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Cardiovascular Pharmacology

Global Overview/Review
Topics discussed:
Autonomic Nervous System
and
Blood Pressure Control
eNotes:
Cardiovascular
Pharmacology

Antihypertensive Drugs
Drugs for Angina

ACE Inhibitors
Calcium Channel
Blockers
Prepared and presented by:
Marc Imhotep Cray, M.D.

Adrenergic Blockers
Cardiac Glycosides

Blood Pressure

Blood Pressure(2)

Autonomic Nervous System and


Blood Pressure Control
Cardiac Output (Output of Pump)
heart rate x stroke volume

Caliber of Arteries & Arterioles


(Flow Resistance)
Neural
sympathetic & parasympathetic NS

Hormonal
Renin-angiotensin-aldosterone system

Local transmitters
Nitric Oxide (NO)

Neural Control of the CVS:


Autonomic Nervous System
Higher Centers
Vasomotor
Center

Carotid Sinus
Brain Stem

Parasympathetic
(Vagus)
-Adrenoceptor

Spinal Cord

Sympathetic
-Adrenoceptor
Arteriole

Baroreceptor Reflexes
in BP Control

BP

Parasympathetic

Sympathetic

Baroreceptor Reflexes
in BP Control
2

BP

Carotid sinus
senses BP

Parasympathetic

Sympathetic

Baroreceptor Reflexes
1 BP
in BP Control
Vasomotor Center responds
with Symp. NS activity
3
and Parasymp. activity

Carotid sinus
senses BP

Parasympathetic

Sympathetic

Baroreceptor Reflexes
in BP Control
3

Vasomotor Center responds


with Symp. NS activity
and Parasymp. activity

BP

Carotid sinus
senses BP

Parasympathetic

Sympathetic

Heart rate
and contractility

4
PVR
9

Baroreceptor Reflexes
in BP Control
Vasomotor Centre responds
with Symp. NS activity
3 and Parasymp. activity

BP

Carotid sinus
senses BP

Parasympathetic

Sympathetic

Heart rate
and contractility

4
PVR

BP
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Blood Pressure Control:


Control of Stroke Volume

Cardiac Output (Output of Pump)


heart rate x stroke volume

Caliber of Arteries & Arterioles (Flow


Resistance)
Neural
sympathetic & parasympathetic NS

Hormonal
Renin-angiotensin-aldosterone system

Local transmitters
Nitric Oxide (NO)

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Stroke volume (SV)


Stroke volume (SV) is volume of
blood pumped by right/left
ventricle of heart in one
contraction
Specifically, it is volume of blood
ejected from ventricles during
systole
Calculation
Its value is obtained by subtracting end-systolic
volume (ESV) from end-diastolic volume (EDV)
for a given ventricle:
SV = EDV ESV
In a healthy 70-kg man, the left ventricular EDV
is 120 ml and the corresponding ESV is 50 ml,
giving a stroke volume of 70 ml.

SV is not all of blood


contained in left ventricle
Normally, only about twothirds of blood in ventricle is
put out with each beat
What blood is actually
pumped from left ventricle
is stroke volume and it,
together with heart rate,
determines the cardiac
output
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Blood Pressure Control:


Control of Stroke Volume
Factors Determining Stroke Volume
Contractility
sympathetic activity increases contractility

End-diastolic volume
Determined by venous filling pressure (distensible
ventricle)
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Blood Pressure Control:

Stroke Volume

Control of Stroke Volume


Venous filling pressure and
stroke volume
The Frank-Starling relationship
Output increases with
increased filling pressure

Overdistended,
output falls

End diastolic volume (filling pressure)


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Blood Pressure Control:


Control of Stroke Volume
What determines venous filling pressure?
Blood volume, mostly contained in a distensible
venous circulation!

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Blood Pressure Control:


Renin-Angiotensin
Cardiac Output (Output of Pump)
heart rate x stroke volume

Caliber of Arteries & Arterioles (Flow


Resistance)
Neural
sympathetic & parasympathetic NS

Hormonal
Renin-angiotensin-aldosterone system

Local transmitters
Nitric Oxide (NO)

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Renin-Angiotensin System
Liver

SENSOR IN
KIDNEY

Angiotensin Precursor
(Circulating)
Renin
(Circulating)
Angiotensin I
OUTCOMES

Angiotensin II
Vasoconstriction
Na+ Retention
K+ Excretion

Aldosterone from
adrenal cortex

AT1 Receptor
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BP Control
Mechanisms
Summary
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Antihypertensive Drugs

See Antihypertensive Agents

Antihypertensive Drug Strategies


Reduce cardiac output
-adrenergic blockers
Ca2+ Channel blockers

Dilate resistance vessels


Ca2+ Channel blockers
Renin-angiotensin system blockers
1 adrenoceptor blockers
Nitrates**

Reduce vascular volume


diuretics
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Calcium Channel Blocking Drugs


Calcium-channel blockers (CCBs)

(Also have uses in treating cardiac rhythm


disturbances & angina)

Membrane
Ca2+ Channels

All cells, voltage or ligand-gated, several types


[Ca2+]e 2.5mM
[Ca2+]i 100nM (maintained by Na+/Ca2+ antiport)
[Ca2+]i Signaling
Actin-myosin interaction
Myocardial membrane depolarization
(Phase 2)
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Effect of Ca2+ Influx:


Muscle Contraction
Ca2+ Channel

Ca2+

Plasma Membrane
Trigger

Sarcoplasmic
Reticulum

Ca2+

Ca2+

contraction (myocardial or vascular)

Actin & Myosin


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Ca2+ Channel Blockers


Cardioselective
verapamil
Non-selective
diltiazem

Vascular selective
dihydropyridines
nifedipine
felodipine
amlodipine

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Ca2+ Channel Blockers


Myocardial selective:
Reduce cardiac contractility
Also reduce heart rate (action on heart rhythm)

BP, heart work


Vascular smooth muscle selective
Reduce vascular resistance

BP, heart work


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1 Adrenoceptor Antagonists
Beta-adrenoceptor antagonists (beta-blockers)

Cardiac 1 Adrenoceptor
Stimulation
Heart rate
contractility
blood pressure
heart work

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Cardiac 1 Adrenoceptor
Blockade
Heart rate
contractility
blood pressure
heart work

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Cardiac 1 Adrenoceptor
Blockers
Metoprolol
Atenolol

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Cardiac 1 Adrenoceptor
Blockers: Clinical Uses
Antiarrhythmic (slows some abnormal fast
rhythms)
Antihypertensive
Antiangina: via reduced heart work

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Blockade of Renin-AngiotensinAldosterone System (RAAS)


1. Angiotensin converting enzyme (ACE)
inhibitors
2. Angiotensin II receptor (AT1) antagonists

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Renin-angiotensin system
Liver

Renal Blood
Flow
Na+ load

Angiotensin Precursor
Renin
Angiotensin I
Angiotensin Converting Enzyme
Angiotensin II

Vasoconstriction
Na+ Retention
K+ Excretion

Aldosterone

AT1 Receptor

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Angiotensin Converting Enzyme


(ACE) Inhibitors
Captopril
Enalapril
anything else ending in -pril
(lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)

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AT1 Blockers (ARBs)


Candesartan,
irbesartan,
others ending in -sartan

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ACE-Inhibitors & AT1 Blockers:


Clinical Uses
reduced vascular resistance
aldosterone salt & H2O retention

Uses
Antihypertensive
Heart failure
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1 Adrenoceptor Blockers
Alpha-adrenoceptor antagonists (alpha-blockers)

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Neural Control of Circulation:


Autonomic NS
Higher Centers
Vasomotor
Center

Carotid Sinus
Brain Stem

Parasympathetic
(Vagus)
-Adrenoceptor

Spinal Cord

Sympathetic
1-Adrenoceptor
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1 Adrenoceptor Blockers
Peripheral vasodilator vascular resistance
Agents:
Prazosin

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Volume Reduction
Reduces cardiac filling pressure (LVEDV/P)
Thus reduces stroke volume and cardiac
output
Independent vascular relaxation with long
term use

See Diuretics eNotes


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Clinical Use of
Antihypertensives
Consequences of chronic high blood pressure
heart failure
arterial disease
kidney failure
strokes
myocardial infarction (heart attack)

Aim of treatment
prevent consequences of high BP
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Drug Treatment of Angina


Antianginal Agents

What is Angina and Why Does it


Happen?
Oxygen demand depends on heart work
Coronary artery partial obstruction (due to
atherosclerosis) limits blood supply to part of the
myocardium
Coronary circulation can meet oxygen demands of
myocardium at rest, but not when heart work increased
by exercise, etc.
Ischemia (O2 deficiency) causes pain: angina

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Determinants of Heart Work

Heart work determined by:


1. Heart rate
2. Cardiac contractility
3. Peripheral resistance
See: Antihypertensive Agents
Physiological Factors Influencing Arterial Pressure for full discussion

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Drug Treatment of Angina:


Limiting Heart Work
Reduce heart rate and contractility
adrenoceptor blockers
Ca2+ channel blockers (verapamil and diltiazem)

Dilate resistance vessels


Ca2+ channel blockers (nifedipine, felodipine,
amlodipine)
Nitrates
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Nitrates
Glyceryl trinitrate
(GTN)

Isosorbide (di)nitrate

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GTN

Vascular Smooth Muscle Cell


R-SH

OrganicNitrate

NO2

R-SH

NO

Nitrosothiols
(R-SNO)

Ester Reductase

+
See : Nitrates, Digoxin and Calcium Channel Blockers
Dr. Paul Forrest
Royal Prince Alfred Hospital

cGMP
RELAXATION

Guanylate Cyclase

GTP

Protein Kinase G

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Nitric Oxide and Vasodilation


After receptor stimulation, Larginine-dependent metabolic
pathway produces nitric oxide
(NO) or thiol derivative (R-NO).
NO causes increase in cyclic
guanosine monophosphate
(cGMP), which causes relaxation
of vascular smooth muscle.
EDRF=endothelium-derived
relaxing factor.
From: Inhaled Nitric Oxide Therapy
ROBERT J. LUNN, M.D.
http://www.mayoclinicproceedings.com/inside.
asp?ref=7003sc

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Use of Nitrates
Very fast, short-lived vascular dilatation (Greater
in venules than arterioles)
lower vascular resistance means less heart work
less heart work means less need for coronary
artery blood flow
therefore, nitrates help chest pain (angina) that
happens during exercise when there is coronary artery
obstruction.
Not used for managing chronic high blood pressure
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Digitalis purpurea (Foxglove)


Cardiostimulatory

Medicines from foxgloves are called "Digitalin". The use of Digitalis purpurea extract
containing cardiac glycosides for the treatment of heart conditions was first described
in the English speaking medical literature by William Withering, in 1785. It is used to
increase cardiac contractility (it is a positive inotrop) and as an antiarrhythmic agent to
control the heart rate, particularly in the irregular (and often fast) atrial fibrillation. It is
therefore often prescribed for patients in atrial fibrillation, especially if they have been
diagnosed with heart failure. From: http://en.wikipedia.org/wiki/Digitalis
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Cardiac Glycosides:
Digoxin

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Digoxin
Mechanism of Action
Na+/K+ ATPase

Outside

Na+ Ca2+

Na+

Na+

Inside
K+

Channels

K+

Pump

Ca2+
Exchanger

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Digoxin blocks
Na+/K+ ATPase
P

Mg2+
ATPase

K+

Mg2+
ATPase
Dig

less efficient Na+/K+ exchange


diminished Na+ gradient
diminished K+ gradient
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Digoxin increases
intracellular Ca2+
Na+

K+

Pump

Na+

Ca2+
Exchanger

diminished Na+ gradient intracellular Ca2+

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Effect of [Ca2+]i
Na+/Ca2+ antiporter
Na+/K+ ATPase

+
+
K
NaNa
+
+
Ca2+
K

Na+

Ca2+ channel

Ca2+
Trigger

Sarcoplasmic
Reticulum

Ca2+

Ca2+

contractility
Actin & Myosin
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Digoxin Effects on Rhythm


Therapeutic
Vagus nerve activity
Slower heart rate
Slower AV conduction

Toxic
Various abnormal rhythms
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Uses of Digoxin
Atrial fast arrhythmias: slows rate
Heart Failure: increases contractile
strength

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Reference Resource

Principles of Pharmacology: The Pathophysiologic


Basis of Drug Therapy Cairo CW, Simon JB, Golan
DE. (Eds.); LLW 2012

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