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Hiurationale For PTreatment of Hypertension
Hiurationale For PTreatment of Hypertension
decreasing heart rate and contractility. Some calciumchannel blockers (most notably the dihydropyridines)
are more selective for the systemic vasculature and
therefore reduce systemic vascular resistance.
General Pharmacology
Heart failure
Heart failure leads to activation of the reninangiotensin-aldosterone system, which causes
increased sodium and water retention by the kidneys.
This in turn increases blood volume and contributes to
the elevated venous pressures associated with heart
failure, which can lead to pulmonary and systemic
edema. The primary use for diuretics in heart failure is
Specific
Drugs
Thiazid
e
chlorothiazide
chlorthalidone
Comments
hydrochlorothia
prototypical drug;
zide
hydroflumethia
zide
indapamide
failure
methyclothiazid
e
metolazone
hypokalemia
metabolic
alkalosis
dehydration
(hypovolemia),
leading to
hypotension
polythiazide
Loop
bumetanide
ethacrynic acid
Thiazi
de
furosemide
hyponatremia
hyperglycemia
in diabetics
hypercholester
olemia;
hypertriglycerid
emia
torsemide
K+amiloride
sparing
eplerenone
aldosterone receptor
antagonist; fewer side
effects than
spironolactone
increased lowdensity
lipoproteins
hyperuricemia
(at low doses)
spironolactone
aldosterone receptor
antagonist; side effect:
gynecomastia
azotemia (in
renal disease
patients)
hypokalemia
triamterene
metabolic
alkalosis
hypomagnese
CA
acetazolamide
inhibito
rs
Loop
Drug Interactions
hypokalemi
a
potentiates
digitalis
toxicity
nonsteroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy
betablockers:
potentiate
hyperglyce
mia,
hyperlipide
mias
corticosteroi
ds: enhance
hypokalemi
a
hypokalemi
a
potentiates
digitalis
toxicity
non-
steroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy
mia
K+sparin
g
Carbo
nic
anhyd
rase
inhibi
tors
hyperuricemia
dehydration
(hypovolemia),
leading to
hypotension
dose-related
hearing loss
(ototoxicity)
hyperkalemia
metabolic
acidosis
gynecomastia
(aldosterone
antagonists)
gastric
problems
including peptic
ulcer
hypokalemia
metabolic
acidosis
corticosteroi
ds: enhance
hypokalemi
a
aminoglycos
ides:
enhance
ototoxicity,
nephrotoxici
ty
ACE
inhibitors:
potentiate
hyperkalemi
a
nonsteroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy
Heart failure
Angina
2.
2.
Cardiac output
3.
Arterial pressure
4.
5.
2.
3.
Vascular smooth muscle has two types of alphaadrenoceptors: alpha1 (1) and alpha2 (2). The 1adrenoceptors are the predominant -receptor located on
vascular smooth muscle. These receptors are linked to Gqproteins that activate smooth muscle contraction through
the IP3 signal transduction pathway. Depending on the tissue
General Pharmacology
The most common side effects are related directly to alphaadrenoceptor blockade. These side effects include dizziness,
Therapeutic Uses
Therapeutic Use of
ACE Inhibitors
Hypertension
Heart failure
Post-myocardial infarction
Hypertension
ACE inhibitors are effective in the treatment of
primary hypertension and hypertension caused by
renal artery stenosis, which causes renindependent hypertension owing to the increased
release of renin by the kidneys. Reducing
angiotensin II formation leads to arterial and
venous dilation, which reduces arterial and venous
pressures. By reducing the effects of angiotensin II
on the kidney, ACE inhibitors cause natriuresis and
diuresis, which decreases blood volume and
cardiac output, thereby lowering arterial pressure.
benazepril
captopril
enalapril
fosinopril
lisinopril
moexipril
quinapril
ramipril
Therapeutic Uses
ARBs are used in the treatment of hypertension
and heart failure in a similar manner as ACE
inhibitors (see ACE inhibitors for details). They are
not yet approved for post-myocardial infarction,
although this is under investigation.
Specific Drugs
ARBs include the following drugs: (Go
to www.rxlist.com for specific drug information)
candesartan
eprosartan
irbesartan
losartan
olmesartan
telmisartan
valsartan
General Pharmacology
Arrhythmias
Therapeutic Indications
CCBs are used to treat hypertension, angina and
arrhythmias.
Hypertension
Therapeutic Use of
Calcium-Channel Blockers
Hypertension
(systemic & pulmonary)
Angina
Arrhythmias
Angina
The anti-anginal effects of CCBs are derived from
their vasodilator and cardiodepressant actions.
Systemic vasodilation reduces arterial pressure,
which reduces ventricular afterload (wall stress)
thereby decreasing oxygen demand. The more
cardioselective CCBs (verapamil and diltiazem)
decrease heart rate and contractility, which leads
to a reduction in myocardial oxygen demand,
which makes them excellent antianginal drugs.
CCBs can also dilate coronary arteries and prevent
or reverse coronary vasospasm (as occurs
in Printzmetal's variant angina), thereby increasing
oxygen supply to the myocardium.
amlodipine
felodipine
isradipine
nicardipine
nifedipine
nimodipine
nitrendipine
General Pharmacology
The one drug in this group, hydralazine, does not fit
neatly into the other mechanistic classes, in part,
Specific Drugs
Several different ganglionic blockers are available for
clinical use; however, only one (trimethaphan
camsylate) is very occasionally used in hypertensive
emergencies or for producing controlled hypotension
during surgery.
Side Effects and Contraindications
Side effects of trimethaphan include prolonged
neuromuscular blockade and potentiation of
neuromuscular blocking agents. It can produce
excessive hypotension and impotence due to its
sympatholytic effect, and constipation, urinary
retention, dry mouth due to it parasympatholytic
effect. It also stimulates histamine release.
General Pharmacology
Nitric oxide (NO), a molecule produced by many cells in
the body, and has several important actions (click here
for details). In the cardiovascular system, NO is
primarily produced by vascular endothelial cells. This
endothelial-derived NO has several important functions
including relaxing vascular smooth muscle
(vasodilation), inhibiting platelet aggregation (antithrombotic), and inhibiting leukocyte-endothelial
interactions (anti-inflammatory). These actions involve
NO-stimulated formation of cGMP. Nitrodilators are
drugs that mimic the actions of endogenous NO by
releasing NO or forming NO within tissues. These drugs
act directly on the vascular smooth muscle to cause
relaxation and therefore serve as endothelialindependent vasodilators.
Coronary
vasodilation
(venous dilation > arterial dilation)
Cardiac
prevents/reverses vasospasm
Specific Drugs
isosorbide dinitrate
isosorbide mononitrate
nitroglycerin
erythrityl tetranitrate
pentaerythritol tetranitrate
sodium nitroprusside
General Pharmacology
Potassium-channel openers are drugs that activate
(open) ATP-sensitive K+-channels in vascular smooth
muscle. Opening these channels hyperpolarizes the
smooth muscle, which closes voltage-gated calcium
channels and decreases intracellular calcium. With less
calcium available to combine with calmodulin, there is
Therapeutic Indications
Being effective arterial dilators, potassium-channel
openers are used in the treatment of hypertension.
These drugs are not first-line therapy for hypertension
because of their side effects, and therefore they are
relegated to treating refractory, severe hypertension.
They are generally used in conjunction with a betablocker and diuretic to attenuate the reflex tachycardia
and retention of sodium and fluid, respectively.
Specific Drugs
Although several potassium-channel openers have
been used in research for many years, only
one, minoxidil, is approved for use in humans for
treating hypertension. (Go to www.rxlist.com for
detailed information on minoxidil)
Side Effects and Contraindications
Common side effects to minoxidil include headaches,
flushing and reflex tachycardia. The potent vasodilator
actions of minoxidil can lead to fluid retention and
edema formation. Reflex cardiac stimulation can
precipitate angina in patients with coronary artery
disease. Minoxidil produces T wave changes in a high
percentage (~60%) of patients under chronic
treatment. One of the most noted side effects of
minoxidil is hypertrichosis, a thickening and enhanced
pigmentation of body hair, and therefore this drug is
more commonly used for treating baldness.
Renin inhibitors are one of four classes of compounds
that affect the renin-angiotensin-aldosterone system,
the other three beingangiotensin converting enzyme
inhibitors (ACEIs), angiotensin receptor blockers
(ARBs) and aldosterone receptor antagonists. Renin
inhibitors produce vasodilation by inhibiting the activity
of renin, which is responsible for stimulating
angiotensin II formation. Renin is a proteolytic enzyme
that is released by the kidneys in response to
sympathetic activation, hypotension, and decreased
sodium delivery to the distal renal tubule (click here for
more details). Once released into the circulation, renin
acts on circulating angiotensinogen to form angiotensin
I. Angiotensin I is then converted to angiotensin II by
angiotensin converting enzyme. Angiotensin II has a
several important actions including vasoconstriction,
stimulation of aldosterone, renal retention of sodium
Arrhythmias
Therapeutic Uses of
Cardioinhibitory Drugs
Hypertension
Angina
Heart failure
Arrhythmias
Beta-blockers
Calcium-channel blockers
Centrally-acting sympatholytics
Beta-blockers
Beta-blockers bind to beta-adrenoceptors located in
cardiac nodal tissue, the conducting system, and
contracting myocytes. The heart has both beta1 (1)
and beta2 (2) adrenoceptors, although the
predominant receptor type in number and function is
1. These receptors primarily bind norepinephrine that
is released from sympathetic adrenergic nerves.
Additionally, they bind norepinephrine
and epinephrine that circulates in the blood. Betablockers prevent the normal ligand (norepinephrine or
epinephrine) from binding to the beta-adrenoceptor by
competing for the binding site. Because there is
generally some level of sympathetic tone on the heart,
beta-blockers are able to reduce sympathetic
influences that normally stimulate chronotropy,
inotropy, dromotropy and lusitropy. These drugs have
an even greater effect when there is elevated
sympathetic activity. Beta-blockers that are used
clinically are either non-selective (1/2) blockers, or
relatively selective 1 blockers. Some beta-blockers
have additional mechanisms of action besides betablockade. Beta-blockers are used for treating
hypertension, angina, myocardial infarction and
arrhythmias.
Calcium-channel blockers
Calcium-channel blockers (CCBs) bind to L-type calcium
channels located on cardiac myocytes and cardiac
nodal tissue (sinoatrial and atrioventricular nodes).
These channels are responsible for regulating the influx
of calcium into cardiomyocytes, which in turn
stimulates cardiac myocyte contraction. In cardiac
nodal tissue, L-type calcium channels play an
important role in pacemaker currents and in phase 0 of
the action potentials. Therefore, by blocking calcium
entry into the cell, CCBs decrease myocardial force
generation (negative inotropy), decreased heart rate
(negative chronotropy), and decrease conduction
velocity within the heart (negative dromotropy
particularly at the atrioventricular node). CCBs are
used in treating hypertension, angina and arrhythmias.
Centrally acting sympatholytics
Centrally acting sympatholytics block sympathetic
activity by binding to and activating alpha2 (2)adrenoceptors located on cardioregulatory cells within
the medulla of the brain. This reduces sympathetic
outflow to the heart, thereby decreasing cardiac output
by decreasing heart rate and contractility. These drugs
are only used for treating hypertension.
Click below on a drug class for more details:
General Pharmacology
Beta-blockers are drugs that bind to betaadrenoceptors and thereby block the binding
Heart
Beta-blockers bind to beta-adrenoceptors located in
cardiac nodal tissue, the conducting system, and
contracting myocytes. The heart has both 1 and
2 adrenoceptors, although the predominant receptor
type in number and function is 1. These receptors
primarily bind norepinephrine that is released from
sympathetic adrenergic nerves. Additionally, they bind
Decrease contractility
(negative intropy)
Vascular Effects
Blood vessels
Vascular smooth muscle has 2-adrenoceptors that are
normally activated by norepinephrine released by
sympathetic adrenergic nerves or by circulating
epinephrine. These receptors, like those in the heart,
are coupled to a Gs-protein, which stimulates the
formation ofcAMP. Although increased cAMP enhances
Hypertension
Angina
Myocardial infarction
Arrhythmias
Heart failure
HT
N
Angi
na
Arr
hy
M CH
Comments
I
F
Nonselective
1/2
metoprol
X
ol
nebivolol X
ISA; long
acting; also
used for
glaucoma
carteolol X
carvedilo
X
l
-blocking
activity
ISA; -blocking
activity
labetalol
nadolol
penbutol
X
ol
ISA
pindolol
ISA; MSA
proprano
X
lol
sotalol
timolol
esmolol
ultra short
acting; intra or
postoperative
HTN
acebutol
ol
atenolol
betaxolol X
MSA;
prototypical
beta-blocker
several other
significant
mechanisms
long acting
primarily used
for glaucoma
1selective
bisoprolo
X
l
ISA
X
MSA
relatively
selective in
most patients;
vasodilating
(NO release)
MSA
Decrease contractility
(negative inotropy)
Vascular effects
Arrhythmias
Smooth muscle relaxation
(vasodilation)
General Pharmacology
Currently approved CCBs bind to L-type calcium
channels located on the vascular smooth muscle,
cardiac myocytes, and cardiac nodal tissue (sinoatrial
and atrioventricular nodes). These channels are
responsible for regulating the influx of calcium into
muscle cells, which in turn stimulates smooth muscle
contraction and cardiac myocyte contraction. In cardiac
nodal tissue, L-type calcium channels play an
important role in pacemaker currents and in phase 0 of
the action potentials. Therefore, by blocking calcium
entry into the cell, CCBs cause vascular smooth muscle
relaxation (vasodilation), decreased myocardial force
generation (negative inotropy), decreased heart rate
(negative chronotropy), and decreased conduction
velocity within the heart (negative dromotropy),
particularly at the atrioventricular node.
Hypertension
Therapeutic Use of
Calcium-Channel Blockers
Therapeutic Indications
CCBs are used to treat hypertension, angina and
arrhythmias.
Hypertension
(systemic & pulmonary)
Angina
Arrhythmias
amlodipine
felodipine
isradipine
nicardipine
nifedipine
nimodipine
nitrendipine
vasospasm) and
arrhythmias. Diltiazem (benzothiazepine class) is
intermediate between verapamil and dihydropyridines
in its selectivity for vascular calcium channels. By
having both cardiac depressant and vasodilator
actions, diltiazem is able to reduce arterial pressure
without producing the same degree of reflex cardiac
stimulation caused by dihydropyridines.
Side Effects and Contraindications
Dihydropyridine CCBs can cause flushing, headache,
excessive hypotension, edema and reflex tachycardia.
The activation of sympathetic reflexes and lack of
direct cardiac effects make dihydropyridines a less
desirable choice for angina. Long-acting
dihydropyridines have been shown to be safer antihypertensive drugs, in part, because of reduced reflex
responses. The cardiac selective, non-dihydropyridine
CCBs can cause excessive bradycardia, impaired
electrical conduction (e.g., atrioventricular nodal
block), and depressed contractility. Therefore, patients
having preexistent bradycardia, conduction defects, or
heart failure caused by systolic dysfunction should not
be given CCBs, especially the cardiac selective, nondihydropyridines. CCBs, especially nondihydropyridines, should not be administered to
patients being treated with a beta-blocker because
beta-blockers also depress cardiac electrical and
mechanical activity and therefore the addition of a CCB
augments the effects of beta-blockade.
General Pharmacology
The sympathetic adrenergic nervous system plays a
major role in the regulation of arterial pressure.
Activation of these nerves to the heart increases the
heart rate (positive chronotropy), contractility (positive
inotropy) and velocity of electrical impulse conduction
(positive dromotropy). The norepinephrine-releasing,
sympathetic adrenergic nerves that innervate the heart
and blood vessels are postganglionic efferent nerves
whose cell bodies originate in prevertebral and
paraveterbral sympathetic ganglia. Preganglionic
sympathetic fibers, which travel from the spinal cord to
the ganglia, originate in the medulla of the brainstem.
Within the medulla are located sympathetic excitatory
neurons that have significant basal activity, which
generates a level of sympathetic tone to the heart and
vasculature even under basal conditions. The
sympathetic neurons within the medulla receive input
from other neurons within the medulla (e.g., vagal
neurons), from the nucleus tractus solitarius (receives
input from peripheral baroreceptors and
chemoreceptors), and from neurons located in the
hypothalamus. Together, these neuronal systems
regulate sympathetic (and parasympathetic) outflow to
the heart and vasculature.
clonidine
guanabenz
guanfacine
-methyldopa