Antihypertensive Drugs

DR. Dr. Nicolaski Lumbuun, SpFK

Clinical Pharmacologist
Faculty of Medicine
 Learning Objectives

• Explain the recent paradigm of treating hypertension

• Describe the Pharmacology of Anti Hypertension Drugs
- Diuretics
- Angiotensin Converting Enzyme (ACE) inhibitors
- Angiotensin Receptor Blockers (ARB)
- Calcium Channel Blockers
- Beta Blockers
- Aldosterone Antagonists
- Alpha Blockers
- Fix dose Combination
 Introduction

• What is Hypertension ?
– What’s the most important thing/how’s the pathophysiology?
– What’s the symptom ?
– How to establish the diagnosis ?
– How to manage the patients?

• 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 Contractility Vasoconstriction

Heart Rate Venous Arteriolar Venous
Circulating
Fluid Volume

Renin
Renal Sympathetic Vascular
Angiotensin
Sodium Nervous Smooth
Aldosterone
Handling System Muscle
System

Vascular remodeling
JNC 7 - 2003
=JNC 8

JAMA. 2014;311(5):507-520
(JNC 8)
Report From the Panel Members Appointed to
the Eighth Joint National Committee (JNC 8)
Dietary Approaches to Stop
Hypertension#

# https://www.nhlbi.nih.gov/health/health-topics/topics/dash
Report From the Panel Members Appointed to
the Eighth Joint National Committee (JNC 8)
 Antihypertensive Agents
Sympatholytic Drugs :
1. Diuretics
6. Alpha-1 Blockers
2. Calcium Channel Blockers
(CCB) 7. Alpha-2 Agonists
3. Angiotensin Converting 8. Peripheral vasodilator
Enzyme Inhibitors (ACE-I) 9. Ganglionic Inhibitors
4. Angiotensin Receptor Blockers 10.Adrenergic Neural
(ARB) Terminal Inhibitors
5. Beta Blocker
* Aldosteron Antagonist (included
as diuretic)
 Antihypertensive Agents

 Therapeutic goals:
To lower the high blood pressure & reduced cardiovascular
morbidity and mortality  increase quality of live

 For most of the HTN patients: life-long treatment of an

asymptomatic disease
 DIURETIC
Mechanism of Action :
Inhibition of
Na++ Reabsorption

 Reduced Circulating Volume

 Reduced Preload
 Reduced Cardiac Output
 Diuretics for hypertension
++++  Thiazides and thiazides-type 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)

 Appropriate for controlling hypertension

 Given once daily

 Diuretics: Thiazides

Distal Convoluted Tubule

- Na/Cl Symport Inhibitors
 Bendroflumethiazide
 Benzthiazide
 Chlorothiazide
 Hydrochlorothiazide
 Hydroflumethiazide
 Methyclothiazide
 Polythiazide
 Diuretics: Thiazides-type

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, thrombocitopenia and
leucopenia.
 Diuretics: Thiazides

 YES: (useful in)  No: (avoid 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
 Patients with type-2 DM
 Patients with hyperlipidemia
 Patients with gout
 Sexually active males
 Glomerular Filtration Rate <
30ml/min
 Diuretics: Others

 Potassium-Sparing Diuretics
Spironolactone ; Amiloride ; Triamterene
 Second line anti-hypertensive drugs
 Used in combination, or for correction of hypokalemia
 Loop of Henle
Furosemide/frusemide [LASIX]; Bumetanide];
Ethacrynic Acid ; Torsemide
 Second line anti-hypertensive drugs
 Used in Congestive Heart Failure, moderate to
severe oedema
 Angiotensin Converting
Enzyme Inhibitors (ACEIs)
&
Angiotensin Receptor Blocker
(ARB)
 ACE Inhibitors
Antihypertensive Mechanisms
 Inhibition action of RAS :
 Decrease circulating RAS
 Inhibit receptors 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)
 ACE Inhibitors ( … pril)

Captopril Moexipril
Enalapril Perindopril
Lisinopril Trandolapril
Benazepril
Fosinopril
Quinapril
Ramipril
Spirapril
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)  No: (avoid in)
 Younger patients  Black American
 Post MI LV dysfunction  Renal artery stenosis
 Patient with heart failure  Fluid-depleted patients
 Diabetic patients  Pregnancy
 Non-diabetic nephropathy  Premenopausal women
 Metabolic disorders who may become pregnant
(hyperlipidemia, gout)
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)
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 Vasomotor center
Volume
Kidneys Cardiac Output
b1 Heart
Renin
b1
Ang I
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

Produce Vasorelaxation Negative Inotropic and

at Arterioles Chronotropic Effects

L-type Ca++ channels

Reduced Peripheral Resistance

Nifed>Dilti+Verap Verap+Dilti>Nifed
 Calcium Channel Blockers

 Dihydropyridines *  Phenylalkylamine
 Amlodipine  Verapamil
 Felodipine
 Isradipine  Benzothiazepine
 Nicardipine  Diltiazem
 Nimodipine
 Nifedipine *
* long-acting or slow-release
formulations should be used
for high blood pressure
 Calcium Channel Blockers

Pharmacologic Effects of Calcium Channel Blockers

Effect Verapamil Diltiazem Dihydropyridines

Peripheral ↑ ↑ ↑↑
Vasodilation
Heart Rate ↓↓ ↓ ↑
Cardiac ↓↓ ↓ 0/↓
Contractility
SA / AV Nodal ↓ ↓ 0
Conduction
Coronary Blood ↑ ↑ ↑↑
Flow
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)  No: (avoid in)

 Elderly patients
 African Americans
 Patients with peripheral
vascular disease
 Patients with
cerebrovascular disease
 Patients with angina
pectoris
 Patients with heart failure
 Patients with heart block
 Patients receiving b-blockers
 Short-acting dihydropiridines:
 Unstable angina
 Recent MI
Beta Blockers ( … lol)
 Afterload
a2 Vasomotor center
Volume
Kidneys Cardiac Output
b1 Heart
Renin
b1
Ang I

Preload
Ang II

BP= CO x TPVR b2 a1
Aldosterone
VSMCs
Resistance arterioles Capacitance venules

TPVR
b - Blockers
 Beta Blockers
Mechanisms and Sites of Action

______________________________

- Reduction in cardiac output

Negative Chronotropic - Inhibition of renin release
- CNS effects
& Inotropic Effects - Reduction in venous return & plasma
volume
- Reduction peripheral resistance
- Improve vascular compliance
- Resetting of baroreceptor levels
- Attenuation of pressor response to
Inhibition of catecholamines (stress, exercise)
Renin Release ______________________________
 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  Beta-1-Selective
 Propranolol [INDERAL]  Acebutolol [SECTRAL] *
 Nadolol [CORGARD]  Atenolol [TENORMIN]
 Carteolol [CARTROL] *  Betaxolol [KERIONE]
 Timolol [BLOCADREN]  Bisoprolol [ZEBETA]
 Pindolol [VISKEN] *  Esmolol [BREVIBLOC]
 Sotalol [BETAPACE]
 Metoprolol [LOPRESSOR ]
 Penbutol [LEVATOL] *
* - 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, Raynaud’s 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)  No: (avoid in)
 Younger patients  Patients with COPD, Type-2
DM
 Anxious patients  Patients with peripheral
 Angina pectoris vascular disease
 Post-MI patient  Raynaud’s syndrome
 2nd and 3rd degree block
 Energetic patients
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)
 Effect of Aldosterone

Prothrombotic Vascular inflammation

Potassium and
effects and injury
magnesium loss
Myocardial
Fibrosis Central
Deleterious Effects of hypertensive
effects
Catecholamine Aldosterone
potentiation Endothelial
dysfunciton
Sodium Ventricular
Retention arrhythtmias

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
a1 - Adrenergic Receptors
Blockers=alpha blockers
 Afterload
a2 Vasomotor center
Volume
Kidneys Cardiac Output
b1 Heart
Renin

Ang I b1

Preload
Ang II

BP= CO x TPVR a1 a1
Aldosterone a1
a1
Resistance arterioles Capacitance venules

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 a2–Agonists
 Afterload
a2 Vasomotor center
Volume
Kidneys Cardiac Output
b1 Heart
Renin

Ang I b1

Preload
Ang II

Aldosterone
BP= CO x TPVR

VSMC
Resistance arterioles Capacitance venules

TPVR Central
a2 Agonists
 Central a2–Agonists

Activation of Pre-synaptic
Diminished CNS Alpha-2 Receptors Reduces
Sympathetic Outflow NE & EPI Release at Synapse

Alpha-2 Agonist
Post-synaptic
Rostral
Effector
Ventrolateral
Medulla
Pre-synaptic Neuron

Alpha-1 Receptor
Alpha-2 Receptor Beta Receptor
NE & EPI
 Central a2–Agonists
 Clonidine
 Methyldopa (first choice for hypertension 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

 ACEI/ARB + Calcium Channel Blocker

 Benazepril + Amlodipine (Lotrel ® )

 Valsartan + Amlodipine (Exforge ®)
 Enalapril + Diltiazem ( Teczem ® )
 Felodipine + Enalapril ( Lexxel ® )
 Hypertension Emergency

• BP reaches levels that are damaging organs.

• Generally occur at BP levels 180mmHg and/or OR 120mmHg,
but can occur at even lower levels in patients whose blood
pressure had not been previously high.
• Impending target organ damage :
• Stroke • Loss of kidney function
• Loss of consciousness • Aortic dissection
• Memory loss • Angina (unstable chest pain)
• Heart attack • Pulmonary edema
• Damage to the eyes and kidneys • Eclampsia
 Treatment

• The primary goal : to determine which patients with acute

hypertension are exhibiting symptoms of end-organ damage
and require immediate intravenous (IV) parenteral therapy.
• Control of hypertensive situations balances the benefits of
immediate decreases in BP against the risk of a significant
decrease in target organ perfusion.
• Pharmacotherapy :
– Sodium nitroprusside
– Labetalol
– Clevedipine
– Nicardipine
Summary
Questions?