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CV Pharmacology-

Antihypertensive Agents
Reading:
Antihypertensive Drugs
Formative Assessment
Practice question
Clinical:
e-Medicine article
Hypertension

Prepared and presented by:


Marc Imhotep Cray, M.D.
BMS and CK/CS Teacher

Normal Control of BP

Normal control of BP: sympathoadrenal


axis-- response to a decrease in BP

Sensed by Central baroreceptors {heart & great


arteries}
Stimulation of -adrenergic systems

increased heart rate (positive chronotropic response)


increased force of contraction (contractility, positive
inotropic response)
increased renin secretion {juxtaglomerular renal cells}

Stimulation of a-adrenoceptor systems: causes


vasoconstriction
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Essential Hypertension
With essential hypertension, mechanisms in the
previous slide function inappropriately

Excessive sympathetic activation


Elevated norepinephrine may promote through vascular
endothelium injury:
vascular hypertrophy
atherogenesis
-adrenergic receptor down-regulation
Reduced endothelium-mediated vascular relaxation
Consequence:

increased vasoconstrictive tone (chronic vasoconstriction)


Excessive sympathetic activation promotes enhanced
peripheral vascular resistance in hypertensive patients

Hypertension Defined
Re: Table in the next slide

New Hypertension Guidelines


Quick Reference Card

Based on recommendations of the


Seventh Report of the Joint
National Committee of Prevention,
Detection, Evaluation, and
Treatment of High Blood Pressure
(JNC VII)

http://www.nhlbi.nih.gov/guideline
s/hypertension/phycard.pdf

Also see: e-Medicine article Hypertension

Classification of Blood
Pressure (JNC VII)
Category

Systemic BP (mm Hg) Diastolic BP (mm Hg)

Normal

<130

<85

High normal

130-139

85-89

Hypertension
Stage 1
Stage 2
Stage 3
Stage 4

140-159
160-169
180-209
210

90-99
100-109
110-119
120

Classification of HTN
Primary Hypertension
Specific cause unknown
90% of the cases
Also known as essential or idiopathic
hypertension
Secondary Hypertension
Cause is known (such as eclampsia of
pregnancy, renal artery disease,
pheochromocytoma)
10% of the cases

Physiological Factors
Influencing Arterial Pressure
Arterial pressure is determined by a
number of interacting factors
Preload & Contractility
Heart rate
Peripheral resistance

Physiological Factors Influencing Arterial


Pressure
Preload & Contractility

As blood volume returning to heart


increases, preload increases and there
is enhanced filling with ventricular
dilation
According to Starling's Law, increased
ventricular stretch usually leads to
increased contractility
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Physiological Factors Influencing Arterial


Pressure
Preload & Contractility(2)

Increased preload and increased


contractility lead to increased stroke
volume and ultimately an increase in
arterial pressure, all other factors
remaining equal
Some antihypertensive drugs
decrease preload
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Physiological Factors Influencing Arterial


Pressure
Preload & Contractility(3)

The Nitrates are an example of preload reducing agents


See: CV Pharmacology
Anti-Anginal Agents Ppt
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Physiological Factors Influencing


Arterial Pressure Heart Rate
Heart rate:
Since product of heart rate and stroke volume equals
cardiac output, an increase in heart rate will increase
arterial blood pressure, all other factors remaining equal

Some antihypertensive agents decrease heart rate (adrenergic receptor antagonists, e.g.)
Heart Rate X Stroke Volume = Cardiac Output (CO)

Cardiac Output X Total Peripheral Resistance (TPR) =


Mean Arterial Pressure (MAP)
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Physiological Factors Influencing Arterial


Pressure Peripheral resistance
Peripheral resistance:
For a given cardiac output, blood
pressure depends only on peripheral
resistance
Some antihypertensive drugs act to
reduce peripheral resistance (Also
known as afterload reducing agents)
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Physiological Factors Influencing


Arterial Pressure
Depending on mechanism of action,
a given antihypertensive may:

Reduce preload
Reduce afterload
Decrease heart rate
Reduce peripheral resistance
Reduce contractility.

Many antihypertensive drugs have


multiple effects
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Anti-Hypertensive Drug
Classes
1.
2.
3.
4.
5.

Diuretics
Sympatholytics
Vasodilators
Calcium Channel Blockers
Angiotensin Converting Enzyme (ACE)
Inhibitor

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Anti-Hypertensive Drug
Classes-1) Diuretics
Thiazides

Potassium Sparing

Loop Diuretics

Hydrochlorothiazide
(HydroDIURIL)
Chlorthalidone
(Hygroton)
Chlorothiazide
(Diuril)
Indapamide (Lozol)
Metolazone
(Zaroxolyn)

Amiloride (Midamor)
Spironolactone
(Aldactone)
Triamterene
(Dyrenium)

Furosemide (Lasix),
Bumetanide (Bumex),
Ethacrynic acid
(Edecrin)
Torsemide
(Demadex)

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Anti-Hypertensive Drug Classes2) Sympatholytics


Centrally Active
Clonidine
(Catapres)
Methyldopa
(Aldomet)
Guanabenz
(Wytensin)
Guanfacine (Tenex)

Adrenergic
Neuron Blocker

Adrenoceptor
Antagonists

Guanadrel (Hylorel)
Guanethidine
(Ismelin)
Reserpine

Labetalol
(Trandate,
Normodyne) (alpha
& beta)
Prazosin (Minipress)
(alpha), Terazosin
(Hytrin) (alpha)

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Anti-Hypertensive Drug Classes3) Vasodilators

Diazoxide
(Hyperstat)

Hydralazine
(Apresoline)

Minoxidil
(Loniten)

Nitroprusside
sodium
(Nipride)

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Anti-Hypertensive Drug Classes4) Calcium Channel Blockers


Dihydropyridines
Amlodipine (Norvasc),
Felodipine (Plendil)
Nimodipine
Isradipine
Nicardipine
Nifedipine

Non-Dihydropyridines
Bepridil (Vascor)
Diltiazem (Cardiazem)
Verapamil (Isoptin, Calan)

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Anti-Hypertensive Drug Classes5) Angiotensin Converting


Enzyme Inhibitors

Benazepril (Lotensin)
Captopril (Capoten)
Enalapril (Vasotec)
Fosinopril (Monopril)
Lisinopril (Prinvivil, Zestril)

Moexipril (Univasc)
Quinapril (Accupril)
Ramipril (Altace)
Losartin (Cozaar), Irbesartin***
***
***angiotensin receptor blocker

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Antihypertensive Agents:
Categories Discussion

Adrenergic agents
Angiotensin-converting enzyme
inhibitors
Angiotensin II receptor blockers
Calcium channel blockers
Diuretics
Vasodilators
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Antihypertensive Agents:
Categories

Adrenergic Agents

Alpha1 blockers
Beta blockers (cardioselective and
nonselective)
Centrally acting alpha blockers
Combined alpha-beta blockers
Peripheral-acting adrenergic agents

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Antihypertensive Agents:
Mechanism of Action
Adrenergic Agents

Alpha1 Blockers (peripherally acting)

Block the alpha1-adrenergic receptors


The SNS is not stimulated
Result: DECREASED blood pressure
Stimulation of alpha1-adrenergic receptors
causes HYPERtension
Blocking alpha1-adrenergic receptors causes
decreased blood pressure
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Antihypertensive Agents:
Adrenergic Agents
Alpha1 Blockers

doxazosin (Cardura)
prazosin (Minipress)
terazosin (Hytrin)

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Antihypertensive Agents:
Mechanism of Action
Adrenergic Agents
Central-Acting Adrenergics

Stimulate alpha2-adrenergic receptors


Sympathetic outflow from the CNS is
decreased
Result: decreased blood pressure

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Antihypertensive Agents:
Adrenergic Agents
Central-Acting Adrenergics

clonidine (Catapres)
methyldopa (Aldomet)
(drug of choice for hypertension in
pregnancy)

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Antihypertensive Agents:
Mechanism of Action
Adrenergic Agents
Adrenergic Neuronal Blockers
(peripherally acting)

Inhibit release of norepinephrine

Also deplete norepinephrine stores

SNS (peripheral adrenergic nerves) is not


stimulated
Result: decreased blood pressure

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Antihypertensive Agents:
Adrenergic Agents
Adrenergic Neuronal Blockers
(peripherally acting)

reserpine
guanadrel (Hylorel)
guanethidine (Ismelin)

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Antihypertensive Agents:
Adrenergic Agents
Therapeutic Uses

Alpha1 blockers (peripherally acting)


Treatment of hypertension
Relief of symptoms of BPH
Management of of severe CHF when used
with cardiac glycosides and diuretics

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Antihypertensive Agents:
Adrenergic Agents
Therapeutic Uses

Central-Acting Adrenergics
Treatment of hypertension, either alone or
with other agents
Usually used after other agents have
failed due to side effects

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Antihypertensive Agents:
Adrenergic Agents
Therapeutic Uses

Central-Acting Adrenergics(2)
Also may be used for treatment of severe
dysmenorrhea, menopausal flushing,
glaucoma
Clonidine is useful in the management of
withdrawal symptoms in opioid- or
nicotine-dependent persons

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Antihypertensive Agents:
Adrenergic Agents
Therapeutic Uses

Adrenergic neuronal blockers


(peripherally acting)
Treatment of hypertension, either alone or
with other agents
Seldom used because of frequent side
effects

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Antihypertensive Agents:
Adrenergic Agents
Side Effects
Most common:
Other:

dry mouth drowsiness


sedation constipation
headaches sleep disturbances
nausea
rash
cardiac disturbances (palpitations)

HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION

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Antihypertensive Agents:
Categories- (ACE Inhibitors)
Angiotensin-Converting Enzyme
Inhibitors (ACE Inhibitors)

Large group of safe and effective drugs


Often used as first-line agents for CHF
and hypertension
May be combined with a thiazide diuretic
or calcium channel blocker
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Antihypertensive Agents:
Mechanism of Action
ACE Inhibitors
RAAS: Renin Angiotensin-Aldosterone
System

When the enzyme angiotensin I is converted


to angiotensin II, the result is potent
vasoconstriction and stimulation of
aldosterone
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Antihypertensive Agents:
Mechanism of Action(2)
ACE Inhibitors

Result of vasoconstriction: increased


systemic vascular resistance and
increased afterload

Therefore, increased BP

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Antihypertensive Agents:
Mechanism of Action(3)
ACE Inhibitors

Aldosterone stimulates water and sodium


resorption.
Result: increased blood volume, increased
preload, and increased B

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Antihypertensive Agents:
Mechanism of Action(4)
ACE Inhibitors

ACE Inhibitors block the angiotensin-converting


enzyme, thus preventing the formation of
angiotensin II.
Also prevent the breakdown of the vasodilating
substance, bradykinin
Result: decreased systemic vascular resistance (afterload),
vasodilation, and therefore, decreased blood pressure
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Diagram illustrates the reninangiotensin-aldosterone axis

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Antihypertensive Agents
ACE Inhibitors
captopril (Capoten)

Short half-life, must be dosed more


frequently
than others

enalapril (Vasotec)

The only ACE inhibitor available in oral and


parenteral forms
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Antihypertensive AgentsACE Inhibitors(2)


lisinopril (Prinivil and Zestril)
quinapril (Accupril)

Newer agents, long half-lives, once-aday dosing


Several other agents available

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Antihypertensive Agents:
Therapeutic Uses
ACE Inhibitors

Hypertension
CHF (either alone or in combination with diuretics
or other agents)
Slows progression of left ventricular hypertrophy
after an MI
Renal protective effects in patients with diabetes
Drugs of choice in hypertensive patients with CHF
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Antihypertensive Agents:
Side Effects
ACE Inhibitors

Fatigue

Dizziness

Headache

Mood changes

Impaired taste
Dry, nonproductive cough, reverses when therapy is
stopped
NOTE: first-dose hypotensive effect may occur!!
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Antihypertensive Agents:
Categories
Angiotensin II Receptor Blockers
(A II Blockers or ARBs)

Newer class
Well-tolerated
Do not cause coughing

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Antihypertensive Agents:
Mechanism of Action
Angiotensin II Receptor Blockers

Allow angiotensin I to be converted to


angiotensin II, but block the receptors that
receive angiotensin II
Block vasoconstriction and release of
aldosterone

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Antihypertensive Agents:
Angiotensin II Receptor Blockers

losartan (Cozaar)
eposartan (Teveten)
valsartan (Diovan)
irbesartan (Avapro)
candesartan (Atacand)
telmisartan (Micardis)
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Antihypertensive Agents:
Therapeutic Uses
Angiotensin II Receptor Blockers

Hypertension
Adjunctive agents for the treatment of CHF
May be used alone or with other agents such
as diuretics

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Antihypertensive Agents:
Side Effects
Angiotensin II Receptor Blockers

Upper respiratory infections


Headache
May cause occasional dizziness, inability to
sleep, diarrhea, dyspnea, heartburn, nasal
congestion, back pain, fatigue

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Antihypertensive Agents:
Categories
Calcium Channel Blockers

Benzothiazepines
Dihydropyridines
Phenylalkylamines

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Antihypertensive Agents:
Mechanism of Action
Calcium Channel Blockers

Cause smooth muscle relaxation by blocking


the binding of calcium to its receptors,
preventing muscle contraction
This causes decreased peripheral smooth
muscle tone, decreased systemic vascular
resistance
Result: decreased blood pressure
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Antihypertensive AgentsCalcium Channel Blockers

Benzothiazepines:

Phenylalkamines:

diltiazem (Cardizem, Dilacor)

verapamil (Calan, Isoptin)

Dihydropyridines:

amlodipine (Norvasc), bepridil (Vascor),


nicardipine (Cardene)
nifedipine (Procardia), nimodipine (Nimotop)

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Antihypertensive Agents:
Therapeutic Uses
Calcium Channel Blockers

Angina
Hypertension
Dysrhythmias
Migraine headaches

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Antihypertensive Agents:
Side Effects
Calcium Channel Blockers

Cardiovascular

Gastrointestinal

hypotension, palpitations, tachycardia


constipation, nausea

Other

rash, flushing, peripheral edema, dermatitis


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Antihypertensive Agents:
Diuretics
Decrease the plasma and extracellular fluid volumes
Results:
decreased preload
decreased cardiac output
decreased total peripheral resistance

Overall effect: decreased workload of the heart,


and decreased blood pressure

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Antihypertensive Agents:
Mechanism of Action
Vasodilators

Directly relaxes arteriolar smooth muscle

Result:

decreased systemic vascular response,

decreased afterload, and


PERIPHERAL VASODILATION

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Nitric Oxide and Vasodilation


After receptor stimulation, L-argininedependent metabolic pathway
produces nitric oxide (NO) or thiol
derivative (R-NO). NO causes
increase in cyclic guanosine
monophosphate (cGMP), which
causes relaxation of vascular smooth
muscle. EDRF=endothelium-derived
relaxing factor.
From: Inhaled Nitric Oxide Therapy
ROBERT J. LUNN, M.D.
From the Department of Anesthesiology, Mayo Clinic
Rochester, Rochester, Minnesota.
http://www.mayoclinicproceedings.com/inside.asp?re
f=7003sc

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Antihypertensive Agents
Vasodilators

diazoxide (Hyperstat)
hydralazine HCl (Apresoline)
minoxidil (Loniten, Rogaine)
sodium nitroprusside (Nipride, Nitropress)

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Antihypertensive Agents:
Therapeutic Uses
Vasodilators

Treatment of hypertension
May be used in combination with other
agents
Sodium nitroprusside and diazoxide IV are
reserved for the management of
hypertensive emergencies

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Antihypertensive Agents:
Side Effects
Vasodilators

Hydralazine:

dizziness, headache, anxiety, tachycardia, nausea


and vomiting, diarrhea, anemia,
dyspnea, edema, nasal congestion

Sodium nitroprusside:

bradycardia, hypotension, possible cyanide toxicity


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Stepwise Approach to Tx of
Antihypertensive
Essential HTN Medication
Sequence

beginning with a low dosage of


either an ACE inhibitor, calcium
channel blocker or beta blocker
and proceeding, if needed to add a
diuretic
and ultimately additional more
powerful drugs, such as centrally
acting sympatholytics, peripheral
vasodilators or combination.
At each step dosages are reviewed and
if the patient's hypertension is
controlled then therapy may be
continued with review for possible
removal of medication.

Figure adapted from Harrison's "Principles of Internal


Medicine, Thirteenth Edition, p. 1128
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Resources
JNC GUIDELINES

The Joint National Committee on Prevention, Detection,


Evaluation, and Treatment of High Blood Pressure (JNC
7)

On the JNC home page, there are a number of important


resources for clinicians as well as patient resources,
including:
JNC 7 Complete Report: The Science Behind the New
Guidelines (86 pages)
JNC 7 Express Highlights "Must Know" Clinical Practice
Updates (34 pages)
JNC 7 Reference Card (2 pages)- A great summary of
Evaluation, Treatment,
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