Control of Cardiovascular Function,
Disorders of Blood Flow and Blood
Pressure, Hyperlipidemia, and
Artherosclerosis
1
INTRODUCTION
2
Sympathetic Nervous System
3
Location
Response to agonist or neurotransmitter
Alpha-1 – activated with norepi
Arteries and veins
Constriction
Bladder neck (internal sphincter)
Constriction
Alpha-2 – activated with norepi
Central nervous system
Inhibits sympathetic outflow
Beta-1 – activated with norepi
Heart, SA node
Increases heart rate (positive chronotropic effect)
Heart, AV node
Increases speed of conduction (positive dromotropic effect)
Heart, ventricular muscle
Increased contractility (positive inotropic effect)
Kidney
Release of renin
- Leads to thicker blood and vasoconstriction (through angiotensin II)
- ultimately leads to increased blood pressure
- do not need to pee
Beta-2 – activated with only epi
Arterioles in skeletal muscle beds
Dilation to bring more blood to muscles
Bronchi
Dilation
Uterus
Relaxation
4
Alpha-1 Receptors
5
Alpha-1 Receptors
• Norepinephrine and epinephrine
• Vasoconstriction of arterioles and veins
• Vasoconstriction of the bladder
– Prevents urination
6
Alpha-2 Receptors
7
Alpha-2 Receptors
• Norepinephrine and epinephrine
• Inhibits sympathetic outflow
8
Beta-1 Receptors
9
Beta-1 Receptors
• Norepinephrine and epinephrine
• Increases heart rate
• Increases speed of conduction
• Increases heart contractility
• Activates the RAAS to increase blood pressure
10
Beta-2 Receptors
11
Beta-2 Receptors
• Epinephrine only
• Arterial dilation
• Bronchodilation
• Relaxation of the uterus
12
Outline of the Lecture
13
Outline of the Lecture
• Review of Hemodynamics
– Blood vessel structure, function
– Regulation of cardiac output
– Mechanisms of blood pressure regulation
• Disorders of blood pressure
– Hypertension
– Orthostatic hypotension
• Drugs that affect blood pressure
• Disorders of arterial circulation
– Hyperlipidemia, atherosclerorosis
• Drugs that lower LDL cholesterol
14
Pulmonary and Systemic Circulation
Description
15
Pulmonary and Systemic Circulation
Description
• Likes this diagram a lot
• Depicts the circulatory system as two systems
that are in tandem and are connected to each
other in the heart
• Left ventricle – aorta – systemic circulation –
right atria – right ventricle – pulmonary artery
– pulmonary circulation
16
Pulmonary and Systemic Circulation
Diagram
17
Pulmonary and Systemic Circulation
Diagram
18
Baxter Corp. (1999)
Differences in the Pulmonary and
the Systemic Systems
19
Differences in the Pulmonary and the
Systemic Systems
• PULMONARY
• Low pressure system
(MPAP 12 mmHg)
• Good for gas exchange
• SYSTEMIC
• High pressure system
(MAP 90-100 mmHg)
• Good for distant
transport, against
gravity so the pressure
needs to be higher
20
How Does Blood Get Back to the
Heart?
Diagram
21
How Does Blood Get Back to the Heart?
22
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p 461
How Does Blood Get Back to the
Heart?
Description
23
How Does Blood Get Back to the Heart?
Description
• Pressure is high in the aorta, low in the large
arteries, even lower in the arterioles, there is
a big drop in capillaries, and gets even lower
as it returns into the right atria
– It is good to have a negative pressure in the right
atria because you will be sucking the blood into
the heart, which is a good thing
24
Principles of Blood Flow
25
Principles of Blood Flow
• Hemodynamics
• Heart is an intermittent pump, blood flow is
pulsatile
– This is not true if the person has a continuous
heart pump
26
Factors Governing the Function
of the Cardiovascular System
27
Factors Governing the Function of the
Cardiovascular System
• Volume
• Pressure
• Resistance
• Flow
28
Determinants of Blood Pressure
29
Determinants of Blood Pressure
BP = CO X Peripheral vascular
resistance
CO = SV X HR
• What determines peripheral vascular
resistance?
30
Resistance of a Tube
Description
31
Resistance of a Tube
Description
• Peripheral vascular resistance – the resistance
to flow in the vascular tree
• The radius of the tube is a huge factor in
delivering flow because it is done to the fourth
power!!!
– Changing the radius of the tube just a little bit
greatly changes the resistance of the flow and
thus the flow itself
32
Resistance of a Tube
Diagram
33
Resistance of a Tube
Diagram
Big factor!
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 452.
Also see p 322, point 2 in Porth, Essentials
34
Volume and Pressure Distribution
Description
35
Volume and Pressure Distribution
Description
• When we get to the arterioles, there is a huge drop in pressure
– The degree of constriction of the arterioles determines the peripheral
vascular resistance, which then makes it important in determining
blood pressure
• 4% of blood is in the left ventricle, 16% in the arteries, 4% in the
capillaries, and 64% in the veins
• Veins are capacitance vessels
– The veins serve as a storage place for the blood
– If we want to increase cardiac output quickly, the veins can constrict
and return the blood to the heart, sending a bolus to the heart to
increase the stroke volume and thus the cardiac output
36
Volume and Pressure Distribution
Diagram
37
Volume and Pressure Distribution
Diagram
Arteriolar tone determines
systemic vascular resistance
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 321.
38
Pulmonary and Circulatory Systems
Diagram, Lehne
39
Pulmonary and Circulatory Systems
Diagram, Lehne
Lehne, 2009, Pharmacology for Nursing Care, 7th ed.,
Elsevier, p 461
40
Layers of the Blood Vessels
41
Layers of the Blood Vessels
• Intima- elastic layer
• Media- smooth muscle
for diameter control
(innervated by the SNS
with alpha receptors)
– Alpha receptors cause
constriction of the vessels
– The arteries have more
smooth muscle than the
veins
• Externa- fibrous and
connective tissue for
support
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 338
42
Resistance Arterioles Maintain
Blood Pressure
43
Resistance Arterioles Maintain Blood Pressure
• Arteries have abundant
smooth muscle. The
diameter of the
artery/arteriole is
determined by the degree
of contraction of the
smooth muscle, which is
mediated by the SNS
(alpha receptors).
• The SNS maintains tone in
the arteries
44
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 338
Blood Vessels and the
Peripheral Circulation
45
Blood Vessels and the
Peripheral Circulation
• Blood vessels are not pipes
– Pipes cannot change their diameters, while blood vessels can
• Blood vessels are dynamic structures
– They constrict and relax to adjust blood flow to meet varying needs of
tissues/organs
• The heart, brain, liver, and kidney require large continuous flow
– There are no alpha receptors on blood vessels going to the brain
because we do not want to ever constrict then
• Skin and skeletal muscle require varying flow of blood, depending
on the situation
– Ex. if you just ate, you will need a lot of blood going to your digestive
tract
46
Arteries and Arterioles
47
Arteries and Arterioles
• Elasticity allows for stretching during systole
• Arterioles have abundant smooth muscle
• Arterioles are the major resistance vessels for circulatory
the system and basically determine the systemic vascular
resistance
• Sympathetic fibers innervate arterioles cause them to
constrict/relax as needed to maintain BP (alpha receptors)
48
Veins and Venules
49
Veins and Venules
• Collect blood from capillaries and carry it back to
the heart
• Enlarge and store large quantities of blood and
are then able to return the stored blood to the
heart when needed
• Contract/expand to accommodate varying
amounts
• Innervated by SNS (alpha receptors)
• Venous constriction can increase the preload to
the heart by conducting stored blood into the
vena cava
– This will increase the cardiac output
50
Veins
51
Veins
• Valves prevent retrograde flow
– Incompetent valves in venous
varicosities
– As we age, the valves may become
incompetent
• Skeletal muscles help compress
veins in “milking manner” up to
heart
• Low pressure system – Pressure
in venules is ~10 mm Hg and in
the vena cava ~0 mmHg
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 339.
52
Endothelial Cells
53
Endothelial Cells
•Endothelial cells line all blood vessels.
•They are normally quite smooth and permit laminar (uninterrupted)
blood flow.
•They also form a tight barrier in larger vessels
•Capillaries are more permissive of small molecules exiting and
entering the vascular system because they possess fenestrations54
Capillaries
55
Capillaries
• Single cell-thick vessels that
connect arterial and venous
segments
• Wall composed of a single
layer of endothelial cells
surrounded by a basement
membrane
– Do not have smooth muscle
• In most vascular beds,
capillaries have
fenestrations that allow
passage of water and small
molecules but not large
proteins.
• The basement membrane
between the endothelial
cells and the outside of the
capillaries is very important
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 341.
56
Vascular Smooth Muscle and
Sympathetic Nervous System
57
Vascular Smooth Muscle and Sympathetic
Nervous System
• Norepinephrine-activated alpha receptors cause calcium
channels in vascular smooth muscle to open, which produces
vasoconstriction
• In some vascular beds, beta-2 receptors promote vasodilation by
decreasing calcium.
• Calcium Causes Contraction in vascular smooth muscle
– The more calcium that is present inside the cell, the more contraction is
present
• Calcium channel blockers prevent vasoconstriction
–
Prevents calcium from going through the calcium channel so the calcium cannot cause contraction
58
Perfusion of Organs
59
Perfusion of Organs
• Tissue blood flow to a given organ is regulated on a
minute-to-minute basis in relation to tissue needs
• Neural mechanisms regulate cardiac output and
systemic vascular resistance (BP) to support local
mechanisms
• Local control includes preferential vasoconstriction or
vasodilation mediated by the SNS or by intrinsic
mechanisms within the organ.
60
Tissue Factors Contributing to
Local Control of Blood Flow
61
Tissue Factors Contributing to Local
Control of Blood Flow
• Factors are released from an organ when it has too much or too
little blood flow.
• In order to increase blood flow
– Histamine
• Would cause dilation of the vessel
• Decrease blood flow
– Serotonin
• Would cause constriction of the vessel
• Are these correct?*
62
Endothelial Control of Vascular
Smooth Muscle
63
Endothelial Control of Vascular Smooth
Muscle
• The endothelium produces factors that act on smooth
muscle to produce vasoconstriction or vasodilation
• Vasodilating substances
– Nitric Oxide
• Vasoconstricting substances
– Angiotensin II, Prostaglandins, Endothelins
• The circulatory system is a dynamic structure that
works to send blood to different organs that need
more or less blood
64
Functional Anatomy of the Heart
65
Functional Anatomy of the Heart
Pericardium:
•Sac around heart
•Normally, has a
little bit of fluid in
it in order to make
movement easier
A “virtual space”
which can become
fluid or blood-filled
(pericardial
effusion).
Porth, 2007, Essential of
Pathophysiology, 2nd ed.,
Lippincott, p. 328.
66
Contraction: Actin and Myosin
Binding
Description
67
Contraction: Actin and Myosin Binding
Description
• Actin and myosin overlap and grab onto each
other
• Calcium is what makes this process work
68
Contraction: Actin and Myosin
Binding
Diagram
69
Contraction: Actin and Myosin Binding
Diagram
Spirito et al., NEJM 336, pg 775, 1997
http://www.sci.sdsu.edu/movies/actin_myosin_gif.html
70
Heart Valves Keep Blood Flow
Unidirectional
Diagram
71
Heart Valves Keep Blood Flow Unidirectional
Semilunar valves
A-V valves
72
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 329.
Function of Heart Valves
73
Function of Heart Valves
• Major function of heart valves: Forward
direction of blood flow
• Open and shut in order to keep blood moving
forward in an unidirectional manner
74
Semilunar Valves
75
Semilunar Valves
• Control blood flow out of ventricles
• Aortic valve
• Pulmonic valve
76
Atroventricular Valves
77
Atroventricular Valves
• Control blood flow between atria and
ventricles
• Tricuspid valve
• Mitral valve
78
Cardiac Conduction System
79
Cardiac Conduction System
• The conduction system stimulates the
myocardium to contract and pump blood
• The conduction system controls the rhythm of
the heart.
• Heart has two conduction systems
– One controls atrial activity
– One that controls ventricular activity
– The two systems communicate when the impulse
that causes atrial contraction travels to the
ventricular system via the A-V node
80
Conduction System
Diagram
81
Conduction System
Diagram
82
SA Node
83
SA Node
• Pacemaker of the heart
– Spontaneously depolarizes
• Impulses originate here
• Located in posterior wall RA
• Causes the atria to contract
• Fires at 60 -100 bpm if it is not innervated by anything
– Can be influenced by the SNS and PNS
• Rate is determined by the autonomic nervous system
– Increase HR: Sympathetic nervous system---NE---beta-1 receptors
– Decrease HR: Parasympathetic nervous system ---acetylcholine--muscarinic receptors
84
AV Node
85
AV Node
• Connects the atria and ventricles, provides one way
conduction
• The speed of conduction of the AV node is much slower
than the fibers in the atria or the ventricle
• At the AV node, the signal stops
– Promotes filling of the ventricles before ejection
• Speed of conduction in the AV node is determined by the
ANS
–
–
The SNS can speed up conduction and make the pause shorter (beta-1)
The PNS can slow conduction down and make the pause longer (muscarinic receptor)
• Can assume pacemaker function if SA fails to discharge
– Can depolarize on its own and cause the ventricles to contract
– Fires at 40 -60 bpm
86
Purkinje Fibers
87
Purkinje Fibers
• Supply the ventricles
– Spread the impulse throughout the ventricular muscle
• Large fibers, rapid conduction for swift and efficient ejection
of blood from heart
• Assume pacemaker of ventricles if AV fails
– Intrinsic rate is 15-40 bpm
Porth, 2007, Essentials of Pathophysiology,
2nd ed., Lippincott, p. 331.
88
ECG
89
ECG
• Electrical events recorded
– Transmitted to the skin via
conduction
• Electrical events precede
mechanical events; know what
they represent!
– P
–
–
–
–
• Atrial depolarization
Pause caused by the AV node
QRS
• Ventricular depolarization
T
• Ventricular repolarization
U wave
• The repolarization of the atria
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott,
p.331 & 333.
90
Cardiac Cycle
91
Cardiac Cycle
• Term used to describe the rhythmic pumping
action of heart
• Cycle divided into 2 parts
– Systole: period during which ventricles are
contracting
– Diastole: period during which ventricles are
relaxed, filling with blood
• Simultaneous changes occur in pressure
(LA,LV, aorta), ventricular volume, ECG, heart
sounds during cardiac cycle
92
The Wiggers Diagram
93
The Wiggers
Diagram
Porth, 2007, Essential of
Pathophysiology, 2nd ed.,
Lippincott, p. 334.
94
The Wiggers Diagram
Description of Pressure
95
The Wiggers Diagram
Description of Pressure
•
•
•
•
•
•
•
•
•
At the beginning of systole, the pressure in the left ventricle is low, starts to
contract (at this point, the aortic and the mitral valve are both closed), as the
ventricle is contracting, pressure builds in the ventricle (isovolumetric contraction)
The dotted line at the beginning is the aortic pressure
The pressure in the ventricle and aorta are the same
Pressure in the ventricle forces the aorta to open
Pressure in the ventricle rises further until it is maximally contracted
Pressure in the aortic route and in the ventricle are equal at this time because the
pressure is the same
When the ventricle pressure is lower than in the aorta, the aortic valve closes
As the ventricle is relaxing, pressure in the ventricle drops a lot
Isometric relaxation period
– Pressure in low
•
Diastole
– The ventricle is relaxed
– Ventricle pressure is staying low
– Volume is increasing because the ventricle is filling
•
•
Fills passively because the mitral valve opens
Pressure between the atria and the ventricle are the same
– The atria contracts to force more blood into the ventricle
96
The Wiggers Diagram
Other Elements
97
The Wiggers Diagram
Other Elements
• The electrical stimuli come before the contractions or relaxations
because the stimulation causes the contraction
• The little increase in atrial volume at the end is called the atrial kick
– Contributes very little to the volume in the left ventricle
• May be important if the heart rate is really fast so the diastole is slow
– May be important to end more to the volume
• Important in people with heart rate who need the kick to help the ventricles
fill more
• At the middle is volume
• EKG
• Heart sounds
98
Ventricular Systole
Diagram
99
Ventricular Systole
Diagram
100
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 334.
Ventricular Systole
Description
101
Ventricular Systole
Description
• Isovolumic (isometric) contraction
• Ejection period.
102
Ventricular Systole
Isovolumic (metric) Contraction
103
Ventricular Systole
Isovolumic (metric) Contraction
• Closure of AV valves (S1), all valves closed.
• No change in ventricular volume
• Ventricles contract
• When ventricular pressures > aortic and
pulmonary pressures, semilunar valves open,
leading to the ejection period
104
Ventricular Systole
Ejection Period
105
Ventricular Systole
Ejection Period
• Stroke volume ejected.
• Ventricles contract, then relax.
• Intraventricular pressures  and become less
than pressures in aorta and pulmonary
arteries
• Blood from large arteries flows back toward
ventricles and aortic/pulmonic valves shut
(S2).
106
Ventricular Diastole
Diagram
107
Ventricular Diastole
Diagram
108
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 334.
Ventricular Diastole
Description
109
Ventricular Diastole
Description
• Ventricular relaxation and filling
• Isovolumic (isometric) relaxation
• Rapid filling period
110
Ventricular Diastole
Isovolumic (metric) Relaxation
111
Ventricular Diastole
Isovolumic (metric) Relaxation
• Semilunar valves closed
• Ventricles relaxed
• No change in ventricular volume, but 
ventricular pressure until it is less than atrial
pressures.
• AV valves open, blood from atria enters
ventricles, leading to rapid filling phase
112
Ventricular Diastole
Rapid Filling Phase
113
Ventricular Diastole
Rapid Filling Phase
• Most ventricular filling in first third of diastole
(S3)
• During the last third, atria contract (atrial
kick).
114
Atrial Contraction
115
Atrial Contraction
• Last third of ventricular diastole
• Gives additional thrust to ventricular filling
• Important during tachycardia or when heart
disease impairs ventricular filling
– May not be important in a person with a normal
heart, especially at physiologic heart rates.
• Fourth heart sound (S4), when present, occurs
when atria contract
– Cannot always hear the S4 heart sound
116
Cardiac Output
117
Cardiac Output
• Cardiac output (CO)
– Amount of blood the heart pumps/minute
– 3.5 - 8.0 L/minute
• In athletes, this could be much higher
• Stroke volume (SV)
– Amount of blood the heart pumps each beat
– 70 ml/beat
• CO = SV x HR
• CO varies with body activities.
– Ex. sleeping vs. exercise
• CO varies by changes in SV and/or HR
– SV – when veins contract
– HR – more beats lead to more blood being pumped out
118
Heart Rate
119
Heart Rate
• Frequency with which blood is ejected from heart
– One way to increase the cardiac output
• As HR  →  CO
• HR is increased by activation of beta-1 receptors and
decreased by activation of muscarinic receptors on the
SA node.
• BUT as HR  →  diastolic filling time
– This occurs when heartrate increases too fast or too much
•  diastolic filling time may  SV and  CO
• Tachycardia can be dangerous because the heart may
not have time to fill adequately →  CO
120
Equation for Cardiac Output
121
122
Stroke Volume Components
123
Stroke Volume Components
• Preload – the amount of blood that is returned to
the heart from the veins
– Ventricular filling (volume)
• Afterload – the pressure that the heart must press
against in order to get the blood out
– Pumping function
– Resistance to ejection of blood from heart
• Contractility – how hard is the heart contracting
– Pumping function of heart
124
Preload (“Volume”)
125
Preload (“Volume”)
• Represents the volume of blood the heart must pump with
each beat
– Ex. if the veins return 100mL to the heart and the heart does
not pump out 100mL, the blood must stay in the heart, which is
bad
• What the veins return to the heart is what the heart must pump out
• Largely determined by venous return and stretch of muscle
fibers
• Venous return
– 64% of blood volume in veins
– Venous constriction mediated by alpha-1 receptors
126
Preload: Frank-Starling Law of
the Heart
127
Preload: Frank-Starling Law of the Heart
•Actin, myosin filaments that overlap and create cross bridge
attachments, which leads to contraction of cardiac muscle
128
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 336.
Preload: Frank-Starling Law of the
Heart
Description
129
Preload: Frank-Starling Law of the Heart
Description
• An intrinsic property of the heart
• The actin and myosin filaments must overlap in order for the contraction
of cardiac muscle
– They may overlap a little, optimally, or too much
• Law – there is an optimal degree of overlap
– This is determined by the end diastolic filling of the heart
– If there is a little bit of volume in the heart, there is a lot of overlap and good
contractility, but once the filaments slide, they cannot slide any more
• This means that there is not a lot of extra space to end into, so filaments cannot contract
a lot
– Optimal overlap leads to the best contractility
– If you overfill the heart and overstretch the filaments, then cardiac output
declines because the filaments cannot touch
• Not affected by the SNS
– Has to do with the filling that the heart gets from the veins
• Optimal overlap leads to increased SV beyond what we would expect from
the increased filling
130
Implications of the Frank-Starling
Law
131
Implications of the Frank-Starling Law
• At normal volumes, as preload increases, stretch
increases, which increases contractility.
– CO goes up both because of the increased volume and
increased contractility
– The increase in contractility is independent of the SNS – it is an
intrinsic property of the heart.
• At high volumes, the cardiac muscle is overstretched and
contractility decreases.
– This is usually seen only in patients with heart failure (covered
in CVII) who have fluid overload.
132
Afterload (“Resistance”)
133
Afterload (“Resistance”)
• The heart must develop a pressure equal to the
aortic pressure in order to open the valve
• Afterload - the amount of pressure the heart must
develop during the period of isovolumic contraction
to open the aortic and pulmonic valves.
• Without valve disease, afterload = diastolic pressure
134
Major Sources of Resistance
135
Major Sources of Resistance
• Arterial pressures are the major sources of resistance
– Right ventricle:
• Pulmonary arterial pressure (low)
– Left ventricle:
• Systemic arterial pressure (high – equal to the diastolic BP in the
absence of valve disease)
136
Diseases of the Semilunar Valves
137
Diseases of the Semilunar Valves
• Disease of the aortic or pulmonic valves 
resistance
– Stenosis/narrowing of the valve
– This means that the heart has to develop an increased
pressure to open the diseased valve.
• The decrease in the valve will have a big impact on resistance,
flow, and afterload because the radius is done to the fourth power
– Diastolic hypertension also increases the pressure
necessary to open the aortic valve.
138
Effect of Afterload on CO
Diagram
139
Effect of Afterload on CO
Diagram
Guyton, 2006, Textbook of Medical Physiology, 11th ed.,Saunders, p. 114.
140
Effect of Afterload on CO
Description
141
Effect of Afterload on CO
Description
• In normal people without disease, afterload has little
impact on cardiac output
– The ventricle can develop the pressures
– Most important thing in determining CO is the preload
• The heart pumps what it receives from the venous system
• In a person with impaired contractility, this curve is
shifted back to the left
– At normal aortic pressures, there may be a decrease in
cardiac output
– With impaired contractility, afterload becomes important
142
Contractility
143
Contractility
• Ability of the heart to change its force of
contraction
– The heart can contract harder when it is needed
• Strongly influenced by number of calcium ions that
are available to participate in the contractile
process.
– Determined by biochemical and biophysical properties
that govern actin and myosin interactions in myocardial
cells (Frank-Starling mechanism).
– Activation of beta-1 receptors in the ventricles by
norepinephrine (SNS) increases the availability of calcium
ions and increases contractility.
• The heart’s contractility can be stimulated by the sympathetic
nervous system
144
Determinants of Blood Pressure
145
Determinants of Blood Pressure
BP = CO X Peripheral vascular resistance
CO = SV X HR
146
Mechanisms of BP Regulation
Arterial Pressure
147
Mechanisms of BP Regulation
Arterial Pressure
• Arterial pressure must remain relatively
constant as blood flow shifts from one area
of body to another
– Feedback mechanisms are short-term and
long-term to regulate the blood pressure to
remain constant
• Method by which arterial pressure is
regulated depends on whether short-term
or long-term adaptation is needed
148
Mechanisms of BP Regulation
ANS, RAAS, Kidneys
149
Mechanisms of BP Regulation
ANS, RAAS, Kidneys
• Autonomic nervous system – short-term
regulation
• RAAS (Renin-angiotensin-aldosterone system) –
longer term regulation of blood pressure
• Kidneys – control blood volume as well as the
RAAS – a long-term mechanism of blood
pressure control.
– The kidneys are very important in long-term
regulation of blood pressure
150
The Baroreceptor Reflex
Diagram
151
The Baroreceptor Reflex
Diagram
Baroreceptors in the
aortic arch and
carotid artery
Autonomic
centers in the
brainstem
Cardiac muscle, cardiac
conduction system, and vascular
smooth muscle.
152
The Baroreceptor Reflex
Description
153
The Baroreceptor Reflex
Description
• Baroreceptors sense pressure in the aortic
arch and the carotid artery
• Send information to the medulla in the
autonomic centers in the brainstem
• Send impulses to the heart and vessels to
lower the blood pressure (if stimulation is too
high) or to raise the blood pressure (if
stimulation is too low)
154
The Sensory Components of the
Baroreceptor Reflex – Chemo and
Stretch Receptors
155
The Sensory Components of the Baroreceptor Reflex –
Chemo and Stretch Receptors
156
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 364.
ANS Regulation of BP – the
Baroreceptor Reflex
157
ANS Regulation of BP – the Baroreceptor Reflex
McCance & Heuther, 2002,
Pathophysiology: The Biologic
Basis for Disease in Adults &
Children, Mosby, p.961
*Be sure you know which receptors are where!!!
158
ANS Regulation of BP – the
Baroreceptor Reflex
Description
159
ANS Regulation of BP – the Baroreceptor Reflex
Description
• Vagus nerve sends signals to the SA node to slow down
the heart
• SNS increases CO by increasing HR and contractility
• SNS innervates arterioles to cause them to constrict
(alpha) to raise blood pressure
• SNS innervates veins to cause them to constrict to
increase preload to increase CO
• Baroreceptor reflex is happening all of the time
• If blood pressure is too low, medulla instructs SNS
centers in spinal cord to send information to the SA
node through beta-1 receptors and the AV node to
speed up the heart
160
Neurotransmitters
161
Neurotransmitters
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 1151.
162
Long-term Regulation of Blood
Pressure
163
Long-term Regulation of Blood Pressure
• Primarily controlled by kidneys
• Neural mechanisms act rapidly, but cannot
maintain their effectiveness over time so the
kidneys are used
• Kidneys’ control in long term is through regulation
of Na+ and H20 balance
– RAAS
– Vasopressin
164
Renin-Angiotensin-Aldosterone
System
Diagram
165
Humoral
Mechanisms:
Reninangiotensinaldosterone
system
MUST KNOW
THIS!
Porth, 2007, Essentials of
Pathophysiology, 2nd ed., Lippincott,
p. 365.
166
Renin-Angiotensin-Aldosterone
System
Description
167
Renin-Angiotensin-Aldosterone System
Description
• When renal blood pressure falls, juxtaglomerular
cells of the kidney acts on renin
• Renin works on angiotensinogen
• Angiotensinogen is converted to angiotensin I
• Angiotensin I becomes angiotensin II
– Angiotensin II constricts arteries and causes the
adrenal cortex to release aldosterone
• Aldosterone increases Na reabsorption, which
increases water reabsorption
168
Vasopressin (Antidiuretic Hormone
(ADH))
Diagram
169
Vasopressin (Antidiuretic Hormone (ADH))
170
Porth, Pathophysiology, Concepts of Altered Health States,
7th
ed., 2005, Lippincott, p. 756.
Vasopressin (Antidiuretic Hormone
(ADH))
Description
171
Vasopressin (Antidiuretic Hormone
(ADH))
Description
• ADH is released in result to changes in serum
osmolality strength
– When dehydrated, the serum osmolalitiy goes up,
which stimulates the hypothalamus
172
The ANS and RAAS Systems Work in
Concert to Maintain Blood Pressure
173
The ANS and
RAAS systems
work in concert
to maintain
blood pressure
Porth, Pathophysiology, Concepts of
Altered Health States, 7th ed., 2005,
Lippincott, p. 756.
174
Which of the following is an
important determinant of cardiac
output in a normal person?
175
Which of the following is an important determinant of
cardiac output in a normal person?
1. Afterload.
2. Heart rate.
3. Venous return
(preload)
4. Total peripheral
resistance.
er
...
...
rip
h
pe
ta
l
To
V
en
ou
s
H
ea
re
tu
rn
rt
ra
te
.
d.
rlo
a
ft
e
A
- Component of
afterload
25% 25% 25% 25%
176
You assess a patient’s pulse to be 40
bpm. He is not an athlete. Given this
HR, the electrical impulses in the
heart are probably originating from:
177
You assess a patient’s pulse to be 40 bpm. He is not an
athlete. Given this HR, the electrical impulses in the
heart are probably originating from:
25% 25% 25% 25%
1.
2.
SA Node
AV Node
- Could be originating in the AV
node
3.
An ectopic atrial focus
- This leads lead to increased
heartrate
r..
.
P
ur
ki
nj
e
ic
to
p
A
n
ec
A
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be
at
r..
.
od
e
N
V
N
A
- Could be originating from here
as well
od
e
Purkinje Fibers
S
4.
178
Angiotensin II causes
179
Angiotensin II causes
ab
te
...
ft
he
ar
A
ll
o
se
d
cr
ea
In
oc
as
V
R
el
ea
se
on
s
of
tr
ic
ti.
..
al
d.
..
1. Release of
aldosterone
2. Vasoconstriction of
arterioles
3. Increased arterial
blood pressure
4. All of the above
o.
..
25% 25% 25% 25%
180
DISORDERS OF BLOOD PRESSURE
REGULATION:
HYPERTENSION AND
ORTHOSTATIC HYPOTENSION
181
Orthostatic Hypotension
182
Orthostatic Hypotension
• Abnormal drop in BP on assumption of the standing
position
– People can actually faint from this
• Defined as a drop in systolic pressure > 20 mm Hg or
drop in diastolic pressure > 10 mm Hg when going
from lying to standing
• In absence of normal circulatory reflexes and/or if
blood volume is decreased, blood pools in lower
part of the body when the standing position is
assumed (decreased venous return), CO  and blood
flow to the brain is inadequate dizziness, syncope
(fainting), or both
• Occurs when the baroreceptor is not working
properly or the person is dehydrated
183
Orthostatic Hypotension
Diagram
184
Orthostatic Hypotension
Diagram
Porth, 2007, Essentials of Pathophysiology, 2nd ed.,
Lippincott, p. 374
185
Compensatory Mechanisms of
Orthostatic Hypotension
186
Compensatory Mechanisms of
Orthostatic Hypotension
• Stand up, drop in blood pressure,
compensated by increased venous return and
increased heart rate
– If you are taking a beta blocker is would prevent
the heart rate from increasing
– Alpha blocker would prevent the vasoconstriction
• Dehydration is a big cause of people fainting
187
Causes of Orthostatic
Hypotension
188
Causes of Orthostatic Hypotension
• Reduced blood volume (dehydration) (reduced preload)
– This is the most common cause of dizziness and fainting, especially
in young, health people.
• Drug-induced orthostatic hypotension
– Impairment of venous return (reduced preload) (Ca2+ channel
blockers)
– Impairment of the baroreceptor reflex (beta blockers, alpha-1
blockers)
– Diuretics (reduced preload)
• Aging – sluggish reflexes, including the baroreceptor reflex
• Bedrest – deconditioning
• Disorders of the autonomic nervous system
– Autonomic neuropathy – neuropathy of all of the nerves
• The autonomic ones may be affected
189
Treatment of Orthostatic
Hypotension
190
Treatment of Orthostatic
Hypotension
• Address the alleviating cause
– Rehydrate, change medications
• Help cope with disorder, prevent falls, injury
– Gradual ambulation (sit on edge of bed, move legs)
– Avoid venodilation (drinking ETOH; exercise in warm
environment)
– Maintain hydration
191
Hypertension
Description
192
Hypertension
Description
• Common health problem in adults
• A leading risk factor for cardiovascular disorders
(myocardial infarction, heart failure, stroke, vascular
disease)
• More common in young men than young women, blacks
compared with whites, in persons from lower
socioeconomic groups, and with increasing age
• Diabetics are more likely to have hypertension and it is
more likely to lead to cardiovascular disease than in
nondiabetics.
193
Primary Hypertension
194
Primary Hypertension
• “Essential hypertension”
• Chronic elevation of BP occurs without
evidence of other disease
• 90-95% of hypertension
– Much more common than secondary
hypertension
195
Secondary Hypertension
196
Secondary Hypertension
• Elevation of BP occurs from some other
disorder
– Kidney disease
– Chronic renal failure
• Kidney thinks that it does not have enough blood flow,
which activates the RAAS
– Disorders of adrenocorticoid hormones
(pheochromocytoma)
197
Hypertension Definitions
198
Hypertension Definitions
• JNC-VII* (June 2003)
–
–
–
–
“Prehypertension” (120-139/80-89)
Stage I (140-159/90-99)
Stage II (160-179/100-109)
Stage III (>180/>110)
*7th
Report of the Joint National Committee on Detection,
Evaluation and Treatment of High Blood Pressure
199
Constitutional Risk Factors
200
Constitutional Risk Factors
• Family history
– Hereditary pattern unclear, genes not identified
• Age related changes
– BP higher with advancing age
• Insulin resistance, metabolic syndrome, diabetes
(especially type II)
• Race
– African Americans more prevalent, early onset, more
severe; greater renal, CV damage
– Less known about other races
201
Lifestyle Risk Factors
202
Lifestyle Risk Factors
• Diet high in Na+ and saturated fats
• Obesity
– When people lose weight, a lot of times it result in their
blood pressure decreasing
• Physical inactivity
• Excessive alcohol consumption
• Oral contraceptives in predisposed women
203
Consequences of Hypertension
204
Consequences of Hypertension
• Usually related to long term effects of HTN on other organs,
“target organ damage”.
• HTN seems to accelerate atherosclerotic vascular disease
(covered later today)
– Heart
• Left ventricular hypertrophy (the heart muscle has to increase in size
to pump blood against the aortic resistance)
• Coronary artery disease (angina, myocardial infarction)
• Heart failure
– Brain
• Stroke or transient ischemic attack
– Chronic kidney disease
– Peripheral vascular disease
– Hypertensive retinopathy
• Usually does not have any symptoms
205
Consequences of HTN
Heart
206
Consequences of HTN
Heart
• Heart: LV
Hypertrophy
–  workload of LV (
afterload); LV tries to
compensate for 
workload.
– LV hypertrophy is
major risk factor for
ischemic heart
disease (myocardial
infarction),
dysrhythmias, heart
failure, sudden death
207
Consequences of HTN
Vascular Damage
208
Consequences of HTN
Vascular Damage
• Coronary arteries – myocardial infarction (CVII)
• Peripheral blood vessels – peripheral vascular
disease
• Kidney – renal failure
• Cerebral blood vessels – stroke
209
Diagnosis of Hypertension
210
Diagnosis of Hypertension
• Repeated BP measurements
– Average of > 2 readings taken at > 2 visits after an
initial screening visit; over several months
• Laboratory tests, x-rays looking for target organ
damage
– There is no specific test for hypertension, but you
can look at the target organs
– ECG, Urinalysis, Hb (erythropoietin in kidneysanemic due to kidney disease), Hct, Na+, K+, Cr
(major indicator of kidney function), glucose,
triglycerides (tells about other factors that may
influence disease), cholesterol
211
Treatment of Hypertension
212
Treatment of Hypertension
• Lifestyle modification is the first line of treatment
– Weight reduction, regular physical exercise, DASH eating
plan (a lot of fruits and vegetables, very little meat),
reduction of dietary sodium intake, moderation of alcohol
intake
• Pharmacologic treatment
• Goal: To achieve and maintain systolic BP below 140
mm Hg and diastolic BP below 90 mm Hg
– The better people control their blood pressure, the less likely
they are to suffer the negative effects of the hypertension on
target organs
213
Sites of Action of Hypertension
Diagram
214
215
Lehne, 2009, Pharmacology for Nursing Care,
67h
ed., Elsevier, p. 500
Pharmacologic Treatment of
Hypertension
216
Pharmacologic Treatment of Hypertension
• Diuretics
• Sympatholytics
• Act on RAAS
• Others
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, Table 46-5, p. 502
217
Sympatholytics
218
Sympatholytics
• Interfere with the sympathetic nervous system
• Beta-adrenergic blockers
• Alpha-1 adrenergic blockers
• Centrally-acting alpha-2 agonists
• Drugs that block norepinephrine release
219
Drugs that Act on the RAAS
220
Drugs that Act on the RAAS
• Renin inhibitor
• ACE inhibitors
• Angiotensin II receptor blockers
• Aldosterone antagonists
221
Other Drugs
222
Other Drugs
• Ca+2 channel blockers
• Direct-acting vasodilators
223
Pharmacologic Treatment
Compliance
224
Pharmacologic Treatment
Compliance
• Compliance is a huge issue
– Lifetime treatment
– Many of the drugs have unpleasant side effects
– Many are expensive
225
Algorithm for Treating
Hypertension
226
Algorithm for Treating Hypertension
Lifestyle modifications
- Increase exercise (aerobic, decrease weight)
Goal BP not met
Stage 1 – thiazide diuretic /consider ACEI, ARB, beta blocker, CCB or
combination
Stage 2 – 2-drug combo (usually a thiazide + ACEI, ARB, beta blocker or
CCB)
Goal BP not met
Optimize dosage or add a drug from a different class
Goal BP not met
Continue adding drugs from other classes until goal is achieved
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 507
227
Classes of Antihypertensive Drugs
Recommended for Initial Therapy in
Patients with High-Risk Comorbid
Conditions
228
Classes of Antihypertensive Drugs Recommended for Initial
Therapy in Patients with High-Risk Comorbid Conditions
Condition
Heart Failure
Drug Classes Recommended for Initial Therapy of HTN
Diuretic
Beta
Blocker
ACEI
ARB
X
X
X
X
X
X
Post MI
X
X
X
Diabetes
X
X
X
X
X
X
Recurrent Stroke
Prevention
X
Aldosterone
Antagonist
X
X
Coronary Artery
Disease Risk
Chronic Kidney
Disease
CCB
X
X
X
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 508
229
Drugs That Affect BP: Diuretics
Diagram
230
Drugs That Affect BP: Diuretics
Diagram
231
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
Classification of Diuretics
232
Classification of Diuretics
• Thiazide diuretics – Hydrochlorothiazide (HCTZ®) and
chlorthalidone
– Most common
• High-ceiling (loop)– Furosemide (Lasix®)
• K+ sparing:
– Non-aldosterone antagonists - Triamterene (Dyrenium®)
– Aldosterone receptor antagonists – Spironolactone (Aldactone)
• Osmotic diuretics – Mannitol
• All diuretics indirectly prevent the reabsorption of water in the kidneys!, most of
them by preventing the reabsorption of
sodium
233
Thiazides
234
Thiazides
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevent re-absorption of sodium in the distal tubule.
235
Thiazides
Hydrochlorthiazide and
Chlorthalidone
Uses
236
Thiazides
Hydrochlorthiazide and Chlorthalidone
Uses
Uses:
• Essential hypertension
– Often first drug used
– May be part of multiple-drug therapy
• Edema
– Preferred drugs for mobilizing edema associated
with incompetent, premenstrual fluid retention, or
mild, moderate heart failure
237
Thiazide Diuretics
Adverse Effects
238
Thiazide Diuretics
Adverse Effects
• Hypokalemia
• Hyponatremia, hypochloremia, dehydration
• Orthostatic hypotension due to the
dehydration
• Avoid in pregnancy if possible
– May reduce placental perfusion (not for
routine use in pregnancy)
• Nocturia if taken at night
239
Thiazide Diuretics
Drug Interactions
240
Thiazide Diuretics
Drug Interactions
• Digoxin→digoxin toxicity (ALL K+-LOSING
DIURETICS)
• Lithium→lithium toxicity (ALL DIURETICS!!!)
– Increase the blood levels of lithium because they
rid the body of water
– Diuretics are contraindicated for people on lithium
• NSAIDS→ Reduced natriuresis/diuresis
• Will reduce the diuretics’ ability to cause diuresis
241
Loop Diuretics
242
Loop Diuretics
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevent the re-absorption of sodium from the
ascending Loop of Henle.
243
Furosemide (Lasix®)
244
Furosemide (Lasix®)
• A second-line diuretic for hypertension but has many
other uses.
• Used primarily for pulmonary edema associated with
congestive heart failure
• Edema of hepatic, cardiac, or renal origin unresponsive
to less efficacious diuretics
– Promotes diuresis in renal impairment
245
Loop Diuretics
Adverse Effects
246
Loop Diuretics
Adverse Effects
•
•
•
•
•
•
Hypokalemia
Hyponatremia, hypochloremia, dehydration
Orthostatic hypotension
Ototoxicity, especially in large doses
Avoid in pregnancy if possible
Nocturia if taken at night
247
Loop Diuretics
Drug Interactions
248
Loop Diuretics
Drug Interactions
• Digoxin – hypokalemia is dangerous with digoxin with
potassium levels are very important with the way that
digoxin works
• Nitrates/other antihypertensives – increased
hypotensive effects
• Other ototoxic drugs (aminoglycoside antibiotics)
• Lithium – lithium toxicity
– ALL diuretics are contraindicated for people on lithium
• NSAIDS can attenuate the diuretic effect of furosemide
249
Potassium-Sparing Diuretics
250
Potassium-Sparing Diuretics
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevent the re-absorption of sodium from the
collecting tubule and duct.
251
Spironolactone - Aldactone
252
Spironolactone - Aldactone®
• Hypertension
• Edema
• Commonly used in combination with
thiazide or loop diuretics
• Effects are delayed
– Takes about one day or so to work
253
Spironolactone (Aldactone®)
Adverse Effects
254
Spironolactone (Aldactone®)
Adverse Effects
• Hyperkalemia
– Avoid the use of potassium supplements
• Avoid salt supplements because they are made of potassium
chloride
– Synergistic with ACE inhibitors and ARBs
• Spironolactone blocks the effects of aldosterone
• ACE inhibitors and ARBs block the secretion of aldosterone
– Can be extremely dangerous
• Can stop your heart!!
• Endocrine effects
– Spironolactone has a steroid structure and can cause a
variety of effects similar to steroid hormones, such as
gynecomastia and impotence in men, menstrual
irregularities, hirsutism, and deepening of the voice in
women
255
Spironolactone (Aldactone®)
Drug Interactions
256
Spironolactone (Aldactone®)
Drug Interactions
• Potassium supplements and salt substitutes
are contraindicated
• ACE inhibitors or ARBs may exacerbate the
tendency to hyperkalemia
• Pregnancy category D because of steroidlike effects on the fetus
257
Triamterene
258
Triamterene
• Often given in combination with a thiazide
– Dyazide = hydrochlorothiazide + triamterene
• Hydrochlorothiazide causes hypokalemia and triamterene causes
hyperkalemia, so the two drugs kind of balance each other out
259
Triamterene
Adverse Effects
260
Triamterene
Adverse Effects
• Hyperkalemia – AVOID K+ supplements
261
Triamterene
Drug Interactions
262
Triamterene
Drug Interactions
• ACE Inhibitors/ARBs: Hyperkalemia potential
• NSAIDS may blunt diuretic effect and
indomethacin may precipitate renal failure
• Take after meals in AM
• Avoid potassium rich diet items -- bananas,
orange juice, salt substitutes (which are likely to
be KCl)
263
Osmotic Diuretics - Mannitol
264
Osmotic Diuretics - Mannitol
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevents re-absorption of water from the proximal
tubule.
265
Mannitol
266
Mannitol
• Must be given parenterally
• Therapeutic uses
– Prophylaxis of renal failure
– Reduction of intracranial pressure
• Draws water out of the brain
– Increased intra-ocular pressure
• When mannitol is in the bloodstream, before it
gets into the renal tubules, it increases the
osmotic pressure of the blood and draws edema
fluid into the vascular system.
• Mannitol is filtered into the glomerulus, drawing
the excess water with it and holding it in the renal
tubules for excretion.
267
Osmotic Diuretics
Adverse Effects
268
Osmotic Diuretics
Adverse Effects
• Edema (caused by mannitol leaving the
circulation and drawing water into the tissues
with it)
– Administer with extreme caution in heart
failure because of its ability to increase
vascular volume and overload the heart.
• Dehydration
• Orthostatic hypotension
269
Osmotic Diuretics
Drug Interactions
270
Osmotic Diuretics
Drug Interactions
• Mannitol is not metabolized, very inert.
• It has no significant drug interactions
271
Drugs Acting on RAAS
Diagram
272
Drugs Acting on RAAS
Diagram
Renin inhibitor
273
Lehne, 2009, Pharmacology for Nursing Care,
7th
ed., Elsevier, p. 500
Renin Inhibition
Diagram
274
Renin
Inhibition
Diagram
275
Renin Inhibitor
Description
276
Renin Inhibitor
Description
• Renin inhibition should prevent all activation of
the renin-angiotensin aldosterone system.
• Only one such drug, aliskiren (Tekturna), is
approved for use as monotherapy or in
combination with hydrochlorothiazide.
• Like other drugs that target the RAAS, aliskiren is
pregnancy category D because of evidence of fetal
harm.
• Not used a lot yet
277
ACE Inhibitors
(ACEI)
278
ACE Inhibitors
(ACEI)
•Introduced in the
late 1980s
•Angiotensin converting
enzyme inhibitors
•Work in the lung
Captopril, lisinopril,
enalapril, and others
- All end in -pril
Porth, 2007, Essential of Pathophysiology, 2nd ed.,
Lippincott, p. 365.
279
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 469
280
Therapeutic Uses of ACEI
281
Therapeutic Uses of ACEI
• Hypertension
• Heart failure
• Protective effects in diabetic nephropathy
– Protect the kidneys
• Post MI prophylaxis
– Prevent a second heart attack in people who
have had one heart attack
• Prevention of MI, stroke, and death in
patients at risk
282
Therapeutic Uses of ACEIs
Hypertension
283
Therapeutic Uses of ACEIs
Hypertension
• Initial responses: reduced formation of angiotensin II
• Prolonged therapy: additional reduction in BP due to
reduced formation of angiotensin II
• REDUCE THE RISK OF CV MORTALITY CAUSED BY HEART
FAILURE
– People who are having heart failure, should be on an ACE
inhibitor or an ARB
• REDUCE THE RISK OF RENAL FAILURE IN DIABETICS
284
Things Not Caused by ACE
Inhibitors
285
Things Not Caused by ACE Inhibitors
• Do not interfere with cardiovascular reflexes
– Do not cause orthostatic hypotension because they do not
interfere with the baroreceptors
• Do not cause hypokalemia but may contribute to the
tendency to hyperkalemia if given with potassiumsparing diuretics.
• Do not induce lethargy, weakness, sexual dysfunction
as other antihypertensives may.
286
ACE Inhibitors
Adverse Effects
287
ACE Inhibitors
Adverse Effects
• Bilateral renal artery stenosis is a contraindication
because these drugs can precipitate acute renal failure in
these patients
– These people need their high blood pressure in order to get the
blood past the stenotic valve and into the kidney
• Dry cough – an effect of increased bradykinin
• First dose hypotension – Most prominent in patients with
very high BP or those on diuretics.
– Should start with a lower dose
• Teratogenic – contraindicated in pregnancy
• Angioedema – due to increased bradykinin, may be very
serious
– Can be very serious if it is present in the mouth of throat
288
Angioedema
Diagram
289
A 75-year-old man presented to the emergency department with diffuse swelling of
his tongue that had begun a few hours earlier. He had been taking 25 mg of captopril
twice daily for the past 3 years because of hypertension. He was treated with
epinephrine, corticosteroids, and antihistamines and the swelling resolved over a
three-hour period. The angioedema was likely due to the angiotensin-converting
enzyme inhibitor.
290
Westra S and de Jager C. N Engl J Med 2006;355:295
ACE Inhibitors
Drug Interactions
291
ACE Inhibitors
Drug Interactions
• Digoxin  Increased digoxin levels
• Lithium  Increased lithium levels/toxicity
• K+ sparing diuretics  hyperkalemia
• Potassium supplements  hyperkalemia
292
ACE Inhibitors
Additional Information
293
ACE Inhibitors
Additional Information
• Can be combined with a thiazide diuretic
• All are oral except for enalaprilat, which is IV
only
• Patients with renal impairment may need
dosage reduction
294
Angiotensin II Receptor Blockers
(ARBs)
295
Angiotensin II
Receptor
Blockers
(ARBs)
Losartan, valsartan,
candesartan, and others
- End in sartan
Porth, 2007, Essential of Pathophysiology, 2nd ed.,
Lippincott, p. 365.
296
ARB Therapeutic Uses
297
ARB Therapeutic Uses
• Widely used
– Not as widely used as the ACE inhibitors
• Hypertension
– Reductions in BP = ACEI
• Heart failure – prevent the progression and improve
outcomes
• Diabetic nephropathy – prevents progression
• Post-MI prophylaxis
• Stroke prevention
298
ARBs
Adverse Effects
299
ARBs
Adverse Effects
• Well tolerated
• Do not cause cough
• Angioedema
– Much more rare than ACE inhibitors
• Fetal harm – contraindicated in pregnancy
• Renal failure
300
ARBs
Drug Interactions
301
ARBs
Drug Interactions
• Hypotensive effects are additive with other
anti-HTN drugs
• Do not cause hyperkalemia but may
contribute if given with potassium-sparing
diuretics
302
Aldosterone
Antagonists
303
Aldosterone
Antagonists
•Spironolactone
•Eplerenone (Inspra)
•Potassium-sparing
diuretics (covered
previously as diuretics)
•Block the aldosterone
receptor
•Promote Na+ and H20
excretion in the
collecting tubule and
duct
304
Porth, 2007, Essential of Pathophysiology,
2nd
ed., Lippincott, p. 365.
Sympatholytics (Antiadrenergics)
Outline
305
Sympatholytics (Antiadrenergics)
Outline
•
•
•
•
•
Beta blockers
Alpha-1 blockers
Alpha/beta blockers
Centrally acting alpha-2 agonists
Adrenergic neuron blockers (inhibit
synthesis or release of norepinephrine)
• Ganglionic blockers (not used, we will not
cover)
306
Sympatholytics (Antiadrenergics)
Diagram
307
Sympatholytics (Antiadrenergics)
Diagram
Sites of Action
308
Lehne, 2009, Pharmacology for Nursing Care,
7th
ed., Elsevier, p. 500
Beta-Adrenergic Blockers
309
Beta-Adrenergic Blockers
• Widely used anti-hypertensive drugs
• Actions in hypertension
– Blockade of cardiac beta-1 receptors→↓HR and
contractility → ↓CO
– Suppress reflex tachycardia caused by vasodilators
– Blockade of beta-1 receptors in JG cells in kidney →
↓ renin release → ↓ RAAS mediated
vasoconstriction (angiotensin II) and volume
expansion (aldosterone)
– Long-term use   peripheral vascular resistance
*Recall from Dr McLeskey’s lecture; Lehne Chapter 18
310
Beta-Adrenergic Blockers
Affinity for Receptors
311
Beta-Adrenergic Blockers
Affinity for Receptors
• Some block both beta-1 and beta-2 receptors
(nonselective)
• Some have greater affinity for beta-1 than beta-2
(“cardioselective”) – but the selectivity is not absolute
• Some are partial agonists – they are said to have
“intrinsic sympathomimetic activity” or ISA
312
Clinical Pharmacology of Some
Beta Blockers
313
Generic/trade name
ISA
Cardioselective (beta1 > beta2)
Acebutolol/Sectal®
+
Atenolol/Tenormin®
0
Esmolol/Brevibloc®
0
Metolprolol/Lopressor®
Slow release/Toprol XL
0
Clinical
Pharmacology
of Some Beta
Blockers
Nonselective (beta1 = beta2)
Pindolol/Visken®
Propranolol/Inderal®
Slow release/Inderal LA®
+++
0
Nonselective alpha/beta blockers
Carvedilol/Coreg®
0
Labetolol/Normodyne® or Trandate®
0
Adapted from Lehne,
2009, Pharmacology for
Nursing Care, 7th ed.,
Elsevier, p. 167
314
Therapeutic Uses of BetaAdrenergic Blockers
315
Therapeutic Uses of Beta-Adrenergic Blockers
Drug
HTN
Angina
Dysrrhythmias
Acebutolol
A
I
A
Atenolol
A
A
I
I
A
A
I
MI
Migraine
Stage
Fright
A
I
I
A
I
Heart
Failure
Cardioselective
Esmolol
Metolprolol
A
A
Nonselective
Pindolol
A
I
Propranolol
A
A
Carvedilol
A
I
Labetolol
A
A
I
A
A
I
Nonselective
alpha/beta
blockers
A – approved; I - investigational
A
A
316
Adapted from Lehne, 2009, Pharmacology for Nursing Care,
7th
ed., Elsevier, p.168
Sympatholytics
Alpha-1 Antagonists
317
Sympatholytics
Alpha-1 Antagonists
Sites of Action
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
318
Alpha-1 Antagonists
319
Alpha-1 Antagonists
•Doxazosin, terazosin, prazosin and others
•End in -azosin
•Block alpha-1 receptors on arterioles and veins  prevent
SNS-mediated vasoconstriction  vasodilation  
peripheral resistance,  venous return to heart
•Doxazosin, terazosin and tamsulosin (Flomax) used for
BPH.
•May actually be used more frequently for this than for
hypertension
320
Alpha-1 Antagonists
Adverse Effects
321
Alpha-1 Antagonists
Adverse Effects
• Not used as first line therapy for hypertension
– Orthostatic hypotension is a big problem
– Sexual side effects are big reasons for
noncompliance
322
Centrally Acting Alpha-2 Agonists
323
Centrally Acting Alpha-2 Agonists
Sites of Action
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
324
Centrally Acting Alpha-2 Agonists
• Clonidine
• Methyldopa (agent of choice for chronic
hypertension in pregnancy – not for pre-eclampsia)
– The only drug that is approved for hypertension in
pregnancy
• Act within brainstem (alpha-2 receptors) to
suppress sympathetic outflow to the heart and
blood vessels → vasodilation,  CO  BP
325
Centrally Acting Alpha-2 Agonists
Adverse Effects
326
Centrally Acting Alpha-2 Agonists
Adverse Effects
•
•
•
•
Dry mouth
Sedation
Hemolytic anemia
Liver disorders
• Rebound hypertension if abruptly stopped
– Could result in a stroke
327
Calcium Channel Blockers
328
Calcium Channel Blockers
• Dihydropyridines
• Non-dihydropyridines
329
Calcium Channel Blockers
Dihydropyridines
330
Calcium Channel Blockers
Dihydropyridines
• Nifedipine
• Amlodipine (Norvasc)
• Used for hypertension
– Promote dilation of arterioles, little effect on veins
331
Calcium Channel Blockers
Non-dihydropyridines
332
Calcium Channel Blockers
Non-dihydropyridines
• Verapamil, diltiazem
• Can be used for hypertension
– Promote dilation of arterioles, little effect on veins
• Also act on heart to slow conduction and
decrease contractility
– May be good or bad
333
Calcium Channels in the Heart
Diagram
334
Calcium Channels in the Heart
Diagram
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 481
335
Calcium Channels in the Heart
Description
336
Calcium Channels in the Heart
Description
• NE – beta receptor – increased activity at
calcium channels – heart – increased HR (SA
node), conduction velocity (AV node), and
contraction (myocardium)
337
Verapamil
338
Verapamil
• Blocks Ca+2 channels in arterioles, heart
– Dilation of peripheral vessels  BP
– Dilation of coronary arteries   coronary perfusion
– Blockade at SA node   HR
– Blockade at AV node   nodal conduction
– Blockade in myocardium   contractile force
• Indications
– Angina pectoris, hypertension, dysrhythmias (Afibrillation, PSVT)
339
Verapamil
Adverse Effects
340
Verapamil
Adverse Effects
• Constipation (why?)
– Block calcium channels in the smooth muscle of the GI
tract, leading to constipation
• Dizziness, facial flushing, headache, edema of
ankles, feet (why?)
– Because of the effect on veins
• Bradycardia, conduction defects (why?)
– Due to effects on the heart rate
341
Nifedipine and Amlodipine
(Dihydropyridines)
342
Nifedipine and Amlodipine
(Dihydropyridines)
• Block Ca+2 channels in arterioles
– Do not have the effects on the heart that
verapamil does
– Used mainly for hypertension
– Dilation of peripheral vessels → BP
– Dilation of coronary arteries →  coronary
perfusion
• Do NOT block cardiac Ca+2 channels at
therapeutic doses
343
Nifedipine and Amlodipine
Indirect (Reflex) Effects
344
Nifedipine and Amlodipine
Indirect (Reflex) Effects
• Lowering BP  baroreceptor reflex → stimulate the
medulla -- firing of SNS to beta receptors in the
heart --- increased heart rate and increases
contractility
– Stimulating the heart may not be desirable in somebody
with heart disease
– Can use a beta blocker along with this in order to
decrease heart rate
• But, nifedipine lacks direct cardiosuppressant actions,
cardiac stimulation is unopposed → HR, 
contractility
• Net effect is the sum of the direct effect (vasodilation)
and the indirect effect (reflex cardiac stimulation)
345
Nifedipine and Amlodipine
Uses
346
Nifedipine and Amlodipine
Uses
• Angina pectoris
– Vasospastic angina, angina of effort
• Hypertension
– Essential hypertension
– Nifedipine – only use sustained-release
formulation for hypertension
• Take whole, do not crush or chew
– Amlodipine has a longer half-life than
nifedipine and does not have a sustainedrelease formulation
347
Nifedipine and Amlodipine
Adverse Effects
348
Nifedipine and Amlodipine
Adverse Effects
• Flushing, dizziness, headache, edema
• Gingival hyperplasia
• Constipation
– This is a big deal
– People have to be on a bowel regimen of stool softeners and fiber
• Do not exacerbate conduction abnormalities because they do not
affect the conduction system of the heart
• Do cause reflex tachycardia →  cardiac oxygen demand → angina
– Give with a beta blocker to counteract this in patients with angina
349
Nifedipine blocks Ca+2 channels
in arterioles. This results in:
350
Nifedipine blocks Ca+2 channels in
arterioles. This results in:
...
of
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ila
tio
n
se
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ec
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s
oc
as
V
pe
H
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in
tr
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..
tr
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- Because you are
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ti.
..
25% 25% 25% 25%
1. Vasoconstriction of
peripheral vessels
2. Vasoconstriction of
coronary arteries
3. Decrease in HR
4. Dilation of
peripheral vessels
351
Hypertensive Emergencies
352
Hypertensive Emergencies
• (SBP >200 mm Hg or DBP >120 mm Hg)
• Symptoms of actual or impending end-organ
damage
– Neurological
– Cardiovascular
– Other
353
Hypertensive Emergencies
Neurological Symptoms
354
Hypertensive Emergencies
Neurological Symptoms
• Hypertensive encephalopathy - the brain does not work well,
person is not oriented
• Cerebral vascular accident/cerebral infarction
– May have an aortic dissection where the lining of the aorta separates
from the other layers, preventing the blood from going forward
• Subarachnoid hemorrhage
• Intracranial hemorrhage
355
Hypertensive Emergencies
Cardiological Symptoms
356
Hypertensive Emergencies
Cardiological Symptoms
• Myocardial ischemia/infarction
• Acute left ventricular dysfunction
• Acute pulmonary edema
• Aortic dissection
357
Hypertensive Emergencies
Other Symptoms
358
Hypertensive Emergencies
Other Symptoms
• Acute renal failure/insufficiency
• Retinopathy
• Eclampsia
• Microangiopathic hemolytic anemia
359
Sodium Nitroprusside-Nitropress
360
Sodium Nitroprusside-Nitropress®
• A very powerful arterial vasodilator
• No reflex tachycardia
• Overshoot hypotension is possible but can be correctly
quickly by stopping or slowing the infusion
• Titrate to blood pressure
– An infusion pump is essential. An arterial line or an
automatic blood pressure cuff must be used to
check BP continuously.
361
Sodium Nitroprusside-Nitropress
Adverse Effects
362
Sodium Nitroprusside-Nitropress
Adverse Effects
• Cyanide poisoning
• Thiocyanate Toxicity
Lehne, 2009, Pharmacology for Nursing Care, 7th
ed., Elsevier, p. 492
363
Adverse Effects
Cyanide Poisoning
364
Adverse Effects
Cyanide Poisoning
• Likely in patients with liver disease
• Avoid prolonged rapid infusion because of the
risk of cyanide poisoning
365
Adverse Effects
Thiocyanate Toxicity
366
Adverse Effects
Thiocyanate Toxicity
• Likely when drug given over days
• CNS effects (disorientation, delirium)
• Avoid infusions > 3 days; monitor plasma
thiocyanate
367
IV Calcium Channel Blockers
368
IV Calcium Channel Blockers
• Can be used for hypertensive emergencies
• Fenoldepam – long half-life
• Nicardipine – long half life
• Clevidipine – short half-life, easy to titrate
• Titrate similarly to sodium nitroprusside
• All can cause reflex tachycardia and hypotension.
369
How do diuretics decrease blood
pressure?
370
How do diuretics decrease blood
pressure?
1. Block beta adrenergic
receptors – beta
blockers
2. Inhibit angiotensin
converting enzyme –
ACE inhibitors
3. Act on renal tubules
to promote water
excretion
4. Act as a vasodilator
d.
..
t..
.
so
va
as
ct
A
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ct
on
a
ng
i
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hi
b
it
a
ta
be
k
lo
c
B
re
na
l
ot
..
ad
r.
..
.
25% 25% 25% 25%
371
Hyperlipidemia Leading to
Atherosclerosis
DISORDERS OF ARTERIAL CIRCULATION
372
Types of Biological Lipids
373
Types of Biological Lipids
• Triglycerides, phospholipids, cholesterol classified as
lipids
• Lipids are chemical substances that are insoluble in
water but soluble in alcohol.
Three types of biological lipids
• Triglycerides
Used as sources for energy metabolism
• Phospholipids
Structural components of lipoproteins, clotting components,
myelin sheath, cell membranes
• Cholesterol
Basis of steroid hormones and an important cell membrane
component
374
Lipoproteins
375
Lipoproteins
• Lipoprotein – a lipid transport
particle
• Lipids (cholesterol, triglycerides)
insoluble in plasma
– Must be transported encapsulated in
lipid transport particles (lipoproteins)
composed of phospholipids and
embedded proteins
– The outside is made of phospholipids
(phosphate group on the outside that
are polar and two fatty acid tails on
the inside)
– Green beans are triglycerides and
orange circles are cholesterolproteins
• Apoproteins are large proteins
contained within the phospholipid
coat of the lipoprotein
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 348.
– Identify which lipid transport particle
it is and help with its docking and
release of lipids
376
Types of Lipoproteins
Description
377
Types of Lipoproteins
Description
• Of the five types of lipoproteins, LDLs and HDLs are the most important
• As the density of the lipoprotein increases, the proportion of triglycerides
decreases and the proportion of cholesterol increases (except LDLs have
more cholesterol than HDLs)
• Chylomicrons
• Come from the GI tract
• Dietary lipids
• VLDL
• Smaller, heavier, more compact, circulate in the blood
• LDL
• Smaller, more compact, heavier, circulate
• HDL
• Smaller, most compact and dense
378
Types of Lipoproteins
379
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 348.
Lipoprotein Synthesis and Transport
Description
380
Lipoprotein Synthesis and Transport
Description
• Synthesized in small intestine, liver
• Liver is important in LDL metabolism
– Removes LDL via LDL receptors
– Place where the HDLs bring the lipids back
• Lipids are transported all over the body
• Chylomicrons in the liver are changed into VLDLs and
then into LDLs
• Circulating to body tissues
• HDLs are bringing the lipids back to the liver
381
Lipoprotein Synthesis and Transport
382
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 349.
HDL
383
HDL
• “Good cholesterol”
• Carries cholesterol FROM tissues back TO the
liver
– This is why there are good
• Prevent atherosclerosis
• High HDL prevents atherosclerosis
– HDLs are scavengers, picking up cholesterol from
deposits in the arteries and bringing it back to the
liver for disposal
• HDL inhibits uptake of LDLs into cells
• Heredity, exercise, moderate ETOH (1-2 drinks
per day for women)  HDLs
• Smoking, diabetes or metabolic syndrome
(sort of a diabetic prodrome) HDLs
384
LDL
385
LDL
• “bad cholesterol”
• Familial defects in LDL receptor –
“familial hypercholesterolemia”
– Inadequate, or defective hepatic uptake of
LDL  circulating LDL
– Have heart attacks and strokes at very early
ages
• “Receptor disease”
386
LDL Receptors in Liver Remove
LDLs from the Blood
387
LDL Receptors in Liver Remove LDLs from the Blood
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
388
Hypercholesterolemia
389
Hypercholesterolemia
Xanthomas (deposits of
cholesterol) develop in certain
areas, including the knuckles.
- Not very common
Porth, 2007, Essentials of Pathophysiology, 2nd ed.,
Lippincott, p. 350.
390
Hypercholesterolemia
Primary
391
Hypercholesterolemia
Primary
•
•
•
•
•
Develops independent of other causes
Defective synthesis of apoproteins
Lack of receptors
Defective receptors
Defects in handling of cholesterol in cell that are
genetically determined
• Familial hypercholesteremia
392
Hypercholesterolemia
Secondary
393
Hypercholesterolemia
Secondary
• Associated with other health problems and behaviors
(high fat diet, obesity, diabetes mellitus)
394
Diagnosis Screening
395
Diagnosis Screening
• All adults 20 years of age and older should
have a fasting lipoprotein profile done every 5
years
– Total cholesterol, LDL, HDL, TG
See Porth, text on page 350-351 for specific recommendations
Also Table 49.4 in Lehne
396
Classification of LDL, Total, and
HDL Cholesterol
397
Classification of LDL, Total, and HDL Cholesterol
Cholesterol
Level (mg/dL)
Total
<200
200-239
>240
Classification
Optimal
Borderline high
High
Cholesterol
Classification
Level (mg/dL)
HDL
cholesterol
<40
Low
>60
High
LDL cholesterol
<100
100-129
130-159
Optimal
Above optimal
Borderline high
160-189
>190
High
Very high
Adapted from Porth, 2007, Essentials of Pathophysiology, 2nd
ed., Lippincott, p. 350.
398
Why are Increased Blood Lipids
so Bad?
399
Why are Increased Blood Lipids so Bad?
• Increased blood lipids, particularly cholesterol, increase
the risk of a vascular disease called atherosclerosis.
– Fatty deposits form in arterial walls
• This increases the risk of clot formation and occlusion of an artery.
– Occluded arteries cause myocardial infarctions, stroke, and
peripheral vascular disease, which may lead to necrosis of part of
the extremity.
• Atherosclerosis leads to arteriosclerosis (hardening of the
arteries) caused by calcium deposits in the walls of the
arteries
– Increases the risk of aneurysms and other vessel wall problems.
400
Atherosclerosis
401
Atherosclerosis
• Atheros (glue/paste)
• Sclerosis (hardening)
• Formation of fibrofatty lesions (atheromas) in
the intimal lining of large and medium sized
arteries (aorta, coronaries, carotids, and many
others)
– Not present in the veins
402
Atherosclerotic Lesions
403
Atherosclerotic Lesions
• Fatty streak
– Thin, flat, yellow discolorations that progressively enlarge by becoming
thicker and more elevated. Present in children. Precursors to
atheromata
• Atheroma
• Fibrous plaque
– Increases in smooth muscle and collagen
• Complicated lesions
– A complicated lesion has a lot of smooth muscle vessels that have
proliferated
– Macrophages eat up the lipids
– This type of lesion can serve as the focus of a clot and represents a
weakness in the artery that may cause problems
– Characterized by thrombosis, fissure, and hematoma formation
404
Atheromatous Plaque
405
Atheromatous Plaque
Plaque
Complicated
Lesion
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 353
406
Definitions
Thrombus, Embolus, Stenosis, Mural
407
Definitions
Thrombus, Embolus, Stenosis, Mural
• Thrombus = clot
• Embolus = a clot that breaks off from its initial
location and travels through the vascular system.
• Stenosis = narrowing or closing off of a vessel (or a
heart valve).
• Mural = wall (a mural thrombus is a clot in the wall of
a vessel or a chamber of the heart)
408
Atherosclerosis Timeline
409
410
410
Progression of Atherosclerosis
411
Robbins & Cotran Pathologic Basis of Disease (7th ed), Elsevier, 2005, p.517
412
Atheromatous Lesion
Diagram
413
414
Atheromas
415
•Atheromas tend to
develop at sites of
turbulent flow – near
branch points and arteries
•As the artheroma
develops, it creates more
of a constriction, which
produces more turbulent
flow and more atheromas.
•See Figure 17.8 in Porth!
Porth, 2007, Essentials of Pathophysiology,
2nd ed., Lippincott, p. 352.
416
Laminar and Turbulent Flow
417
Laminar and Turbulent Flow
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 323.
418
Lifestyle Risk Factors for
Atherosclerosis
419
Lifestyle Risk Factors for
Atherosclerosis
• Many people have more than one of these risk factors
• Age
– Men > 45 y.o.; women > 55 y.o. (or premature menopause)
• Removing ovaries at an earlier age, will accelerate women’s risk
of atherosclerosis
• Family History
– MI before 55 y.o. in father or before 65 y.o. mother
• Current cigarette smoking
– If you stop smoking, the risk decreases quickly
• Hypertension (BP > 140/90)
• Hyperlipidemia
– Low HDL (< 40 mg/dL)
– High LDL
• Diabetes mellitus
420
Risk Factors
Markers
421
Risk Factors
Markers
• C-reactive protein (CRP)
– Marker of inflammation; may be a better than LDL?
– Not very specific because you can have inflammation for many
different reasons
• Homocysteine
– Inhibits coagulation, causes endothelial damage, important in
initial phases?
– It is good to be elevated and bad to be low
– Not a great predictor of athlerosclerosis
• Serum lipoprotein (a)
– Part of the LDL; promotes foam cells
– If it is elevated, it is a risk factor
• Infectious agents
– Chlamydia pneumoniae
422
Clinical Manifestations of
Vascular Disease
423
Clinical Manifestations of Vascular Disease
Cotran (1999) pg. 499
424
Management of Hyperlipidemia
425
Management of Hyperlipidemia
•
Reduction in LDL is primary target for cholesterol-lowering therapy, particularly for
people at risk for CHD*
– It is not as easy to raise the HDL as it is to lower the LDL
– Age, family history of premature CHD, cigarette smoker, hypertension, low HDL, diabetes mellitus
•
Some evidence that when lipids are lowered, at least with statin drugs, that
atheromatous changes regress.
– This is a very good thing
•
Dietary changes*
•
Lifestyle changes
•
Pharmacologic treatment
–  calories,  saturated fats,  cholesterol
–  physical activity, smoking cessation, weight loss
*See Porth, Table 17-1, page 351 and Lehne, Table 49-4, p. 551
* See Lehne, Table 49-6, pg. 556
426
Lipid-Lowering Drugs
Diagram
427
Lipid-Lowering Drugs
Diagrams
428
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 349.
Mechanisms of Lipid-Lowering
Drugs
429
Mechanisms of Lipid-Lowering Drugs
•
1.
2.
3.
4.
5.
Mechanisms:
Affect cholesterol production by the liver
Remove cholesterol from bloodstream
LDL receptors
Cholesterol absorption from intestine
 intravascular conversion of VLDL and IDL to
LDL
430
Classes of Drugs Used in Treatment
of Hypercholesterolemia
431
Classes of Drugs Used in Treatment of
Hypercholesterolemia
•
•
•
•
•
HMG-CoA reductase inhibitors (statins)
Bile acid-binding resins
Cholesterol absorption inhibitor agents
Niacin and its congeners
Fibric acid derivatives
432
Types of Statins
433
Types of Statins
•
•
•
•
•
•
•
All end in -statin
Atorvastatin [Lipitor]
Fluvastatin [Lescol]
Lovastatin [Mevacor] - generic
Provastatin [Pravachol]
Rosuvastatin [Crestor]
Simvastatin [Zocor] - generic
434
Statins
Beneficial Actions
435
Statins
Beneficial Actions
• Reduce cholesterol synthesis in liver
•  LDL receptors (most important)
–  LDLs from the circulation, which is desirable
•  HDLs
•  TG
436
Statins
Timing
437
Statins
Timing
• Results within 2 weeks; maximal 4-6 weeks
• If drug is stopped, serum cholesterol returns
to pretreatment levels (lifelong treatment),
unless the person has lost substantial weight
438
Statins LDL Receptors in Liver ->
 LDLs
439
Statins LDL Receptors in Liver ->  LDLs
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
440
Statins
Actions
441
Statins
Actions
• Cardiovascular actions
– Reduce inflammation at plaque sites
– Improve endothelial cell function
– Enhance blood vessel dilation
– Reduce the risk of thrombosis
• Increased bone formation
– Enhance osteoblast activity   risk of osteoporosis
and fractures
442
Statins
Therapeutic Uses
443
Statins
Therapeutic Uses
• Hypercholesterolemia
• Prevention of cardiovascular events
– MI, stroke, angina
• Diabetes
– ADA: Pts > 40 y.o. with total cholesterol > 135 mg/dLregardless of LDL
– ACP: All pts with type 2 diabetes with coronary artery
disease, even if they don’t have high cholesterol; all adults
with type 2 diabetes plus one CV risk factor - even if they
don’t have high cholesterol
444
Statins
Side Effects
445
Statins
Side Effects
• Myopathy (inflammation of the
muscle)/rhabdomyolysis (total muscle
breakdown)
– Report unexplained muscle weakness,
tenderness
– Rhabdomyolysis can be fatal
– Rosuvastatin higher risk
• Hepatotoxicity
– Monitor liver enzymes every 6-12 months
– Avoid use for patients with viral or alcoholic
hepatitis
446
Statins
Drug Interactions
447
Statins
Drug Interactions
• Fibrates and ezetimibe
– Also  cholesterol, so their activity might be
additive to statins
– Can also cause myopathy, so the danger from
that would also be increased
• Inhibitors of cytochrome P450 like ketoconazole,
erythromycin, HIV protease inhibitors, etc., inhibit
the metabolism of statins and raise blood levels 
 risk of adverse effect
448
Bile Acid Sequestrants
449
Bile Acid Sequestrants
• Cholestyramine, colestipol, and colesevelam
• Biologically inert, insoluble in water, cannot be
absorbed from GI tract, simply pass through intestine,
excreted in feces
450
Bile Acid Sequestrants
Actions
451
Bile Acid Sequestrants
Actions
• Absorb bile acids in the intestine and keep them
from being reabsorbed into the bloodstream.
– New bile acids must be synthesized, which requires
cholesterol.
– LDLs are internalized into liver cells as a source of
cholesterol.
– This lowers LDLs.
• Reduce LDL cholesterol
– Maximal reduction within one month (20%)
– LDL levels return to pre-treatment levels when drug is
discontinued
452
Bile Acid Sequestrants
Diagram
453
Bile Acid Sequestrants
Diagram
Prevent the absorption
of cholesterol in the
intestine
454
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 349.
 Bile acid reabsorption (GI) 
synthesis in liver   need for
cholesterol  LDL receptors
455
 Bile acid reabsorption (GI)  synthesis in liver 
 need for cholesterol  LDL receptors
456
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
Bile Acid Sequestrants
Therapeutic Use
457
Bile Acid Sequestrants
Therapeutic Use
• Reduce LDL cholesterol
– Drug plus diet ->  LDL by 15-30%
• Usually combined with statin
–  LDL by 50%
458
Bile Acid Sequestrants
Adverse Effects
459
Bile Acid Sequestrants
Adverse Effects
• Devoid of systemic effects because they are
not absorbed
• GI symptoms (except colesevelam) because it
swells up in the GI tract (drink it)
– Constipation
– Bloating
– Indigestion
– Nausea
460
Bile Acid Sequestrants
Drug Interactions
461
Bile Acid Sequestrants
Drug Interactions
• Cannot take a lot of medications because it will
absorb medications and keep them from being
absorbed
• Decreased absorption of:
–
–
–
–
–
Warfarin
-Acetaminophen
Thiazides
-Beta blockers
Digoxin
-Corticosteroids
Iron
-Thyroid hormones
Fat-soluble vitamins A, D, E, and K (except colesevelam)
– Take oral medications 1 hour before or 4 hours
after the bile acid sequestrant.
462
Cholesterol Absorption Inhibitors
Ezetimibe (Zetia®)
463
Ezetimibe (Zetia®)
Mechanism of Action
464
Ezetimibe (Zetia®)
Mechanism of Action
• Mechanism of action
• Acts on cells in the brush border of the
intestine and inhibits cholesterol absorption
– Does not actually absorb the cholesterol like the
previous drug
• Blocks absorption of dietary cholesterol and
cholesterol secreted in bile
• Lowers total cholesterol, LDLs, TG and raises
HDLs
465
Ezetimibe (Zetia®)
Use
466
Ezetimibe (Zetia®)
Use
• Used as adjunct to diet modification
• Can be used as monotherapy or with a statin
– Recent evidence that the combo of ezetimibe and
simvastin (Vytorin) actually worsened plaques
rather than making them better.
467
Ezetimibe (Zetia)
Drug Interactions
468
Ezetimibe (Zetia)
Drug Interactions
• Statins -  risk of liver damage
• Fibrates – both  the concentration of cholesterol
in the bile   the risk of gallstones, which is
precipitated solid cholesterol
• Bile-acid sequestrants- impair the absorption of
ezetimibe
• Cyclosporine- inhibits metabolism of ezetimibe 
 its concentration.
469
Nicotinic Acid (Niacin) [Niacor,
Niaspan]
470
Nicotinic Acid (Niacin) [Niacor, Niaspan]
Decreases production of
VLDLs by inhibiting
lipolysis in adipose
tissue   LDL
471
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 349.
Nicotinic Acid (Niacin)
472
Nicotinic Acid (Niacin)
• Effect on plasma lipoproteins:
– Reduces triglycerides (20 – 50%) and LDLs (5-25%)
– Raises HDLs (15-35%)
– Drug of choice to lower triglyceride levels in patients at
risk for pancreatitis.
– More effective when combined with statin
– Triple therapy (nicotinic acid, statin, bile-acid
sequestrant)  LDL 70%
• Nicotinic acid is also a B-vitamin, but doses as a
vitamin are much smaller than as a lipid-lowering
drug.
473
Nicotinic Acid
Adverse Effects
474
Nicotinic Acid
Adverse Effects
• Intense flushing of the head and neck in nearly all
patients– diminishes in several weeks, attenuated
with aspirin
• GI upset – take with food
• Hepatotoxic – follow liver enzymes
• Raises blood levels of homocysteine, a substance
thought to increase cardiovascular risk. To
counteract this, add folic acid supplements.
• Hyperglycemia – use with caution in diabetics
475
Fibric Acid Derivatives (Fibrates)
476
Fibric Acid Derivatives (Fibrates)
- Gemfibrozil [Lopid]
- Fenofibrate [Tricor]
1. Increase lipoprotein
lipase →  VLDLs
and  TG storage in
adipose tissue (
serum TG)
2. Also  HDL
3. No effect on LDL
477
Porth, 2007, Essentials of Pathophysiology,
2nd
ed., Lippincott, p. 349.
Fibric Acid Derivatives
Adverse Effects
478
Fibric Acid Derivatives
Adverse Effects
• Gallstones – Increase biliary cholesterol saturation
→ increase risk of gallstones
• Myopathy – like the statins, can cause myopathy
• Hepatotoxicity – like the statins, fibric acid
derivatives are hepatotoxic; Monitor liver enzymes
• Because of overlapping adverse effects, the combo
of a statin and a fibric acid derivative should be used
with great caution.
• Pregnancy category C
479
Fibric Acid Derivatives
Drug Interactions
480
Fibric Acid Derivatives
Drug Interactions
• Warfarin – Gemfibrozil increases the efficacy
of warfarin by displacing it from protein
binding sites.
– Follow INR closely
• Use with caution in statins because of the
increase in risk of myopathy
481
Which of the following drugs are
insoluble in water, cannot be
absorbed from the GI tract and pass
through the intestine?
482
Which of the following drugs are insoluble in
water, cannot be absorbed from the GI tract and
pass through the intestine?
id
N
ic
o
tin
ac
ic
id
ac
..
br
ic
Fi
C
M
G
H
B
ile
ac
oA
id
re
d
se
q
uc
.
u.
..
1. Bile acid sequestrants
2. HMG Co-A reductase
inhibitors
3. Fibric acid derivatives
4. Nicotinic acid
de
...
25% 25% 25% 25%
483
Which of the following drug classes
has been shown to reverse
atherosclerotic changes?
484
Which of the following drug classes has been
shown to reverse athrosclerotic changes?
25% 25% 25% 25%
in
ia
c
N
u.
..
se
q
id
ac
ile
B
Fi
br
ic
ac
id
St
at
in
s
de
...
1. Statins
2. Fibric acid
derivatives
3. Bile acid
sequestrants
4. Niacin
485
Questions?
486