antihypertensive agents

Category Systemic BP (mm Hg) Diastolic BP (mm Hg)

Normal <130 <85

High normal 130-139 85-89

HypertensionStage 1 140-159 90-99Stage 2 160-169 100-109

Stage 3 180-209110-119 Stage 4

210 120

Blood Pressure = Blood Pressure = Cardiac Output X Peripheral ResistanceCardiac Output X Peripheral Resistance

Preload Contractility Preload Contractility Heart Heart

RateRate CirculatingCirculatingFluid VolumeFluid Volume

RenalRenalSodiumSodium

HandlingHandling

SympatheticSympatheticNervousNervousSystemSystem

ReninRenin AngiotensinAngiotensinAldosteroneAldosterone

SystemSystem

ArteriolarArteriolarVenousVenousVasoconstrictionVasoconstriction

VenousVenous

Vascular Vascular Smooth Smooth MuscleMuscle

Vascular remodelingVascular remodeling

V VVasomotor center

AfterloadAfterload

VolumeVolumeKidneysKidneys

PreloadPreload

Renin

Ang II

Aldosterone BP= CO x TPVRBP= CO x TPVR

11

22 11

11

Resistance arterioles Capacitance venules

Total Peripheral Vascular Resistance (TPVR)Total Peripheral Vascular Resistance (TPVR)

Ang I

Cardiac Output Cardiac Output HeartHeart

22

TPVRTPVR

VSMCsVSMCsVascularVascularSmooth Smooth MuscleMuscleCellsCells

Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators

Adrenergic Agents◦Alpha1 blockers◦Beta blockers (cardioselective and nonselective)

◦Centrally acting alpha blockers◦Combined alpha-beta blockers◦Peripheral-acting adrenergic agents

Mechanism of action of beta-adrenoblockers(anaprilin, atenolol, methoprolol etc.)

in case of arterial hypertension

β-adrenoblockers

β1-adrenoreceptors of heart

Cardiac output

Angiotensine ΙΙ Renin

Aldosterone

Holding sodium and water

Peripheral resistance of vessels

Volume of blood circulation

Decreasing of blood pressure

NO production

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II

Aldosterone

11

22 11

11


PVRPVR

Ang I


22

- Blockers- Blockers

VSMCsVSMCs

??

??

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11

22 11

11


TPVRTPVR

Ang I


22

- Blockers- Blockers

VSMCsVSMCs

??

??

Negative ChronotropicNegative Chronotropic& Inotropic Effects& Inotropic Effects

Inhibition ofInhibition ofRenin ReleaseRenin Release

____________________________________________________________

- Reduction in cardiac output- Reduction in cardiac output- Inhibition of renin release- Inhibition of renin release- CNS effects- CNS effects- Reduction in venous return - Reduction in venous return and plasma volumeand plasma volume- Reduction in peripheral resistance- Reduction in peripheral resistance- Improvement in vascular - Improvement in vascular compliancecompliance- Resetting of baroreceptor levels- Resetting of baroreceptor levels- Effects on - Effects on prejunctionalprejunctionalreceptorsreceptors

- Attenuation of pressor response to - Attenuation of pressor response to catecholamines (stress, exercise) catecholamines (stress, exercise) ____________________________________________________________

Cardioselectivity (Beta-1 vs Beta-2 )

Intrinsic Sympathomimetic Activity (ISA; partial agonistic activity)

Affinity for alpha-1 adrenergic receptors (Labetalol, Carvedilol)

Beta BlockersBeta Blockers

Beta-1,2-Non-Selective Propranolol [INDERAL] Nadolol [CORGARD] Carteolol [CARTROL] * Timolol [BLOCADREN] Pindolol [VISKEN] * Sotalol [BETAPACE] Penbutol [LEVATOL] *

Beta-1-Selective Acebutolol [SECTRAL] * Atenolol [TENORMIN] Betaxolol [KERIONE] Bisoprolol [ZEBETA] Esmolol [BREVIBLOC] Metoprolol [LOPRESSOR ]

Beta-1,2/Alpha 1SelectiveBeta-1,2/Alpha 1Selective LabetalolLabetalol [TRANDATE, NORMODYNE] [TRANDATE, NORMODYNE]

Carvedilol Carvedilol [COREG][COREG]

* - ISA

XX

Side Effects: Bronchospasm Bradicardia/heart block Mask and prolong the symptoms of hypoglycemia Abrupt withdrawal can precipitate MI Cold extremities, Raynaud’s phenomenon,

intermittent claudication Decreased exercise tolerance; fatigue, depression

and impotence CNS: sleep disturbance, vivid dreams, nightmares Effects of plasma lipids

Beta BlockersBeta Blockers

Adrenergic AgentsAlpha1 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

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11


TPVRTPVR

Ang I


22

11 Receptors Receptors

BlockersBlockers

11

11

11

11

11

Inhibition of VasoconstrictionInhibition of VasoconstrictionInduced by EndogenousInduced by Endogenous

Catecholamines atCatecholamines atArterioles and VeinsArterioles and Veins

Reduced Peripheral ResistanceReduced Peripheral Resistanceandand

Reduced PreloadReduced Preload

Adrenergic AgentsAlpha1 Blockers doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin)

Adrenergic AgentsCentral-Acting Adrenergics clonidine (Catapres) methyldopa (Aldomet)

(drug of choice for hypertension in pregnancy)

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11


TPVRTPVR

Ang I


22

CentralCentralAgonistsAgonists

11

VSMCVSMC

X

X X

X

X

Diminished CNSDiminished CNSSympathetic OutflowSympathetic Outflow

Alpha-2 AgonistAlpha-2 Agonist

NE & EPINE & EPI

Pre-synaptic NeuronPre-synaptic Neuron

Alpha-2 ReceptorAlpha-2 Receptor

Alpha-1 ReceptorAlpha-1 ReceptorBeta ReceptorBeta Receptor

Post-synapticPost-synapticEffectorEffector

Activation of Pre-synapticActivation of Pre-synapticAlpha-2 Receptors ReducesAlpha-2 Receptors Reduces

NE & EPI Release at SynapseNE & EPI Release at Synapse

RostralRostralVentrolateralVentrolateral

MedullaMedulla

Central Central 22–Agonists–AgonistsCentral Central 22–Agonists–Agonists

A n g i o t e n s i n II

Peripheral resistance Renal function

Cardiovascular structure

RapidPressor Response

1. Direct vasoconstriction

2. Enhancement of peripheral noradrenergic neurotransmission 3. Increased central (CNS) sympathetic discharge

4. Release of catecholamines from adrenal medulla

1. Increases Na+ reabsorption

2. Releases aldosterone from adrenal cortex

3. Altered renal hemodynamics: - renal vasoconstriction - increased noradrenergic neurotransmission in kidney - Increased renal sympathetic tone (CNS)

SlowPressor Response

Cardiovascular Hypertrophy and Remodeling

1. Non-hemodynamic effects: - Increased expression of proto-oncogenes - Increased production of growth factors - Increased synthesis of extracellular matrix proteins

2. Hemodynamic effects: - Increased afterload (cardiac) - Increased wall tension (vascular)

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11

22 11

11


TPVRTPVR

Ang I


22

ACE IACE Inhibitorsnhibitors

VSMCsVSMCs

Angiotensinogen Ang IAng II

Renin (renal)

Renin

Angiotensinogen

Angiotensinogen Ang I

mRNA

AT1

Ang II

AT1

A C E

ACE

(autocrine)

(paracrine)

(endocrine)

mRNARenin

mRNAA C E

endothelialcell

tissuetissue

(VSM cells)(VSM cells)

(myocyte ) (myocyte )

(liver)

mRNAA C E

mRNAmRNA

Renin

Angiotensinogen

Angiotensinogen

Ang IACE

Ang II

Local (tissue) RAS:Local (tissue) RAS:Intrinsic; Extrinsic

blood vessel

Bradykinin

A C E A C E

Kallikrein Renin

Angiotensin II

Angiotensin I

Angiotensinogen

Angiotensin Converting Enzyme

ACEIsACEIs

Kininogens

Inactive Peptides

BK receptorsBK receptors AT-1 receptorsAT-1 receptors

ACEIsACEIs

20 mmHg

Afferentarteriole

Bowman’scapsule

Efferentarteriole

Arterialpressure +

Angiotensin II+

Angiotensin II+ +

INTRAGLOMERULAR PRESSUREINTRAGLOMERULAR PRESSURE

excess glomerular pressure

hyperfiltration microalbuminuria

ACEIs : ACEIs : Prevention of renal disease Prevention of renal disease

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

Result of vasoconstriction: increased systemic vascular resistance and increased afterload

Therefore, increased BP

ACE Inhibitors Aldosterone stimulates water and sodium

resorption. Result: increased blood volume, increased

preload, and increased B

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

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 lisinopril (Prinivil and Zestril) and quinapril

(Accupril) Newer agents, long half-lives, once-a-day

dosing Several other agents available

Kininogens

Bradykinin

Inactive PeptidesA C E A C E

Kallikrein Renin

Endothelial Cell

Plasminogen Activators

Angiotensin II

Angiotensin I

Angiotensinogen

PAI-1 +

ACE Inhibitors vs AT1 Antagonists

++

tPA

A C E Is

PAI-1

Example: Fibrinolytic SystemExample: Fibrinolytic System

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11

22 11

11


TPVRTPVR

Ang I


22

Ang II ReceptorAng II ReceptorBlockersBlockers

VSMCsVSMCs

Ang II

Ang II

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

Angiotensin II Receptor Blockers losartan (Cozaar) eposartan (Teveten) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) telmisartan (Micardis)

Calcium Channel Blockers Benzothiazepines Dihydropyridines Phenylalkylamines

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11


TPVRTPVR

Ang I


22

Calcium Channel Calcium Channel BlockersBlockers

CaCa++++

L-type CaL-type Ca++++ channelschannels

AV

11

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

Negative Inotropic andNegative Inotropic andChronotropic EffectsChronotropic EffectsProduce VasorelaxationProduce Vasorelaxation

at Arteriolesat Arterioles

Reduced Peripheral ResistanceReduced Peripheral Resistance

Verap+Dilti>NifedVerap+Dilti>NifedNifed>Dilti+VerapNifed>Dilti+Verap

Block transmembrane entry of calcium into arteriolar smooth Block transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes thus inhibiting excitation-muscle cells and cardiac myocytes thus inhibiting excitation-contractioncontraction

L-type CaL-type Ca++++ channels channels

Calcium Channel Blockers Benzothiazepines:

◦ diltiazem (Cardizem, Dilacor)

Phenylalkamines:

◦ verapamil (Calan, Isoptin)

Dihydropyridines:

◦ amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene)

◦ nifedipine (Procardia), nimodipine (Nimotop)

Calcium Channel Blockers Angina Hypertension Dysrhythmias Migraine headaches

Calcium Channel Blockers Cardiovascular

◦ hypotension, palpitations, tachycardia

Gastrointestinal◦ constipation, nausea

Other◦ rash, flushing, peripheral edema, dermatitis

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11

22 11

11


TPVRTPVR

Ang I


22

DIURETICSDIURETICS

VSMCsVSMCs

Inhibition ofInhibition ofSodium ReabsorptionSodium Reabsorption

Reduced Circulating VolumeReduced Circulating VolumeReduced PreloadReduced PreloadReduced Cardiac OutputReduced Cardiac Output

DiureticsDiuretics DiureticsDiuretics

Carbonic anhydrase inhibitors Loop diuretics Osmotic diuretics Potassium-sparing diuretics Thiazide and thiazide-like diuretics

Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride resorption.

Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance.

Potent diuresis and subsequent loss of fluid

Decreased fluid volume causes:◦ Reduced BP

◦ Reduced pulmonary vascular resistance

◦ Reduced systemic vascular resistance

◦ Reduced central venous pressure

◦ Reduced left ventricular end-diastolic pressure

Potassium depletion

Edema associated with CHF or hepatic or renal diseaseControl of hypertensionBody System EffectHematologic Agranulocytosis,

neutropenia, thrombocytopenia

Metabolic Hypokalemia, hyperglycemia,

hyperuricemia

Used in the treatment of patients in the early, oliguric phase of ARF

To promote the excretion of toxic substances

Reduction of intracranial pressure Treatment of cerebral edema

Convulsions Thrombophlebitis Pulmonary congestion

Also headaches, chest pains, tachycardia,

blurred vision, chills, and fever

amiloride (Midamor) spironolactone (Aldactone) triamterene (Dyrenium)

V VVasomotor center

AfterloadAfterload


PreloadPreload

Renin

Ang II


11

22 11

11


TPVRTPVR

Ang I


22

Aldosterone Aldosterone AntagonistsAntagonists

VSMCsVSMCs

antihypertensive agents

Documents

vs beta

cardioselectivity beta

carvedilol beta blockersbeta

cardiac output inhibition

adrenergic receptors

isaxxside effects

plasma volume reduction

hgnormalblood pressure