Antihypertensives
Bushra A. Hadi
Objectives:
1.
2.
3.
4.
5.
6.
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.
Hypertension: The Silent Killer
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Heart Attack
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Stroke
Kidney Failure
CRITICAL POINT!
Hypertension- asymptomatic
Morbidity and mortality due to end organ damage
Determinants of Arterial Pressure
Mean Arterial
Pressure
Blood
Volume
=
Stroke
Volume
X
Heart
Rate
Contractility Filling Pressure
Blood Volume
Venous Tone
Arteriolar
Diameter
CRITICAL POINT!
Change any physical factors
controlling CO and/or
TPR and MAP can be
altered.
Mechanisms Controlling CO and TPR
1. Neural
SymNS
PSNS
2. Hormonal
Renal
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. Diagnosis- 3- 6 independent measurements.
2. Determination of primary vs. secondary hypertension.
3. If secondary, treat underlying pathology.
4. If primary, initiate lifestyle changes
smoking cessation
weight loss
diet
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stress reduction
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less alcohol
etc.
5. 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
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6. Ca++ Channel Blockers
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7. Vasodilators
CRITICAL POINTS!
1. Each designed for specific control system
2. Often used in combination
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
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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
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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
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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-->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;
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5. Contraindications
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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
b Adrenergic Antagonists
Drugs: propranolol (Inderal); metoprolol (Lopressor)
atenolol (Tenormin); nadolol (Corgard);
pindolol (Visken)
1. Sites of Action
b-1
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b-1
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
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
Anti-Angiotensin II Drugs
Angiotensin II Formation
1.
Angiotensin Converting EnzymeInhibitors
enalopril (Vasotec);
quinapril (Accupril);
fosinopril (Monopril);
moexipril (Univasc);
lisinopril (Zestril, Prinivil);
benazepril (Lotensin);
captopril (Capoten)
Angiotensinogen
ACE
Ang I
Renin
2. Ang II Receptor Antagonists
losartan (Cozaar);
candesartan (Atacand);
valsartan (Diovan)
Lung
VSM
Brain
Kidney
Adr Gland
Ang I

AT1
Ang II
ACE

AT2
Ang II
Anti-Angiotensin II Drugs, cont
3. Effect on Cardiovascular System
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 Volume
Aldosterone
Vasopressin
 CO
 HR/SV
Angiotensin II
Norepinephrine
 SymNS
 CO
 Angiotensin II
Vasoconstriction
 SymNS
 TPR
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 ActionVascular smooth muscle
2. Mechanism of ActionBlocks Ca++ channel
decreases/prevents contraction
3. Effect on Cardiovascular system
Vascular relaxation
Decreased TPR
Na+ Ca++
K+
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
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+
hydralazine
Ca++
Ca++
K+
minoxidil
diazoxide
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
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
4. b-blockers
Other- 5. ACE inhibitors
Lung, VSM, Kidney, CNS
CRITICAL POINTS!
Receptor antag.
2. a-antag.
5. ang II antag.
7. Vasodilators
6. Ca++ antag.
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 p’col targets.
1. Diuretics
4. b-blockers
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.
Baroreflexes
1) MAP= set point
2) Reflexes defend set point
1) Arterial Baroreflexes
2) Pressure/Natriuresis
3) Change in MAP opposed by
reflex response to maintain
set pressure.
4) Hypertension- pressure resets
to higher level-defended by
reflex systems.
CRITICAL POINT!
**Multiple therapies often needed
to block reflex compensation.
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CO X SVR=
MAP