Pharmacology II (lecture 5)

Antihypertensive agents

Dr. Leena Abdulaziz Muhamed

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Overview:
• Hypertension is the most
common cardiovascular
disease.

• It is defined conventionally
as a sustained increase in
blood pressure ≥140/90
mm Hg.

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• Arterial blood pressure is a function of cardiac
output and peripheral vascular resistance.

• Physiologically blood pressure is maintained

by moment to moment regulation of cardiac
output and peripheral vascular resistance (at
the arterioles, postcapillary venules, the heart
and the kidney).
• Hypertension results from increased peripheral
vascular smooth muscle tone, which leads to
increased arteriolar resistance and reduced
capacitance of the venous system
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Mechanism of regulation of blood pressure:

1. Baroreceptors and the sympathetic nervous

system.

2. Renin-angiotensin-aldosterone system.

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essential hypertension vs secondary hypertension:

• Correctable causes of hypertension include

phaeochromocytoma, steroid-secreting tumours of the
adrenal cortex or narrowing (coarctation) of the aorta.

But most cases involve no obvious cause and are

grouped as essential hypertension.

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• Persistently raised arterial pressure leads to
hypertrophy of the left ventricle and remodelling
of resistance arteries, with narrowing of the
lumen, and predisposes to atherosclerosis.

• Ultimately life threatening hypertesion is

associated with rapidly progressive microvascular
occlusive disease in the kidney (with renal
failure), brain (hypertensive encephalopathy),
congestive heart failure, and pulmonary edema.

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Antihypertensive drugs:
• Drugs lower blood pressure by actions on
peripheral resistance, cardiac output, or both.

1. effect on cardiac output:

inhibiting myocardial contractility, or

decreasing ventricular filling pressure (actions on

the venous tone or on blood volume via renal
effects)

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Antihypertensive drugs:
2. effect on peripheral resistance:
Acting on smooth muscle to cause relaxation of
resistance vessels, or

Interfering with the activity of systems that

produce constriction of resistance vessels (e.g., the
sympathetic nervous system, the renin–angiotensin
system [RAS])

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Antihypertensive drugs:
• Classification of Antihypertensive Drugs by
Their Primary Site or Mechanism of Action:
– Diuretics
– Drugs that alter sympathetic function
– Ca+2 channel blockers
– Angiotensin-converting enzyme inhibitors (ACEIs)
– AngII receptor antagonists (ARBs)
– Direct Renin Inhibitor
– Vasodilators
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Diuretics:
• Diuretics lower blood pressure primarily by
depleting body sodium stores.
• Initially, diuretics reduce blood pressure by
reducing blood volume and cardiac out put;
peripheral vascular resistance may increase.
• After several weeks of therapy, cardiac output
returns toward normal while peripheral vascular
resistance declines.
• Omitting or underutilizing a diuretic is a frequent
cause of “resistant hypertension.”
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Diuretics:(cont.)
• diuretic agents have antihypertensive effects
when used alone, and they enhance the
efficacy of virtually all other antihypertensive
drugs.
1. Thiazide diuretics:
– They decrease blood pressure in both the lying
down and standing positions.
– postural hypotension is rarely observed except in
elderly, volume-depleted patients.
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Diuretics:(cont.)
1. Thiazide diuretics:(cont.)
– Thiazides are useful in combination therapy with a variety
of other antihypertensive agents.
– they are particularly useful in the treatment of black or
elderly patients.
– They are not effective in patients with inadequate kidney
function.
– Even though more diuresis can be achieved with higher
doses of these diuretics, some evidence suggests that
higher doses (higher than 25mg daily) are not generally
more efficacious in lowering blood pressure in patients
with normal renal function.
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Diuretics:(cont.)
2. Loop diuretics:
– Loop diuretics may be particularly useful in
patients with azotemia or with severe edema
associated with a vasodilator such as minoxidil.

– They can act even in patients with poor renal

function or who have not responded to thiazides
or other diuretics.

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Diuretics:(cont.)
3. K+ sparing diuretics:
– They are used in the medical treatment of patients
with hyperaldosteronism.
– Triamterene is a K+ sparing diuretic that
decreases the risk of hypokalemia in patients
treated with a thiazide diuretic but does not have
efficacy in lowering blood pressure by itself.
– Aldosterone receptor antagonists in particular
also have a favorable effect on cardiac function in
people with heart failure.
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 Drugs that alter sympathetic function:
• Early sympathetic drugs used as antihypertensive
agents include:
– centrally acting α2 Adrenergic agonist, and

– other drugs that interfere with the function of the

sympathetic nervous system (adrenergic neuron
blockers and neuronal uptake inhibitor)

• Also drugs that alter sympathetic function include

antagonists of α and β adrenergic receptors.
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 Drugs that alter sympathetic function:
1. α1 adrenergic receptors blockers:
– Initially, α1 adrenergic receptor antagonists reduce
arteriolar resistance and increase venous capacitance;
this causes a sympathetically mediated reflex
increase in heart rate and plasma renin activity.

– During long-term therapy, vasodilation persists, but

cardiac output, heart rate, and plasma renin activity
return to normal.

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Drugs that alter sympathetic function:
1. α1 adrenergic receptors blockers:
– They cause a variable amount of postural
hypotension, depending on the plasma volume.

– They also reduce plasma concentrations of

triglycerides and total LDL cholesterol and increase
HDL cholesterol.

– First-dose phenomenon is A major precaution

regarding their use.

– α1 Receptor antagonists are not recommended as

monotherapy for hypertensive patients
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Drugs that alter sympathetic function:
2. β Adrenergic receptor blockers:
– They affects the regulation of the circulation
through a number of mechanisms, including a
reduction in myocardial contractility, heart rate,
and cardiac output.

– They also block β receptors of the juxtaglomerular

complex, reducing renin secretion and thereby
diminishing production of circulating AngII.

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Drugs that alter sympathetic function:
2. β Adrenergic receptor blockers:
– Some members of this class of drugs have
additional effects unrelated to their capacity to
bind to βadrenergic receptors, e.g.:
• labetalol is an α receptor antagonist

• Nebivolol promotes endothelial cell dependent

vasodilation via activation of the NO pathway

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Drugs that alter sympathetic function:
2. β Adrenergic receptor blockers:
– β receptor antagonists are highly preferred drugs
for hypertensive patients with conditions such as
MI, ischemic heart disease, or congestive heart
failure.

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Drugs that alter sympathetic function:
3. Centrally acting α2 Adrenergic agonist :
– Centrally acting sympathoplegic drugs were once
widely used in treatment of hypertension, but
these drugs are rarely used today with the
exception of clonidine.

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Drugs that alter sympathetic function:
3. Centrally acting α2 Adrenergic agonist :
– Methyldopa is a centrally acting antihypertensive
agent. It is a prodrug that is metabolized in
adrenergic neurons to α-methyldopamine, which
then is converted to α-methylnorepinephrine. α-
Methylnorepinephrine acts in the central nervous
system (CNS) to inhibit adrenergic neuronal
outflow from the brainstem
– Methyldopa is a preferred drug for treatment of
hypertension during pregnancy based on its
effectiveness and safety for both mother and
26 fetus.
Drugs that alter sympathetic function:
3. Centrally acting α2 Adrenergic agonist :
– Clonidine, Guanabenz, and Guanfacine stimulate
the α2A subtype of α2 adrenergic receptors in the
brainstem, resulting in a reduction in sympathetic
outflow from the CNS, and at higher doses they
can activate α2B subtype of α2 receptors on
vascular smooth muscle cells.

– The CNS effects are such that this class of drugs

is not a leading option for monotherapy of
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hypertension.
Drugs that alter sympathetic function:
3. Centrally acting α2 Adrenergic agonist :
– They effectively lower blood pressure in some
patients who have not responded adequately to
combinations of other agents.

– Clonidine has been used in hypertensive patients

for the diagnosis of pheochromocytoma.

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Drugs that alter sympathetic function:
4. Adrenergic neuron blockers :
– These drugs lower blood pressure by preventing
normal physiologic release norepinephrine from
postganglionic sympathetic nerons.

– Guanadrel specifically inhibits the function of

peripheral postganglionic adrenergic neurons. It
acts as a “false neurotransmitter”: It is present in
storage vesicles, depletes the normal transmitter,
and can be released by stimuli that normally
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release NE, but is inactive at adrenergic receptors.
Drugs that alter sympathetic function:
5. neuronal uptake inhibitor:
– Reserpine (an alkaloid) binds tightly to
adrenergic storage vesicles in central and
peripheral adrenergic neurons and remains bound
for prolonged periods of time. The interaction
inhibits the vesicular catecholamine transporter,
so that nerve endings lose their capacity to
concentrate and store NE and dopamine.
– Both cardiac output and peripheral vascular
resistance are reduced during long-term therapy
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with reserpine.
Ca+2 channel blockers:
• Ca +2 channel blockers lower blood pressure
by relaxing arteriolar smooth muscle and
decreasing peripheral vascular resistance.
• In the case of the dihydropyridines,
tachycardia may occur from the adrenergic
stimulation of the SA node; this response is
generally quite modest except when the drug
is administered rapidly.
• Tachycardia is typically minimal to absent
31with verapamil and diltiazem
Ca+2 channel blockers:
• Ca+2 channel blockers are effective when used
alone or in combination with other drugs for
the treatment of hypertension.

• There may be a greater frequency of

achieving blood pressure control with Ca+2
channel blockers as monotherapy in elderly
subjects and in African-Americans.

• Also these drugs may be a preferred treatment

32in patients with isolated systolic hypertension.
ACE inhibitors:
• Captopril was the first such agent to be
developed for the treatment of hypertension.
Since then, enalapril, lisinopril, quinapril,
ramipril, benazepril, moexipril, fosinopril,
trandolapril, and perindopril also have
become available.
• Mechanism of action:
– These drugs block the ACE that cleaves
angiotensin I to form the potent vasoconstrictor
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angiotensin II.
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ACE inhibitors:
• Pharmacodynamics:
– ACE inhibitors cause only a small fall in arterial
pressure in healthy human subjects who are
consuming restricted amount of salt, but a much
larger fall in hypertensive patients, particularly
those in whom renin secretion is enhanced (e.g.
in patients receiving diuretics).

– ACEIs affect capacitance and resistance vessels,

and reduce cardiac load as well as arterial
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pressure.
ACE inhibitors:
• Pharmacodynamics:
– They do not affect cardiac contractility, so cardiac
output normally increases.
– They act preferentially on angiotensin-sensitive
vascular beds, which include those of the kidney,
heart and brain.
– The converting enzyme is also responsible for the
breakdown of bradykinin. ACE inhibitors
decrease angiotensin II and increase bradykinin
levels.
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ACE inhibitors:
• Pharmacokinetics:
– Captopril has a short plasma half-life (about 2 h)
and must be given 2 or 3 times daily. Later ACE
inhibitors have a longer duration of action
(enalaprilat has a half-life of about 11 hours and
lisinopril has a half-life of 12 hours).

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ACE inhibitors:
• Clinical uses:
– Hypertension,
– Cardiac failure,
– Following myocardial infarction (especially when
there is ventricular dysfunction),
– In people at high risk of ischaemic heart disease,
– Diabetic nephropathy,
– Progressive renal insufficiency.
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ACE inhibitors:
• Adverse effects:
– hypotension, especially after the first dose and
especially in patients with heart failure who have
been treated with loop diuretics, in whom the
renin–angiotensin system is highly activated.
– dry cough is the commonest persistent adverse
effect.
– angioedema (painful swelling in tissues which
can be lifethreatening if it involves the airway)
– Patients with severe bilateral renal artery
stenosis predictably develop renal failure if
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treated with ACEIs.