Antihypertensive drugs

Learning Objectives:

1. List the anti-hypertensive agents, their general target and mechanisms of action.

2. Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications.

3. Understand strategies for hypertension management

associated with other pathologies.

by the end of this session, you can

　 Ideal BP ： <120/80mmHg

Normal BP ： <130/85mmHg

High normal range ： <130 ～ 139 / 85 ～ 89mmHg

HTN ：≥ 140/90mmHg （ 18.7/12.0kPa)

Stage 1 : 140 ～ 159 / 90 ～ 99mmHg

Stage 2: 160 ～ 179 / 100 ～ 109mmHg

Stage 3: ≥ 180 / 110 mmHg

the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure,

Definition & Classification of HTN

Determinants of Arterial Pressure

Mean Arterial Pressure = ×

ArteriolarDiameter

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 Sym NS 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

Types and Etiology of Hypertension

1. Essential Hypertension No known cause.

CRITICAL POINT!Pharmacological Therapy used primarily for essential hypertension.

General 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 alcohol

etc.

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

Classes of Antihypertensive Agents

1. Diuretics2. Peripheral Adrenergic Antagonists

4. Adrenergic Antagonists3. Central Sympatholytics (agonists)

5. Anti-angiotensin II Drugs(RAASI)6. Ca++ Channel Blockers7. Vasodilators

Pharmacological Treatment

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

Major groups of drugs

MAIN CLASSES ( First line agents)A – ACEIs & ARBsB - ß- blockersC – Ca channel blockersD – DiureticsOthers – Vasodilators

Central sympathetic outflow inhibitors

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 ActionUrinary Na+ excretionUrinary water excretion

Extracellular Fluid and/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO

Chronic decrease in TPR, normal CO

1. Site of Action Renal Nephron

?

Vasodilatory effects of Diuretics

Na Na Ca Ca

Na Prostaglandin( PGE2), Kinin

Na sensitivity to vasoconstrictor,

Noradrenalin (NA)

AgⅠ AgⅡ

ACE

Aldosterone

Angiotensinogen

Renin

RAAS

hydrolyzation

Na

Na retention

K excretion

Jaxtaglomerular cell

Diuretics (cont)4. Adverse Reactions

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

5. Contraindicationshypersensitivity, compromised kidney functioncardiac glycosideshypovolemia,hyponatremia

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)

2. Mechanism of ActionCompetitive antagonist at receptors on vascular

smooth muscle.

Peripheral Adrenergic Antagonists

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

Drugs: prazosin (Minipres); terazosin (Hytrin)

1. Site of Action- peripheral arterioles, smooth muscle

3. Effects on Cardiovascular SystemVasodilation, reduces peripheral resistance

5. Contraindications Hypersensitivity

Peripheral Adrenergic Antagonists, cont.

4. Adverse effectsnausea; drowsiness; postural hypotenstion;1st dose syncope

6. Therapeutic Considerationsno reflex tachycardia; 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 imidazoline-1

CNS adrenergic stimulation Peripheral sympathoinhibition

Decreased norepinephrine release

2. Mechanism of Action

3. Effects on Cardiovascular SystemDecreased NE-->vasodilation--> Decreased TPR

CRITICAL POINT!Stimulation of receptors in the medulla decreases peripheral

sympathetic activity, reduces tone, vasodilation and decreases TPR.

4. Adverse Effectsdry mouth; sedation; impotence;

Central Sympatholytics (-2 Agonists); cont.

5. Therapeutic Considerationsgenerally not 1st line drugs;prolonged use--salt/water retention, add diureticRebound increase in blood pressure

drenergic Antagonists– “olol” names

Drugs: propranolol (Inderal); metoprolol (Lopressor)atenolol (Tenormin); nadolol (Corgard);pindolol (Visken)

1. Sites of Action

2. Mechanism of Actioncompetitive antagonist at adrenergic receptors

SNS Heart Kidney

The mechanism for reduction of BP of β-R blockers

β-R blockers

Blockade of β1-R on heart

Cardiacoutrput

Peripheralresistance

Renin AngiotensinII

Aldosterone

sodium, water retention blood volume

Decrease in BP

Blockade of β-R in peripheraland central nervous system

Inhibit NA release and vasomotor center

PGI2

synthesis

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- protective

Anti-Angiotensin II Drugs

Angiotensin II Formation

2. Ang II Receptor Antagonists – “sartan” names losartan (Cozaar); candesartan (Atacand);

valsartan (Diovan)

1. Angiotensin Converting Enzyme-

Inhibitors – “pril” names 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

Peripheralresistance

Renin

Aldosterone

sodium, water retention

Decrease in BP

AngiotensinI

AngiotensinII

Angiotensinogen Bradykinin

inactive

Increased prostaglandin

synthsis

vasodilation

Peripheralresistance

vasoconstrition

Increase in BP

ACE inhibitors

ARB

ACE

RAAS and its inhibitors

Anti-Angiotensin II Drugs, cont

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

Mnemonic for CAPTOPRIL side effects: Cough, Angioedema, Proteinuria, Taste change, hypOtension, Pregnancy problems, Rash, Increased renin, Lower pressure (lack of vasoconstriction)

4. Contraindicationspregnancy; hypersensitivity; bilateral renal stenosis

5. 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: Phenylalkylamines; Dihydropyridines; Benzothiazepines Verapamil ; Nifedipine; Diltiazem ; Very Nice Drug

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 Considerationsnifedipine t1/2 3-4h

amlodipine t1/2 35-50h nitrendipine t1/2 8-12h

t.i.d ===q8h

4. Adverse Effectsnifedipine --Increase SymNS activity;

headache; dizziness; peripheral edema

?** long-acting or slow-release formulations should be used for high blood pressure

VasodilatorsDrugs: 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

Vasodilators, Cont

3. Effect on cardiovascular systemvasodilation, decrease TPR

4. Adverse Effects reflex tachycardia Increase SymNS activity (hydralazine, minoxidil,diazoxide)

lupus (hydralazine)

hypertrichosis (minoxidil)cyanide toxicity (nitroprusside)

5. Therapeutic Considerations

nitroprusside- iv only, emergency use for severe hypertension

Sites and Mechanisms of Action

1. Antihypertensives mechanistically specific, and alter blood

pressure through physiologically diverse effects on CO/TPR.2. All organ systems and/or effector mechanisms are pharmacologic targets.

3. -2 agonists-blockers Receptor antag.

2. antag. 5. ang II antag. 7. Vasodilators 6. Ca++ antag.

1. Diuretics-blockers

Other- 5. ACE inhibitorsVSM, 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

临床用药原则 principles of medication

- 长期用药 Long-time/lifelong medication

- 小剂量用药 the least effective dose

- 联合用药 combination

- 选用长效药 long acting medication

- 避免血压波动 avoid fluctuation of BP

- 避免突然停药 Avoid sudden withdrawal

Summary

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.