Partial Agonists
Pindolol, Acebutolol, and Penbutolol
Particularly beneficial for patients with brady-
arrhythmias or peripheral vascular disease.
Nadolol and carteolol, nonselective -receptor
antagonists, are not appreciably metabolized and
are excreted to a considerable extent in the urine.
Betaxolol and bisoprolol are
1-
selective blockers that
are primarily metabolized in the liver but have long
half-lives.
Pindolol, acebutolol, and penbutolol are partial
agonists, ie, blockers with some intrinsic
sympathomimetic activity. They lower blood
pressure by decreasing vascular resistance and
appear to depress cardiac output or heart rate less
than other blockers, perhaps because of
significantly greater agonist than antagonist effects
at
2
receptors.
MIXED ALPHA AND BETA BLOCKER
E Labetalol
useful in treating the HPN of
pheochromocytoma and hypertensive
emergencies.
E Carvedilol
reduces mortality in patients with heart
failure and is therefore particularly
useful in patients with both heart
failure and hypertension.
Nebivolol is a
1
-selective blocker with
vasodilating properties that are not mediated
by blockade. D-Nebivolol has highly selective
1

blocking effects, while the L-isomer causes
vasodilation; it is marketed as a racemic
mixture.
Esmolol
beta1-selective blocker
rapidly metabolized by RBC esterases.
It has a short half-life (9 minutes)
administered by constant IV infusion.
loading dose: 0.51 mg/kg, followed by a
constant infusion.
used for management of intraoperative and
postoperative hypertension, and when
hypertension is associated with tachycardia.
ALPHA-1 BLOCKERS
Uses:
E Hypertension
E Benign prostatic hyperplasia (BPH)
Adverse Effects:
E Orthostatic hypotension
E Salt and water retention
E SYNCOPE
first-dose phenomenon
Chapter 12 ANTI-ANGINAL DRUGS
ANGINA PECTORIS
E medical term for chest pain or discomfort due
to coronary heart disease.
E a symptom of a condition called myocardial
ischemia.
Angina, or angina pectoris, is the medical term used
to describe the temporary chest discomfort that
occurs when the heart is not getting enough blood.
"a strangling feeling in the chest".
anginais chest pain due to ischemia of the heart
muscle, generally due to obstruction or spasm of
thecoronary arteries. The main cause of
Insufficient blood supply is called ischemia.
UNDERLYING CAUSES:
Atherosclerotic change of the vascular wall
Spasmodic constriction of coronary artery
Angina pectoris is Coronary Artery Disease, due
to atherosclerosis of the arteries feeding the heart.
TYPES OF ANGINA:
1. Stable Angina- or chronic stable angina (Also
known as effort angina, or classic angina)
o The stable form of angina is the most common
type of angina. This is commonly seen in
smokers, and patients suffering from
hypertension, as these conditions cause
obstruction in the blood vessels.
o is atheromatous obstruction of the large
coronary vessels
o episodes of chest discomfort are usually
predictable occur on exertion (such as running
to catch a bus) or under mental or emotional
stress.
o Normally the chest discomfort is relieved with
rest, nitroglycerin or both.
2. Unstable Angina- Angina at rest("crescendo
angina;) the chest pain is unexpected
o Unstable Form of Angina
o This form of angina is not as common as the
stable form. It is seen in more severe cases,
where there is tremendous blockage in the
blood vessels.
o Unstable angina, an acute coronary syndrome,
is said to be present when episodes of angina
occur at rest and when there is a change in the
character, frequency, and duration of chest pain
as well as precipitating factors in patients with
previously stable angina. Unstable angina is
caused by episodes of increased epicardial
coronary artery tone or small platelet clots
occurring in the vicinity of an atherosclerotic
plaque.
o The discomfort may be more severe and
prolonged than typical angina or be the first
time a person has angina.
3. Prinzmetal's Angina- also called Variant Angina
or Vasospastic Angina
o Prinzmetal Form of Angina
o There is a form of angina experienced at
night, which can be disruptive to sleep.
o usually occurs spontaneously, and unlike
typical angina, it nearly always occurs when
a person is at rest.
o It doesn't follow physical exertion or
emotional stress, either.
o Attacks can be very painful and usually
occur between midnight and 8 a.m.

Classification
Class 0: Asymptomatic
Class 1: Angina with strenuous Exercise
Class 2: Angina with moderate exertion
Class 3: Angina with mild exertion
Walking 1-2 level blocks at normal pace
Climbing 1 flight of stairs at normal pace
Class 4: Angina at any level of physical exertion

ANTI-ANGINAL DRUGS
O Organic Nitrates
O Calcium Channel Blockers
O eta-Blockers
Increasing cGMP: As indicated in Figures 121 and
122, cGMP facilitates the dephosphorylation of
myosin light chains, preventing the interaction of
myosin with actin. Nitricoxide is an effective
activator of soluble guanylyl cyclase and acts mainly
through this mechanism. Important molecular
donors of nitric oxide include nitroprusside (see
Chapter 11) and the organic nitrates used in angina.
Decreasing intracellular Ca
2+
:Calcium channel
blockers predictably cause vasodilation because
they reduce intracellular Ca
2+
, a major modulator of
the activation of myosin light chain kinase (Figure
121). ( blockers and calcium channel blockers
reduce Ca
2+
influx in cardiac muscle, thereby
reducing rate, contractility, and oxygen
requirement under most circumstances.)
Stabilizing or preventing depolarization of the
vascular smooth muscle cell membrane: The
membrane potential of excitable cells is stabilized
near the resting potential by increasing potassium
permeability. Potassium channel openers, such as
minoxidil sulfate (see Chapter 11) increase the
permeability of K
+
channels, probably ATP-
dependent K
+
channels. Certain newer agents under
investigation for use in angina (eg, nicorandil) may
act, in part, by this mechanism.
Increasing cAMP in vascular smooth muscle cells:
As shown in Figure 121, an increase in cAMP
increases the rate of inactivation of myosin light
chain kinase, the enzyme responsible for triggering
the interaction of actin with myosin in these cells.
This appears to be the mechanism of vasodilation
caused by
2
agonists, drugs that are not used in
angina (because they cause too much cardiac
stimulation) and by fenoldopam, a D
1
agonist used
in hypertensive emergencies
NITROGLYCERIN
Organic Nitrates
E the prototype drug
E Although it is used in the manufacture of
dynamite, the formulations of nitroglycerin
used in medicine are not explosive.
E The conventional sublingual tablet form of
nitroglycerin may lose potency when stored in
plastic containers as a result of volatilization
and adsorption to plastic surfaces.
Therefore, oral bioavailability of the traditional
organic nitrates (eg, nitroglycerin and isosorbide
dinitrate) is very low (typically < 1020%). For this
reason, the sublingual route, which avoids the first-
pass effect, is preferred for achieving a therapeutic
blood level rapidly.
Mechanism of Action in Smooth Muscle
Nitroglycerin is denitrated by glutathione S -
transferase in smooth muscle and other cells. Free
nitrite ion is released, which is then converted to
nitric oxide (see Chapter 19). A different unknown
enzymatic reaction releases nitric oxide directly
from the parent drug molecule. As shown in Figure
122, nitric oxide (or an S-nitrosothiol derivative)
causes activation of guanylyl cyclase and an
increase in cGMP, which are the first steps toward
smooth muscle relaxation.
Isosorbide Dinitrate (ISDN)
E converted to 5-mononitrate metabolite =
active metabolite
E (5-10 mg SL)
Isosorbide Mononitrate (ISMN)
E With 100% bioavailability
The 5-mononitrate metabolite of isosorbide
dinitrate is an active metabolite of the latter drug
and is available for oral use as isosorbide
mononitrate. It has a bioavailability of 100%.
Amyl Nitrite
E Highly volatile liquid.
E Stored in fragile glass, ampules packed in a
protective cloth covering.
E The inhalation route provides very rapid
absorption
E The sublingual route avoids the hepatic first-
pass effect
E It induces conversion of hemoglobin to
methemoglobin (methemoglobinemia) which
can lead to cyanosis
Because of its unpleasant odor and short duration
of action, amyl nitrite is now obsolete for angina.
Scientific studies of the process have shown that
erection requires relaxation of the nonvascular
smooth muscle of the corpora cavernosa.
Sildenafil (Viagra) acts to increase cGMP by
inhibiting its breakdown by phosphodiesterase
isoform 5 (PDE-5).
Furthermore, sildenafil potentiates the action of
nitrates used for angina, and severe hypotension
and a few myocardial infarctions have been
reported in men taking both drugs. It is
recommended that at least 6 hours pass between
use of a nitrate and the ingestion of sildenafil.
Sildenafil also has effects on color vision, causing
difficulty in blue-green discrimination. Two similar
PDE-5 inhibitors, tadalafil and vardenafil, are
available.


1. Acute Adverse Effects
E The major acute toxicities of organic nitrates
are direct extensions of therapeutic
vasodilation:
E orthostatic hypotension
E tachycardia
E throbbing headache
2. Tolerance
E Tachyphylaxis
E Monday headache and dizziness
As previously noted, diminished release of nitric
oxide resulting from depletion of tissue thiol
compounds may be partly responsible for tolerance
to nitroglycerin.
Rationale:
continuous use of the drugs causes depletion of
sulfhydryl moieties in vascular smooth muscles
Nicorandil is a nicotinamide nitrate ester that has
vasodilating properties in normal coronary arteries
but more complex effects in patients with angina.
Clinical studies suggest that it reduces both preload
and afterload. It also provides some myocardial
protection via preconditioning by activation of
cardiac K
ATP
channels. One large trial showed a
significant reduction in relative risk of fatal and
nonfatal coronary events in patients receiving the
drug. Nicorandil is currently approved for use in the
treatment of angina in Europe and Japan and has
been submitted for approval in the USA.

Pharmacokinetics
E orally active agents
E high first-pass effect, high plasma protein
binding, and extensive metabolism.
E Verapamil and diltiazem are also used by the
intravenous route
Action: decrease O2 demand by lowering aortic
pressure
Verapamil, the first clinically useful member of this
group, was the result of attempts to synthesize
more active analogs of papaverine, a vasodilator
alkaloid found in the opium poppy.
Nifedipine is the prototype of the dihydropyridine
family of calcium channel blockers; dozens of
molecules in this family have been investigated, and
seven are currently approved in the USA for angina
and other indications. Nifedipine is the most
extensively studied of this group, but the properties
of the other dihydropyridines can be assumed to be
similar to it unless otherwise noted.

Verapamil
Diltiazem
Nifedipine
Amlodipine-6590%
Nisoldipine< 10%
Nifedipine
devoid of a cardiodepressant effect, but may give
rise to reflex tachycardia and an associated increase
in O2 demand
may be useful in chronic stable, or in variant angina
In coronary spasm, calcium antagonists can induce
spasmolysis and improve blood flow.
inhibition of calcium influx can cause serious cardiac
depression, including cardiac arrest, bradycardia,
atrioventricular block, and heart failure
Constipation is particularly common with verapamil.

E are extremely useful in the management of
stable angina.
+ hemodynamic effects:
decreased heart rate, blood pressure, and contractility
which decrease myocardial oxygen
requirements at rest and during exercise.
Undesirable effects of -blocking agents in angina
include an increase in end-diastolic volume and an
increase in ejection time, both of which tend to
increase myocardial oxygen requirement. These
deleterious effects of -blocking agents can be
balanced by the concomitant use of nitrates as
described below.
Metoprolol tablet
useful in the mgt of chronic stable angina pectoris
Propranolol
Nonselective competitive antagonist at
adrenoceptors
Decreased heart rate, cardiac output, and blood
pressure decreases myocardial oxygen demand
Prophylaxis of angina for other applications, see
Chapters 10, 11, and 13
Oral and parenteral, 46 h duration of action
Toxicity: Asthma, atrioventricular block, acute heart
failure, sedation Interactions: Additive with all
cardiac depressants

E Hypertensive patients
monotherapy with either slow-release
or long-acting calcium channel blockers
or Beta-blockers
E Normotensive patients = long-acting nitrates
Propranolol with Nifedipine
Nifedipine and Verapamil
E Unstable angina
Antiplatelet agents with NTG, Beta
blockers
E Refractory cases CCBs
E Acute treatment of vasospastic angina pectoris
Nitrovasodilators
Calcium channel blockers
E Relieve and prevents ischemic
episodes
New Anti-anginal Drugs

E Ranolizine- Inhibits late sodium current in heart
also may modify fatty acid oxidation, QT
interval prolongation, nausea, constipation,
dizziness
The metabolic modulators (eg, trimetazidine) are
known as pFOX inhibitors because they partially
inhibit the fatty acid oxidation pathway in
myocardium. Because metabolism shifts to
oxidation of fatty acids in ischemic myocardium, the
oxygen requirement per unit of ATP produced
increases. Partial inhibition of the enzyme required
for fatty acid oxidation (long-chain 3-ketoacyl
thiolase, LC-3KAT) appears to improve the
metabolic status of ischemic tissue. Ranolazine was
initially assigned to this group of agents. However, it
is now believed that the primary mechanism of
therapeutic action of ranolazine involves reduced
contractility.
E Ivadradine- Investigational inhibitor of
sinoatrial pacemaker; reduction of heart rate
reduces oxygen demand
So-called bradycardic drugs, relatively selective I
f

sodium channel blockers (eg, ivabradine), reduce
cardiac rate by inhibiting the hyperpolarization-
activated sodium channel in the sinoatrial node. No
other significant hemodynamic effects have been
reported. Ivabradine appears to reduce anginal
attacks with an efficacy similar to that of calcium
channel blockers and blockers. The lack of effect on
gastrointestinal and bronchial smooth muscle is an
advantage of ivabradine, and FDA approval is
expected.
Chapter 14
ARRHYTHMIA
Definitions:
E normal sinus rhythm (60-90bpm), SA node
pacemaker
E arrhythmia; any abnormality of firing rate,
regularity or site of origin of cardiac impulse or
disturbance of conduction that alters the
normal sequence of activity of atria and
ventricles.

Occurrence:
80% of patients with acute myocardial
infarctions
50% of anaesthetized patients
about 25% of patients on digitalis
Heart condition where disturbances in
Pacemaker impulse formation
Contraction impulse conduction
Combination of the two
Results in rate and/or timing of contraction of heart
muscle that is insufficient to maintain normal
cardiac output (CO)

1. Characteristics:
a. Flutter- very rapid but regular contractions
b. Tachycardia- increased rate
c. Bradycardia- decreased rate
d. Fibrillation- disorganized contractile activity
2. Sites involved:
a) ventricular
b) atrial
c) sinus
d) AV node
e) Supraventricular (atrial myocardium or AV node)
Arrhythmias are abnormal heart rhythms
Heart rate <60/min is bradycardia; >100/min is
tachycardia
In flutter contraction rates can be 200-300/min
In fibrillation contraction of myocardial cells is
uncoordinated & pumping ineffective
Ventricular fibrillation is life-threatening
TYPES OF ARRHYTMIA:

E Premature Beats
E Supraventricular Arrhythmias
- Atrial Fibrillation
- Atrial Flutter
- Paroxysmal Supraventricular Tachycardia
- Wolff-Parkinson-White Syndrome
E Ventricular Arrhythmias
- Ventricular Tachycardia
- Ventricular Fibrillation
O Bradyarrhythmias
Premature (Extra) Beats- Premature beats are the
most common type of arrhythmia. They're harmless
most of the time and often don't cause any
symptoms.
Premature beats that occur in the atria (the heart's
upper chambers) are called premature atrial
contractions, or PACs. Premature beats that occur in
the ventricles (the heart's lower chambers) are called
premature ventricular contractions, or PVCs.
Supraventricular Arrhythmias
Supraventricular arrhythmias are tachycardias (fast
heart rates) that start in the atria or atrioventricular
(AV) node. The AV node is a group of cells located
between the atria and the ventricles.
Atrial Fibrillation
AF is the most common type of serious arrhythmia. It
involves a very fast and irregular contraction of the
atria.
AF has two major complicationsstroke and heart
failure.
Atrial Flutter
Atrial flutter is similar to AF. However, the heart's
electrical signals spread through the atria in a fast
and regularinstead of irregularrhythm.
Paroxysmal Supraventricular Tachycardia
PSVT is a very fast heart rate that begins and ends
suddenly. PSVT occurs because of problems with the
electrical connection between the atria and the
ventricles.
Ventricular Arrhythmias
These arrhythmias start in the heart's lower
chambers, the ventricles. They can be very
dangerous and usually require medical care right
away.
Coronary heart disease, heart attack, a weakened
heart muscle, and other problems can cause
ventricular arrhythmias.
Ventricular Tachycardia
Ventricular tachycardia is a fast, regular beating of
the ventricles that may last for only a few seconds or
for much longer.
Ventricular Fibrillation
V-fib occurs if disorganized electrical signals make
the ventricles quiver instead of pump normally.
Without the ventricles pumping blood to the
body, sudden cardiac arrest and death can occur
within a few minutes.
Bradyarrhythmias
Bradyarrhythmias occur if the heart rate is slower
than normal. If the heart rate is too slow, not enough
blood reaches the brain. This can cause you to pass
out.

Heart Physiology
P - atria depolarization
QRS - ventricle depolarization
PR - conduction A-V
T - ventricle repolarization
QT - duration ventricle of repolarization


Phases of Action Potential
0-Upstroke
1-Early fast repolarization
2-Plateua
3-Repolarization
4-Diastole
Phase 0
Phase 0 is the rapid depolarization phase. The slope of
phase 0 represents the maximum rate of depolarization
of the cell and is known as dV/dt
max
. This phase is due to
the opening of the fast Na
+
channels causing a rapid
increase in the membrane conductance to Na
+
(G
Na
) and
thus a rapid influx of Na
+
ions (I
Na
) into the cell.
opening of fast Na channels and rapid depolarization
Phase 1
Phase 1 of the action potential occurs with the
inactivation of the fast Na
+
channels. The transient net
outward current causing the small downward deflection
of the action potential is due to the movement of K
+
and
Cl
-
ions
initial rapid repolarization
Phase 2
This "plateau" phase of the cardiac action potential is
sustained by a balance between inward movement of
Ca
2+
(I
Ca
) through L-type calcium channels and outward
movement of K
+
through the slow delayed
rectifier potassium channels, I
Ks
.
plateau phase
Phase 3
During phase 3 (the "rapid repolarization" phase) of the
action potential, the L-type Ca
2+
channels close, while
the slow delayed rectifier (I
Ks
) K
+
channels are still open.
This ensures a net outward current, corresponding to
negative change in membrane potential, thus allowing
more types of K
+
channels to open.
REPOLARIZATION
Phase 4
Phase 4 is the resting membrane potential. This is the
period that the cell remains in until it is stimulated by
an external electrical stimulus (typically an adjacent
cell). This phase of the action potential is associated
with diastole of the chamber of the heart.
resting phase (resting membrane potential)
CLASSIFICATION: (Singh Vaughan Williams
classification)
1. Class I Na
+
Channel Blockers- agents interfere
with the sodium (Na
+
) channel.
Class I agents are called Membrane Stabilizing
agents. The 'stabilizing' word is used to describe
the decrease of excitogenicity of the plasma
membrane which is brought about by these
agents.
2. Class II Beta blockers- are anti-sympathetic
nervous system agents. Most agents in this class
are beta blockers.
3. Class III K
+
Chanel Blockers-
affect potassium (K
+
) efflux.
4. Class IV - Ca
++
Channel Blockers-
affect calcium channels and the AV node.
5. Class V agents work by other or unknown
mechanisms.
CLASS 1-A
E Fast Channel Blocker
E MOA:
prolong the Action potential duration
(APD) and dissociate from the channel with
intermediate kinetics
E Depress Phase 0
E slow conduction moderately
E prolong membrane repolarization
Examples:
+ QUINIDINE
+ PROCAINAMIDE
+ DISOPYRAMIDE
Ia lengthens the action potential (right shift)
fast-channel blockers-affect QRS complex
Class Ia: Disopyramide, Quinidine, Procainamide
Double Quarter Pounder
Police Department Questions (Procainamide,
Disopyramide, Quinidine)
Clinical Uses:
Ventricular arrhythmias
prevention of paroxysmal recurrent atrial
fibrillation (triggered by vagal overactivity)
procainamide in Wolff-Parkinson-White syndrome
Quinidine has actions similar to those of
procainamide: it slows the upstroke of the action
potential and conduction, and prolongs the QRS
duration of the ECG, by blockade of sodium
channels. The drug also prolongs the action
potential duration by blockade of several potassium
channels. Its toxic cardiac effects include excessive
QT interval prolongation and induction of torsade
de pointes arrhythmia. Toxic concentrations of
quinidine also produce excessive sodium channel
blockade with slowed conduction throughout the
heart.
Extracardiac Effects
Gastrointestinal adverse effects of diarrhea, nausea,
and vomiting are observed in one third to one half
of patients. A syndrome of headache, dizziness, and
tinnitus (cinchonism) is observed at toxic drug
concentrations. Idiosyncratic or immunologic
reactions, including thrombocytopenia, hepatitis,
angioneurotic edema, and fever, are observed
rarely.
Procainamide is the drug of second choice (after
lidocaine) in most coronary care units for the
treatment of sustained ventricular arrhythmias
associated with acute myocardial infarction.
Procainamide has ganglion-blocking properties.
This action reduces peripheral vascular resistance
and can cause hypotension, particularly with
intravenous use. However, in therapeutic
concentrations, its peripheral vascular effects are
less prominent than those of quinidine.
Hypotension is usually associated with excessively
rapid procainamide infusion or the presence of
severe underlying left ventricular dysfunction.
Toxicity
Procainamide's cardiotoxic effects include excessive
action potential prolongation, QT interval
prolongation, and induction of torsade de pointes
arrhythmia and syncope. Excessive slowing of
conduction can also occur. New arrhythmias can be
precipitated.
The most troublesome adverse effect of long-term
procainamide therapy is a syndrome resembling
lupus erythematosus and usually consisting of
arthralgia and arthritis.
Disopyramide are very similar to those of
procainamide and quinidine. Its cardiac
antimuscarinic effects are even more marked than
those of quinidine. Therefore, a drug that slows
atrioventricular conduction should be administered
with disopyramide when treating atrial flutter or
fibrillation.
Toxicity
Toxic concentrations of disopyramide can
precipitate all of the electrophysiologic disturbances
described under quinidine. As a result of its
negative inotropic effect
Disopyramide's atropine-like activity accounts for
most of its symptomatic adverse effects: urinary
retention (most often, but not exclusively, in male
patients with prostatic hyperplasia), dry mouth,
blurred vision, constipation, and worsening of
preexisting glaucoma
CLASS 1-B
E Modest depression of conduction
E Shorten membrane repolarization
E have no significant effects on the APD and
dissociate from the channel with rapid kinetics
Examples:
+ LIDOCAINE
+ MEXILITINE
+ PHENYTOIN
+ TOCAINIDE
Ib shortens the action potential (left shift)
Do not affect QRS complex
Class IbLidocaine, Mexiletine, Tocainide, Phenytoin
Lettuce, Mayo, Tomato, Potato
The Little Poor Man (Tocainide, Lidocaine,
Phenytoin, Mexiletine)
Uses:
treatment and prevention during and immediately
after myocardial infarction, though this practice is
now discouraged given the increased risk
of asystole
ventricular tachycardia
atrial fibrillation
Lidocaine has a low incidence of toxicity and a high
degree of effectiveness in arrhythmias associated
with acute myocardial infarction. It is used only by
the intravenous route.
Lidocaine is the agent of choice for termination of
ventricular tachycardia and prevention of
ventricular fibrillation after cardioversion in the
setting of acute ischemia
Toxicity: Lidocaine is one of the least cardiotoxic of
the currently used sodium channel blockers.
Proarrhythmic effects, including sinoatrial node
arrest, worsening of impaired conduction, and
ventricular arrhythmias, are uncommon with
lidocaine use. In large doses, especially in patients
with preexisting heart failure, lidocaine may cause
hypotensionpartly by depressing myocardial
contractility.
Lidocaine's most common adverse effectslike
those of other local anestheticsare neurologic:
paresthesias, tremor, nausea of central origin,
lightheadedness, hearing disturbances, slurred
speech, and convulsions.
Mexiletine is an orally active congener of lidocaine.
Its electrophysiologic and antiarrhythmic actions
are similar to those of lidocaine. (The
anticonvulsant phenytoin [see Chapter 24] also
exerts similar electrophysiologic effects and has
been used as an antiarrhythmic.) Mexiletine is used
in the treatment of ventricular arrhythmias. These
are predominantly neurologic, including tremor,
blurred vision, and lethargy. Nausea is also a
common effect.
CLASS 1-C
E Depress Phase 0, short depression on
conduction, mild or no effect on repolarization
E Minimal effects on the APD and dissociate from
the channel with slow kinetics.
Examples:
+ FLECAINIDE
+ PROFAPENONE
+ MORICIZINE
Ic does not significantly affect the action potential
(no shift)
Class
IcMoricizine, Flecainide, PropafenoneMore Fries Ple
ase. (note there are two "M"s in the mnemonic,
but moricizine and more can clarify which is
which)For Pushing Ecstasy (Flecainide,
Propafenone, Encainide)
Uses: prevents paroxysmal atrial fibrillation
treats recurrent tachyarrhythmias of
abnormal conduction system.
Contraindicated immediately post-myocardial
infarction.
Flecainide is a potent blocker of sodium and
potassium channels with slow unblocking kinetics.
It is currently used for patients with otherwise
normal hearts who have supraventricular
arrhythmias. It has no antimuscarinic effects.
Flecainide is very effective in suppressing
premature ventricular contractions.
Propafenone has some structural similarities to
propranolol and possesses weak B-blocking activity.
Its spectrum of action is very similar to that of
quinidine, but it does not prolong the action
potential. Its sodium channel-blocking kinetics are
similar to that of flecainide.
The drug is used primarily for supraventricular
arrhythmias. The most common adverse effects are
a metallic taste and constipation; arrhythmia
exacerbation can also occur.
Moricizine is an antiarrhythmic phenothiazine
derivative that was used for treatment of
ventricular arrhythmias. It is a relatively potent
sodium channel blocker that does not prolong
action potential duration. Moricizine has been
withdrawn from the US market.
CLASS II- BETA- BLOCKERS
E Class 2 action is sympatholytic.
E Drugs with this action reduce -adrenergic
activity in the heart.
E Cardioselective
E Some have intrinsic sympathomimetic activity
E Some have marked direct membrane effects
E Some prolong the cardiac action potential.
Examples:
Propranolol, Esmolol, Metoprolol
Class II agents are conventional beta blockers. They
act by blocking the effects of catecholamines at
the
1
-adrenergic receptors, thereby decreasing
sympathetic activity on the heart. These agents are
particularly useful in the treatment
of supraventricular tachycardias. They decrease
conduction through the AV node.
Class II agents include atenolol, esmolol,
propranolol, and metoprolol.
Uses: decrease myocardial infarction mortality
prevent recurrence of tachyarrhythmias
Propranolol and similar drugs have antiarrhythmic
properties by virtue of their -receptorblocking
action and direct membrane effects.
Although blockers are fairly well tolerated, their
efficacy for suppression of ventricular ectopic
depolarizations is lower than that of sodium
channel blockers. However, there is good evidence
that these agents can prevent recurrent infarction
and sudden death in patients recovering from acute
myocardial infarction
Esmolol is a short-acting blocker used primarily as
an antiarrhythmic drug for intraoperative and other
acute arrhythmias. See Chapter 10 for more
information. Sotalol is a nonselective -blocking drug
that prolongs the action potential (class 3 action).

CLASS III K CHANNEL BLOCKERS
E Drugs That Prolong Effective Refractory Period
by Prolonging Action Potential
E Prolong repolarization and increase
refractoriness
E These drugs prolong action potentials, usually
by blocking potassium channels in cardiac
muscle or enhancing inward current
E Most drugs with this action block the rapid
component of the delayed rectifier potassium
current, IKr.

Examples:
BRETYLIUM , IBUTILIDE, AMIODARONE
Class III agents predominantly block the potassium
channels, thereby prolonging repolarization.
[5]
Since
these agents do not affect the sodium channel,
conduction velocity is not decreased. The
prolongation of the action potential duration and
refractory period, combined with the maintenance
of normal conduction velocity, prevent re-entrant
arrhythmias. Inhibiting potassium channels, slowing
repolarization, results in slowed atrial-ventricular
myocyte repolarization. Class III agents have the
potential to prolong the QT interval of the EKG.
Sotalol is also a beta blocker
[2]
Amiodarone has Class
I, II, III & IV activity
Uses:In Wolff-Parkinson-White syndrome
(sotalol:) ventricular tachycardias and atrial
fibrillation
(Ibutilide:) atrial flutter and atrial fibrillation
In the USA, amiodarone is approved for oral and
intravenous use to treat serious ventricular
arrhythmias. However, the drug is also highly
effective for the treatment of supraventricular
arrhythmias such as atrial fibrillation. As a result of
its broad spectrum of antiarrhythmic action, it is
very extensively used for a wide variety of
arrhythmias. Amiodarone has unusual
pharmacokinetics and important extracardiac
adverse effects. Dronedarone, an analog that lacks
iodine atoms, is under investigation.
Amiodarone markedly prolongs the action potential
duration (and the QT interval on the ECG) by
blockade of I
Kr
.
Extracardiac Effects: Amiodarone causes peripheral
vasodilation.
Toxicity: Amiodarone may produce symptomatic
bradycardia and heart block in patients with
preexisting sinus or atrioventricular node disease
The WolffChaikoff effect is a reduction in thyroid
hormone levels caused by ingestion of a large
amount of iodine.
Amiodarone blocks the peripheral conversion of
thyroxine (T4 ) to triiodothyronine (T
3
). It is also a
potential source of large amounts of inorganic
iodine. Amiodarone may result in hypothyroidism or
hyperthyroidism
Dronedarone is a structural analog of amiodarone
and lacks iodine atoms. The design was intended to
eliminate action of the parent drug on thyroxine
metabolism and to modify the half-life of the drug.
Dronedarone doubled the interval between
episodes of atrial fibrillation recurrence in patients
with paroxysmal or persistent atrial fibrillation. It is
the first antiarrhythmic drug to demonstrate a
reduction in mortality or hospitalization in patients
with atrial fibrillation.
Vernakalant is an investigational multi-channel
blocker that was developed for the treatment of
atrial fibrillation.
Vernakalant prolongs the atrial effective refractory
period and slows conduction over the
atrioventricular node.
Adverse effects of vernakalant include dysgeusia
(disturbance of taste), sneezing, paresthesia, cough,
and hypotension.
Sotalol has both B-adrenergic receptor-blocking
(class 2) and action potential prolonging (class 3)
actions. The drug is formulated as a racemic mixture
of D- and L-sotalol. All the -adrenergic blocking
activity resides in the L-isomer; the D- and L-isomers
share action potential prolonging actions. B-
Adrenergic blocking action is not cardioselective
and is maximal at doses below those required for
action potential prolongation.
Sotalol is well absorbed orally with bioavailability of
approximately 100%.
Dofetilide is 100% bioavailable. Dofetilide is
approved for the maintenance of normal sinus
rhythm in patients with atrial fibrillation. It is also
effective in restoring normal sinus rhythm in
patients with atrial fibrillation.
Ibutilide slows cardiac repolarization by blockade of
the rapid component (I
Kr
) of the delayed rectifier
potassium current.
Intravenous ibutilide is used for the acute
conversion of atrial flutter and atrial fibrillation to
normal sinus rhythm. The drug is more effective in
atrial flutter than atrial fibrillation, with a mean
time to termination of 20 minutes. The most
important adverse effect is excessive QT interval
prolongation and torsade de pointes.
Sotalol is approved for the treatment of life-
threatening ventricular arrhythmias and the
maintenance of sinus rhythm in patients with atrial
fibrillation. It is also approved for treatment of
supraventricular and ventricular arrhythmias in the
pediatric age group. Sotalol decreases the threshold
for cardiac defibrillation.
CLASS IV- CALCIUM CHANNEL BLOCKERS
E SLOW CHANNEL BLOCKERS
E MOA:
blockade of the cardiac calcium current.
This action slows conduction in regions where the
action potential upstroke is calcium dependent, eg, the
sinoatrial and atrioventricular nodes.
E Verapamil is the prototype of this group.
E Diltiazem
E Bepridil
These drugs, of which verapamil is the prototype,
were first introduced as antianginal agents and are
discussed in greater detail in Chapter 12. Verapamil
and diltiazem also have antiarrhythmic effects. The
dihydropyridines do not share antiarrhythmic
efficacy and may precipitate arrhythmias.
They decrease conduction through the AV node,
and shorten phase two (the plateau) of the cardiac
action potential.
Cardiac Effects: Verapamil blocks both activated
and inactivated L-type calcium channels.
Extracardiac Effects
Verapamil causes peripheral vasodilation, which
may be beneficial in hypertension and peripheral
vasospastic disorders.
In this setting, hypotension and ventricular
fibrillation can occur. Verapamil's negative inotropic
effects may limit its clinical usefulness in diseased
hearts (see Chapter 12). Verapamil can induce
atrioventricular block when used in large doses or in
patients with atrioventricular nodal disease. This
block can be treated with atropine and -receptor
stimulants.
Therapeutic Use: Supraventricular tachycardia is
the major arrhythmia indication for verapamil.
Adenosine or verapamil are preferred over older
treatments (propranolol, digoxin, edrophonium,
vasoconstrictor agents, and cardioversion) for
termination. Verapamil can also reduce the
ventricular rate in atrial fibrillation and flutter. It
only rarely converts atrial flutter and fibrillation to
sinus rhythm. Verapamil is occasionally useful in
ventricular arrhythmias
Adverse extracardiac effects include constipation,
lassitude, nervousness, and peripheral edema.
Diltiazem appears to be similar in efficacy to
verapamil in the management of supraventricular
arrhythmias, including rate control in atrial
fibrillation. An intravenous form of diltiazem is
available for the latter indication and causes
hypotension or bradyarrhythmias relatively
infrequently.
Bepridil has action potential- and QT-prolonging
actions that theoretically may make it more useful
in some ventricular arrhythmias but also create the
risk of torsade de pointes.
Bepridil is only rarely used, primarily to control
refractory angina.
MISCELLANEOUS AGENTS
E Certain agents used for the treatment of
arrhythmias do not fit the conventional class 1
4 organization.
E These include:
Digitalis
Adenosine
Magnesium
Potassium
Adenosine is a nucleoside that occurs naturally
throughout the body.
MOA: involves activation of an inward rectifier K+
current and inhibition of calcium current. The
results of these actions are marked
hyperpolarization and suppression of calcium-
dependent action potentials.
Adenosine is currently the drug of choice for
prompt conversion of paroxysmal supraventricular
tachycardia to sinus rhythm because of its high
efficacy (9095%) and very short duration of action.
Toxicity: Adenosine causes flushing in about 20% of
patients and shortness of breath or chest burning
(perhaps related to bronchospasm) in over 10%.
Induction of high-grade atrioventricular block may
occur but is very short-lived. Atrial fibrillation may
occur. Less common toxicities include headache,
hypotension, nausea, and paresthesias.
Magnesium
Originally used for patients with digitalis-induced
arrhythmias who were hypomagnesemic,
magnesium infusion has been found to have
antiarrhythmic effects in some patients with normal
serum magnesium levels. The mechanisms of these
effects are not known, but magnesium is recognized
to influence Na
+
,K
+
ATPase, sodium channels,
certain potassium channels, and calcium channels.
Magnesium therapy appears to be indicated in
patients with digitalis-induced arrhythmias if
hypomagnesemia is present; it is also indicated in
some patients with torsade de pointes even if
serum magnesium is normal.
Potassium
The effects of increasing serum K+ can be
summarized as
(1) a resting potential depolarizing action
(2) a membrane potential stabilizing action, caused
by increased potassium permeability.
Hypokalemia results in an increased risk of early
and delayed afterdepolarizations, and ectopic
pacemaker activity, especially in the presence of
digitalis. Hyperkalemia depresses ectopic
pacemakers (severe hyperkalemia is required to
suppress the sinoatrial node) and slows conduction.
Because both insufficient and excess potassium is
potentially arrhythmogenic, potassium therapy is
directed toward normalizing potassium gradients
and pools in the body.
Chapter 13 HEART FAILURE
Heart Failure
+ A cardiac disorder that impairs the ability of the
ventricle to deliver adequate quantities of
blood to the metabolizing tissues during normal
activity or at rest .
+ Heart failure is a progressive disease that is
characterized by a gradual reduction in cardiac
performance, punctuated in many cases by
episodes of acute decompensation, often
requiring hospitalization.
+ Heart failure occurs when cardiac output is
inadequate to provide the oxygen needed by
the body. It is a highly lethal condition, with a 5-
year mortality rate conventionally said to be
about 50%. The most common cause of heart
failure in the USA is coronary artery disease,
with hypertension also an important factor.
Two major types of failure may be
distinguished. Approximately 50% of patients
have systolic failure, with reduced mechanical
pumping action (contractility) and reduced
ejection fraction. The remaining group has
diastolic failure, with stiffening and loss of
adequate relaxation playing a major role in
reducing filling and cardiac output; ejection
fraction may be normal even though stroke
volume is significantly reduced.

A. CLASS I degree of effort necessary to elicit HF
symptoms equals to those that would limit
normal individuals.
B. CLASS II degree of effort necessary to elicit HF
symptoms occurs with ordinary exertion.
C. CLASS III degree of effort necessary to elicit HF
symptoms occurs with less- than-ordinary
exertion.
D. CLASS IV degree of effort necessary to elicit
HF symptoms occurs while at rest.
Functional classification generally relies on the New
York Heart Association functional classification. The
classes (I-IV) are:
Class I: no limitation is experienced in any activities;
there are no symptoms from ordinary activities.
Class II: slight, mild limitation of activity; the patient
is comfortable at rest or with mild exertion.
Class III: marked limitation of any activity; the
patient is comfortable only at rest.
Class IV: any physical activity brings on discomfort
and symptoms occur at rest.

1. Low-output versus high-output failure
A. LOW OUTPUT
most common type
metabolic demands are within normal limits
but the heart is unable to meet them.
B. HIGH OUTPUT
metabolic demands (hyperthyroidism
anemia), and the heart is unable to meet them
A. LEFT-SIDED FAILURE
if blood cannot be adequately pumped from
the left ventricle to the peripheral circulation
and it accumulates within the left ventricle
the fluid portion of the blood backs up into
pulmonary alveoli, producing pulmonary
edema.
B. RIGHT-SIDED FAILURE
when blood cannot be pumped from the
right ventricle into the lungs and
accumulates within the right ventricle
-when blood is not pumped from the right
ventricle, the fluid portion of the blood backs up
throughout the body.
CLINICAL EVALUATION:
A. Fluid accumulation behind the left ventricle
SIGNS AND SYMPTOMS
1. DYSPNEA
2. DRY, WHEEZING COUGH
3. EXCERTIONAL FATIGUE AND WEAKNESS
4. NOCTURIA
Both paroxysmal nocturnal dyspnea and orthopnea
result from the volume pooling in the recumbent
position and can be relieved by propping up the
patient with pillows or having the patient upright
B. Fluid accumulation behind the right side of the
heart
SIGNS AND SYMPTOMS
1. tightness and swelling
2. Nausea, vomiting, anorexia, bloating or
abdominal pain on exertion
3. hepatic and visceral engorgement resulting
from venous pressure elevation.
4. Hepatomegaly (a tender, enlarged liver)
5. Bilateral leg edema
6. pitting ankle edema
DIGITALIS GLYCOSIDES
1. Digoxin
E Used in conjunction with diuretics, ACE
inhibitors, -adrenergic blockers to improve the
symptoms and clinical status of patients with
HF.


MECHANISM OF ACTION:
E inhibit Na+/K+ ATPase, the membrane-bound
transporter often called the sodium pump.
E second, a relative reduction of calcium
expulsion from the cell by the sodium-calcium
exchange caused by the increase in intracellular
sodium.
Digitalis is the genus name for the family of plants
that provide most of the medically useful cardiac
glycosides, eg, digoxin. Such plants have been
known for thousands of years but were used
erratically and with variable success until 1785,
when William Withering, an English physician and
botanist, published a monograph describing the
clinical effects of an extract of the purple foxglove
plant (Digitalis purpurea, a major source of these
agents).
Digoxin, the only cardiac glycoside used in the USA,
is 6580% absorbed after oral administration
The most common cardiac manifestations of
digitalis toxicity include atrioventricular junctional
rhythm, premature ventricular depolarizations,
bigeminal rhythm, and second-degree
atrioventricular blockade. However, it is claimed
that digitalis can cause virtually any arrhythmia.
Effects on Other Organs
Cardiac glycosides affect all excitable tissues,
including smooth muscle and the central nervous
system. The gastrointestinal tract is the most
common site of digitalis toxicity outside the heart.
The effects include anorexia, nausea, vomiting, and
diarrhea. This toxicity is caused in part by direct
effects on the gastrointestinal tract and in part by
central nervous system actions.
Central nervous system effects include vagal and
chemoreceptor trigger zone stimulation. Less often,
disorientation and hallucinationsespecially in the
elderlyand visual disturbances are noted. The
latter effect may include aberrations of color
perception. Gynecomastia is a rare effect reported
in men taking digitalis.


Interactions with Potassium, Calcium, and
Magnesium
Potassium and digitalis interact in two ways. First, they
inhibit each other's binding to Na
+
,K
+
ATPase; therefore,
hyperkalemia reduces the enzyme-inhibiting actions of
cardiac glycosides, whereas hypokalemia facilitates
these actions. Second, abnormal cardiac automaticity is
inhibited by hyperkalemia (see Chapter 14). Moderately
increased extracellular K
+
therefore reduces the effects
of digitalis, especially the toxic effects.
Calcium ion facilitates the toxic actions of cardiac
glycosides by accelerating the overloading of
intracellular calcium stores that appears to be
responsible for digitalis-induced abnormal automaticity.
Hypercalcemia therefore increases the risk of a digitalis-
induced arrhythmia. The effects of magnesium ion
appear to be opposite to those of calcium. These
interactions mandate careful evaluation of serum
electrolytes in patients with digitalis-induced
arrhythmias.
DIURETICS
E Given to patients with fluid retention
MOA:
E to reduce venous pressure and ventricular
preload.
E They are best used in conjunction with an ACE
inhibitor and -adrenergic blockers.
E Cause reduction in jugular venous pressures,
peripheral edema, and pulmonary congestion.
E Also improve exercise tolerance
THIAZIDE diuretics
Weak diuretic, commonly used
lose their effectiveness in HF patients with
moderately impaired renal function.
LOOP diuretics
furosemide, ethacrynic acid, and bumetanide
preferred diuretics that have the ability to increase
sodium excretion to 20-25% of the filtered load.
maintain the efficacy until renal function is
impaired.
Furosemide
useful as a rapid-acting IV agent in reversing
pulmonary edema, due to its direct dilating effects
on pulmonary vasculature.
POTASSIUM-SPARING diuretics
may help avoid the exacerbating effects of
hypokalemia
weaker diuretic effect
ALDOSTERONE ANTAGONISTS: Spironolactone
VASODILATORS
E reduce pulmonary congestion
E increase cardiac output
E effective in acute heart failure because they
provide a reduction in preload (through
venodilation), or reduction in afterload (through
arteriolar dilation), or both
INDIVIDUAL AGENTS :
NITROPRUSSIDE is administered IV in doses 0f 0.3-
10g/kg/min to provide potent dilation of both
arteries and veins.
HYDRALAZINE decreases afterload and increases
cardiac output.
PRAZOSIN -adrenergic blocker acts as a balanced
arteriovenous dilator.
NITRATES- Venous dilation by nitrates increases
venous pooling, which decreases preload.
COMBINATION THERAPY
A. HYDRALAZINE with ISOSORBIDE DINITRATE to
reduce afterload or with NITROGLYCERIN to reduce
preload for treating chronic HF.
also reduce damaging remodeling of the heart
COMBINATION THERAPY
*combination of these agents should not be used as
initial therapy over ACE inhibitors, but should be
considered in those patients who are intolerant of
ACE inhibitors.
ACE INHIBITORS
E First line agents in the treatment of HF
E Have beneficial effect on cardiac remodeling.
E Reduce peripheral resistance and thereby
reduce afterload
E They also reduce salt and water retention (by
reducing aldosterone secretion) and in that way
reduce preload
Aliskiren, a renin inhibitor recently approved for
hypertension, is in clinical trials for heart failure.
Preliminary results suggest an efficacy similar to
that of ACE inhibitors.
ACE INHIBITORS
interferes with stimulation of aldosterone release
indirectly reducing retention of sodium and water
decreases venous return and preload.
can be added to a diuretic.
Also indicated for patients with left ventricular
dysfunction without symptoms of HF.
Indicated for long-term management of chronic HF
and recommended in combination with a -
adrenergic blocker, diuretic and usually digoxin.
ACE INHIBITORS Side effects:hypotension, dizziness,
reduced renal function, cough, and potassium
retention
discontinue the drug for several days and try to
restart at lower dose.


OMAPATRILAT
E A newer class of drugs that inhibit both ACE and
neutral endopeptidase, an enzyme that
inactivates bradykinin and natriuretic peptide
E Increase exercise tolerance and reduces
morbidity and mortality.
E Causes a significant incidence of angioedema.
B-ADRENERGIC BLOCKING AGENTS
E Unlike ACE inhibitors that strictly work by
blocking the effects of the renin-angiotensin
system, -adrenergic blockers interfere with the
sympathetic nervous system.
E Similar to ACE inhibitors have been shown to
decrease the risk of death and hospitalization as
well as to improve the status of the HF patients.
E Studies with bisoprolol, carvedilol, and
metoprolol showed a reduction in mortality in
patients with stable severe heart failure but this
effect was not observed with another -
blocker, bucindolol.
Used in conjunction with diuretics, ACE inhibitors
and usually digoxin
should not be taken without diuretics in patients
with a current or recent history of fluid retention to
avoid its development and to maintain sodium
balance
-adrenergic blockers initiated with low doses and
titrated upward slowly as tolerated.
Side effects : fatigue, hypotension, bradycardia and
heart block
should be monitored
Carvedilol is the first -adrenergic blocker approved
by the FDA for the management of chronic HF
Initiation of carvedilol should not be undertaken
until the patient is stable without fluid overload or
hypotension and on concomitant medications,
which include diuretics, digoxin and ACE inhibitors.
ADR:bradycardia and the potential for heart block,
Reduce the dose
INOTROPIC AGENTS
E Used in the emergency treatment of patients
with HF and in patients refractory to or unable
to take digitalis.
A. DOPAMINE (IV)
low doses of 2-5g/kg/min
stimulate specific dopamine receptors within the
kidney to increase renal blood flow and thus
increase urine output.
moderate disease of 5-10g/kg/min, increase
cardiac output in HF patients.
*high doses >10g/kg/min
alpha peripheral activity increases, resulting in
increased TPR and pulmonary pressures.
used in acute heart failure and may be particularly
helpful if there is a need to raise blood pressure.
when the infusion exceeds 8-9g/kg/min, should be
monitored for tachycardia.
B. DOBUTAMINE (IV)
patients who are unresponsive to, or adversely
affected by, dopamine may benefit from
dobutamine in doses of 5-20 9g/kg/min.
dobutamine resembles dopamine chemically.
dobutamine does not directly affect renal receptors
and does not act as a renal vasodilator.
It increases urinary output only through increased
cardiac output.
This drug produces an increase in cardiac output
together with a decrease in ventricular filling
pressure
Intermittent dobutamine infusion may benefit some
patients with chronic heart failure.
Some tachycardia and an increase in myocardial
oxygen consumption have been reported
C. INAMRINONE (IV)
Bipyridines
Inamrinone (previously called amrinone) and
milrinone are bipyridine compounds that inhibit
phosphodiesterase isozyme 3 (PDE-3).
nonglycoside, nonsympathomimetic inotropic
agents. A derivative of bipyridine, has both a
positive inotropic effect and a vasodilating effect.
MOA: Inhibits phosphodiesterases (cardiac cells),
increases the amount of cyclic adenosine
monophosphate (cAMP).
used in patients with HF that have been refractory
to treatment with other inotropic agents.
PRECAUTIONS and MONITORING EFFECTS :
Inamrinone , unstable, active orally , monitored for
hypotension.
ADR:Thrombocytopenia dose-dependent and
asymptomatic.
Ventricular rates may increase in patients with atrial
flutter or fibrillation.
cause bone marrow and liver toxicity
D. MILRINONE (IV)
1. similar to inamrinone, possesses both inotropic
and vasodilatory properties.
2. has been used as short-term management to
treat patients with HF
Inamrinone and milrinone
IV only
only for acute heart failure or for an exacerbation of
chronic heart failure.
PRECAUTIONS and MONITORING EFFECTS
reduce infusions in renally impaired patients
Monitor blood pressure and heart rate due to its
vasodilatory effects and its potential to induce
arrhythmias.
additional side effects: mild to moderate headache,
tremor, and thrombocytopenia
OTHER INOTROPIC AGENTS:
A. NESIRITIDE (Natrecor)
A synthetic form of the endogenous peptide brain
natriuretic peptide (BNP)
a recombinant form of human B-type natriuretic
peptide, which is a naturally occurring hormone
secreted by the ventricles.
approved for the IV treatment of patients with
acutely decompensated HF associated with
shortness of breath at rest or with minimal activity.
it binds to natriuretic peptide receptors in blood
vessels, resulting in increased production in
guanosine 35 cGMP in target tissues, which
mediates vasodilation.
In HF, nesiritide reduces pulmonary capillary wedge
pressure and systemic vascular resistance.
Also produces diuresis
Excessive hypotension is the most common adverse
effect
B. Bosentan and tezosentan, orally active competitive
inhibitors of endothelin (see Chapter 17), have been
shown to have some benefits in experimental
animal models with heart failure, but results in
human trials have been disappointing. Bosentan is
approved for use in pulmonary hypertension (see
Chapter 11). It has significant teratogenic and
hepatotoxic effects.
C. Levosimendan
an investigational drug that sensitizes the troponin
system to calcium
also appears to inhibit phosphodiesterase and
cause some vasodilation in addition to its inotropic
effects.
Related peptides include atrial natriuretic peptide
(ANP) and urodilatin, a similar peptide produced in
the kidney. Carperitide and ularitide, respectively,
are investigational synthetic analogs of these
endogenous peptides and are in clinical trials.
D. Istaroxime is an investigational steroid derivative
that increases contractility by inhibiting Na
+
,K
+

ATPase (like cardiac glycosides) but in addition,
facilitates sequestration of Ca
2+
by the SR. The latter
action may render the drug less arrhythmogenic
than digoxin. Istaroxime is in Phase II clinical trials