Antihypertensive Drugs

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

Ways of Lowering Blood Pressure

MAP = CO X TPR

Reduce cardiac output (blockers, Ca2+ channel

blockers)

Reduce plasma volume

(diuretics)

Reduce peripheral vascular

resistance (vasodilators)

Major Risk Factors That Increase

Mortality in Hypertension
Smoking
Dyslipidemias
Diabetes
Age

Mellitus

>60
Gender: men, postmenopausal women
Family history

"Individualized Care"
Risk

factors considered
Monotherapy is instituted
Non pharmacological therapy tried first
Considerations for choice of initial
monotherapy:

Renin status
Coexisting cardiovascular conditions
Other conditions

Treatment Thresholds for Essential Hypertension

Stages

Risk group A

Risk Group B

Risk Group C

(no major risk

factors, no target
organ damage)

One or more major

risk factors
(except diabetes),
no organ damage

Target organ
damage and/or
diabetes

High
Normal

Lifestyle
Modification

Lifestyle
Modification

Lifestyle
Modification and
Drug Therapy

Stage 1

Lifestyle
Modification (up
to 12 months)

Lifestyle
Modification and
Drug Therapy

Lifestyle
Modification and
Drug Therapy

Stages 2
and 3

Lifestyle
Modification and
Drug Therapy

Lifestyle
Modification and
Drug Therapy

Lifestyle
Modification and
Drug Therapy

Monotherapy for Hypertension

ACE inhibitors and ATII antagonists

Diuretics
-adrenoceptor blockers
1-adrenoceptor blockers

Ca2+ channel blockers

Benzothiazide Diuretics
Mechanism

of action

Indications

Monotherapy for mild-moderate HTN

Adjunct agent
Usually necessary in severe HTN

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 volumeexpanded forms of hypertension

-Adrenoceptor blockers
Mechanism

of Action:
-adrenoceptor antagonism

Why

blood pressure reduction?

Reduction of Cardiac output

Reduction of renin release
Central nervous system - reduction of sympathetic
outflow

Types of -blockers:

Non selective
Prototype: Propranolol (others: nadolol, timolol, pindolol,
labetolol)

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

Non selective and cardioselective -blockers are EQUALLY

effective in reducing blood pressure

Other Properties Relevant to

Antihypertensive Effect:
Intrinsic

sympathomimetic activity.
Mixed antagonism.

Therapeutic Use in Hypertension

Monotherapy
most

effective in high renin

hypertension
hypertension with coronary
insufficiency
low cost to patient

Adverse Effects
Bradycardia
Heart

failure
Bronchospasm
Coldness of extremities
Withdrawal effects
Glucose metabolism

5.

Adverse Effects (Cont)

CNS

effects
Pregnancy
Rise in plasma triglyceride concentration; decrease in
HDL cholesterol
Drug interactions:

NSAID'S - can blunt effect of -blockers

Epinephrine - causes severe hypertension in presence of
-blockade
Ca2+channel blockers Conduction effects on heart are
additive w/ blockers.

-Adrenoceptor Blockers
Mechanism

of action: blockade of vascular

adrenoceptors
Non selective (1 and 2) blockers:
Phentolamine, phenoxybenzamine and
dibenamine
Selective (1) prototype: prazosin (others:
terazosin, doxazosin, trimazosin)

Therapeutic Use in Hypertension

selective ( and ) blockers: used for
treatment of hypertensive crises in
pheochromocytoma
Selective (1) blockers
Non

Monotherapy
Adjunctive

therapy

Administration of 1-Adrenoceptor
Blockers
Read
The
Book

Side effects of 1-adrenoceptor

blockers
First

dose phenomenon
Tachycardia
GI effects (rare)

Adverse Effects of Non Specific Adrenoceptor Blockers

Postural

hypotension
Reflex tachycardia
Fluid retention

Other Sympatholytics
Guanethidine
Ganglionic

blockers

Guanethidine
Mechanism

of action
Therapeutic use

Ganglionic Blockers (Trimethaphan)

Mechanism

of action
Therapeutic use

Drugs Interacting With the Reninangiotensin System

ACE inhibitors
ATII antagonists

Physiology of Renin-Angiotensin
System
Details:

Katzung,
Chapter 17

Receptor Subtypes for Angiotensin

AT1

AT1A

AT1B

Prototype antagonist: Losartan

AT2 Primary antagonist available is PD123177

AT3? AT4

Angiotensin Converting Enzyme

(ACE) Inhibitors
Mechanism

of Action: Inhibition of
angiotensin II formation
Competitive inhibition of angiotensin
converting enzyme reduces circulating ang II,
reducing vascular tone.

Systemic Effects of ACE Inhibitors

Reduction

in systemic arteriolar resistance,

systolic, diastolic and mean arterial
pressure.
Regional hemodynamic effects:

Increased regional blood flow in proportion to

ang II sensitivity of the vascular bed
Increased large artery compliance
Cardiac output and heart rate unchanged

Aldosterone

secretion reduced

Types of ACE Inhibitors

Active

molecules: Captopril, Lisinopril,

Enalaprilat
Prodrugs: Enalapril, Benazepril, Fosinopril,
Quinapril, Ramipril, Moexipril, Spirapril

Therapeutic Uses in Hypertension

One of the initial choices for monotherapy of mild to

moderate hypertension
Well tolerated as monotherapy. Drugs of choice in
diabetes mellitus with hypertension
Most effective in high renin hypertension
More effective in white vs. Black patients
Excellent for patients with concomitant congestive
heart failure, LVH, cardiac arrhythmias or diabetes
mellitus, consider in asthma instead of -blockers
Efficacy enhanced by diuretics

Administration
Captopril
Prodrugs:

inactive prodrug is hydrolyzed

in vivo to active compound, e.g., enalapril
to enalaprilat
Lisinopril

ACE Inhibitor Adverse Reactions

Hypotension
Renal

insufficiency
Cough
Hyperkalemia
Hyperreninemia

Minor Adverse Effects of ACE

Inhibitors
Ageusia
Skin

rash
Proteinuria
Neutropenia

Pharmacology of AT-Receptor
Antagonists
Losartan
Valsartan
Candesartan
*sartan

Mechanism of Action of ATII

Antagonists
Molecular:

Competitive inhibitor of AT1

receptors. Blocks ability of angiotensins II and
III to stimulate pressor and cell proliferative
effects

Antihypertensive
Cell

effects

growth effects

Lack

of bradykinin effects

Clinical Indications for ATII

Antagonists
Hypertension
Heart

failure
Prevention of restenosis following angioplasty

Ca2+ Channel Blockers

One of the initial choices for monotherapy of mild to

moderate hypertension
all CEB's are equally effective when used as
monotherapy for Stage 1 hypertension
Verapamil and diltiazem are vasodilators that do not
cause reflex tachycardia due to direct inhibition of
cardiac automaticity
Best in low renin hypertension: Blacks and elderly
do not cause fluid retention

Hydralazine

Direct acting vasodilator: liberates NO from vascular endothelium

which stimulates the production of cGMP in vascular smooth
muscle, resulting in relaxation (arterioles > veins)
Can NOT be used for monotherapy
Bioavailability dependent on genetic factors (fast or slow
acetylators)
Tachycardia with palpitations, hypotension OFTEN
Lupus-like syndrome may occur with chronic use that is reversible
upon continuation
Never use as first choice; Try in refractory hypertension as part of
a multidrug regimen

Minoxidil
Prodrug

of minoxidil N-O sulfate, which is a

direct acting vasodilator
Mechanism: K+ channel opener, causes
membrane hyperpolarization, reducing ability
of smooth muscle to contract.
Other K channel openers: pinacidil,
diazoxide
refractory hypertension
Long duration of action (>24 hours)

Minoxidil Adverse Effects

Fluid

and water retention: can lead to

pulmonary hypertension
Tachycardia and increased cardiac output:
can progress to congestive heart failure
Hypertrichosis: Occurs in all patients who
take therapeutic doses of minoxidil for a
prolonged time

Centrally Acting Sympatholytics:

2-Adrenoceptor Agonists
Methyldopa
Clonidine
Guanabenz
Guanfacine

2-Adrenoceptor Agonists
Mechanisms of Action

Central Action: Stimulation of 2 adrenoceptors in the

brainstem reduces sympathetic tone, causing a centrally
mediated vasodilatation and reduction in heart rate

Prejunctional action: Stimulation of 2 adrenoceptors

located prejunctionally on peripheral neurons reduces
norepinephrine release
Vascular smooth muscle: 2 adrenoceptors located on
vascular smooth muscle open Ca2+ channels and cause
vasoconstriction. Not evident clinically unless given
intravenously

Mechanisms of Action (cont.)

Clonidine,

guanabenz and guanfacine:

Direct acting adrenoceptor agonists.
2

-methyldopa:

Prodrug taken up by
central adrenergic neurons and
converted to the adrenoceptor agonist
-methylnorepinephrine.
2

Therapeutic Uses in Hypertension

Not

generally used for monotherapy of mild to

moderate hypertension
Considerations

fluid retention: must use diuretic

Direct acting 2 adrenoceptor agonists: effective
in lowering blood pressure in ALL patients.
Direct acting 2 adrenoceptor agonists are equally
efficacious but more efficacious than -methyldopa

Other Use
Clonidine

is useful in diagnosis of
pheochromocytoma. Clonidine (single 0.3 mg
dose) will reduce plasma norepinephrine
concentration to below 500 pg/ml in tumor-free
patients.

Administration: Methyldopa
Short

plasma half life (2 hours) but longer

action (peak at 6-8 hours, duration 24 hours
Once or twice daily dosing due to long action
Action prolonged in patients with renal
insufficiency

Administration: Clonidine,
Guanabenz and Guanfacine
Orally active, good absorption, usually given
twice daily
Clonidine: available as a sustained release
transdermal patch (avoids withdrawal
syndrome)

Adverse Effects of 2-Adrenoceptor

Agonists
Hypotension

especially in volume depleted

patients
Sedation: more prominent for direct acting 2
adrenoceptor agonists - 50% of patients
Withdrawal syndrome: hypertension,
tachycardia, nervousness and excitement.

Adverse Effects Unique to

Methyldopa:
Heart

block (methyldopa)
Immunological changes: positive Coombs test
(20% after 1 year), lupus like syndrome,
leukopenia, red-cell aplasia
Altered liver function 5%
Hyperthermia
Reduced mental acuity

Adverse Effects of Clonidine, et al:

Dry

mouth, nasal stuffiness

Contact dermatitis with clonidine patch: 20%
Vivid dreams
Restlessness
Depression (infrequent)

 2-Adrenoceptor Agonist Drug

Interactions
Diuretics

enhance hypotensive action

Tricyclic antidepressants inhibit clonidine's
action

Reserpine
Molecular mechanism of action: Inhibition of
noradrenergic function.

Reserpine binds to storage vesicles and releases

norepinephrine and serotonin.
Storage vesicles are destroyed and nerve ending loses
capacity to store and release norepinephrine and
serotonin
Pharmacological consequences: reduction of cardiac
output and TPR

Reserpine
Extremely

long acting
Tolerated well (as well as diuretic plus
propranolol in Veteran's cooperative study)
CNS effects:

Sedation, loss of concentration

psychotic depression. Depression: insidious
progression that can lead to suicide