Nicolaski Lumbuun Clinical Pharmacologist Medical Faculty, Pelita Harapan University

Antihypertensive Drug
Clinical Pharmacology of Oral Antihypertensive Drugs

Introduction

What is Hypertension ?
Whats

the symptom ? How to establish the diagnosis ?

How to measure the blood pressure (bmj.2001 322:1043-47)

How

to prepare the patients How to prepare the instrument How to do the measurement appropriately

Blood Pressure = Cardiac Output X Peripheral Resistance

Preload
Circulating Fluid Volume
Renin Angiotensin Aldosterone System Vascular Smooth Muscle

Contractility Heart Rate

Vasoconstriction
Venous Arteriolar Venous

Renal Sodium Handling

Sympathetic Nervous System

Vascular remodeling

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR

b2

a1 VSMCs Vascular Smooth Muscle Cells

Resistance arterioles

Capacitance venules

TPVR

Total Peripheral Vascular Resistance (TPVR)

Antihypertensive Agents
Sympatholytic Drugs

1. Diuretics 2. Calcium Channel Blockers 3. Angiotensin Converting Enzyme Inhibitors 4. Angiotensin Receptor Antagonists 5. Peripheral Vasodilators

6. Alpha-1 Blockers 7. Beta Blockers 8. Alpha-2 Agonists 9. Ganglionic Inhibitors 10.Adrenergic Neural Terminal Inhibitors

Antihypertensive Agents
Therapeutic goals in hypertension
To lower the high blood pressure and reduced cardiovascular morbidity and mortality increase quality of live

For most of the HTN patients: life-long

treatment of an asymptomatic disease

Diuretics

Diuretics
Inhibition of Sodium Reabsorption

Reduced Circulating Volume Reduced Preload Reduced Cardiac Output

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR

b2

a1 VSMCs Vascular Smooth Muscle Cells

Resistance arterioles

Capacitance venules

TPVR

Total Peripheral Vascular Resistance (TPVR)

Renal Circulation

Nephron

Diuretics
++++

Thiazides and thiazides-like diuretics

Aldosterone antagonists Potassium sparing diuretics Loop diuretics

++
+ +

Diuretics: Thiazides
Initial effects: natriuresis, diuresis,

reduced extracellular and circulating volume) Chronic effect: reduction in peripheral vascular resistance (direct vasodilating effect) Combination with ACEIs and beta blockers Given once daily

Diuretics: Thiazides
Distal Convoluted Tubule - Na/Cl Symport Inhibitors

Bendroflumethiazide
Benzthiazide Chlorothiazide Hydrochlorothiazide Hydroflumethiazide Methyclothiazide Polythiazide

Diuretics: Thiazides-like
Distal Convoluted Tubule - Na / Cl Symport Inhibitors

Sulfonamide related compounds

Chlorthalidone [HYGROTON] Indapamide [Natrilix] Metolazone Longer acting and more powerful.

Diuretics: Thiazides
Side Effects
At low doses thiazides are well tolerated Hypokalemia Lipid elevation Glucose intolerance Hyperuricemia Hypercalcemia Very rarely: severe rash, tombocitopenia and leucopenia.

Diuretics: Thiazides
YES: (useful in)
Elderly patients African Americans Patient with mild or
incipient heart failure When cost is crucial When salt intake is high Sexually active females Combined with other first line antihypertensive drugs

No: (avoid in)

Patients with NIDDM Patients with
hyperlipidemia

Patients with gout Sexually active males Glomerular Filtration Rate

< 30ml/min

Diuretics
Potassium-Sparing Diuretics
Amiloride ; Triamterene

Second line anti-hypertensive drugs Used in combination, or for correction of hypokalemia Loop of Henle
Fuosemide [LASIX]; Bumetanide]; Ethacrynic Acid ; Torsemide

Second line anti-hypertensive drugs Used in hypertensive patient with chronic

renal disease for volume/salt control

Aldosterone Antagonists

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR

b2

a1 VSMCs

Resistance arterioles

Capacitance venules

TPVR

Aldosterone Antagonists

Aldosterone Antagonists
Aldosterone Functions: Classical Renal-Ion Transport Site of Action: Collecting duct
Increases Na++ reabsorption (Active)

Increases K+ excretion (Passive?)

Increases H+ excretion (Active & passive)

Aldosterone Antagonists
Prothrombotic effects Myocardial Fibrosis Catecholamine potentiation Vascular inflammation and injury

Potassium and magnesium loss

Central hypertensive effects Endothelial dysfunciton Ventricular arrhythtmias

Deleterious Effects of Aldosterone

Sodium Retention

Cardiovascular Disease
McMahon EG: Current Opinion Pharmacol, 1:190-196, 2001

Aldosterone Antagonists
Indication Spironolactone [ALDACTON]

- Hyperaldosteronism
- In severe heart failure (NYHA Class IV), improves survival and reduces hospitalization (RALES Study) Adverse effects : Hyperkalemia, Gynecomastia, menstrual irregular

Eplerenone
- Hypertension and post-MI heart failure (EPHESUS study) - Anti-oxidant effects (?) - Less adverse effects (gynecomastia) - More expensive

Beta Blockers ( lol)

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR

b2

a1 VSMCs

Resistance arterioles

Capacitance venules

TPVR

b - Blockers

Beta Blockers
Mechanisms and Sites of Action
______________________________

Negative Chronotropic & Inotropic Effects

- Reduction in cardiac output

Inhibition of Renin Release

- Inhibition of renin release - CNS effects - Reduction in venous return and plasma volume - Reduction peripheral resistance - Improve vascular compliance - Resetting of baroreceptor levels - Attenuation of pressor response to catecholamines (stress, exercise) ______________________________

Beta Blockers
Cardioselectivity (Beta-1 vs Beta-2 )
Intrinsic Sympathomimetic Activity (ISA;
partial agonistic activity)

Affinity for alpha-1 adrenergic receptors

(Labetalol, Carvedilol)

Beta Blockers
Approved for hypertension and for one or more of following indications: Angina pectoris Myocardial Infarction Ventricular arrhythmia Migraine prophylaxis Heart Failure Perioperative Hypertension

Beta Blockers ( lol)

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 ]
* - ISA

Beta-1,2/Alpha 1Selective Labetalol [TRANDATE, NORMODYNE] Carvedilol [COREG]

Beta Blockers
Side Effects:

Bronchospasm Bradicardia/heart block Mask and prolong the symptoms of hypoglycemia Abrupt withdrawal can precipitate MI Cold extremities, Raynauds phenomenon, intermittent claudication Decreased exercise tolerance; fatigue, depression and impotence CNS: sleep disturbance, vivid dreams, nightmares Effects of plasma lipids

Beta Blockers
YES: (useful in)
Younger patients Anxious patients Angina pectoris Post-MI patient

No: (avoid in)

Patients with COPD IDDM Pateints with peripheral

vascular disease Raynauds syndrome 2nd and 3rd degree block Energetic patients

Angiotensin Converting Enzyme Inhibitors (ACEIs) & Angiotensin Resptor Blocker (ARB)

ACE Inhibitors Antihypertensive Mechanisms

Inhibition of circulating RAS Inhibition of tissue and vascular RAS Modulation of sympathetic activity Decreased formation of endothelin from
endothelium Increased formation of bradykinin and vasodilatory prostaglandins Decreased sodium retention (decreased aldosterone secretion, and/or increased renal blood flow)

ACEIs : Prevention of vascular disease *

VSMC growth VSMC migration

ACEIs

Ang II

Matrix synthesis

BK

Platelet aggregation
t-PA t-PA inhibitor

* - HOPE Study

ACEIs : Prevention of renal disease

INTRAGLOMERULAR PRESSURE
Arterial pressure Afferent arteriole
Bowmans capsule
+

Angiotensin II

+
20 mmHg

++

Angiotensin II
Efferent arteriole excess glomerular pressure

hyperfiltration microalbuminuria

ACE Inhibitors ( pril)

Captopril Enalapril Lisinopril Benazepril Fosinopril Quinapril Ramipril Spirapril Moexipril Perindopril Trandolapril

ACE Inhibitors: ( pril)

Side effects
Cough ( 10% of pts who receive this drugs) Hypotension (first dose effect) Hyperkalemia Angioedema Renal Insufficiency Fetal injury (2nd & 3rd trimesters) High-dose Captopril Adverse effects ( Neutropenia, Impaired taste, Proteinuria )

ACE Inhibitors ( pril)

YES: (useful in)

Younger patients Post MI LV dysfunction Patient with heart failure Diabetic patients Non-diabetic nephropathy Metabolic disorders (hyperlipidemia, gout)

No: (avoid in)

Renal artery stenosis Fluid-depleted patients Pregnancy Premenopausal women who may become pregnant

Angiotensin Receptor Blockers (ARBs)

Ang II Receptor Blockers (...sartans)

Sartans are selective and competitive antagonists of
angiotensin II type 1 (AT1) receptors and do not inhibit AT2 receptors

The physiological function of angiotensin II is mediated

by AT1 receptors (vasoconstriction, catecholamine release, aldosterone synthesis, and renal sodium and water retention)

Actions of Angiotensin II
Site of Action
Myocyte, Cardiocyte Sympathetic Nerve Endings Glomeruli

Cellular Effect
IP3 and Ca++ increase Protein kinase C Fibroblast stimulation Enhanced NE release Efferent arteriolar constriction Enlarges glomerular pores Renin inhibition Synthesis of Aldosterone Increase of plasminogen activator inhibitor-1

Consequence
Constriction Expression of protooncogenes; cell growth Enhanced Vasoconstriction Promotes microalbuminuria Proteinuria Relief of raised intraglomerular pressure Increased sodium retention and kaliuresis Impaired fibrinolysis

Juxtaglomerular Apparatus Adrenal Cortex Fibrinolytic System

Ang II Receptor Blockers (...sartans)

Losartan Valsartan Irbesartan Candesartan Eprosartan Tasosartan Telmisartan

Ang II Receptor Blockers (...sartans)

Side effects
Dizziness Angioedema has been reported rarely Hyperkalemia, comparable with that seen in

patients treated with ACEIs Risk of fetal injury and death; should not be use during the 2nd and 3rd trimester of pregnancy Risk of symptomatic hypotension in hypovolemic patients

Except for the absence of cough, Yes (useful in) and No (avoid in) same as for ACE inhibitors

Calcium Channel Blockers (CCBs)

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1
AV

Preload
Ang II
Aldosterone

BP= CO x TPVR
Ca++

Resistance arterioles

Capacitance venules

L-type Ca++ channels

TPVR

Calcium Channel Blockers

Calcium Channel Blockers Mechanisms and Sites of Action

Block transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes thus inhibiting excitation-contraction
Negative Inotropic and Chronotropic Effects

Produce Vasorelaxation at Arterioles L-type Ca++ channels

Reduced Peripheral Resistance Nifed>Dilti+Verap Verap+Dilti>Nifed

Calcium Channel Blockers

Dihydropyridines * Amlodipine Felodipine Isradipine Nicardipine Nimodipine Nifedipine *
Phenylalkylamine Verapamil Benzothiazepine Diltiazem

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

Calcium Channel Blockers

Pharmacologic Effects of Calcium Channel Blockers
Effect
Peripheral Vasodilation Heart Rate Cardiac Contractility SA / AV Nodal Conduction Coronary Blood Flow

Verapamil

Diltiazem

Dihydropyridines

0/ 0

Calcium Channel Blockers

Side effects Facial Flushing Headaches Non-pitting ankle edema Constipation Increased CHD mortality controversy: 1995 vs. 1997-2000 data (SYST-EUR
study)

Calcium Channel Blockers

YES: (useful in)
Elderly patients African Americans Patients with peripheral
vascular disease

No: (avoid in)

Patients with heart failure Patients with heart block Patients receiving b-blockers Short-acting dihydropiridines:

Patients with
cerebrovascular disease

Patients with angina

pectoris

Unstable angina Recent MI

a1 - Adrenergic Receptors Blockers

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR

a1 a1
Capacitance venules

a1

a1

Resistance arterioles

TPVR

a1 Receptors Blockers

a1- Receptor Blockers

Inhibition of Vasoconstriction Induced by Endogenous Catecholamines at Arterioles and Veins

Reduced Peripheral Resistance and Reduced Preload

a1- Receptor Blockers

Prazosin Terazosin
Doxazosin [ Tamsulosin for BPH]

Old drugs
Alpha-1 + Alpha 2 Blockers Phenoxybenzamine Phentolamine

a1- Receptor Blockers

Side effects:
First dose hypotension Dizziness, lethargy, fatigue Palpitation, syncope Peripheral edema Incontinence ALLHAT study results: Not to be used as first-line agents

Central a2Agonists

Afterload a2 Volume
Kidneys
Renin Ang I

Vasomotor center

b1

Cardiac Output Heart

b1 Preload

Ang II
Aldosterone

BP= CO x TPVR VSMC

Resistance arterioles

Capacitance venules

TPVR

Central a2 Agonists

Central a2Agonists
Diminished CNS Sympathetic Outflow Activation of Pre-synaptic Alpha-2 Receptors Reduces NE & EPI Release at Synapse
Alpha-2 Agonist
Rostral Ventrolateral Medulla

Post-synaptic Effector

Pre-synaptic Neuron Alpha-1 Receptor Beta Receptor

Alpha-2 Receptor

NE & EPI

Central a2Agonists
Clonidine Methyldopa (first choice for hipertension
in pregnancy)

Old drugs:
[ Guanfacine] [ Guanabenz ]

Combination Drugs in Hypertension

ACE Inhibitor + Diuretic
Benazepril + HCTZ ( Lotensin HCT ) Captopril + HCTZ ( Capozide) Enalapril + HCTZ (Vaseretic ) Lisinopril + HCTZ ( Prinzide , Zestoretic ) Moexipril + HCTZ ( Uniretic ) Quinapril + HCTZ ( Accuretic )

Ang II Receptor Antagonist + Diuretic

Losartan + HCTZ( Hyzaar ) Irbesartan +HCTZ( Avalide ) Valsartan + HCTZ ( Diovan HCT )

Combination Drugs in Hypertension

Beta-Blocker + Diuretic
Atenolol + Chlorthalidone ( Tenoretic ) Bisoprolol + HCTZ ( Ziac ) Metoprolol + HCTZ ( Lopressor HCT ) Propranolol + HCTZ ( Inderide , Inderide LA ) Timolol + HCTZ (Timolide ) Betaxolol + Chlorthalidone ( Kerledex ) Labetalol + HCTZ ( Normozide , Trandate HCT )

Combination Drugs in Hypertension

ACE Inhibitor + Calcium Channel Blocker

Amlodipine + Benazepril (Lotrel ) Enalapril + Diltiazem ( Teczem ) Felodipine + Enalapril ( Lexxel )

Combination Drugs in Hypertension

Alpha-1 Blocker + Diuretic Alpha-2 Agonist + Diuretic
Prazosin + Polythiazide ( Minizine )

Clonidine + Chlorothalidone ( Combipress ) Methyl-dopa + HCTZ ( Aldoril ) Reserpine + HCTZ ( Hydropress ) Reserpine + Chlorthalidone; Reserpine Demi-Regroton,
Regroton Guatethidine + HCTZ ( Esimil )

Neuronal Terminal Inhibitor + Diuretic

Oral Antihypertensive Agents:

Diuretics

Beta Blockers ACE Inhibitors Calcium Channel Blockers Essential Hypertension AT1 Receptor Antagonists Alpha Blocker Alpha1 Blockers a2 - agonist AT1Antagonist Alpha2 Agonists ACE Inhibitor Vasodilators Ganglionic blockers

Summary

Dr. Rx Rational

Vasodilators

Drug of choice

Beta Blocker

Ca++ Antagonist

Diuretic

Questions?