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Antihypertensives. Steven L. Bealer Rm 408C BPRB 7-7706 [email protected] ---------------------------------------------------------------- Recommended reading: Katzung, 9th Ed.; Chap. 11 (pg. 160-183) Goodman and Gilman, 11th Ed.;

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Antihypertensives

Steven L. Bealer

Rm 408C BPRB

7-7706

[email protected]

----------------------------------------------------------------

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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Stroke

Kidney Failure

Heart Attack

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.

Contractility

Filling Pressure

Blood Volume

VenousTone


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1. Neural

SymNS

PSNS

2.Hormonal

Renal

Ang II

Adrenal

Catecholamines

Aldosterone

3. Local Factors

Artery

Vein

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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1. Diagnosis- 3- 6 independent measurements.

2. Determination of primary vs. secondary hypertension.

3. If secondary, treat underlying pathology.

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-->vasodilation--> 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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b Adrenergic Antagonists

Drugs: propranolol (Inderal); metoprolol (Lopressor)

atenolol (Tenormin); nadolol (Corgard);

pindolol (Visken)

1. Sites of Action

b-1

b-1

2. Mechanism of Action

competitive antagonist at b- adrenergic receptors


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4. Adverse Effects

impotence; bradycardia;

fatigue; exercise intolerance;

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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2. Ang II Receptor Antagonists

losartan (Cozaar);

candesartan (Atacand);

valsartan (Diovan)

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)

Angiotensinogen

Ang I

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

nifedipine- 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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NO

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+

Na+

Ca++

Ca++

hydralazine


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6. Therapeutic Considerations

nitroprusside- iv only

hydralazine- safe for pregnancy

diazoxide- emergency use for severe hypertension

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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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.

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


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