Antihypertensives

nurdiana
 Objectives:
1. Know mechanisms of blood pressure regulation and
cardiovascular pathophysiology which chronically
increase blood pressure (Review).
2. Understand types and etiologies of major forms of
clinical hypertension.
3. General treatment strategy for hypertension.
4. Know major classes of anti-hypertensive agents, their
general sites and mechanisms of action.
5. Identify specific, widely used, antihypertensive agents,
sites of action, mechanisms of action, indications and
contraindications.
6. Understand strategies for hypertension management
associated with other pathologies.
 Hypertension: The Silent Killer

Heart Attack Stroke Kidney Failure

CRITICAL POINT!
Hypertension- asymptomatic
Morbidity and mortality due to end organ damage
 Determinants of Arterial Pressure
Blood
Volume
Mean Arterial
Pressure = X Arteriolar
Diameter

Stroke Heart
Volume Rate CRITICAL POINT!
Change any physical factors
controlling CO and/or
Contractility Filling Pressure TPR and MAP can be
altered.
Blood Volume Venous Tone
 Mechanisms Controlling CO and TPR

1. Neural 2. Hormonal
SymNS Renal
PSNS Ang II
Adrenal
Catecholamines
Aldosterone

Artery Vein 3. Local Factors

CRITICAL POINTS!
1. These organ systems and mechanisms control physical factors of
CO and TPR
2. Therefore, they are the targets of antihypertensive therapy.
Summary-Types and Etiology of Hypertension
1. White coat hypertension office or environmental
2. Secondary hypertension- due to specific organ
pathology
1. renal artery stenosis
2. pheochromocytoma
3. aortic coarctation
4. adrenal tumor
3. Essential Hypertension
No known cause.
CRITICAL POINT!
Pharmacological Therapy used
primarily for essential hypertension.
 Summary
General Treatment Strategy of Hypertension

1. Determination of primary vs. secondary hypertension.

2. If secondary, treat underlying pathology.
3. If primary, initiate lifestyle changes
smoking cessation
weight loss
diet
stress reduction
less alcohol
etc.
4. Pharmacological treatment.
CRITICAL POINTS!
Goal- normalize pressure- decrease CO and/or TPR
Strategy- alter volume, cardiac and/or VSM function
 Pharmacological Treatment
Classes of Antihypertensive Agents
1. Diuretics
2. Peripheral a-1 Adrenergic Antagonists
3. Central Sympatholytics (a-2 agonists)
4. b-Adrenergic Antagonists
5. Anti-angiotensin II Drugs
6. Ca++ Channel Blockers
7. Vasodilators

CRITICAL POINTS!
1. Each designed for specific control system
2. Often used in combination
Sites of action of the major
classes of antihypertensive
drugs
 1. Diuretics
1. Thiazides
hydrochlorothiazide (HydroDIURIL, Esidrix);
chlorthalidone (Hygroton)
2. Loop diuretics
furosemide (Lasix); bumetadine (Burmex);
ethacrynic acid (Edecrin)
3. K+ Sparing
amiloride (Midamor); spironolactone (Aldactone);
triamterene (Dyrenium)
4. Osmotic
mannitol (Osmitrol); urea (Ureaphil)
5. Other
Combination - HCTH + triamterene (Dyazide)
acetazolamide (Diamox)
 Diuretics (cont)
1. Site of Action
Renal Nephron
2. Mechanism of Action
Urinary Na+ excretion
Urinary water excretion
Extracellular Fluid
and/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO
Chronic decrease in TPR, normal CO
Mechanism(s) unknown
 Diuretics (cont)
4. Adverse Reactions
dizziness,
electrolyte imbalance/depletion,
hypokalemia,
hyperlipidemia,
hyperglycemia (Thiazides)
gout

5. Contraindications
hypersensitivity,
compromised kidney function
cardiac glycosides (K+ effects)
hypovolemia,
hyponatremia
 Diuretics (cont)
6. Therapeutic Considerations
Thiazides (most common diuretics for HTN)
Generally start with lower potency diuretics
Generally used to treat mild to moderate HTN
Use with lower dietary Na+ intake,
and K+ supplement or high K+ food
K+ Sparing (combination with other agent)

Loop diuretics (severe HTN, or with CHF)

Osmotic (HTN emergencies)

Maximum antihypertensive effect reached

before maximum diuresis- 2nd agent indicated
Peripheral a-1 Adrenergic Antagonists
Drugs: prazosin (Minipres); terazosin (Hytrin)
1. Site of Action- peripheral arterioles, smooth muscle

CRITICAL POINT!
Major mechanism/site of SymNS control of blood pressure.
 Peripheral a-1 Adrenergic Antagonists, cont.
2. Mechanism of Action
Competitive antagonist at a-1 receptors on vascular
smooth muscle.

3. Effects on Cardiovascular System

Vasodilation, reduces peripheral resistance
CRITICAL POINT!
Blocking a-receptors on vascular smooth muscle allows
muscle relaxation, dilation of vessel, and reduced resistance.
 Peripheral a-1 Adrenergic Antagonists, cont.
4. Adverse effects
nausea; drowsiness; postural hypotenstion;
1st dose syncope
5. Contraindications
Hypersensitivity
6. Therapeutic Considerations
no reflex tachycardia; small 1st dose;
does not impair exercise tolerance
useful with diabetes, asthma, and/or
hypercholesterolemia
use in mild to moderate hypertension
often used with diuretic, b antagonist
 Central Sympatholytics (a-2 Agonists)
Drugs: clonidine (Catapres), methyldopa (Aldomet)
1. Site of Action
CNS medullary
cardiovascular centers
clonidine; direct a-2 agonist
methyldopa: false neurotrans.
2. Mechanism of Action
CNS a-2 adrenergic stimulation
Peripheral sympathoinhibition
Decreased norepinephrine release
3. Effects on Cardiovascular System
Decreased NE-->vasodilation--> Decreased TPR
CRITICAL POINT!
Stimulation of a-2 receptors in the medulla decreases peripheral
sympathetic activity, reduces tone, vasodilation and decreases TPR.
 Central Sympatholytics (a-2 Agonists); cont.

4. Adverse Effects
dry mouth; sedation; impotence;
with Fe 2+ absorption methyldopa (70 %)
5. Contraindications : mental depression

6. Therapeutic Considerations
generally not 1st line drugs;
prolonged use--salt/water retention, add diuretic
Rebound increase in blood pressure
Drug of choice for pregnancyfetus safe
 b Adrenergic Antagonists
Drugs: propranolol (Inderal); metoprolol (Lopressor)
atenolol (Tenormin); nadolol (Corgard);
pindolol (Visken)
1. Sites of Action

b-1
QuickTime and a
Photo - JPEG decompressor
are needed to see this picture.

2. Mechanism of Action
competitive antagonist at b- adrenergic receptors
 b Adrenergic Antagonists, cont.

3. Effects on Cardiovascular System

a. Cardiac-- HR, SV CO
b. Renal-- Renin Angiotensin II TPR

4. Adverse Effects
impotence; bradycardia;
fatigue; exercise intolerance;
5. Contraindications
asthma; diabetes; bradycardia;
hypersensitivity
 b-Adrenergic Antagonists, cont.
6. Therapeutic Considerations
Selectivity
nadolol (Corgard) non selective, but 20 hr 1/2 life
metoprolol (Lopresor) b-1 selective, 3-4 hr 1/2 life
Risky in pulmonary disease even selective b-1,
Available as mixed a/b blocker available-labetalol
(Trandate, Normodyne)
Use post myocardial infarction- protective
Use with diuretic- prevent reflex tachycardia
Effective for adolesence not aged
 Anti-Angiotensin II Drugs
Angiotensin II Formation
1. Angiotensin Converting Enzyme- 2. Ang II Receptor Antagonists
Inhibitors losartan (Cozaar);
enalapril (Vasotec); candesartan (Atacand);
quinapril (Accupril); valsartan (Diovan)
fosinopril (Monopril);
moexipril (Univasc);
lisinopril (Zestril, Prinivil);
benazepril (Lotensin);
captopril (Capoten)
Angiotensinogen ACE Ang I
Ang I Lung
VSM

Ang II
AT1

Brain ACE
AT2
Kidney
Adr Gland
Ang II
Renin
 Anti-Angiotensin II Drugs, cont
3. Effect on Cardiovascular System

Volume HR/SV Angiotensin II

Aldosterone Angiotensin II Vasoconstriction
Vasopressin Norepinephrine SymNS
CO SymNS
TPR
CO
 Anti-Angiotensin II Drugs, cont

4. Adverse Effects
hyperkalemia
angiogenic edema (ACE inhib); cough (ACE inhib);
rash; itching;
5. Contraindications
pregnancy; hypersensitivity; bilateral renal stenosis
6. Therapeutic Considerations:
use with diabetes or renal insufficiency;
adjunctive therapy in heart failure;
often used with diuretic;
Enalapril, iv for hypertensive emergency
 Ca++ Channel Blockers
Drugs: verapamil (Calan); nifedipine (Procardia);
diltiazem (Cardizem); amlodipine (Norvasc)

1. Site of Action-
Vascular smooth muscle

2. Mechanism of Action-
Blocks Ca++ channel
decreases/prevents contraction
K+
3. Effect on Cardiovascular system Na+ Ca++
Vascular relaxation
Decreased TPR
 Ca++ Channel Blockers, cont.
4. Adverse Effects
nifedipine --hypotension; tachycardi
headache; dizziness; peripheral edema
5. Contraindications
Congestive heart failure; pregnancy and lactation;
Post-myocardial infarction
6. Therapeutic Considerations
verapamil- mainly cardiac; interactions w/ cardiac
glycosides
nifedipine- mainly arterioles
diltiazem-both cardiac and arterioles
at high doses, AV node block may occur;
nifedipine may increase heart rate (reflex)
 Vasodilators
Drugs: hydralazine (Apresoline); minoxidil (Loniten);
nitroprusside (Nipride); diazoxide (Hyperstat I.V.);
fenoldopam (Corlopam)
1. Site of Action- vascular smooth muscle
2. Mechanism of action nitroprusside

NO
fenoldopam
DA

Na+ Ca++ K+ minoxidil
diazoxide
Ca++
hydralazine
 Vasodilators, Cont
3. Effect on cardiovascular system
vasodilation, decrease TPR
4. Adverse Effects
reflex tachycardia
Increase SymNS activity (hydralazine, minoxidil,diazoxide)
lupus (hydralazine)
hypertrichosis (minoxidil)
cyanide toxicity (nitroprusside)
5. Contraindications : fenoldopam glaucoma
6. Therapeutic Considerations
nitroprusside- iv only
hydralazine- safe for pregnancy
diazoxide- emergency use for severe hypertension
 Summary
Sites and Mechanisms of Action

3. a-2 agonists Receptor antag.

4. b-blockers 1. Diuretics
2. a-antag.
5. ang II antag. 4. b-blockers
Other- 5. ACE inhibitors
Lung, VSM, Kidney, CNS 7. Vasodilators
6. Ca++ antag.
CRITICAL POINTS!
1. Can alter CO/TPR at number of sites and/or mechanisms.
2. Antihypertensives mechanistically specific, and alter blood
pressure through physiologically diverse effects on CO/TPR.
3. All organ systems and/or effector mechanisms are pcol targets.
 Hypertension treatment with
some common co-existing conditions
Heart Failure
ACE inhibitors
Diuretics
Myocardial Infarction
b-blockers
ACE inhibitors
Diabetes
ACE Inhibitors
AVOID- b-blockers
Isolated systolic hypertension (Older persons)
Diuretics preferred
calcium channel antagonist
 Treatment Strategy with
Some Common co-existing Conditions, cont

Renal Insufficiency
ACE Inhibitors
Angina
b-blocker
Calcium channel antagonists
Asthma
Ca++ channel blockers
AVOID- b-blockers
 Summary Important Points
Hypertensive Agents
Each class of antihypertensive agent:

1. has as specific mechanism of action,

2. acts at one or more major organ systems,
3. on a major physiological regulator of blood pressure,
4. reduces CO and/or TPR to lower blood pressure,
5. has specific indications, contraindications, and
therapeutic advantages and disadvantages
associated with the mechanism of action.
 Algorithm for Treatment of Hypertension
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling With Compelling

Indications Indications

Stage 1 Hypertension Stage 2 Hypertension Drug(s) for the compelling

(SBP 140159 or DBP 9099 mmHg) (SBP >160 or DBP >100 mmHg) indications
Thiazide-type diuretics for most. 2-drug combination for most (usually Other antihypertensive drugs
May consider ACEI, ARB, BB, CCB, thiazide-type diuretic and (diuretics, ACEI, ARB, BB, CCB)
or combination. ACEI, or ARB, or BB, or CCB) as needed.

Not at Goal
Blood Pressure

Optimize dosages or add additional drugs

until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
 Baroreflexes
1) MAP= set point
2) Reflexes defend set point
1) Arterial Baroreflexes QuickTime and a
TIFF (LZW) decompressor

2) Pressure/Natriuresis
are needed to see this picture.

3) Change in MAP opposed by

reflex response to maintain
set pressure.
4) Hypertension- pressure resets
to higher level-defended by QuickTime and a
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are needed to see this picture. Quick Time and a

reflex systems.
TIFF (LZW) dec ompressor
are needed to s ee this pic ture.

CRITICAL POINT! CO X SVR=

**Multiple therapies often needed
to block reflex compensation. MAP
Steven L. Bealer
Rm 408C BPRB
7-7706
steve.bealer@deans.pharm.utah.edu
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Recommended reading:
Katzung, 9th Ed.; Chap. 11 (pg. 160-183)
Goodman and Gilman, 11th Ed.;
Chap. 30 Renin and angiotensin; pp. 789-822
Chap. 33 Therapy for Hypertension; pp. 871-900
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