Antihypertensive Drugs

Definition

Elevation of arterial blood pressure above

140/90 mm Hg. Can be caused by:
• an underlying disease process
(secondary hypertension)
• Renal artery stenosis
• Hyperaldosteronism
• pheochromocytoma
• idiopathic process (primary or essential
hypertension)
Mortality Is Related to Blood
Pressure
Major Risk Factors That Increase
Mortality in Hypertension

 Smoking
 Dyslipidemias
 Diabetes Mellitus
 Age >60
 Gender: men, postmenopausal women
 Family history
Treatment Rationale

Short-term goal of antihypertensive therapy:

Reduce blood pressure

• Primary (essential) hypertension

• Secondary hypertension
Treatment Rationale

Long-term goal of antihypertensive therapy:

Reduce mortality due to hypertension-induced disease
 Stroke
 Congestive heart failure
 Coronary artery disease
 Nephropathy
 Peripheral artery disease
 Retinopathy
 Treatment Thresholds for Essential Hypertension

Stages Risk group A Risk Group B Risk Group C

(no major risk One or more major Target organ
factors, no target risk factors damage and/or
organ damage) (except diabetes), diabetes
no organ damage

High Lifestyle Lifestyle Lifestyle

Modification Modification Modification and
Normal Drug Therapy

Stage 1 Lifestyle Lifestyle Lifestyle

Modification (up Modification and Modification and
to 12 months) Drug Therapy Drug Therapy

Stages 2 Lifestyle Lifestyle Lifestyle

Modification and Modification and Modification and
and 3 Drug Therapy Drug Therapy Drug Therapy
Kieran McGlade Nov 2001 Department of General Practice QUB
 Therapeutic targets
Measured in clinic Mean daytime ABPM
or home measurement

Blood Pressure No diabetes Diabetes No diabetes Diabetes

Optimal <140/85 <140/80 <130/80 <130/75
Audit Standard <150/90 <140/85 <140/85 <140/80

The audit standard reflects the minimum recommended levels of BP control. Despite best practice, it may not be
achievable in some treated hypertensive patients.
NB: Both systolic and diastolic targets should be reached

British Hypertension Society Guidelines

Kieran McGlade Nov 2001 Department of General Practice QUB
Ways of Lowering Blood Pressure

 Reduce cardiac output (ß-

blockers, Ca2+ channel
blockers)

 Reduce plasma volume

(diuretics)

 Reduce peripheral
vascular resistance
(vasodilators)

MAP = CO X TPR
Physiologic Components of BP
Heart
HR

Veins
Stroke Arteries
Volume
SVR
 Thiazide Diuretics
• Mechanism: inhibit Na/K pumps in
Veins
the distal tubule
• Examples:
•Hydrocholorthiazide 12.5-25 mg daily
Thiazides •Chlorthalidone 12.5-50 mg daily

• Effective first line agent and

provides synergistic benefit
• As single agent more effective if
CrCl >30 ml/min
• Compelling indications: HF, High
CAD risk, Diabetes, Stroke, ISH
Thiazide diuretics: considerations
• Long-term hypokalemia appears to
increase mortality.
• K-sparing diuretics are superior to K
supplementation when diuretics used.
• Most efficacious in “low renin” or
volume-expanded forms of hypertension
 Diuretics:
Sites of Action
Carbonic Anhydrase
Inhibitors Thiazides
Eg: Acetazolamide Eg: Chlorothiazide
HCO3- Na+
Cl-

Na+ K+ - Sparing
Eg: ?

Na+ K+
Loop Diuretics Cl-
Eg: Furosemide K+
 Loop Diuretics
• Mechanism: Inhibit Na/K/Cl ATPase
Veins
in ascending loop of henle
• Examples:
•Furosemide 20 mg BID
Thiazides
• Typically only beneficial in patients
Loops with resistant HTN and evidence of
fluid; effective if CrCl <30 ml/min
• MUST be dosed at least twice daily
(Lasix = Lasts six hours)
• Administer AM and lunch time to
avoid nocturia
Aldosterone Receptor Antagonists
• Mechanism: inhibit aldosterone’s
Veins
effect at the receptor, reducing Na
and water retention
• Examples:
Thiazides •Spironolactone 25 mg daily
Loops • Can provide as much as 25 mmHg
Aldosterone Ant. BP reduction on top of 4 drug
regimen in resistant hypertension
• Monitor SCr and K
• Compelling indications: HF

Am J Hypertension. 2003; 16:925-930.

 Nitrates
• Mechanism: Direct venodilation by
Veins
release of nitric oxide
• Examples:
•Isosorbide dinitrate 10 mg TID
Thiazides •IMDUR 30 mg daily
Loops
• In renal patients with resistant
Aldosterone Ant. hypertension addition to 3-4 drug
Nitrates regimen may help get patient to
goal
• Provide 8h nitrate free interval daily
• Compelling indications: Angina
 ACEI & ARB’s
• Mechanism: Inhibit vasoconstriction
Veins by inhibiting synthesis or blocking
action of angiotensin II; provides
balanced vasdilation
• Examples:
Thiazides •Enalapril 2.5-40 mg daily –BID
Loops •Lisinopril 5 – 40 mg daily
Aldosterone Ant.
•Irbesartan 150-300 mg daily
Nitrates
•Losartan 25-100 mg Daily - BID

• Monitor: SCr, K
ACEI
ARB • Compelling indications: HF, post-MI,
High CAD risk, Diabetes, CKD,
Stroke
 Beta Blockers
• Mechanism: Competitively inhibit
Heart the binding of catecholamines to
beta-adrenergic receptors
• Examples:
•Atenolol 25-100 mg PO daily
Beta Blockers
•Metoprolol 25 -100 mg PO daily or BID
•Carvedilol 6.25-25 mg PO BID

• Monitor: HR, Blood Glucose in DM

• Not contraindicated in asthma or
COPD but use caution
• Compelling indications: HF, post-MI,
High CAD risk, Diabetes
 ß-Adrenoceptor blockers
• Mechanism of Action:
ß-adrenoceptor antagonism

• Why blood pressure reduction?

– Reduction of Cardiac output
– Reduction of renin release
– Central nervous system - reduction of
sympathetic outflow
 Types of ß-blockers:
• Non selective
Prototype: Propranolol (others: nadolol, timolol, pindolol,
labetolol)

• Cardioselective
Prototype: Metoprolol (others: atenolol, esmolol, betaxolol)

• Non selective and cardioselective ß-blockers are EQUALLY

effective in reducing blood pressure
 Adverse Effects

• Bradycardia
• Heart failure
• Bronchospasm
• Coldness of extremities
• Withdrawal effects
• Glucose metabolism
Alpha2 Agonists: Central Acting Agents
• Mechanism: false neurotransmitters
Heart reduce sympathetic outflow
reducing sympathetic tone
• Examples:
•Clonidine 0.1-0.6 mg PO BID-TID; patch
Beta Blockers
•Methyldopa, Guanabenz, Guanfacine
Diltiazem
Verapamil • Monitor: HR
• Side effects often limiting: Dry
Via Central mouth, orthostasis, sedation
Mechanism: • Clonidine patch can be useful in
Clonidine elderly patients with labile blood
pressure
• Withdrawal: real at doses > 0.3 mg
 Diltiazem and Verapamil
• Mechanism: Decrease calcium
Heart influx into cells of vascular smooth
muscle and myocardium
• Examples:
•Diltiazem 60-480mg q6h to daily
Beta Blockers
•Verapamil 60-480 q8h to daily
Diltiazem
Verapamil • Monitor: HR
• Verapamil causes constipation
• Relatively contraindicated in heart
failure
• Compelling indications: Diabetes,
High CAD risk
Dihydropyridine Calcium Channel Blockers
• Mechanism: Decrease calcium
influx into cells of vascular smooth
Arteries
muscle
• Examples:
•Amlodipine 2.5-10 mg PO daily
Dihydropyridine
CCBs •Felodipine2.5-10 mg PO daily
•Do not use immediate release
nifedipine

• Monitor: Peripheral edema, HR (can

cause reflex tachycardia)
• Good add on agent if cost is not an
issue
 Vasodilators
• Mechanism: Direct vasodilation of
arterioles via increased intracellular
Arteries
cAMP
• Examples:
•Hydralazine 20-400 mg BID-QID
Dihydropyridine
CCBs •Minoxidil 2.5-40 mg PO daily-BID
Hydralazine • Monitor: HR (can cause reflex
Minoxidil tachycardia), Na/Water retention
• Hydralazine is an alternative in HF if
ACEI contraindicated
• Consider minoxidil in refractory
patients on multi-drug regimens
 Alpha1 Blockers
• Mechanism: Inhibit peripheral post-
Arteries synaptic alpha1 receptors causing
vasodilation
• Examples:
Dihydropyridine •Terazosin 1 – 20 mg daily
CCBs •Doxazosin 1 – 16 mg daily
Hydralazine • Cause marked orthostatic
Minoxidil hypotension, give dose at bedtime
Alpha1 Blockers • Consider only as add on therapy
• Can be beneficial in patients with
BPH
 a-Adrenoceptor Blockers

• Mechanism of action: blockade of

vascular a-adrenoceptors
• Non selective (a1 and a2) blockers:
Phentolamine, phenoxybenzamine and
dibenamine
• Selective (a1) prototype: prazosin
(others: terazosin, doxazosin,
trimazosin)
Adverse Effects of Non Specific
a-Adrenoceptor Blockers

• Postural hypotension
• Reflex tachycardia
• Fluid retention
 ACEI & ARB’s
• Mechanism: Inhibit vasoconstriction
by inhibiting synthesis or blocking
Arteries action of angiotensin II; provides
balanced vasdilation
• Examples:
Dihydropyridine •Enalapril 2.5-40 mg daily –BID
CCBs
•Lisinopril 5 – 40 mg daily
Hydralazine
•Irbesartan 150-300 mg daily
Minoxidil
•Losartan 25-100 mg Daily - BID
Alpha1 Blockers
ACEI • Monitor: SCr, K
ARB • Compelling indications: HF, post-MI,
High CAD risk, Diabetes, CKD,
Stroke
Monotherapy for Hypertension
• ACE inhibitors and ATII antagonists
• Diuretics
• ß-adrenoceptor blockers
• a1-adrenoceptor blockers
• Ca2+ channel blockers
Pharmacologic Sites of Action
Veins Heart
Arteries

Thiazides Beta Blockers Dihydropyridine

Loops Diltiazem CCBs
Aldosterone Ant. Verapamil Hydralazine
Nitrates Minoxidil
Via Central Alpha1 Blockers
ACEI Mechanism: ACEI
ARB Clonidine ARB
 Algorithm for Treatment of Hypertension
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling With Compelling

Indications Indications

Stage 1 HTN (SBP 140–159 or
DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB,
CCB, or combination.
Stage 2 HTN (SBP >160 or DBP
>100 mmHg)
2-drug combination for most
(usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.

Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

 Logical Combinations

b- ACE a-
Diuretic CCB
blocker inhibitor blocker
Diuretic -  -  

b-blocker  - * - 

CCB - * -  

ACE inhibitor  -  - 

a-blocker     -
* Verapamil + beta-blocker = absolute contra-indication

Kieran McGlade Nov 2001 Department of General Practice QUB

 Compelling Indications for
Individual Drug Classes
Compelling Initial Therapy Clinical Trial Basis
Indication Options

Heart failure THIAZ, BB, ACEI, ACC/AHA Heart Failure

ARB, ARA Guideline, MERIT-HF,
COPERNICUS, CIBIS, SOLVD,
AIRE, TRACE, ValHEFT, RALES
Postmyocardial BB, ACEI ACC/AHA Post-MI Guideline,
infarction BHAT, SAVE, Capricorn,
EPHESUS

High CAD risk THIAZ, BB, ACEI, ALLHAT, HOPE, ANBP2, LIFE,
CCB CONVINCE
 Compelling Indications for
Individual Drug Classes
Compelling Initial Therapy Clinical Trial Basis
Indication Options

Diabetes ACEI, ARB, CCB, NKF-ADA Guideline, UKPDS,

THIAZ, BB, ALLHAT

Chronic kidney ACEI, ARB NKF Guideline, Captopril Trial,

disease RENAAL, IDNT, REIN, AASK

Recurrent stroke THIAZ, ACEI PROGRESS

prevention