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

2

Blood Pressure(2)

3

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)

4

Neural Control of the CVS:
Autonomic Nervous System
Higher Centers
Vasomotor
Center

Carotid Sinus
Brain Stem

Parasympathetic
(Vagus)
-Adrenoceptor

Spinal Cord

Sympathetic
-Adrenoceptor
Arteriole

5

Baroreceptor Reflexes
in BP Control

1

 BP

Parasympathetic

Sympathetic

6

Baroreceptor Reflexes
in BP Control
2

1

 BP

Carotid sinus
senses  BP

Parasympathetic

Sympathetic

7

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

2

Carotid sinus
senses  BP

Parasympathetic

Sympathetic

8

Baroreceptor Reflexes
in BP Control
3

Vasomotor Center responds
with  Symp. NS activity
and  Parasymp. activity

1

2

 BP

Carotid sinus
senses  BP

Parasympathetic

4

Sympathetic

 Heart rate
and contractility

4
 PVR
9

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

2

1

 BP

Carotid sinus
senses  BP

Parasympathetic

4

Sympathetic

 Heart rate
and contractility

4
 PVR

5

 BP
10

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)

11

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
12

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)
13

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)
14

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

15

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)

16

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
17

BP Control
Mechanisms
Summary
18

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
20

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)
22

Effect of Ca2+ Influx:
Muscle Contraction
Ca2+ Channel

Ca2+

Plasma Membrane
“Trigger”

Sarcoplasmic
Reticulum

Ca2+

Ca2+

 contraction (myocardial or vascular)

Actin & Myosin
23

Ca2+ Channel Blockers
• Cardioselective
– verapamil
• Non-selective
– diltiazem

• Vascular selective
– dihydropyridines
• nifedipine
• felodipine
• amlodipine

24

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
25

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

Cardiac 1 Adrenoceptor
Stimulation
•  Heart rate
•  contractility
 blood pressure
 heart work

27

Cardiac 1 Adrenoceptor
Blockade
•  Heart rate
•  contractility
  blood pressure
  heart work

28

Cardiac 1 Adrenoceptor
Blockers
• Metoprolol
• Atenolol

29

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

30

Blockade of Renin-AngiotensinAldosterone System (RAAS)
1. Angiotensin converting enzyme (ACE)
inhibitors
2. Angiotensin II receptor (AT1) antagonists

31

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

32

Angiotensin Converting Enzyme
(ACE) Inhibitors
• Captopril
• Enalapril
• anything else ending in -pril
– (lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)

33

AT1 Blockers (ARB’s)
• Candesartan,
• irbesartan,
• others ending in -sartan

34

ACE-Inhibitors & AT1 Blockers:
Clinical Uses
•  reduced vascular resistance
•  aldosterone   salt & H2O retention

Uses
• Antihypertensive
• Heart failure
35

1 Adrenoceptor Blockers
Alpha-adrenoceptor antagonists (alpha-blockers)

36

Neural Control of Circulation:
Autonomic NS
Higher Centers
Vasomotor
Center

Carotid Sinus
Brain Stem

Parasympathetic
(Vagus)
-Adrenoceptor

Spinal Cord

Sympathetic
1-Adrenoceptor
37

1 Adrenoceptor Blockers
• Peripheral vasodilator   vascular resistance
• Agents:
– Prazosin

38

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
39

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
40

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”

42

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

43

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
44

Nitrates
• Glyceryl trinitrate
(GTN)

• Isosorbide (di)nitrate

45

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

46

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

47

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
48

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
49

Cardiac Glycosides:
Digoxin

50

Digoxin
Mechanism of Action
Na+/K+ ATPase

Outside

Na+ Ca2+

Na+

Na+

Inside
K+

Channels

K+

Pump

Ca2+
Exchanger

51

Digoxin blocks
Na+/K+ ATP’ase
P

P

Mg2+
ATP’ase

K+

Mg2+
ATP’ase
Dig

 less efficient Na+/K+ exchange
 diminished Na+ gradient
 diminished K+ gradient
52

Digoxin increases
intracellular Ca2+
Na+

K+

Pump

Na+

Ca2+
Exchanger

diminished Na+ gradient   intracellular Ca2+

53

Effect of  [Ca2+]i
Na+/Ca2+ antiporter
Na+/K+ ATP’ase

+
+
K
NaNa
+
+
Ca2+
K

Na+

Ca2+ channel

Ca2+
“Trigger”

Sarcoplasmic
Reticulum

Ca2+

Ca2+

  contractility
Actin & Myosin
54

Digoxin Effects on Rhythm
Therapeutic
•  Vagus nerve activity
– Slower heart rate
– Slower AV conduction

Toxic
• Various abnormal rhythms
55

Uses of Digoxin
• Atrial fast arrhythmias: slows rate
• Heart Failure: increases contractile
strength

56

Reference Resource

Principles of Pharmacology: The Pathophysiologic
Basis of Drug Therapy Cairo CW, Simon JB, Golan
DE. (Eds.); LLW 2012

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