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Antihypertensives

Ita ArmyantiFarmakologi PSPD FK UNTANModul Kardiovaskular 2013----------------------------------------------------------------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

18/04/23 2kardiovaskular/2013

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

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Heart Attack Stroke Kidney Failure

CRITICAL POINT! Hypertension- asymptomatic Morbidity and mortality due to end organ damage


Determinants of Arterial Pressure

Mean Arterial Pressure = X Arteriolar

Diameter

BloodVolume

StrokeVolume

HeartRate

Filling PressureContractility

Blood Volume Venous Tone

CRITICAL POINT!Change any physical factors controlling

CO and/or TPR and MAP can be altered.


Mechanisms Controlling CO and TPR

Artery Vein

2. Hormonal Renal Ang II Adrenal Catecholamines Aldosterone

3. Local Factors

1. Neural SymNS PSNS

CRITICAL POINTS!1. These organ systems and mechanisms control physical factors of CO and TPR2. Therefore, they are the targets of antihypertensive therapy.


2. Secondary hypertension- due to specific organ pathology1. renal artery stenosis2. pheochromocytoma3. aortic coarctation4. adrenal tumor

Summary-Types and Etiology of Hypertension

1. White coat hypertensionoffice or environmental

3. Essential Hypertension No known cause.

CRITICAL POINT!Pharmacological Therapy used primarily for essential hypertension.


SummaryGeneral Treatment Strategy of Hypertension

1. Diagnosis- 3- 6 independent measurements.

2. Determination of primary vs. secondary hypertension.3. If secondary, treat underlying pathology.

5. Pharmacological treatment.

4. If primary, initiate lifestyle changessmoking cessationweight lossdietstress reductionless alcoholetc.



CRITICAL POINTS! Goal- normalize pressure- decrease CO and/or TPR Strategy- alter volume, cardiac and/or VSM function


Classes of Antihypertensive Agents1. Diuretics

2. Peripheral Adrenergic Antagonists

4. Adrenergic Antagonists

3. Central Sympatholytics (agonists)

5. Anti-angiotensin II Drugs

6. Ca++ Channel Blockers

7. VasodilatorsQuickTime™ and a

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Pharmacological Treatment

CRITICAL POINTS!1. Each designed for specific control system2. Often used in combination


1. Diuretics1. Thiazides

hydrochlorothiazide (HydroDIURIL, Esidrix);chlorthalidone (Hygroton)

2. Loop diureticsfurosemide (Lasix); bumetadine (Burmex);ethacrynic acid (Edecrin)

3. K+ Sparingamiloride (Midamor); spironolactone (Aldactone);triamterene (Dyrenium)

4. Osmotic mannitol (Osmitrol); urea (Ureaphil)

5. OtherCombination - HCTH + triamterene (Dyazide)acetazolamide (Diamox)


Diuretics (cont)

2. Mechanism of Action

Urinary Na+ excretionUrinary water excretion

Extracellular Fluid and/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO

Chronic decrease in TPR, normal COMechanism(s) unknown

1. Site of Action Renal Nephron


Diuretics (cont)4. Adverse Reactions

dizziness, electrolyte imbalance/depletion,hypokalemia, hyperlipidemia,hyperglycemia (Thiazides)gout

5. Contraindicationshypersensitivity, compromised kidney functioncardiac 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 reachedbefore maximum diuresis- 2nd agent indicated




Peripheral Adrenergic AntagonistsDrugs: prazosin (Minipres); terazosin (Hytrin)

1. Site of Action- peripheral arterioles, smooth muscle



CRITICAL POINT!Major mechanism/site of SymNS control of blood pressure.


2. Mechanism of ActionCompetitive antagonist at receptors on vascular

smooth muscle.

3. Effects on Cardiovascular SystemVasodilation, reduces peripheral resistance

Peripheral Adrenergic Antagonists, cont.

CRITICAL POINT! Blocking -receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance.


5. Contraindications Hypersensitivity

Peripheral Adrenergic Antagonists, cont.4. Adverse effects

nausea; drowsiness; postural hypotenstion;

1st dose syncope

6. Therapeutic Considerationsno reflex tachycardia; small 1st dose; does not impair exercise toleranceuseful with diabetes, asthma, and/or

hypercholesterolemiause in mild to moderate hypertensionoften used with diuretic, antagonist




Central Sympatholytics (-2 Agonists)Drugs: clonidine (Catapres), methyldopa (Aldomet)

1. Site of ActionCNS medullary cardiovascular centers

clonidine; direct -2 agonist

methyldopa: “false neurotrans.”

CNS adrenergic stimulation Peripheral sympathoinhibition

Decreased norepinephrine release

2. Mechanism of Action

3. Effects on Cardiovascular System

Decreased NE-->vasodilation--> Decreased TPR

CRITICAL POINT!Stimulation of receptors in the medulla decreases peripheral sympathetic activity, reduces tone, vasodilation and decreases TPR.


5. Contraindications

4. Adverse Effectsdry mouth; sedation; impotence;

Central Sympatholytics (-2 Agonists); cont.

6. Therapeutic Considerationsgenerally not 1st line drugs;methyldopa drug of choice for pregnancy

prolonged use--salt/water retention, add diureticRebound increase in blood pressure








drenergic AntagonistsDrugs: propranolol (Inderal); metoprolol (Lopressor)

atenolol (Tenormin); nadolol (Corgard);pindolol (Visken)

1. Sites of Action



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2. Mechanism of Actioncompetitive antagonist at adrenergic receptors


drenergic Antagonists, cont.

3. Effects on Cardiovascular System

a. Cardiac-- HR, SV CO

b. Renal-- Renin Angiotensin II TPR

5. Contraindicationsasthma; diabetes; bradycardia; hypersensitivity

4. Adverse Effectsimpotence; bradycardia;

fatigue; exercise intolerance;


drenergic Antagonists, cont.

6. Therapeutic ConsiderationsSelectivity nadolol (Corgard) non selective, but 20 hr 1/2 life metoprol (Lopresor) selective, 3-4 hr 1/2 lifeRisky in pulmonary disease even selective , Available as mixed blocker available-labetalol

(Trandate, Normodyne)Use post myocardial infarction- protectiveUse with diuretic- prevent reflex tachycardia


Anti-Angiotensin II DrugsAngiotensin II Formation

2. Ang II Receptor Antagonists losartan (Cozaar); candesartan (Atacand); valsartan (Diovan)

1. Angiotensin Converting Enzyme- Inhibitors enalopril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten)

Ang I

Ang II

ACE

ACE

Ang II

Renin

Angiotensinogen

Ang IAT1

AT2

LungVSMBrainKidneyAdr Gland


3. Effect on Cardiovascular System

Anti-Angiotensin II Drugs, cont

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Volume Aldosterone Vasopressin

CO

Angiotensin II

Vasoconstriction

TPR

SymNS

HR/SV Angiotensin II Norepinephrine

CO

SymNS


Anti-Angiotensin II Drugs, cont

4. Adverse Effectshyperkalemiaangiogenic edema (ACE inhib); cough (ACE inhib); rash; itching;

5. Contraindicationspregnancy; 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 BlockersDrugs: verapamil (Calan); nifedipine (Procardia);

diltiazem (Cardizem); amlodipine (Norvasc)

2. Mechanism of Action- Blocks Ca++ channeldecreases/prevents contraction

3. Effect on Cardiovascular systemVascular relaxationDecreased TPR

1. Site of Action- Vascular smooth muscle

K+Ca++Na+


Ca++ Channel Blockers, cont.

5. ContraindicationsCongestive heart failure; pregnancy and lactation;Post-myocardial infarction

6. Therapeutic Considerationsverapamil- mainly cardiac; interactions w/ cardiac

glycosidesnifedipine- mainly arteriolesdiltiazem-both cardiac and arterioles

at high doses, AV node block may occur; nifedipine may increase heart rate (reflex)

4. Adverse Effectsnifedipine --Increase SymNS activity;

headache; dizziness; peripheral edema


VasodilatorsDrugs: hydralazine (Apresoline); minoxidil (Loniten);

nitroprusside (Nipride); diazoxide (Hyperstat I.V.);fenoldopam (Corlopam)

1. Site of Action- vascular smooth muscle

2. Mechanism of action

minoxidildiazoxide

hydralazine

fenoldopamNO

nitroprusside

Ca++

Ca++Na+ K+

DA


Vasodilators, Cont3. 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 hypertension18/04/23 28kardiovaskular/2013

SummarySites and Mechanisms of Action

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.

3. -2 agonists-blockers

Receptor antag. 2. antag. 5. ang II antag.7. Vasodilators6. Ca++ antag.

1. Diuretics-blockers

Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS

CRITICAL POINTS!


Hypertension treatment with some common co-existing conditions

Heart FailureACE inhibitorsDiuretics

Myocardial Infarction-blockersACE inhibitors

DiabetesACE InhibitorsAVOID- blockers

Isolated systolic hypertension (Older persons)Diuretics preferredcalcium channel antagonist


Renal InsufficiencyACE Inhibitors

AnginablockerCalcium channel antagonists

AsthmaCa++ channel blockersAVOID- blockers

Treatment Strategy with Some Common co-existing Conditions, cont


Summary Important PointsHypertensive 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

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CO X SVR= MAP

1) MAP= set point2) Reflexes defend set point

1) Arterial Baroreflexes2) 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. QuickTime™ and a

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Documents

essential hypertension

hypertension management

secondary hypertension

mechanisms of action

andor tpr strategy

sites of action

pharmacological therapy

blood pressure review