Cvi fall 2011
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Transcript of Cvi fall 2011
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Control of Cardiovascular Function, Disorders of Blood Flow & Blood
Pressure, Hyperlipidemia & Artherosclerosis
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• 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
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Pulmonary and Systemic Circulation
Baxter Corp. (1999)
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Differences in the Two 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
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Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p 461
How does blood get back to the heart?
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Principles of Blood Flow• Hemodynamics
• Heart is an intermittent pump, blood flow is pulsatile
• Factors governing the function of the CV system– Volume– Pressure– Resistance– Flow
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Determinants of Blood Pressure
BP = CO X Peripheral vascular resistance
CO = SV X HR
What determines peripheral vascular resistance?
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Resistance of a Tube
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 452.
Also see p 322, point 2 in Porth, Essentials
Big factor!
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Volume & Pressure Distribution
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 321.
Arteriolar tone determines systemic vascular resistance
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Same concept from Lehne
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p 461
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All Blood Vessels Have 3 Layers
• Intima- elastic layer• Media- smooth muscle
for diameter control (innervated by the SNS with alpha receptors)
• Externa- fibrous and connective tissue for support
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 338
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Resistance Arterioles Maintain Blood Pressure
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 338
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).
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Blood Vessels and the Peripheral Circulation
• 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
• Skin, skeletal muscle require varying flow
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Arteries, Arterioles• Elasticity allows for stretching during systole
• Arterioles have abundant smooth muscle
• Arterioles are the major resistance vessels for circulatory system and basically determine the systemic vascular resistance
• Sympathetic fibers innervate arterioles cause them to constrict/relax as needed to maintain BP (alpha receptors)
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Veins, Venules
• Collect blood from capillaries, carry back to heart
• Enlarge and store large quantities of blood• 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
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Veins• Valves prevent retrograde flow
– Incompetent valves in venous varicosities
• 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.
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Endothelial Cells
Endothelial cells line all blood vessels. They are normally quite smooth and permit laminar blood flow. They also form a tight barrier in larger vessels, but in capillaries are more permissive of small molecules exiting and entering the vascular system.
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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
• In most vascular beds, capillaries have fenestrations that allow passage of water and small molecules but not large proteins.
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 341.
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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
• Calcium channel blockers prevent vasoconstriction
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Perfusion of Organs• Tissue blood flow to a given organ is regulated on
minute-to-minute basis in relation to tissue needs
• Neural mechanisms regulate CO 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.
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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.
• Increase blood flow– Histamine
• Decrease blood flow– Serotonin
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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
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Functional Anatomy of the Heart
Pericardium: Sac around heart
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 328.
A “virtual space” which can become fluid or blood-filled (pericardial effusion).
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Contraction: Actin & Myosin Binding
http://www.sci.sdsu.edu/movies/actin_myosin_gif.html
Spirito et al., NEJM 336, pg 775, 1997
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Heart Valves Keep Blood Flow UnidirectionalSemilunar valves: Control blood flow out of ventricles
Aortic valve
Pulmonic valve
A-V valves: Control blood flow between atria & ventricles
Tricuspid valve
Mitral valve
Major function of heart valves: Forward direction of blood flow
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 329.
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Cardiac Conduction System• The conduction system stimulates the myocardium to
contract & 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
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SA Node• Pacemaker of the heart
• Impulses originate here
• Located in posterior wall RA
• Fires at 60 -100 bpm
• Rate is determined by the autonomic nervous system (beta-1 receptors increase HR and muscarinic receptors decrease it).
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 331.
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AV Node• Connects the atria &
ventricles, provides one way conduction
• Speed of conduction is determined by the ANS
• Can assume pacemaker function if SA fails to discharge– Fires at 40 -60 bpm
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 331.
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Purkinje Fibers• Supply the ventricles
• Large fibers, rapid conduction for swift & efficient ejection of blood from heart
• Assume pacemaker of ventricles if AV fails– Intrinsic rate is 15-40
bpmPorth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 331.
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ECG
• Electrical events recorded• Electrical events precede
mechanical events; know what they represent!– P– QRS– T
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p.331 & 333.
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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
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Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 334.
The Wiggers diagram
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Ventricular Systole
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 334.
Isovolumic (isometric) contractionClosure of AV valves (S1), allvalves closed. No change in ventricular volume, ventricles contract. When ventricular pressures > aortic & pulmonary pressures, semilunar valves open, leading to the - Ejection period.Stroke volume ejected.Ventricles contract, then relax.Intraventricular pressures and become less than pressures in aorta & pulm. artery. Blood from large arteries flows back toward ventricles and aortic/pulmonic valves shut (S2).
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Ventricular Diastole
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 334.
Ventricular relaxation & filling.
Isovolumic (isometric) relaxation:Semilunar valves closed, ventricles relax. No change in ventricular volume, but ventricular pressure until it’s less than atrial pressures. AV valves open, blood from atria enters ventricles ->
Rapid filling period.Most ventricular filling in first third of diastole.(S3) During the last third, atria contract (atrial kick).
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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
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Definitions• Cardiac output (CO)
– Amount of blood the heart pumps/minute– 3.5 - 8.0 L/minute
• Stroke volume (SV)– Amount of blood the heart pumps each beat– 70 ml/beat
• CO = SV x HR• CO varies with body activities.• CO varies by changes in SV and/or HR
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Heart Rate• Frequency with which blood is ejected from heart• 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 diastolic filling time may SV & CO• Tachycardia can be dangerous because the heart may not
have time to fill adequately → CO
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Stroke Volume Components
• Preload – Ventricular filling (volume)
• Afterload– Resistance to ejection of blood from heart
• Contractility– Pumping function of heart
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Preload (“Volume”)
• Represents the volume of blood the heart must pump with each beat
• 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
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Preload: Frank-Starling Law of the HeartActin, myosin filaments that overlap and create cross bridge attachments leads to contraction of cardiac muscle
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 336.
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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.
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Afterload (“Resistance”)• The amount of pressure the heart must develop during the
period of isovolumic contraction to open the aortic and pulmonic valves.
• 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)
• 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.– Diastolic hypertension also increases the pressure necessary to
open the aortic valve.
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Effect of Afterload on CO
Guyton, 2006, Textbook of Medical Physiology, 11th ed.,Saunders, p. 114.
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Implications of the Afterload/CO Curve
• At normal afterloads, in people with normal hearts, afterload is not an important factor in cardiac output.– Normally, preload is a much more important
determinant of CO.– The normal heart pumps what it gets from the
venous system.
• In people with heart failure (CVII), afterload becomes an important determinant of CO.
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Contractility• Ability of the heart to change its force of
contraction• 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 increases the availability of calcium ions and increases contractility.
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Determinants of Blood Pressure
BP = CO X Peripheral vascular resistance
CO = SV X HR
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Mechanisms of BP Regulation
• Arterial pressure must remain relatively constant as blood flow shifts from one area of body to another
• Method by which arterial pressure is regulated depends on whether short-term or long-term adaptation is needed
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Mechanisms of BP Regulation
• Autonomic nervous system – short-term regulation
• RAAS (Renin-angiotensin-aldosterone system) – longer term regulation
• Kidneys – control blood volume as well as the RAAS – a long-term mechanism of blood pressure control.
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The Baroreceptor Reflex
Baroreceptors in the aortic arch and carotid artery
Autonomic centers in the brainstem
Cardiac muscle, cardiac conduction system, and vascular smooth muscle.
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The Sensory Components of the Baroreceptor Reflex – Chemo and Stretch Receptors
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 364.
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ANS Regulation of BP – the Baroreceptor Reflex
Be sure you know which receptors are where!!!
McCance & Heuther, 2002, Pathophysiology: The Biologic Basis for Disease in Adults & Children, Mosby, p.961
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Neurotransmitters
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 1151.
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Long-term Regulation of BP
• Primarily controlled by kidneys
• Neural mechanisms act rapidly, but can’t maintain their effectiveness over time
• Kidneys’ control in long term is thru regulation of Na+ and H20 balance
– RAAS – Vasopressin
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Humoral Mechanisms:
Renin-angiotensin-aldosterone
system
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 365.
MUST KNOW THIS!
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Vasopressin (Antidiuretic Hormone (ADH))
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 756.
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Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 756.
The ANS and RAAS systems work in concert.
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Which of the following is an important determinant of cardiac output in a normal person?
25% 25%25%25%1. Afterload.
2. Heart rate.
3. Venous return (preload)
4. Total peripheral resistance.
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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. SA Node
2. AV Node
3. An ectopic atrial focus
4. Purkinje Fibers
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Angiotensin II causes:
25% 25%25%25%
1. Release of aldosterone
2. Vasoconstriction of arterioles
3. Increased arterial blood pressure
4. All of the above
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Disorders of Blood Pressure Regulation:
Hypertension and Orthostatic Hypotension
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Orthostatic Hypotension• Abnormal drop in BP on assumption of the
standing position
• 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
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Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 374
Orthostatic Hypotension
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Causes• 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
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Treatment
• Alleviating cause– Rehydrate, change meds
• 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
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Hypertension• 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.
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Hypertension
• PRIMARY• “Essential hypertension”• Chronic elevation of BP
occurs without evidence of other disease
• 90-95% of hypertension
• SECONDARY• Elevation of BP
occurs from some other disorder– Kidney disease
– Chronic renal failure
– disorders of adrenocorticoid hormones (pheochromocytoma)
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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
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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
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Lifestyle Risk Factors
• Diet high in Na+ & saturated fats
• Obesity
• Physical inactivity
• Excessive alcohol consumption
• Oral contraceptives in predisposed women
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Consequences of HTN• 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, coronary artery disease (angina, myocardial infarction), heart failure
– Brain• Stroke or transient ischemic attack
– Chronic kidney disease– Peripheral vascular disease– Retinopathy
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Consequences of HTN• Heart: LV
Hypertrophy workload of LV (
afterload); LV tries to compensate for workload.
– LV hypertrophy is major risk factor for ischemic heart disease, dysrhythmias, heart failure, sudden death
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Consequences of HTN
• Vascular damage– Coronary arteries – myocardial infarction
(CVII)– Peripheral blood vessels – peripheral vascular
disease– Kidney – renal failure– Cerebral blood vessels – stroke
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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– ECG, Urinalysis, Hb, Hct, Na+, K+, Cr, glucose,
triglycerides, cholesterol
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Treatment of Hypertension• Lifestyle modification is the first line of treatment
– Weight reduction, regular physical exercise, DASH eating plan, 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
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Lehne, 2009, Pharmacology for Nursing Care, 67h ed., Elsevier, p. 500
Sites of Action
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Pharmacologic Treatment
• Diuretics• Sympatholytics
– Beta-adrenergic blockers
– Alpha-1 adrenergic blockers
– Centrally-acting alpha-2 agonists
– Drugs that block norepinephrine release
• Act on RAAS– Renin inhibitor
– ACE inhibitors
– Angiotensin II receptor blockers
– Aldosterone antagonists
• Others– Ca+2 channel blockers
– Direct-acting vasodilators
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, Table 46-5, p. 502
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Pharmacologic Treatment
• Compliance is a huge issue– Lifetime treatment– Many of the drugs have unpleasant side effects– Many are expensive
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Algorithm for Treating Hypertension
Lifestyle modifications
Goal BP not met
Stage 1 – thiazide diuretic /consider ACEI,ARB, beta blocker, CCB or combinationStage 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
Continue adding drugs from other classes until goal is achieved
Goal BP not met
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 507
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Classes of Antihypertensive Drugs Recommended for Initial Therapy in Patients with High-Risk Comorbid Conditions
Condition Drug Classes Recommended for Initial Therapy of HTN
Diuretic Beta
Blocker
ACEI ARB CCB Aldosterone Antagonist
Heart Failure X X X X X
Post MI X X X
Coronary Artery Disease Risk
X X X X
Diabetes X X X X X
Chronic Kidney Disease
X X
Recurrent Stroke Prevention
X X
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 508
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Drugs That Affect BP: Diuretics
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
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Classification of Diuretics• Thiazide diuretics – Hydrochlorothiazide (HCTZ®) &
chlorthalidone• 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 re-absorption of water in the kidneys!
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Thiazides
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevent re-absorption of sodium in the distal tubule.
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Thiazides: hydrochlorthiazide & chlorthalidone
Uses:
• Essential hypertension– Often first drug used– May be part of multiple-drug therapy
• Edema– Preferred drugs for mobilizing edema associated
with mild, moderate heart failure
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Thiazide Diuretics• Adverse Effects
– Hypokalemia– Hyponatremia, hypochloremia, dehydration– Orthostatic hypotension– Avoid in pregnancy if possible
• May reduce placental perfusion (not for routine use in pregnancy)
– Nocturia if taken at night
• Drug Interactions– Digoxin→digoxin toxicity (ALL K+-LOSING
DIURETICS)– Lithium→lithium toxicity (ALL DIURETICS!!!)– NSAIDS→ Reduced natriuresis/diuresis
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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.
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Furosemide (Lasix®)
• A second-line diuretic for hypertension but has many other uses.
• Used 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
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Loop Diuretics: Adverse Effects
• Hypokalemia
• Hyponatremia, hypochloremia, dehydration
• Orthostatic hypotension
• Ototoxicity
• Avoid in pregnancy if possible
• Nocturia if taken at night
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Loop Diuretics: Drug Interactions
• Digoxin – hypokalemia is dangerous with digoxin• Nitrates/other antihypertensives – increased
hypotensive effects• Other ototoxic drugs (aminoglycoside antibiotics)• Lithium – lithium toxicity• NSAIDS can attenuate the diuretic effect of furosemide
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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.
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Spironolactone - Aldactone®
• Hypertension
• Edema
• Commonly used in combination with thiazide or loop diuretics
• Effects are delayed
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Spironolactone (Aldactone®)
• Adverse effects– Hyperkalemia
• Avoid use of potassium supplements• Synergistic with ACE inhibitors and ARBs
– 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
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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 steroid-like
effects on the fetus
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Triamterene
• Often given in combination with a thiazide– Dyazide = hydrochlorothiazide + triamterene
• Adverse Effect– Hyperkalemia – AVOID K+ supplements
• 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)
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Osmotic Diuretics -Mannitol
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 445
Prevents re-absorption of water from the proximal tubule.
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Mannitol• Must be given parenterally• Therapeutic uses
– Prophylaxis of renal failure– Reduction of intracranial pressure– 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.
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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
• Drug Interactions– Mannitol is not metabolized, very inert.– It has no significant drug interactions
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Drugs Acting on RAAS
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
Renin inhibitor
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Renin inhibition
99
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Renin Inhibitor
• 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.
100
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101Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 365.
ACE Inhibitors(ACEI)
Captopril, lisinopril, enalapril, and others
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102Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 469
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Therapeutic Uses of ACEI• Hypertension
• Heart failure
• Protective effects in diabetic nephropathy
• Post MI prophylaxis
• Prevention of MI, stroke, and death in patients at risk
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Therapeutic Uses of ACEIs: HTN
• Initial responses: reduced formation of angiotensin II• Prolonged therapy: additional reduction in BP• Do not interfere with cardiovascular reflexes• Do not cause hypokalemia but may contribute to the
tendency to hyperkalemia if given with potassium-sparing diuretics.
• Do not induce lethargy, weakness, sexual dysfunction as other antihypertensives may.
• REDUCE THE RISK OF CV MORTALITY CAUSED BY HEART FAILURE
• REDUCE THE RISK OF RENAL FAILURE IN DIABETICS
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ACE Inhibitors: Adverse Effects• Bilateral renal artery stenosis is a contraindication
because these drugs can precipitate acute renal failure in these patients
• Dry cough – an effect of increased bradykinin• First dose hypotension – Most prominent in patients
with very high BP or those on diuretics.• Teratogenic – contraindicated in pregnancy• Angioedema – due to increased bradykinin, may be
very serious
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Westra S and de Jager C. N Engl J Med 2006;355:295
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.
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ACE Inhibitors: Drug Interactions
• Digoxin Increased digoxin levels• Lithium Increased lithium levels/toxicity• K+ sparing diuretics hyperkalemia• Potassium supplements hyperkalemia
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ACE Inhibitors
• 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
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109Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 365.
Angiotensin IIReceptorBlockers(ARBs)
Losartan, valsartan, candesartan, and others
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ARB Therapeutic Uses
• Hypertension– Reductions in BP = ACEI
• Heart failure – prevent the progression and improve outcomes
• Diabetic nephropathy – prevents progression• Post-MI prophylaxis• Stroke prevention
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ARBs• Adverse effects
– Well tolerated– Do not cause cough– Angioedema– Fetal harm – contraindicated in pregnancy– Renal failure
• Drug interactions– Hypotensive effects are additive with other
anti-HTN drugs– Do not cause hyperkalemia but may contribute
if given with potassium-sparing diuretics
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Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 365.
Aldosterone Antagonists
SpironolactoneEplerenone (Inspra)
Potassium-sparing diuretics (covered previously as diuretics)
PromoteNa+ & H20 excretion in the collecting tubule & duct
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Drugs That Affect BP: Sympatholytics (Antiadrenergics)
• 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)
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Drugs That Affect BP: Sympatholytics (Antiadrenergics)
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
Sites of Action
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Beta-Adrenergic Blockers*
• Widely used anti-hypertensive drugs
• Actions in hypertension– Blockade of cardiac beta-1 receptors→↓HR,
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 McPherson’s lecture; Lehne Chapter 18
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Beta-Adrenergic Blockers
• 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
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Generic/trade name ISA
Cardioselective (beta1 > beta2)
Acebutolol/Sectal® +
Atenolol/Tenormin® 0
Esmolol/Brevibloc® 0
Metolprolol/Lopressor®
Slow release/Toprol XL
0
Nonselective (beta1 = beta2)
Pindolol/Visken® +++
Propranolol/Inderal®
Slow release/Inderal LA®
0
Nonselective alpha/beta blockers
Carvedilol/Coreg® 0
Labetolol/Normodyne® or Trandate® 0
Clinical Pharmacology of Some Beta
Blockers
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 167
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Therapeutic UsesDrug HTN Angina Dysrrhy-
thmiasMI Migraine Stage
FrightHeart Failure
Cardioselective
Acebutolol A I A
Atenolol A A I A I I
Esmolol I A
Metolprolol A A I A I A
Nonselective
Pindolol A I I
Propranolol A A A A A I
Nonselective alpha/beta blockers
Carvedilol A I A A
Labetolol A
Adapted from Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p.168A – approved; I - investigational
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Sympatholytics - Alpha-1 antagonists
Sites of Action
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
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Alpha-1 Antagonists*•Doxazosin, terazosin, prazosin and others
•Block alpha-1 receptors on arterioles and veins prevent SNS-mediated vasoconstriction vasodilation peripheral resistance, venous return to heart
•Not used as first line therapy for hypertension–Orthostatic hypotension is a big problem–Sexual side effects are big reasons for noncompliance
•Doxazosin, terazosin and tamsulosin (Flomax) used for BPH.
*Recall Dr McPherson’s lecture; Lehne Chapter 18
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Centrally Acting Alpha-2 Agonists
Sites of Action
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500
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Centrally Acting Alpha-2 Agonists
• Clonidine, methyldopa (agent of choice for chronic hypertension in pregnancy – not for pre-eclampsia)
• Act within brainstem (alpha-2 receptors) to suppress sympathetic outflow to the heart and blood vessels → vasodilation, CO BP
• Cause dry mouth, sedation, hemolytic anemia, liver disorders
• Rebound hypertension if abruptly stopped
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Calcium Channel Blockers
• Dihydropyridines– Nifedipine– Amlodipine (Norvasc)– Promote dilation of arterioles, little effect on veins
• Non-dihydropyridines– Verapamil, diltiazem– Promote dilation of arterioles, little effect on veins– Also act on heart to slow conduction and decrease
contractility
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124Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 481
Calcium Channels in the Heart
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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
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Verapamil: Adverse Effects
• Constipation (why?)
• Dizziness, facial flushing, headache, edema of ankles, feet (why?)
• Bradycardia, conduction defects (why?)
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Nifedipine and amlodipine (dihydropyridines)
• Block Ca+2 channels in arterioles– Dilation of peripheral vessels → BP– Dilation of coronary arteries → coronary
perfusion
• Do NOT block cardiac Ca+2 channels at therapeutic doses
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Nifedipine & Amlodipine:Indirect (reflex) Effects
• Lowering BP baroreceptor reflex → firing of SNS to beta receptors in the heart
• 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)
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Nifedipine & 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 sustained-release formulation
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Nifedipine & Amlodipine: Adverse Effects
• Flushing, dizziness, headache, edema • Gingival hyperplasia• Constipation• Do not exacerbate conduction abnormalities• Do cause reflex tachycardia → cardiac
oxygen demand → angina – Give with a beta blocker to counteract this in
patients with angina
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Nifedipine blocks Ca+2 channels in arterioles. This results in:
25% 25%25%25%1. Vasoconstriction
of peripheral vessels
2. Vasoconstriction of coronary arteries
3. Decrease in HR
4. Dilation of peripheral vessels
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Hypertensive Emergencies
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(SBP >200 mm Hg or DBP >120 mm Hg)
Symptoms of actual or impending end-organ damage
Neurological Hypertensive encephalopathy Cerebral vascular accident/cerebral infarction Subarachnoid hemorrhage Intracranial hemorrhage
Cardiovascular Myocardial ischemia/infarction Acute left ventricular dysfunction Acute pulmonary edema Aortic dissection
Other Acute renal failure/insufficiency Retinopathy Eclampsia Microangiopathic hemolytic anemia
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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.
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Adverse Effects• Cyanide poisoning
– Likely in pts with liver disease
– Avoid prolonged rapid infusion
• Thiocyanate Toxicity– Likely when drug given
over days
– CNS effects (disorientation, delirium)
– Avoid infusions > 3 days; monitor plasma thiocyanate
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 492
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IV Calcium Channel Blockers
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.
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How do diuretics decrease blood pressure?
25% 25%25%25%1. Block beta adrenergic receptors
2. Inhibit angiotensin converting enzyme
3. Act on renal tubules to promote water excretion
4. Act as a vasodilator
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Disorders of Arterial Circulation
Hyperlipidemia Leading to Atherosclerosis
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Hyperlipidemia
• Triglycerides, phospholipids, cholesterol classified as lipids; chemical substances insoluble in water but soluble in alcohol.
• Three types of biological lipids• Triglycerides
Used as sources for energy metabolism
• PhospholipidsStructural components of lipoproteins, clotting components, myelin sheath, cell membranes
• CholesterolBasis of steroid hormones and an important cell membrane component
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Lipoproteins • Lipids (cholesterol, triglycerides) insoluble in plasma
• Encapsulated in lipid transport particles (lipoproteins) composed of phospholipids and embedded proteins
• Apoproteins are large proteins contained within the phospholipid coat of the lipoprotein
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 348.
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Five Types of Lipoproteins
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 348.
-Of the five, 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
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Lipoprotein Synthesis & Transport
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 349.
Synthesis in small intestine, liver
Liver important in LDL metabolism; removes LDL via LDL receptors
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HDL• “Good cholesterol”• Carries cholesterol FROM tissues TO liver• 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• Exercise, moderate ETOH HDLs• Smoking, diabetes or metabolic syndrome
(sort of a diabetic prodrome) HDLs
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LDL
• Familial defects in LDL receptor – “familial hypercholesterolemia”– Inadequate, or defective hepatic uptake of
LDL circulating LDL
• “Receptor disease”
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LDL Receptors in Liver Remove LDLs from the Blood
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
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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
• Secondary– Associated with other health
problems & behaviors (high fat diet, obesity, diabetes mellitus)
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 350.
Xanthomas (deposits of cholesterol) develop in certain areas, including the knuckles.
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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 recommendationsAlso Table 49.4 in Lehne
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Classification of LDL, Total, and HDL CholesterolCholesterol
Level (mg/dL)Classification
Total
<200 Optimal
200-239 Borderline high
>240 High
LDL cholesterol
<100 Optimal
100-129 Above optimal
130-159 Borderline high
160-189 High
>190 Very high
Cholesterol Level (mg/dL)
Classification
HDL cholesterol
<40 Low
>60 High
Adapted from Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 350.
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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.
• Atherosclerosis leads to arteriosclerosis (hardening of the arteries) which increases the risk of aneurysms and other vessel wall problems.
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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)
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Atherosclerotic Lesions
• Fatty streak– Thin, flat, yellow discolorations that
progressively enlarge by becoming thicker and more elevated. Present in children. Precursors to atheromata?
• Fibrous atheromatous plaque
• Complicated lesions
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Atheromatous Plaque
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 353
Plaque ComplicatedLesion
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Definitions
• 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)
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153153
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154Robbins & Cotran Pathologic Basis of Disease (7th ed), Elsevier, 2005, p.517
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156Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 352.
Atheromas tend to develop at sites of turbulent flow – near branch points
As the artheroma develops, it creates more of a constriction, which produces more turbulent flow.
See Figure 17.8 in Porth!
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Laminar & Turbulent Flow
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 323.
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Risk Factors for Atherosclerosis
• Age– Men > 45 y.o.; women > 55 y.o. (or premature
menopause)
• Family History– MI before 55 y.o. in father or before 65 y.o. mother
• Current cigarette smoking• Hypertension (BP > 140/90)• Hyperlipidemia
– Low HDL (< 40 mg/dL)– High LDL
• Diabetes mellitus
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Risk Factors• C-reactive protein (CRP)
– Marker of inflammation; better than LDL?
• Homocysteine– Inhibits coagulation, causes endothelial damage, important
in initial phases?
• Serum lipoprotein (a)– Part of the LDL; promotes foam cells
• Infectious agents– Chlamydia pneumoniae
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Clinical Manifestations of Vascular Disease
Cotran (1999) pg. 499
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Management
• Reduction in LDL is primary target for cholesterol-lowering therapy, particularly for people at risk for CHD*– 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.
*See Porth, Table 17-1, page 351 and Lehne, Table 49-4, p. 551
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Management
• Dietary changes* calories, saturated fats, cholesterol
• Lifestyle changes physical activity, smoking cessation, weight loss
• Pharmacologic treatment
* See Lehne, Table 49-6, pg. 556
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Lipid-Lowering Drugs
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 349.
Mechanisms:1. Affect cholesterol
production by liver2. Remove cholesterol
from bloodstream3. LDL receptors4. Cholesterol
absorption from intestine
5. intravascular conversion of VLDL and IDL to LDL
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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
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Statins
• Atorvastatin [Lipitor]
• Fluvastatin [Lescol]
• Lovastatin [Mevacor]
• Provastatin [Pravachol]
• Rosuvastatin [Crestor]
• Simvastatin [Zocor]
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Statins• Beneficial Actions:
– Reduce cholesterol synthesis in liver LDL receptors (most important) LDLs HDLs TG
• Timing:– Results within 2 weeks; maximal 4-6 weeks
– If drug is stopped, serum cholesterol returns to pretreatment levels (lifelong treatment)
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Statins LDL Receptors in Liver -> LDLs
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
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Statins
• Cardiovascular actions– Reduce inflammation at plaque sites– Improve endothelial cell function– Enhance blood vessel dilation– Reduce risk of thrombosis
• Increased bone formation– Enhance osteoblast activity risk of osteoporosis,
fractures
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Statins: Therapeutic Uses
• Hypercholesterolemia• Prevention of cardiovascular events
– MI, stroke, angina
• Diabetes– ADA: Pts > 40 y.o. with total cholesterol > 135 mg/dL-
regardless 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
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Statins: Side Effects
• Myopathy/rhabdomyolysis– Report unexplained muscle weakness,
tenderness– Rosuvastatin higher risk
• Hepatotoxicity– Monitor liver enzymes every 6-12 months– Avoid use for pts with viral, alcoholic hepatitis
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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
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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
• 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
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Bile Acid Sequestrants
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 349.
Prevent the absorption of cholesterol in the intestine
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Bile acid reabsorption (GI) synthesis in liver need for cholesterol LDL receptors
Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158
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Therapeutic Use
• Reduce LDL cholesterol
– Drug plus diet -> LDL by 15-30%
• Usually combined with statin LDL by 50%
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Adverse effects
• Devoid of systemic effects
• GI symptoms (except colesevelam)– Constipation– Bloating– Indigestion– Nausea
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Bile Acid Sequestrants Drug Interactions
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.
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Cholesterol Absorption Inhibitors
Ezetimibe (Zetia®)
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Ezetimibe (Zetia®)• Mechanism of action
– Acts on cells in the brush border of the intestine and inhibits cholesterol absorption
– Blocks absorption of dietary cholesterol and cholesterol secreted in bile
• Lowers total cholesterol, LDLs, TG and raises HDLs
• 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.
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Ezetimibe (Zetia): Drug Interactions
• Statins - risk of liver damage• Fibrates – both the concentration of cholesterol
in the bile the risk of gallstones• Bile-acid sequestrants- impair the absorption of
ezetimibe• Cyclosporine- inhibits metabolism of ezetimibe
its concentration.
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Nicotinic Acid (Niacin) [Niacor, Niaspan]
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 349.
Decreases production of VLDLs by inhibiting lipolysis in adipose tissue LDL
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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.
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Nicotinic Acid: Adverse Effects
• Intense flushing of the head & neck in nearly all pts– diminishes in several weeks, attenuated with aspirin
• GI upset – take with food• Hepatotoxic – follow liver enzymes• Raises blood levels of homocyteine, a substance
thought to increase cardiovascular risk. To counteract this, add folic acid supplements.
• Hyperglycemia – use with caution in diabetics
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Fibric Acid Derivatives (Fibrates)
Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 349.
- Gemfibrozil [Lopid]- Fenofibrate [Tricor]
1. Increase lipoprotein lipase → VLDLs and TG storage in adipose tissue ( serum TG)
2. Also HDL3. No effect on LDL
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Fibric acid derivativesAdverse effects
• Gallstones – Increase biliary cholesterol saturation → increase risk of gallstones
• Myopathy – like the statins, can cause myopathy• Heptatotoxicity – 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
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Fibric acid derivativesDrug 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
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Which of the following drugs are insoluble in water, cannot be absorbed from the GI tract and pass through the intestine?
25% 25%25%25%1. Bile acid sequestrants
2. HMG Co-A reductase inhibitors
3. Fibric acid derivatives
4. Nicotinic acid
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Which of the following drug classes has been shown to reverse athrosclerotic
changes?
Sta
tins
Fib
ric a
cid
de...
Bile
aci
d seq
u...
Nia
cin
25% 25%25%25%
1. Statins
2. Fibric acid derivatives
3. Bile acid sequestrants
4. Niacin
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Questions?