Drugs affecting CVS

Hypertension
• Hypertension can be defined as a
condition in which blood pressure
is elevated to an extent where
benefit is obtained from blood
pressure lowering.
 Hypertension
• There is no clear-cut blood pressure
threshold separating normal from
hypertensive individuals.

• The risk of complications is related to

the extent that blood pressure is
elevated.
 Hypertension
• WHO has identified hypertension as
one of the most important
preventable causes of premature
morbidity and mortality in
developed and developing countries.
• Hypertension should not be seen as a risk

factor in isolation and

• decisions on management should not focus

on blood pressure alone but on total

cardiovascular risk.
• The complications of hypertension include
– stroke,
– myocardial infarction,
– heart failure ,
– renal failure and
– dissecting aortic aneurysm.
• An aortic aneurysm is
an enlargement
(dilatation) of
the aorta.
• They usually cause no
symptoms except when
ruptured
• Small reductions in blood pressure result in
substantial reductions in the relative risks of
these complications.
• For correct diagnosis, careful measurement
of blood pressure is necessary on several
occasions using well-maintained and
validated equipment.
• Non-pharmacological interventions are
important and include
– weight reduction,
– avoidance of excessive salt and alcohol,
– increased intake of fruit and vegetables and
– regular dynamic exercise.
– Avoid smoking
• Other cardiovascular risk factors
such as smoking, hyperlipidaemia
and diabetes should be addressed.
• A large selection of antihypertensive drugs is available.

• It is important to use a drug that is free from adverse

effects.

• The most appropriate choice of initial drug therapy

depends on
– the age and racial origin of the patient,

– as well as the presence of other medical conditions

• For younger white patients an ACE inhibitor
is recommended as first line treatment.
• For older patients and black people, a
calcium channel blocker or thiazide diuretic is
an appropriate initial choice.
• Many people need combination of drugs to
achieve adequate blood pressure control.
• Medication should be convenient to take and
adverse effects should be avoided.
 β-Adrenoceptor Blocking Agents
• Beta-blockers are used for treating
– hypertension,
– angina,
– myocardial infarction,
– arrhythmias and heart failure.
Catecholamine Receptors

• Adrenoceptors have 3 main classes: α1, α2 and β

• Each of these major classes has three subtypes:

– α1A, α1B and α1D

– α2A, α2B and α2C

– β1, β2 and β3

• Each of the adrenergic receptor subtypes is a member of the

G protein-coupled receptor superfamily.
Location of β-adrenergic receptors
• β1- mainly in the heart
and in the kidneys.
• β2-mainly in lungs, GIT,
liver, uterus, vascular
smooth muscle
• β3- fat cells.
• Adrenergic antagonists: Also called
sympatholytics bind to adrenergic receptor.
• Divided into two:
• Alpha blocker
• Beta blocker
 Alpha blocker

• Alpha 1 adrenergic antagonist block the binding

of NE to the smooth muscle receptor.
• Results vasodilation and BP is reduced
• Non-selective alpha blocker: alpha 1 and alpha 2
receptors. Eg. Phentolamine and
phenoxybenzamine
• They are used in the treatment of hypertension
caused by pheochromocytoma (tumour of the
adrenal glands secrete E and NE).
• Nonselective block alpha 2
receptor
• α2-adrenoceptors located on the
sympathetic nerve terminals that
inhibit the release of
norepinephrine and therefore act
as a feedback mechanism for
modulating the release of
norepinephrine.
• Blockade of these receptors
results in more NE release
• NE then stimulate beta 1 receptor
in the heart: tachycardia and even
cardiac arrhythmias
• Selective alpha blocker: Prazosin,
doxazosin
 Beta-blockers
• Beta-blockers are drugs that bind to
beta-adrenoceptors and thereby block the
binding of norepinephrine and epinephrine
to these receptors.
• This inhibits normal sympathetic effects that
act through these receptors.
• Therefore, beta-blockers are sympatholytic
drugs.
• Beta-blockers bind to beta-adrenoceptors
located in cardiac nodal tissue,
the conducting system, and contracting
myocytes.
• The heart has both β1 and β2 adrenoceptors
• β1 is the predominant receptor.
• These receptors primarily bind NE/E that is
released from sympathetic adrenergic
nerves.
• Beta-blockers prevent NE from binding to the
beta-receptor by competing for the binding
site.
 • Beta-adrenoceptors are
coupled to a Gs-proteins
• activate adenylyl cyclase
to form cAMP from ATP.
• increased cAMP activates
a cAMP-dependent
protein kinase (PK-A)
• phosphorylates calcium
channels,
• causes increased calcium
entry into the cell

Fig: Role of sympathetic stimulation on heart

 • Increased calcium entry
during action potentials
leads to enhanced
release of calcium by
the sarcoplasmic
reticulum in the heart;

• these actions increase

inotropy (contractility).

Fig: Role of sympathetic stimulation on heart

 • Gs-protein activation
also increases heart
rate (chronotropy).

• PK-A also
phosphorylates sites on
the sarcoplasmic
reticulum, which lead to
enhanced release of
calcium.

Fig: Role of sympathetic stimulation on heart

• β-blockers are currently recommended as
first-line drug therapy for hypertension when
concomitant disease is present for example,
with heart failure.
• These drugs are efficacious but have some
contraindications.
 Actions
• The β-blockers reduce blood pressure
primarily by decreasing cardiac output .
• They may also decrease sympathetic outflow
from the central nervous system (CNS) and
inhibit the release of renin from the kidneys,
• thus decreasing the formation of angiotensin
II and the secretion of aldosterone.
Figure: Actions of β-adrenoceptor blocking agents.
https://www.youtube.com/watch?v=bY6IWVgFCrQ

https://www.youtube.com/watch?v=qTPqjDD0vhY
• The first generation of beta-blockers were
non-selective.
• Second generation beta-blockers are more
cardioselective for β1adrenoceptors.
• This relative selectivity can be lost at higher
drug doses.
• Third generation beta-blockers possess
vasodilator actions through blockade of
vascular alpha-adrenoceptors.
 Actions
• The prototype β-blocker is propranolol, which
acts at both β1 and β2 receptors.
• Selective blockers of β1 receptors, such as
metoprolol and atenolol, are among the most
commonly prescribed β-blockers.
 Actions
• The selective β-blockers may be administered
cautiously to hypertensive patients who also
have asthma, for which propranolol is
contraindicated due to its blockade of
β2-mediated bronchodilation.
• β2 receptor is also present in arteries of the
skeletal muscle: What will be the effect of
non-selective adrenoreceptor blocker?
 Therapeutic uses
• Subsets of the hypertensive population: The
β-blockers are more effective for treating
hypertension in white than in black patients
and in young compared to elderly patients.
 Therapeutic uses
• Conditions that discourage the use of
β-blockers for example,
– severe chronic obstructive lung disease,
– chronic congestive heart failure, or
– severe symptomatic occlusive peripheral vascular
disease are more commonly found in the elderly
and in diabetics.
 Therapeutic uses
• Hypertensive patients with concomitant
diseases:
• The β-blockers are useful in treating
conditions that may coexist with
hypertension, such as supraventricular
tachyarrhythmia, previous myocardial
infarction, angina pectoris, chronic heart
failure, and migraine headache.
 Pharmacokinetics
• The β-blockers are orally active.
• Propranolol undergoes extensive and highly
variable first-pass metabolism.
• The β-blockers may take several weeks to
develop their full effects.
 Adverse effects
Common effects:
• The β-blockers may cause bradycardia and
CNS side effects such as fatigue, lethargy,
insomnia, and hallucinations; these drugs can
also cause hypotension .
• The β-blockers may decrease libido and cause
impotence. [Note: Drug-induced sexual
dysfunction can severely reduce patient
compliance].
Figure: Some adverse effects of β-blockers.
 Adverse effects
Alterations in serum lipid patterns:
• The β-blockers may disturb lipid metabolism,
decreasing high-density lipoprotein
cholesterol (HDL-C) and increasing plasma
triacylglycerol.
 Adverse effects
Drug withdrawal:
• Abrupt withdrawal may induce angina,
myocardial infarction, or even sudden death in
patients with ischemic heart disease.
• Therefore, the dose of these drugs must be
tapered over 2 to 3 weeks in patients with
hypertension and ischemic heart disease.
• https://www.youtube.com/watch?v=15U9bN
174bk