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

2
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 ß-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

3
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
 ß-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

4
Hypertension Defined
Re: Table in the next slide
 Based on recommendations of the
Seventh Report of the Joint
National Committee of Prevention,
Detection, Evaluation, and
Treatment of High Blood Pressure
(JNC VII)
Also see: e-Medicine article Hypertension
New Hypertension Guidelines
Quick Reference Card
http://www.nhlbi.nih.gov/guideline
s/hypertension/phycard.pdf

5
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 1 140-159 90-99
Stage 2 160-169 100-109
Stage 3 180-209 110-119
Stage 4  210  120

6
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

7
Physiological Factors
Influencing Arterial Pressure
Arterial pressure is determined by a
number of interacting factors
 Preload & Contractility
 Heart rate
 Peripheral resistance

8
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

9
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

10
Physiological Factors Influencing Arterial
Pressure
Preload & Contractility(3)
The Nitrates are an example of preload reducing agents
See: CV Pharmacology
Anti-Anginal Agents Ppt

11
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 (ß-
adrenergic receptor antagonists, e.g.)
 Heart Rate X Stroke Volume = Cardiac Output (CO)
 Cardiac Output X Total Peripheral Resistance (TPR) =
Mean Arterial Pressure (MAP)

12
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)

13
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

14
Anti-Hypertensive Drug
Classes
1. Diuretics
2. Sympatholytics
3. Vasodilators
4. Calcium Channel Blockers
5. Angiotensin Converting Enzyme (ACE)
Inhibitor

15
Anti-Hypertensive Drug
Classes-1) Diuretics
Thiazides
•Hydrochlorothiazide
(HydroDIURIL)
•Chlorthalidone
(Hygroton)
•Chlorothiazide
(Diuril)
•Indapamide (Lozol)
•Metolazone
(Zaroxolyn)
Potassium Sparing
•Amiloride (Midamor)
•Spironolactone
(Aldactone)
•Triamterene
(Dyrenium)
Loop Diuretics
•Furosemide (Lasix),
Bumetanide (Bumex),
Ethacrynic acid
(Edecrin)
•Torsemide
(Demadex)

16
Anti-Hypertensive Drug Classes-
2) Sympatholytics
Centrally Active
•Clonidine
(Catapres)
•Methyldopa
(Aldomet)
•Guanabenz
(Wytensin)
•Guanfacine (Tenex)
Adrenergic
Neuron Blocker
•Guanadrel (Hylorel)
•Guanethidine
(Ismelin)
•Reserpine
Adrenoceptor
Antagonists
• Labetalol
(Trandate,
Normodyne) (alpha
& beta)
•Prazosin (Minipress)
(alpha), Terazosin
(Hytrin) (alpha)

17
Anti-Hypertensive Drug Classes-
3) Vasodilators
Diazoxide
(Hyperstat)
Hydralazine
(Apresoline)
Minoxidil
(Loniten)
Nitroprusside
sodium
(Nipride)

18
Anti-Hypertensive Drug Classes-
4) Calcium Channel Blockers
•Dihydropyridines
•Amlodipine (Norvasc),
Felodipine (Plendil)
•Nimodipine
•Isradipine
•Nicardipine
•Nifedipine
•Non-Dihydropyridines
•Bepridil (Vascor)
•Diltiazem (Cardiazem)
•Verapamil (Isoptin, Calan)

19
Anti-Hypertensive Drug Classes-
5) 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

20
Antihypertensive Agents:
Categories Discussion
 Adrenergic agents
 Angiotensin-converting enzyme
inhibitors
 Angiotensin II receptor blockers
 Calcium channel blockers
 Diuretics
 Vasodilators

21
Antihypertensive Agents:
Categories
 Adrenergic Agents
 Alpha1 blockers
 Beta blockers (cardioselective and
nonselective)
 Centrally acting alpha blockers
 Combined alpha-beta blockers
 Peripheral-acting adrenergic agents

22
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

23
Antihypertensive Agents:
Adrenergic Agents
Alpha1 Blockers
 doxazosin (Cardura)
 prazosin (Minipress)
 terazosin (Hytrin)

24
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

25
Antihypertensive Agents:
Adrenergic Agents
Central-Acting Adrenergics
 clonidine (Catapres)
 methyldopa (Aldomet)
(drug of choice for hypertension in
pregnancy)

26
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

27
Antihypertensive Agents:
Adrenergic Agents
Adrenergic Neuronal Blockers
(peripherally acting)
 reserpine
 guanadrel (Hylorel)
 guanethidine (Ismelin)

28
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

29
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

30
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

31
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

32
Antihypertensive Agents:
Adrenergic Agents
Side Effects
Most common: dry mouth drowsiness
sedation constipation
Other: headaches sleep disturbances
nausea rash
cardiac disturbances (palpitations)
HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION

33
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

34
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

35
Antihypertensive Agents:
Mechanism of Action(2)
ACE Inhibitors
 Result of vasoconstriction: increased
systemic vascular resistance and
increased afterload
 Therefore, increased BP

36
Antihypertensive Agents:
Mechanism of Action(3)
ACE Inhibitors
 Aldosterone stimulates water and sodium
resorption.
 Result: increased blood volume, increased
preload, and increased B

37
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

38
Diagram illustrates the renin-
angiotensin-aldosterone axis

39

40
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

41
Antihypertensive Agents-
ACE Inhibitors(2)
lisinopril (Prinivil and Zestril)
quinapril (Accupril)
 Newer agents, long half-lives, once-a-
day dosing
 Several other agents available

42
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

43
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!!

44
Antihypertensive Agents:
Categories
Angiotensin II Receptor Blockers
(A II Blockers or ARBs)
 Newer class
 Well-tolerated
 Do not cause coughing

45
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

46
Antihypertensive Agents:
Angiotensin II Receptor Blockers
 losartan (Cozaar)
 eposartan (Teveten)
 valsartan (Diovan)
 irbesartan (Avapro)
 candesartan (Atacand)
 telmisartan (Micardis)

47
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

48
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

49
Antihypertensive Agents:
Categories
Calcium Channel Blockers
 Benzothiazepines
 Dihydropyridines
 Phenylalkylamines

50
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

51
Antihypertensive Agents-
Calcium Channel Blockers
 Benzothiazepines:
 diltiazem (Cardizem, Dilacor)
 Phenylalkamines:
 verapamil (Calan, Isoptin)
 Dihydropyridines:
 amlodipine (Norvasc), bepridil (Vascor),
nicardipine (Cardene)
 nifedipine (Procardia), nimodipine (Nimotop)

52
Antihypertensive Agents:
Therapeutic Uses
Calcium Channel Blockers
 Angina
 Hypertension
 Dysrhythmias
 Migraine headaches

53
Antihypertensive Agents:
Side Effects
Calcium Channel Blockers
 Cardiovascular
 hypotension, palpitations, tachycardia
 Gastrointestinal
 constipation, nausea
 Other
 rash, flushing, peripheral edema, dermatitis

54
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

55
Antihypertensive Agents:
Mechanism of Action
Vasodilators
 Directly relaxes arteriolar smooth muscle
 Result: decreased systemic vascular response,
decreased afterload, and
PERIPHERAL VASODILATION

56
Nitric Oxide and Vasodilation
After receptor stimulation, L-arginine-
dependent 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

57
Antihypertensive Agents
Vasodilators
 diazoxide (Hyperstat)
 hydralazine HCl (Apresoline)
 minoxidil (Loniten, Rogaine)
 sodium nitroprusside (Nipride, Nitropress)

58
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

59
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

60
Stepwise Approach to Tx of
Essential HTN
 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
Antihypertensive
Medication Sequence

61
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,