Obat Hipertensi Mr.steven

8/11/2019 Obat Hipertensi Mr.steven

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Antihypertensives

Steven L. BealerRm 408C BPRB7-7706

steve.bealer@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. 789-822Chap. 33 Therapy for Hypertension; pp. 871-900Online; www.AccessMedicine.com


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Objectives: 1. Know mechanisms of blood pressure regulation and

cardiovascular pathophysiology which chronicallyincrease blood pressure (Review).

2. Understand types and etiologies of major forms ofclinical 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.


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Hypertension: The Silent Killer

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Heart Attack Stroke Kidney Failure

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


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Determinants of Arterial Pressure

Mean ArterialPressure = X Arteriolar

Diameter

Blood

Volume

StrokeVolume

HeartRate

Filling PressureContractility

Blood Volume Venous Tone

CRITICAL POINT!Change any physical factors

controlling CO and/orTPR and MAP can bealtered.


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Mechanisms Controlling CO and TPR

Artery Vein

2. HormonalRenalAng II

AdrenalCatecholaminesAldosterone

3. Local Factors

1. NeuralSymNSPSNS

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


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2. Secondary hypertension- due to specific organ pathology

1. 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.


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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 changes

smoking cessationweight lossdietstress reductionless alcohol

etc.

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


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Classes of Antihypertensive Agents1. Diuretics2. Peripheral a-1 Adrenergic Antagonists

4. b- Adrenergic Antagonists3. Central Sympatholytics ( a-2 agonists)

5. Anti-angiotensin II Drugs 6. Ca++ Channel Blockers 7. Vasodilators

Pharmacological Treatment

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


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1. Diuretics 1. Thiazides

hydrochlorothiazide (HydroDIURIL, Esidrix);chlorthalidone (Hygroton)

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

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

4. Osmoticmannitol (Osmitrol); urea (Ureaphil)

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


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Diuretics (cont)

2. Mechanism of Action Urinary Na+ excretion

Urinary water excretion

Extracellular Fluidand/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO

Chronic decrease in TPR, normal COMechanism(s) unknown

1. Site of ActionRenal Nephron


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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 diureticsGenerally used to treat mild to moderate HTNUse with lower dietary Na+ intake,

and K+ supplement or high K+ foodK+ 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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2. Mechanism of Action

Competitive antagonist at a-1 receptors on vascularsmooth muscle.

3. Effects on Cardiovascular SystemVasodilation, reduces peripheral resistance

Peripheral a-1 Adrenergic Antagonists, cont .

CRITICAL POINT!Blocking a -receptors on vascular smooth muscle allows

muscle relaxation, dilation of vessel, and reduced resistance.


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5. ContraindicationsHypersensitivity

Peripheral a-1 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, b antagonist

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

1. Site of ActionCNS medullarycardiovascular centers

clonidine; direct a -2 agonistmethyldopa: false neurotrans.

CNS a-2 adrenergic stimulationPeripheral sympathoinhibition

Decreased norepinephrine release

2. Mechanism of Action

3. Effects on Cardiovascular SystemDecreased 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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5. Contraindications

4. Adverse Effectsdry mouth; sedation; impotence;

Central Sympatholytics ( a -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

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b Adrenergic Antagonists Drugs: propranolol (Inderal); metoprolol (Lopressor)

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

1. Sites of Action


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2. Mechanism of Actioncompetitive 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. Contraindicationsasthma; diabetes; bradycardia;hypersensitivity

4. Adverse Effectsimpotence; bradycardia;fatigue; exercise intolerance;


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b-Adrenergic Antagonists, cont. 6. Therapeutic Considerations

Selectivitynadolol (Corgard) non selective, but 20 hr 1/2 lifemetoprol (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

2. Ang II Receptor Antagonistslosartan (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 I AT1

AT2

LungVSMBrainKidneyAdr Gland


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3. Effect on Cardiovascular System

Anti-Angiotensin II Drugs, cont

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VolumeAldosteroneVasopressin

CO

Angiotensin II

Vasoconstriction

TPR

SymNS

HR/SV

Angiotensin II Norepinephrine

CO

SymNS


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Anti-Angiotensin II Drugs, cont

4. Adverse Effectshyperkalemiaangiogenic 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)

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+


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Ca++ Channel Blockers, cont.

5. ContraindicationsCongestive heart failure; pregnancy and lactation;

Post-myocardial infarction6. Therapeutic Considerations

verapamil- mainly cardiac; interactions w/ cardiacglycosides

nifedipine- mainly arteriolesdiltiazem-both cardiac and arterioles

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

4. Adverse Effects

nifedipine --Increase SymNS activity;headache; dizziness; peripheral edema


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Vasodilators Drugs: hydralazine (Apresoline); minoxidil (Loniten);

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

1. Site of Action- vascular smooth muscle2. Mechanism of action

minoxidildiazoxide

hydralazine

fenoldopamNO

nitroprusside

Ca++

Ca++ Na+ K+

DA


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Vasodilators, Cont 3. Effect on cardiovascular system

vasodilation, decrease TPR

4. Adverse Effectsreflex tachycardiaIncrease SymNS activity (hydralazine, minoxidil,diazoxide)

lupus (hydralazine)

hypertrichosis (minoxidil)cyanide toxicity (nitroprusside)

5. Contraindications

6. Therapeutic Considerationsnitroprusside- iv onlyhydralazine- safe for pregnancydiazoxide- emergency use for severe hypertension


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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 pcol targets.

3. a -2 agonists 4. b-blockers Receptor antag.2. a- antag.5. ang II antag.

7. Vasodilators6. Ca++ antag.

1. Diuretics4. b-blockers

Other- 5. ACE inhibitorsLung, VSM, Kidney, CNSCRITICAL POINTS!


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Hypertension treatment withsome common co-existing conditions

Heart FailureACE inhibitorsDiuretics

Myocardial Infarctionb-blockersACE inhibitors

DiabetesACE InhibitorsAVOID- b- blockers

Isolated systolic hypertension (Older persons)Diuretics preferredcalcium channel antagonist


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Renal InsufficiencyACE Inhibitors

Angina

b- blockerCalcium channel antagonists

AsthmaCa++ channel blockers

AVOID- b- blockers

Treatment Strategy with

Some Common co-existing Conditions, cont


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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 associatedwith the mechanism of action.


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Thank you

Obat Hipertensi Mr.steven

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