cvi fall 2011

Control of Cardiovascular Function, Disorders of Blood Flow & Blood

Pressure, Hyperlipidemia & Artherosclerosis

• 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

Pulmonary and Systemic Circulation

Baxter Corp. (1999)

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

Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p 461

How does blood get back to the heart?

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

Determinants of Blood Pressure

BP = CO X Peripheral vascular resistance

CO = SV X HR

What determines peripheral vascular resistance?

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!

Volume & Pressure Distribution

Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 321.

Arteriolar tone determines systemic vascular resistance

Same concept from Lehne

Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p 461

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

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).

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

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)

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

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.

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.

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.

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

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.

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

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

Functional Anatomy of the Heart

Pericardium: Sac around heart

A “virtual space” which can become fluid or blood-filled (pericardial effusion).

Contraction: Actin & Myosin Binding

http://www.sci.sdsu.edu/movies/actin_myosin_gif.html

Spirito et al., NEJM 336, pg 775, 1997

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

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

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).

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

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.

• 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.

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

The Wiggers diagram

Ventricular Systole

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).

Ventricular Diastole

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).

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

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

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

Stroke Volume Components

• Preload – Ventricular filling (volume)

• Afterload– Resistance to ejection of blood from heart

• Contractility– Pumping function of heart

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

Preload: Frank-Starling Law of the HeartActin, myosin filaments that overlap and create cross bridge attachments leads to contraction of cardiac muscle

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.

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.

Effect of Afterload on CO

Guyton, 2006, Textbook of Medical Physiology, 11th ed.,Saunders, p. 114.

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.

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.

Determinants of Blood Pressure

BP = CO X Peripheral vascular resistance

CO = SV X HR

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

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.

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.

The Sensory Components of the Baroreceptor Reflex – Chemo and Stretch Receptors

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

Neurotransmitters

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

Humoral Mechanisms:

Renin-angiotensin-aldosterone

system

MUST KNOW THIS!

Vasopressin (Antidiuretic Hormone (ADH))

The ANS and RAAS systems work in concert.

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.

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

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

Disorders of Blood Pressure Regulation:

Hypertension and Orthostatic Hypotension

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

Orthostatic Hypotension

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

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

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.

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)

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

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

Lifestyle Risk Factors

• Diet high in Na+ & saturated fats

• Obesity

• Physical inactivity

• Excessive alcohol consumption

• Oral contraceptives in predisposed women

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

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

Consequences of HTN

• Vascular damage– Coronary arteries – myocardial infarction

(CVII)– Peripheral blood vessels – peripheral vascular

disease– Kidney – renal failure– Cerebral blood vessels – stroke

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

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

Lehne, 2009, Pharmacology for Nursing Care, 67h ed., Elsevier, p. 500

Sites of Action

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

Pharmacologic Treatment

• Compliance is a huge issue– Lifetime treatment– Many of the drugs have unpleasant side effects– Many are expensive

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

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

Recurrent Stroke Prevention

Drugs That Affect BP: Diuretics

Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 500

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!

Thiazides

Prevent re-absorption of sodium in the distal tubule.

Thiazides: hydrochlorthiazide & chlorthalidone

• 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

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

Loop Diuretics

Prevent the re-absorption of sodium from the ascending Loop of Henle.

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

Loop Diuretics: Adverse Effects

• Hypokalemia

• Hyponatremia, hypochloremia, dehydration

• Orthostatic hypotension

• Ototoxicity

• Avoid in pregnancy if possible

• Nocturia if taken at night

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

Potassium-Sparing Diuretics

Prevent the re-absorption of sodium from the collecting tubule and duct.

Spironolactone - Aldactone®

• Hypertension

• Edema

• Commonly used in combination with thiazide or loop diuretics

• Effects are delayed

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

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

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)

Osmotic Diuretics -Mannitol

Prevents re-absorption of water from the proximal tubule.

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.

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

Drugs Acting on RAAS

Renin inhibitor

Renin inhibition

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.

101Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 365.

ACE Inhibitors(ACEI)

Captopril, lisinopril, enalapril, and others

102Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 469

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

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

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

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.

ACE Inhibitors: Drug Interactions

• Digoxin Increased digoxin levels• Lithium Increased lithium levels/toxicity• K+ sparing diuretics hyperkalemia• Potassium supplements hyperkalemia

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

109Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 365.

Angiotensin IIReceptorBlockers(ARBs)

Losartan, valsartan, candesartan, and others

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

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

Aldosterone Antagonists

SpironolactoneEplerenone (Inspra)

Potassium-sparing diuretics (covered previously as diuretics)

PromoteNa+ & H20 excretion in the collecting tubule & duct

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)

Drugs That Affect BP: Sympatholytics (Antiadrenergics)

Sites of Action

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

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

Generic/trade name ISA

Cardioselective (beta1 > beta2)

Acebutolol/Sectal® +

Atenolol/Tenormin® 0

Esmolol/Brevibloc® 0

Metolprolol/Lopressor®

Slow release/Toprol XL

Nonselective (beta1 = beta2)

Pindolol/Visken® +++

Propranolol/Inderal®

Slow release/Inderal LA®

Nonselective alpha/beta blockers

Carvedilol/Coreg® 0

Labetolol/Normodyne® or Trandate® 0

Clinical Pharmacology of Some Beta

Blockers

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

Sympatholytics - Alpha-1 antagonists

Sites of Action

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

Centrally Acting Alpha-2 Agonists

Sites of Action

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

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

124Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 481

Calcium Channels in the Heart

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

Verapamil: Adverse Effects

• Constipation (why?)

• Dizziness, facial flushing, headache, edema of ankles, feet (why?)

• Bradycardia, conduction defects (why?)

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

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)

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

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

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

Hypertensive Emergencies

(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

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.

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

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.

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

Disorders of Arterial Circulation

Hyperlipidemia Leading to Atherosclerosis

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

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

Five Types of Lipoproteins

-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

Lipoprotein Synthesis & Transport

Synthesis in small intestine, liver

Liver important in LDL metabolism; removes LDL via LDL receptors

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

• Familial defects in LDL receptor – “familial hypercholesterolemia”– Inadequate, or defective hepatic uptake of

LDL circulating LDL

• “Receptor disease”

LDL Receptors in Liver Remove LDLs from the Blood

Robbins & Cotran Pathologic Basis of Disease (7th ed), 2005, Elsevier, p.158

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)

Xanthomas (deposits of cholesterol) develop in certain areas, including the knuckles.

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

Classification of LDL, Total, and HDL CholesterolCholesterol

Level (mg/dL)Classification

<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.

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.

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)

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

Atheromatous Plaque

Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 353

Plaque ComplicatedLesion

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)

153153

154Robbins & Cotran Pathologic Basis of Disease (7th ed), Elsevier, 2005, p.517

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!

Laminar & Turbulent Flow

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

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

Clinical Manifestations of Vascular Disease

Cotran (1999) pg. 499

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

Management

• Dietary changes* calories, saturated fats, cholesterol

• Lifestyle changes physical activity, smoking cessation, weight loss

• Pharmacologic treatment

* See Lehne, Table 49-6, pg. 556

Lipid-Lowering Drugs

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

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

Statins

• Atorvastatin [Lipitor]

• Fluvastatin [Lescol]

• Lovastatin [Mevacor]

• Provastatin [Pravachol]

• Rosuvastatin [Crestor]

• Simvastatin [Zocor]

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)

Statins LDL Receptors in Liver -> LDLs

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

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

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

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

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

Bile Acid Sequestrants

Prevent the absorption of cholesterol in the intestine

Bile acid reabsorption (GI) synthesis in liver need for cholesterol LDL receptors

Therapeutic Use

• Reduce LDL cholesterol

– Drug plus diet -> LDL by 15-30%

• Usually combined with statin LDL by 50%

Adverse effects

• Devoid of systemic effects

• GI symptoms (except colesevelam)– Constipation– Bloating– Indigestion– Nausea

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.

Cholesterol Absorption Inhibitors

Ezetimibe (Zetia®)

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.

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.

Nicotinic Acid (Niacin) [Niacor, Niaspan]

Decreases production of VLDLs by inhibiting lipolysis in adipose tissue LDL

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.

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

Fibric Acid Derivatives (Fibrates)

- Gemfibrozil [Lopid]- Fenofibrate [Tricor]

1. Increase lipoprotein lipase → VLDLs and TG storage in adipose tissue ( serum TG)

2. Also HDL3. No effect on LDL

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

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

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

Which of the following drug classes has been shown to reverse athrosclerotic

changes?

25% 25%25%25%

1. Statins

2. Fibric acid derivatives

3. Bile acid sequestrants

4. Niacin

Questions?

cvi fall 2011

Health & Medicine

cvi distribution center

cvi clinical trial research manager in an era of big...

cvi accepts, published online ahead of print ... -...

coti's cvi implementation

gettingstarted cvi

cvi statistics talk 2011 · cvi statistics michael lavalley...

babies with cvi

session 7: wednesday october 21, 2015: cvi. housekeeping ...

gettingstarted_ver2010 labwindows cvi

cvi optical specifications

cvi summer/fall 2012 newsletter

fall 2011 fall 2011

labwindows/cvi user interface reference...

xtr110 cvi

quickreference labwindows cvi

labwindowstm/cvi tm -...

cvi accepts, published online ahead of print on 10 august...

cvi results

cvi - panjabdigilib.org

cvi quarterly cvi quarterly