Antihypertensive Agents

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Antihypertensives
Steven L. Bealer Rm 408C BPRB 7-7706 steve.bealer_at_
deans.pharm.utah.edu -----------------------------
----------------------------------- 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
Online www.AccessMedicine.com
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Objectives

• Know mechanisms of blood pressure regulation and
  cardiovascular pathophysiology which chronically
  increase blood pressure (Review).
• Understand types and etiologies of major forms of
  clinical hypertension.
• General treatment strategy for hypertension.
• Know major classes of anti-hypertensive agents,
  their general sites and mechanisms of action.
• Identify specific, widely used, antihypertensive
  agents, sites of action, mechanisms of action,
  indications and contraindications.
• Understand strategies for hypertension management
  associated with other pathologies.

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Hypertension The Silent Killer
CRITICAL POINT! Hypertension- asymptomatic
Morbidity and mortality due to end organ damage
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Determinants of Arterial Pressure
Blood Volume
Mean Arterial Pressure

X
Arteriolar Diameter
Stroke Volume
Heart Rate

• CRITICAL POINT!
• Change any physical factors controlling CO and/or
  TPR and MAP can be altered.

Filling Pressure
Contractility
Blood Volume
Venous Tone
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Mechanisms Controlling CO and TPR

• CRITICAL POINTS!
• 1. These organ systems and mechanisms control
  physical factors of CO and TPR
• 2. Therefore, they are the targets of
  antihypertensive therapy.

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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.
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Summary General Treatment Strategy of
Hypertension
4. If primary, initiate lifestyle
changes smoking cessation weight
loss diet stress reduction less alcohol etc.
5. Pharmacological treatment.
CRITICAL POINTS! Goal- normalize pressure-
decrease CO and/or TPR Strategy- alter
volume, cardiac and/or VSM function
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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!
• Each designed for specific control system
• Often used in combination

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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)
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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
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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
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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
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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.
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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 ?-receptors on
vascular smooth muscle allows muscle
relaxation, dilation of vessel, and reduced
resistance.
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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,
? antagonist
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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--gtvasodilation--gt Decreased TPR
CRITICAL POINT! Stimulation of a-2 receptors in
the medulla decreases peripheral sympathetic
activity, reduces tone, vasodilation and
decreases TPR.
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Central Sympatholytics (a-2 Agonists) cont.
4. Adverse Effects dry mouth sedation
impotence
5. Contraindications
6. Therapeutic Considerations generally not 1st
line drugs methyldopa drug of choice for
pregnancy
prolonged use--salt/water retention, add
diuretic Rebound increase in blood pressure
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1. Sites of Action
b-1
b-1
2. Mechanism of Action competitive antagonist at
b- adrenergic receptors
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b Adrenergic Antagonists, cont.
3. Effects on Cardiovascular System
a. Cardiac-- ? HR, ? SV? ? CO
b. Renal-- ? Renin ? ? Angiotensin II ? ? TPR
5. Contraindications asthma diabetes
bradycardia hypersensitivity
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b-Adrenergic Antagonists, cont.
6. Therapeutic Considerations Selectivity
nadolol (Corgard) non selective, but 20 hr 1/2
life metoprol (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
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Anti-Angiotensin II Drugs
Angiotensin II Formation

• Angiotensin Converting Enzyme-
• Inhibitors

enalopril (Vasotec)
quinapril (Accupril) fosinopril
(Monopril) moexipril (Univasc)
lisinopril (Zestril, Prinivil)
benazepril (Lotensin) captopril
(Capoten)
Ang I

Angiotensinogen
ACE
Lung VSM Brain Kidney Adr Gland
?
Ang I
AT1
Ang II
ACE
AT2
?
Ang II
Renin
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Anti-Angiotensin II Drugs, cont
3. Effect on Cardiovascular System
?
?
Volume Aldosterone Vasopressin
Angiotensin II
?
HR/SV Angiotensin II Norepinephrine
Vasoconstriction
?
SymNS
?
SymNS
?
CO
?
TPR
?
CO
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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
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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
Ca
Na
3. Effect on Cardiovascular system Vascular
relaxation Decreased TPR
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Ca Channel Blockers, cont.
4. Adverse Effects nifedipine --Increase SymNS
activity 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 nif
edipine- mainly arterioles diltiazem-both
cardiac and arterioles at high doses, AV node
block may occur nifedipine may increase
heart rate (reflex)
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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
fenoldopam
DA
?
?
?
minoxidil diazoxide
K
Ca
Na
Ca
hydralazine
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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
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Summary Sites and Mechanisms of
Action
3. ?-2 agonists
Receptor antag. 2. a-antag. 5. ang II
antag. 7. Vasodilators 6. Ca antag.
4. b-blockers
1. Diuretics 4. b-blockers
Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS
CRITICAL POINTS!
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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
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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
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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.
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Baroreflexes

• MAP set point
• Reflexes defend set point
• Arterial Baroreflexes
• Pressure/Natriuresis
• Change in MAP opposed by reflex response to
  maintain set pressure.
• Hypertension- pressure resets to higher
  level-defended by reflex systems.
• CRITICAL POINT!
• Multiple therapies often needed to block reflex
  compensation.

CO X SVR MAP