1. Cardiovascular Pharmacology
Global Overview/Review
Topics discussed:
Autonomic Nervous System
and
Blood Pressure Control
Antihypertensive Drugs
Drugs for Angina
ACE Inhibitors
Calcium Channel
Blockers
Adrenergic Blockers
Cardiac Glycosides
Prepared and presented by:
Marc Imhotep Cray, M.D.
eNotes:
Cardiovascular
Pharmacology

2. 2
Blood Pressure

3. Blood Pressure(2)
3

4. 4
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)

5. 5
Spinal Cord
Brain Stem
Carotid Sinus
Parasympathetic
(Vagus)
Sympathetic
-Adrenoceptor
-Adrenoceptor
Vasomotor
Center
Higher Centers
Neural Control of the CVS:
Autonomic Nervous System
Arteriole

6. 6
Parasympathetic
Sympathetic
Baroreceptor Reflexes
in BP Control  BP1

7. 7
Carotid sinus
senses  BP
Parasympathetic
Sympathetic
2
Baroreceptor Reflexes
in BP Control  BP1

8. 8
Carotid sinus
senses  BP
Parasympathetic
Sympathetic
Vasomotor Center responds
with  Symp. NS activity
and  Parasymp. activity
2
3
Baroreceptor Reflexes
in BP Control  BP1

9. 9
Carotid sinus
senses  BP
Parasympathetic
Sympathetic
 PVR
 Heart rate
and contractility
Vasomotor Center responds
with  Symp. NS activity
and  Parasymp. activity
2
3
4
4
Baroreceptor Reflexes
in BP Control  BP1

10. 10
Carotid sinus
senses  BP
Parasympathetic
Sympathetic
 PVR
 Heart rate
and contractility
Vasomotor Centre responds
with  Symp. NS activity
and  Parasymp. activity
Baroreceptor Reflexes
in BP Control
 BP
2
3
4
4 5
 BP1

11. 11
• 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)
Blood Pressure Control:
Control of Stroke Volume

12. 12
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
• SV is not all of blood
contained in left ventricle
• Normally, only about two-
thirds 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
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.

13. 13
Factors Determining Stroke Volume
• Contractility
–  sympathetic activity increases contractility
• End-diastolic volume
– Determined by venous filling pressure (distensible
ventricle)
Blood Pressure Control:
Control of Stroke Volume

14. 14
Venous filling pressure and
stroke volume
• The Frank-Starling relationship
StrokeVolume
End diastolic volume (filling pressure)
Output increases with
increased filling pressure
Overdistended,
output falls
Blood Pressure Control:
Control of Stroke Volume

15. 15
What determines venous filling pressure?
• Blood volume, mostly contained in a distensible
venous circulation!
Blood Pressure Control:
Control of Stroke Volume

16. 16
• 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)
Blood Pressure Control:
Renin-Angiotensin

17. 17
Renin-Angiotensin System
Renin
(Circulating)
Liver
Angiotensin Precursor
(Circulating)
Angiotensin I
AT1 Receptor
Aldosterone from
adrenal cortex
SENSOR IN
KIDNEY
Vasoconstriction
Na+ Retention
K+ Excretion
Angiotensin II
OUTCOMES

18. 18
BP Control Mechanisms Summary

19. Antihypertensive Drugs
See Antihypertensive Agents

20. 20
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

21. (Also have uses in treating cardiac rhythm
disturbances & angina)
Calcium Channel Blocking Drugs
Calcium-channel blockers (CCBs)

22. 22
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)

23. 23
Effect of Ca2+ Influx:
Muscle Contraction
Ca2+ Channel
Sarcoplasmic
Reticulum
Actin & Myosin
Ca2+
Ca2+
“Trigger”
 contraction (myocardial or vascular)
Plasma Membrane
Ca2+

24. 24
Ca2+ Channel Blockers
• Cardioselective
– verapamil
• Vascular selective
– dihydropyridines
• nifedipine
• felodipine
• amlodipine
• Non-selective
– diltiazem

25. 25
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

26. 1 Adrenoceptor Antagonists
Beta-adrenoceptor antagonists (beta-blockers)

27. 27
Cardiac 1 Adrenoceptor
Stimulation
•  Heart rate
•  contractility
 blood pressure
 heart work

28. 28
Cardiac 1 Adrenoceptor
Blockade
•  Heart rate
•  contractility
  blood pressure
  heart work

29. 29
Cardiac 1 Adrenoceptor
Blockers
• Metoprolol
• Atenolol

30. 30
Cardiac 1 Adrenoceptor
Blockers: Clinical Uses
• Antiarrhythmic (slows some abnormal fast
rhythms)
• Antihypertensive
• Antiangina: via reduced heart work

31. 31
Blockade of Renin-Angiotensin-
Aldosterone System (RAAS)
1. Angiotensin converting enzyme (ACE)
inhibitors
2. Angiotensin II receptor (AT1) antagonists

32. 32
Renin-angiotensin system
Renin
Liver
Angiotensin Precursor
Angiotensin I
Angiotensin II
Angiotensin Converting Enzyme
AT1 Receptor
Renal Blood
Flow
Na+ load
Aldosterone
Vasoconstriction
Na+ Retention
K+ Excretion

33. 33
Angiotensin Converting Enzyme
(ACE) Inhibitors
• Captopril
• Enalapril
• anything else ending in -pril
– (lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)

34. 34
AT1 Blockers (ARB’s)
• Candesartan,
• irbesartan,
• others ending in -sartan

35. 35
ACE-Inhibitors & AT1 Blockers:
Clinical Uses
•  reduced vascular resistance
•  aldosterone   salt & H2O retention
Uses
• Antihypertensive
• Heart failure

36. 36
1 Adrenoceptor Blockers
Alpha-adrenoceptor antagonists (alpha-blockers)

37. 37
Neural Control of Circulation:
Autonomic NS
Spinal Cord
Brain Stem
Carotid Sinus
Parasympathetic
(Vagus)
Sympathetic
1-Adrenoceptor
-Adrenoceptor
Vasomotor
Center
Higher Centers

38. 38
1 Adrenoceptor Blockers
• Peripheral vasodilator   vascular resistance
• Agents:
– Prazosin

39. 39
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

40. 40
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

41. Drug Treatment of Angina
Antianginal Agents

42. 42
• 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”
What is Angina and Why Does it
Happen?

43. 43
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

44. 44
• Reduce heart rate and contractility
–  adrenoceptor blockers
– Ca2+ channel blockers (verapamil and diltiazem)
• Dilate resistance vessels
– Ca2+ channel blockers (nifedipine, felodipine,
amlodipine)
– Nitrates
Drug Treatment of Angina:
Limiting Heart Work

45. 45
Nitrates
• Glyceryl trinitrate
(GTN)
• Isosorbide (di)nitrate

46. 46
GTN
NO2
-
OrganicNitrate
Ester Reductase
R-SH
R-SH
NO Nitrosothiols
(R-SNO)
Guanylate Cyclase
+
GTPcGMP
Protein Kinase GRELAXATION
Vascular Smooth Muscle Cell
See : Nitrates, Digoxin and Calcium Channel Blockers
Dr. Paul Forrest
Royal Prince Alfred Hospital

47. 47
Nitric Oxide and Vasodilation
After receptor stimulation, L-
arginine-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

48. 48
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

49. 49
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

50. 50
Cardiac Glycosides:
Digoxin

51. 51
Digoxin
Mechanism of Action
Outside
Inside
Na+
K+
Na+
Ca2+
Na+
Pump ExchangerChannels
Ca2+
K+
Na+/K+ ATPase

52. 52
Digoxin blocks
Na+/K+ ATP’ase
ATP’ase
P
Mg2+
K+
ATP’ase
P
Mg2+
Dig
 less efficient Na+/K+ exchange
 diminished Na+ gradient
 diminished K+ gradient

53. 53
Digoxin increases
intracellular Ca2+
Na+
K+
Na+
Ca2+
Pump Exchanger
diminished Na+ gradient   intracellular Ca2+

54. 54
Effect of  [Ca2+]i
Na+/K+ ATP’ase
Ca2+ channel
Sarcoplasmic
Reticulum
Actin & Myosin
Na+/Ca2+ antiporter
  contractility
Na+K+
Ca2+
Ca2+
“Trigger”
Na+
Na+
K+
Ca2+
Ca2+

55. 55
Digoxin Effects on Rhythm
Therapeutic
•  Vagus nerve activity
– Slower heart rate
– Slower AV conduction
Toxic
• Various abnormal rhythms

56. 56
Uses of Digoxin
• Atrial fast arrhythmias: slows rate
• Heart Failure: increases contractile
strength

57. 57
Reference Resource
Principles of Pharmacology: The Pathophysiologic
Basis of Drug Therapy Cairo CW, Simon JB, Golan
DE. (Eds.); LLW 2012