Pathopharmacology Exam #4

The circulatory system is composed of...

vessels, fluid, pump

How does blood flow?

from systemic to pulmonary to systemic circulation

5 structures of circulation

arteries (transport blood to the tissues, high pressure system)
arterioles (regulate amount of blood flow to the tissues)
capillaries (exchange of fluid, oxygen, nutrients, hormones and waste products)
venules (collect blood from the capillaries)
veins (transport blood back to the heart, reservoir for blood, low pressure system)

Arteries vs. Veins

-Arteries have *thick walls* to withstand the pressure of blood pumped by the hearts.
-Veins have *walls with a thinner muscle layer and larger lumen.* *valve*

What does blood flow depend on?

differences between the pressure in the arterial and venous vessels supplying the organ

blood flow resistance

Blood viscosity=thickness
Vessel % of RBCs

length=longer and more resistant
Vessel radium=half diameter

blood flow velocity

velocity decreases as blood moves from the aorta to the capillaries

blood flow vascular compliance

volume the vessel can accommodate for a given increase in pressure

Three facts about the heart (think size, weight, bib)

weighs 1 lb
size of a fist
pumps 2.4 oz of blood per beat

Left heart circulatory system

- thick-walled ventricle
- high pressure pump
- receive blood from lungs
- pumps to systemic circulation

Right heart circulatory system

- thin-walled ventricle
- low-pressure pump
- receives blood from the systemic circulation
- pumps to lungs

How does blood flow through the heart?

Inferior and superior vena cava (1) dump blood into the right atrium (2)
Right ventricle (3)
2 pulmonary arteries (4) that lead to the lungs (5) where blood becomes oxygenated
Pulmonary veins (6) bring blood from the lungs back to the left atrium (7)
Left ventricle (8) is large and muscular to pump blood into the aorta (9) and to the rest of the body (10)
Eventually blood will be pumped back to each vena cava (1)

Flow through the chambers of the heart

body-->right atrium-->right ventricle-->lungs-->left atrium--> left ventricle

Anatomy of the heart

refer to picture

Which is the only vein in the body that carries oxygenated blood?

pulmonary veins

Which is the only artery in the body that carries deoxygenated blood?

pulmonary arteries

Layers of the heart wall

pericardium, myocardium, endocardium

Pericardium

- protects against inflammation and infection
- prevents displacement of the heart
- contains pain receptors, elicits changes in BP and heart rate

Myocardium

- thickest layer
- cardiac muscle

endocardium

- internal lining of myocardium
- connects with arteries, capillaries, and veins to create continuous closed system

the cardiac cycle

1. Diastole
- atria fill
- all valves closed
2. Diastole
- increased atrial pressure opens AV valves
- ventricles fill
3. Systole Begins
- atria contract and empty
- ventricles are full
4. Systole
- ventricles begin contraction
- pressure closes AV valves
- atria relax
5. Systole
- ventricles contract
- increased pressure in ventricles
- aortic and pulmonary valves open
- blood ejected into aorta and pulmonary artery
6. Diastole
- ventricles empty
- ventricles relax
- aortic and pulmonary valves close

right coronary artery

- Conus: supplies R upper ventricle
- Right Marginal Branch: supplies R ventricle
- Posterior Descending: supplies to smaller branches of both ventricles

left coronary artery

- Left anterior descending artery (LAD): supplies left and right ventricle
- Circumflex artery: supplies left atrium and lateral wall of left ventricle

Is coronary blood flow higher during diastole or systole?

Answer: Diastole
*flow is determined by the pressure gradient across the coronary bed*
- diastole: 2/3 resting (filling)
- systole: 1/3 contracting (ejecting)

collateral circulation

- normally some arterial anastomoses (connections) exist within the coronary circulation
- when occlusion occurs slowly over time, there's a greater chance of adequate collateral circulation developing

What is an occlusion?

closure of a blood vessel due to blockage

myocardial metabolism

cardiac muscle depends on constant production of ATP for energy

energy is used for:
- muscle contraction and relaxation
- electrical excitation

cardiac output

- volume of blood ejected by ventricle in 1 min (normal for adult is 5L/min)
- cardiac output=heart rate x stroke volume
- others factors determining cardiac output (preload, after load, myocardial contractility)

What is stroke volume?

Amount of blood ejected by the ventricle with EACH CONTRACTION
- applies equally to both ventricles
- important in cardiac output
- correlates with cardiac function

How is cardiac output regulated?

extrinsic control (outside the heart)
- autonomic nervous system
- hormones

intrinsic control (inside the heart)
- rhythm and rate
- force of contraction
- end-diastolic volume

How does sympathetic stimulation regulate the cardiac system?

- increased myocardial contractility
- increased heart rate
- increased venous return

How does parasympathetic stimulation regulate the cardiac system?

- decreased heart rate

How does endocrine responses regulate the cardiac system?

- thyroid hormone
- epinephrine

Preload

mechanical state of the heart at the end of diastole with the ventricles at their maximum volume

*increased preload increases stroke volume*

factors influencing this:
- the amount of blood entering the ventricle during diastole
- blood left in ventricle after systole

frank sterling law of the heart

The stroke volume of the left ventricle will increase as the left ventricular volume increases due to the myocyte stretch (preload) causing a more forceful systolic contraction

- says the greater the volume of blood within the ventricle the greater the force of contraction

What happens when the heart rate increases?

diastolic filling time is reduced
decreased coronary artery filling
heart has to overcome high pressure in aorta to eject blood (consumers more oxygen)

What increases preload?

-Increased central venous pressure
-Vasoconstriction
-Increased total blood volume
-Decreased heart rate

What decreases preload?

- decreased blood pressure
- decreased blood volume
- gravity (standing upright)
- ventricular diastolic failure (hypertrophy)
- mitral and tricuspid valve stenosis

What is afterload?

Force resistance to eject blood from the ventricles
- determined by peripheral resistance (ex: after load is increased by a high diastolic pressure resulting form excessive vasoconstriction)
- Important determinant of myocardial energy consumption

What increases after load?

aortic and pulmonary valve stenosis
systemic and/or pulmonary hypertension
increased systemic vascular resistance (peripheral vascular resistance)

Ejection Fraction

Fractions of blood ejected by the left ventricle during systole (calculated by dividing the stroke volume by the end-diastolic volume)

Normal ejection fraction is 60-70%

Increased EF results from sympathetic stimulation

Decreased EF is primary symptom of ventricular failure

cardiac reserve

The ability of the heart to increase output in response to increased demand

Components:
- heart rate increases
- stroke volume increases
- cardiac output increases
- oxygen use increases (is supply greater than demand)

Myocardial Oxygen Supply

Factors that affect supply:
- coronary artery anatomy
- diastolic pressure
- diastolic filling time
- O2 supply vs O2 demand

What is blood pressure? (diastolic, systolic, MAP)

the pressure in the aorta is caused by the left ventricle as blood is pumped

systolic: arterial pressure during ventricular contraction (affected by stroke volume, aortic stiffness, and ejection velocity)

diastolic: arterial pressure during ventricular relaxation (affected by total peripheral resistance heart rate)

Mean arterial pressure (MAP): average pressure in the arteries during cardiac cycle

BP ranges (normal, elevated, hypertension stage 1, hypertension stage 2, hypertensive crisis)

normal: 120/80
elevated: 120-129/less than 80
hypertension stage 1: 130-139/80-89
hypertension stage 2: 140 or higher/90 or higher
hypertensive crisis: higher than 180/higher than 120

Baroreceptor control of BP

baroreceptors are stretch receptors in thin areas of blood vessels. send impulses to CV center to regulate blood pressure.
- baroreceptors in aortic walls and carotid arteries

orthostatic hypotension

decrease in both systolic and diastolic pressures with standing
- caused by: immobility, volume loss, medications
- symptoms: dizziness, blurred vision, syncope
- treatment: slow transitions, fluid adjustments, medication

Primary/idiopathic hypertension

Risk factors:
- aging
- male
- African American
- family history
- smoking
- obesity
- stress
- cause of at least 90% of those with HTN
- chronic and progressive
- often no acute symptoms
- sustained BP of great than 140/90 (increased systolic, increase diastole, both)

Pathology of HTN

- Multi-causal increase in total peripheral resistance
possible defect in sodium excretion
- High metabolic demands of increased body mass
smooth muscle hypertrophy
- Possible defect in sodium excretion
- Smooth muscle hypertrophy

African Americans and HTN

Develop HTN at a younger age
affects women more than men
More aggressive and results in more severe organ damage
Produce less renin (do not respond to renin-inhibiting medication)
- respond better to calcium channel blockers and diuretics
Increased risk of angioedema when taking ACE inhibitors

Hispanic Americans and HTN

Less likely to receive treatment for HTN
Have lower rates of BP control than Whites and African Americans

Gender Differences in HTN

- HTN more common in men before 45 years
- HTN more common in women after 64 years
- HTN is 2-3 times more common in women who take oral contraceptives
- Women (70-79 years) have poorest BP control regardless of treatment

Secondary HTN

Due to identifiable cause (renal and vascular disease, endocrine disorders)
Possible to treat cause directly

Malignant HTN

Rapidly progressing HTN
Diastolic can be greater than 120mm Hg

Treatment of HTN

Lifestyle changes
- stop smoking
- sodium restriction (DASH diet)
- alcohol restriction
- exercise
- weight loss if needed
- proper K and Ca intake

Medication that active with RAAS

- angiotensin-converting enzyme inhibitors
- angiotensin II receptor blockers (ARB)
- Direct Renin Inhibitors
- Aldosterone Antagonists

What does the renin-angiotensin-aldosterone system do?

Regulate BP
Regulate blood volume
Regulate fluid and electrolyte balance

Order of Renin Angiotensin Aldosterone System

1. drop in BP/fluid volume
2. renin release from kidneys
3. angiotensin from liver
4. renin acts on angiotensin to form angiotensin I
5. ACE release from lungs
6. ACE acts on angiotensin I to form angiotensin II
7. Angiotensin II acts on blood vessels stimulating vasoconstriction
8. Angiotensin II acts on adrenal gland to stimulate release of aldosterone
9. Aldosterone acts on kidneys to stimulate reabsorption of salt and water

angiotensin converting enzyme (ACE)

Mechanism of action: reduces levels of angiotensin II (vasodilation, decreased blood volume/cardiac and vascular remodeling, potassium retention, fetal injury) AND increases levels of bradykinin (vasodilation, cough, angioedema)

Pharmacokinetics: administered orally, converted to the active form in the liver, excreted by the kidney

Adverse effects: persistent dry irritating nonproductive cough, hyperkalemia, renal failure, angioedema, fetal injury during the 2/3 trimester

Common ACE inhibitors

end in "pril"
lisinopril
captopril
enalapril
ramipril

Angiotensin II Receptor Blockers (ARBs)

Mechanism of action:
- blocks access of angiotensin II to receptors in blood vessels
- prevent angiotensin II from inducing pathologic changes in cardiac structure
- cause dilation of arterioles and veins
- reduce excretion of potassium
- decrease release of aldosterone
- increase renal excretion of sodium and water

*avoid use due to FETAL HARM*

Pharmacokinetics: metabolized in liver AND excreted by kidneys

Adverse effects: dizziness, hypotension, hyperkalemia, increase in BUN/Cr, angioedema

Note: do not inhibit Kinase II or increase bradykinin (reduce risk of developing cough/angioedema in comparison to ACE-I)

Common ARBs

End in "sartan"
Losartan
Valsartan
Candesartan

Direct Renin Inhibitors (DRIs) - Aliskiren

Mechanism of action: binds tightly with renin and inhibits cleavage of angiotensinogen into angiotensin I

Administered Orally (bioavailability is decreased when administered with high-fat meal)

Excreted by kidney

Side effects: angioedema, cough, diarrhea, hyperkalemia, fetal injury/death

Aldosterone Antagonists

Used to treat hypertension AND heart failure

Mechanism of action: blocks receptors for aldosterone in kidney AND promotes retention of potassium/excretion of salt + water

Side effects: hyperkalemia

Pharmacokinetics: absorption is not affected by food

Common Aldosterone Antagonists

Spironolactone: older drug - causes more side effects, binds with receptors for other steroid hormones
Eplerenone: selective aldosterone receptor blocker, less selective - has fewer side effects than spironolactone

Vasodilators

Reduce peripheral resistance systemically (reducing workload of heart by dilating veins/arteries)
- this leads to better balance of O2 supply and demand in the heart muscle
- wide variety of therapeutic applications

adverse effects: postural hypotension, reflex tachycardia, expansion of blood volume

Common vasodilators

- Hydralazine
- Sodium Nitroprusside

Hydralazine:

- selective dilation of arterioles (decreases after load)
- mechanism of action unknown
- postural hypertension is minimal

therapeutic uses (essential hypertension, hypertensive crisis, heart failure)

adverse effects: reflex tachycardia, increased blood volume, systemic lupus redness, headache

drug interactions: avoid excessive hypotension (so antihypertensive agents), combined with beta blocker

Sodium Nitroprusside

- fast acting antihypertensive agent
- causes venous and arteriolar dilation
- administration: IV infusion
- Onset: immediate (BP returns to pretreatment level in minutes when stopped)
- used for hypertensive emergencies

Adverse Effects: excessive hypotension, cyanide poisoning, thiocyanate toxicity when used for more than three days (disorientation, psychosis, delirium)

What is heart failure?

Heart failure is the inability of the heart to pump sufficient blood to meet the needs for oxygen and nutrients.
- ventricular dysfunction
- reduced cardiac output
- insufficient tissue perfusion
- fluid retention

Symptoms:
- edema and weight gain secondary to fluid retention
- tachycardia
- increased heart size on chest x-ray
- oliguria due to decreased renal perfusion

Etiology of Heart Failure

inadequate tissue perfusion, volume overload, chronic hypertension, MI, valvular heart disease, coronary artery disease, congenital heart disease, dysrhythmias, aging of the myocardium

Physiologic changes Cardiac Remodeling

ventricular dilation, ventricular wall hypertrophy, reduced left ventricular EF, increased sympathetic tone through activation of baroreceptors
- increased HR, contractility, myocardial O2 demand
- increased venous return
- increased arterial tone

What does left sided heart failure look like?

- paroxysmal nocturnal dyspnea
- elevated pulmonary capillary wedge pressure
- pulmonary congestion (cough, crackles, wheezes, blood-tinged sputum, tachypnea)
- restlessness
- confusion
- exertion dyspnea
- fatigue
- cyanosis

What does right sided heart failure look like?

- fatigue
- increased peripheral venous pressure
- ascites
- enlarged liver/spleen
- may be secondary to chronic pulmonary problems
- distended jugular viens
- anorexia/complaints of GI distress
- weight gain
- dependent edema

Role of Natriuretic Peptides

stretching of atria and dilation of ventricles stimulates release of ANP and BNP
- promotes dilation of arteries/viens
- promotes loss of salt/water through kidney
- counteracts effect of RAAS

as heart failure progresses, effects of ANP/BNP become overwhelmed by RAAS
- measurement of circulating BNP is important indicator of cardiac status in heart failure patients
- high levels of BNP indicate poor chance of survival
- Normal BNP levels < 100 pictograms/mL

Cycle of cardiac compensatory responses

cardiac remodeling --> reduced cardiac output --> compensatory responses (cardiac dilation, activation of sympathetic nervous system + renin-angiotensin-aldosterone system, retention of water and increased blood volume) --> (increased HR Venous Pressure Arterial Pressure) -->

cardiac conduction system

the ability of the heart to pump occurs as a result of electrical stimulation to cardiac cells
- the electrical activity of the heart causes contraction and blood flow

cardiac tissue properties determine the generation and transmission of electrical impulses
- it is possible to have electrical activity without the heart pumping

properties of cardiac tissue

automaticity: ability to initiate an impulse
- cells act as a syncytium (work as one, only cardiac cells have this ability)
- spontaneous depolarization of resting cell membrane

conductivity: ability for impulse to move along membrane in orderly manner
- spreads from cell to cell at the same time

excitability: ability to be electrically stimulated

contractility: ability to respond mechanically to an impulse
- determined by how much the muscle fibers are stretched at end of diastole

The polarized state of the heart is

No electrical activity takes place
the cell is ready to accept a stimulus
- intracellular ion = potassium
- extracellular ion = sodium and calcium

The depolarized state of the heart is

sodium and calcium move into cell
potassium moves out of the cell

The repolarized state of the heart is

potassium moves into the cell
calcium and sodium move out of the cell

sinoartrial node (SA node)

located in the upper right corner of the right atrium where the superior vena cava joins the atrium
- hearts pacemaker
- generates impulses 60-100 times per minute

atrioventricular (AV) node

located in the floor of the right atrium
responsible for delaying impulses for 0.04 seconds
prevents the ventricle from contracting quickly
allows cardiac muscle to stretch to fullest peak (starlings law)

Bundle of His (AV bundle)

tract of tissues that extends into ventricles next to septum
promotes rapid impulse conduction through ventricle
impulse travels faster down the left than the right (supplies left ventricle)
permits both ventricles to contract simultaneously

Purkinje fibers

extends from bundle of His into endocardium
conducts impulses rapidly through muscle to assist with depolarization/contraction

What is cardiac action potential?

waves of depolarization followed by repolarization
generated by movement of ions
ion fluctuation is related to channels in cell membrane
two types of action potential channels (fast and slow)

fast channels

Phase 0 (rapid depolarization, influx Na ions, speed of phase 0 determines velocity)
Phase 1 (rapid partial repolarization, Medications do not affect this)
Phase 2 (Ca enters cell, medications that act on this phase reduce myocardial contractility)
Phase 3 (potassium leaves cell, repolarization is delayed by drugs that block potassium channels)
Phase 4 (gives cardiac cells automaticity, 2 types of electrical activity possible: membrane potential remains stable, membrane goes through spontaneous depolarization)

Slow channels

Phase 0 (slow influx of Ca, rate of depolarization is slow)
Phase 1 (slow channels lack a Phase 1)
Phase 2/3 (medication do not affect)
Phase 4 (Sa/Av node depolarization, Sa depolarizes quick, determines HR)

Electrocardiogram

Graphic display of the electrical forces generated by the heart
- records electrical impulses from the surface of the body on graph paper
- used to diagnose

Major components of an ECG:
- p wave (depolarization in atria)
- QRS complex (depolarization of the ventricles)
- T wave (repolarization of ventricles)
(PR interval, QT interval, ST segement)

How does an impulse travel through the cardiac conduction system?

An impulse normally is generated in the sinus node and travels through the atria to the AV node, down the bundle of His and Purkinje fibers, and to the ventricular myocardium

ECG Deflections

P wave - atrial depolarization, SA node fire
QRS complex - ventricular depolarization ventricles contract
T wave - ventricular repolarization
P-R interval - tramission of impulse from Sa to Av node
S-T segment - end of ventricular depolarization and beginning of repolarization reflects ischemia, cardiac injury, potassium abnormalities
Q-T interval - used to measure the effect of cardiac measurements

dysrhythmia

Abnormal heart rhythm
- arises from impulse formation disturbances
- tachydysrhythmias: supraventricular (SVT) and ventricular
- virtually all drugs that treat dysrhythmias can also cause them

Generation of dysrhythmias is when

One or both of the following situations occurs:
• Disturbed impulse formation or automaticity
• Disturbed impulse conduction (AV block, Reentry)

Principles of Antidysrhythmic Drug Therapy

-Balancing risks and benefits
•Consider properties of dysrhythmias:
*Sustained vs. nonsustained
*Asymptomatic vs. symptomatic
*Supraventricular vs. ventricular
-Acute and long-term treatment phases
-Minimizing risk

Classification of antidysrhythmic drugs

Vaughan Williams classification
Class I: sodium channel blockers
Class II: beta blockers
Class III: potassium channel blockers
Class IV: calcium channel blockers
Other: adenosine, digoxin, and ibutilide

Class 1A agents

Quinidine
Procainamide

effects on the heart
- blocks sodium channels
- slows impulse conduction
- delays repolarization
- blocks vagal input to the heart

effects on the ECG
- widens QRS complex
- Prolongs the QT interval

therapeutic uses
- supra ventricular and ventricular dysrhythmias

adverse effects
- diarrhea (33%)
- cinchonism (ringing in ears, nausea, vertigo)
- cardiotoxicity (reduced conduction throughout the heart)
- arterial embolism
- hypotension

drug interactions
- digoxin

Class 1B agents

Lidocaine

effect on heart and ECG
- blocks cardiac sodium channels
- reduces automaticity in ventricles and his-purkinje system
- accelerates repolarization
- primary works on ventricular dysrhythmias

adverse effects - CNS effects
- drowsiness
- confusion
- paresthesias

Class 1C agents

Flecainide
Propafenone

delay ventricular repolarization
decrease cardiac conduction
all class 1C agents can exacerbate existing dysrthymias and create new ones

Class 2 beta blockers

Beta-adrenergic blocking agents
Four approved to treat dysrhythmias:
- Propranolol
- Acebutolol
- Esmolol
_ Sotalol

Nonselective beta-adnergic antagonist

effects on heart and ECG
- decrease automaticity of the SA node
- decreased velocity of conduction through Av node
- decreased myocardial contractility

Therapeutic use
- dysrhythmias caused by excessive sympathetic stimulation

adverse effects
- heart block
- heart failure
- Av block
- Sinus arrest
- hypotension
- bronchospasm (in asthma patients)

Class 3 agents

channel blockers: Amiodarone
- can be increased by grapefruit juice
- can be reduced by cholestyramine
- risk of severe dysrhythmias increased by diuretics
- combining with a beta blocker can lead to excessive slowing of the heart

therapeutic use
- for life-threatening ventricular dysrhythmias only
- recurrent ventricular fibrillation
- recurrent hemodynamically unstable ventricular tachycardia

effects on the heart and ECG
- reduced automaticity in the SA Node
- Reduced contractility
- reduced conduction velocity
- QRS widening
- prolongation of the PR and QT intervals

drug interactions (increases levels)
- quinidine
- diltiazem
- warfarin
- digoxin

adverse effects
- protracted half-life
- pulmonary toxicity
- cardiotoxicity
- toxicity in pregnancy and breast-feeding
- optic neuropathy

adverse effects
- bradycardia
- hypotension
- heart block
- peripheral edema
- constipation
- can elevate digoxin levels
- increased risk when combined with a beta blocker