Download Pharm Chapter 24 [4-20

Pharm Chapter 24: Pharm of Cardiac Contractility
Heart failure is most often caused by systolic dysfunction of the left ventricle
-
-
Symptoms are dyspnea (difficulty breathing) and peripheral edema
The left ventricle in heart failure is unable to maintain enough stroke volume despite normal
filling volumes, and the left ventricle end-diastolic volume increases to try and preserve the
stroke output
Once you get beyond a certain end-diastolic volume, left ventricle diastolic pressures start to
increase, leading to increased left atrial and pulmonary capillary pressures, leading to interstitial
and pulmonary edema and increased right heart and pulmonary artery pressures
o The increased right heart pressure causes systemic venous hypertension and peripheral
edema
Positive inotrope – agents that increase the contractile force of heart myocytes
The heart’s job is to receive deoxygenated blood from the body, send it to the lungs to get oxygenated,
and then send this oxygenated blood to the body
To send the blood to the body, the left ventricle must develop enough tension to overcome the
resistance to ejection the peripheral circulation has
Contractile state of the myocardium – the relationship between the tension generated during systole,
and the extent of left ventricle filling during diastole
Preload – amount of blood in the ventricles before systole
Afterload – resistance the left ventricle ejects against
Myocardial contractility is the main determinant of cardiac output
Cardiac muscle contracts when action potentials depolarize the plasma membranes of the heart muscle
cells
-
To go from excitation to contraction:
o Voltage-gated calcium channels open
o Intracellular calcium increases
o Contractile proteins are activated
o Actin and myosin interact to shorten the contractile elements
Sarcolemma – myocyte plasma membrane – pic page 424
Sarcoplasmic reticulum (SR) – internal membrane that encircles the myofibrils
Myofibrils – rope-like units that have very organized contractile proteins
-
Interaction between the contractile proteins causes shortening of heart muscle
Page 425 – definitions for heart anatomy
Each heart myocyte has myofibrils and mitochondria surrounded by a specialized plasma membrane
called the sarcolemma
-
Invaginations of the sarcolemma, called T-tubules, are avenues for calcium influx
In the cell, lots of SR stores calcium for use in contraction
Extracellular calcium enters through the sarcolemma and its T-tubules during the action
potential
This trigger calcium binds to channels on the SR membrane, causing release of lots of
“activation” calcium into the cytoplasm
Increased cytoplasmic calcium initiates myofibril contraction
The sarcomere is the functional unit of the myofibril
-
Each sarcomere has interdigitating bands of actin and myosin
A bands – areas of overlapping actin and myosin
Z lines – borders of each sarcomere
I bands – areas of actin without overlapping myosin
During heart contraction, the I bands get shorter, and the Z lines approach one another, while
the A bands maintain a constant length
Increased calcium in the cytoplasm is the link between excitation and contraction
-
During the ventricle action potential, calcium influx through L-type calcium channels in the
sarcolemma causes an increase in the cytoplasmic calcium concentration
This “trigger calcium” stimulates the ryanodine receptor in the SR membrane, causing release
of stored calcium from the SR into the cytoplasm
Once calcium concentration in the cytoplasm gets high enough, calcium binds to troponin C,
inducing a shape change in tropomyosin that releases the inhibitory protein troponin I
Releasing troponin I exposes an interaction site for myosin on the actin filament
When myosin binds to actin, this initiates the contraction cycle
Myocyte contraction – page 425 pic of contraction
-
Each myosin filament is studded with flexible heads that form reversible cross-bridges with
actin filaments
During contraction, myosin moves along actin filaments, causing shortening of sarcomere length
Actin filament is made of 2 actin polymers wound around one another, 3 troponin proteins, and
tropomyosin
When there’s no calcium, tropomyosin is oriented on actin so that it inhibits the interaction of
actin with myosin
4 steps to the contraction cycle:
o
-
-
-
Heart contraction starts with hydrolysis of ATPADP by myosin – this energizes the
myosin head
o Calcium released from the SR binds to troponin C, causing a shape change in
tropomyosin that allows myosin to form an active complex with actin
o When ADP dissociates from myosin, it allows the myosin head to bend – this pulls the Z
lines closer together, and shortens the I band
 This contracted state is often called the rigor complex, because muscle will
remain in this contracted state unless there is enough ATP to displace the
myosin head from the actin
o When a new ATP binds to myosin, it allows the actin-myosin complex to dissociate
 Calcium also dissociates from troponin C
o Then the cycle repeats
So actin-myosin cross-bridges are formed, then the myosin heads bend at their hinges, and then
there’s detachment of the cross-bridges
o This all allows myosin filament to “walk up” the actin filament in both directions, pulling
the 2 ends of the sarcomere together
The sarcomere cross-bridges depend on ATP
o Myosin has ATP hydrolase (ATPase) activity to provide the energy used to drive
contraction, and reset contractile proteins to allow for relaxation
o If there isn’t enough ATP available for the cross-bridge cycle, myosin and actin remain
“locked” together, and the myocardium can’t relax
o This is why ischemia makes it so that the actin and myosin can’t do systolic contraction
(you’re stuck and can’t proceed) or diastolic relaxation (you’re stuck so actin and myosin
can’t separate)
Increased muscle length (stretch) exposes more sites for calcium binding and actin-myosin
interaction, and causes more release of calcium from the SR
Frank-Starling law – an increase in the end-diastolic volume of the left ventricle leads to an increase in
ventricular stroke volume during systole
3 major ways to control calcium cycling and contractility in heart myocytes:
-
At the sarcolemma – sodium pump and sodium-calcium exchanger
At the SR – calcium channels and pumps regulate calcium release and reuptake
Neurohumoral influences – help regulate the first 2 ways, especially the β-adrenergics
In the sarcolemma, the 3 main proteins involved in calcium regulation are the sodium/potassium ATPase
(aka sodium pump), sodium-calcium exchanger, and the calcium-ATPase (aka calcium pump)
-
The sodium pump is crucial to maintain both the resting membrane potential and
concentration gradients of sodium and potassium across the sarcolemma – page 426
Sodium-calcium exchanger is an antiport that exchanges sodium and calcium in both directions
across the sarcolemma
-
-
-
Changes in the concentration of either sodium or calcium inside or outside the cell, affect the
direction and magnitude of sodium-calcium exchange
o Under normal conditions, the low intracellular sodium concentration favors sodium
influx and calcium efflux
The sodium pump and sodium-calcium exchanger are coupled
o Digoxin is the most famous drug that acts as an inotropic agent by inhibiting the sodium
pump
The sarcolemma calcium pump helps in calcium homeostasis by actively removing calcium from
the cytoplasm after heart contraction
High ATP favors calcium removal and relaxation, directly via the calcium pump, and indirectly via
the sodium pump
Since calcium signaling is important in both heart contraction and relaxation, the heart has a system to
regulate calcium flux during the heart cycle
-
-
-
In the SR, the calcium release channel (ryanodine receptor) and the calcium pump
(sarcoendoplasmic reticulum calcium ATPase, SERCA), are critical to regulate contractility
Contraction needs both enough calcium release into the cytoplasm to stimulate contraction, and
enough calcium reuptake into the SR to allow relaxation and replenish calcium stores
Concentrations of both calcium and ATP in the cytoplasm regulate the activity of both the
ryanodine receptor and SERCA
Trigger calcium opens the ryanodine receptor
o Cytoplasmic calcium concentration is directly related to the # of receptors that open
o There’s also a safety mechanism where high calcium levels lead to the making of the
calcium-calmodulin complex, which inhibits calcium release by decreasing the open time
of the ryanodine receptor
o High levels of ATP favor the open channel shape, so it facilitates SR calcium release into
the cytoplasm
Cytoplasmic calcium also stimulates the SERCA, which pumps calcium back into the SR
o This prevents any positive feedback cycle that could irreversibly deplete the SR of
calcium
o As calcium pumps refill the SR, the rate of calcium reuptake slows because of the
decreasing cytoplasmic calcium
o ATP favors SERCA activity, and decreased ATP impairs calcium reuptake
 Impaired calcium reuptake causes the rate and extent of diastolic relaxation to
decrease in ischemic myocardium
Phospholamban – SR membrane protein that inhibits SERCA
o High levels of cAMP stimulate protein kinase A to phosphorylate phospholamban, which
reverses its inhibition of SERCA
o So phospholamban controls the rate of relaxation by regulating calcium reuptake into
the SR
 Unphosphorylated phospholamban slows relaxation

Phosphorylated phospholamban accelerates relaxation
During contraction:
-
Extracellular calcium enters the heart myocyte through calcium channels in the sarcolemma
This trigger calcium induces release of calcium from the SR into the cytoplasm
The increased cytoplasmic calcium facilitates myofibril contraction
During relaxation:
-
-
The sodium-calcium exchanger (NCX) removes calcium from the cytoplasm, using the sodium
gradient as a driving force
The sodium/potassium ATPase (sodium pump) maintains the sodium gradient, keeping the heart
myocyte hyperpolarized
o The sodium pump is inhibited by phospholemman
o Phosphorylating phospholemman with protein kinase A (PKA) removes the inhibition,
increasing sodium removal and indirectly enhancing sodium/calcium exchange
SERCA in the SR membrane is inhibited by phospholamban
o PKA phosphorylates phospholamban to disinhibit the calcium ATPase, allowing storage
of the cytoplasmic calcium in the SR
o A sarcolemma calcium ATPase (calcium pump) also helps to maintain calcium
homeostasis by actively removing calcium from the cytoplasm
β1-adrenergics promote heart performance
-
-
β receptor agonists increase β1-adrenergic caused increases in calcium entry during systole
o More calcium increases shortening of the heart muscle during contraction
o This positive inotropic effect results in a greater stroke volume
β agonists also have a positive chronotropic effect – means they increase heart rate
Inotropic and chronotropic effects increase cardiac output (so HR x SV = CO)
o This is a fancy way of saying cardiac output = heart rate x stroke volume
β agonists also improve heart performance by enhancing the rate and extent of diastolic
relaxation, called a positive lusitropic effect
o This allows for enough left ventricle filling and preserves the left ventricle end-diastolic
volume, despite the decrease in diastolic filling time from increased heart rate
In peripheral circulation:
-
β2 adrenergics vasodilate vascular smooth muscle
o So stimulating a β2 receptor decreases systemic vascular resistance and afterload
α1 receptors vasoconstrict vascular smooth muscle
o So stimulating an α1 receptor increases systemic vascular resistance and afterload
The symp nervous system is mediated by activation of adrenergic receptors in the heart and
peripheral system
o
-
Stimulation of β adrenergic G protein-coupled receptors induces a shape change that
activates adenylyl cyclase and increases cAMP levels
o Higher levels of cAMP activate protein kinase A (PKA), which then phosphorylates many
things in the cell, like L-type calcium channels in the sarcolemma, and phospholamban
in the SR membrane
 Phosphorylating the sarcolemma calcium channels increases contractility
 Phosphorylation of phospholamban releases its inhibition of SERCA, allowing
calcium to be pumped from the cytoplasm back into the SR
 This is a way β1’s can enhance diastolic relaxation
 PKA also dishibitis the sarcolemma sodium pump, and enhances sarcolemma
sodium/calcium exchange
o cAMP is then converted to AMP by phosphodiesterase, ending the β1 effect
o Page 427 – effects of increased cAMP in the heart cell
Receptors
o Alpha 1 – vasoconstriction from phospholipase C
o Alpha 2 – vasodilation from inhibiting adenylyl cyclase
o Beta 1 – symps at heart (↑HR and SV) and kidney from activating adenylyl cyclase
o Beta 2 – muscle relaxation (including vessels and lungs) from protein kinase A inhibiting
myosin
Increased stretch of the sarcomeres exposes more calcium binding sites on troponin C, making more
sites available for actin-myosin cross-bridge making
-
This increases the sensitivity of the contractile proteins to calcium
Phosphorylation of troponin I by protein kinase A, from increasd cAMP, decreases contractile
protein sensitivity to calcium
Many diseases or heart problems can replace myocardium with fibrous tissue, which decreases heart
contractility
-
The most common cause of contractile dysfunction is coronary artery disease (CAD) resulting in
MI
Other causes of contractile problems include systemic hypertension and valvular heart disease
All of these causes of contractility problems are problems that don’t start in the heart
Idiopathic cardiomyopathy is a heart myocyte problem that leads to left ventricle problems
Progressive contractility problems of the myocardium leads to systolic heart failure
o Heart failure can happen for reasons other than contractile dysfunction too
 Acute MI and restrictive cardiomyopathy causes problems with left ventricle
relaxation and/or filling, leading to decreased chamber compliance, and
elevated left ventricular diastolic pressure
 This abnormal elevation of intraventricular pressure can happen in the presence
of normal systolic function, so it’s called diastolic heart failure (aka heart failure
with preserved ejection fraction
Problems at the cell level that cause decreased heart contractility include problems with calcium
homeostasis, changes in regulation and expression of contractile proteins, and changes in β-adrenergic
pathways – page 428 (normal is on the left, and each of the3 pathways is on the right)
-
-
-
Changes in calcium homeostasis cause prolonged action potentials
o In normal myocardium, calcium homeostasis is controlled by calcium channels like the
sodium/calcium exchanger (NCX) and calcium ATPase (SERCA)
o In failing myocardium, diastolic calcium stays high because phospholamban isn’t
phosphorylated, so it inhibits SERCA, so you can’t put Ca2+ back in the SR
o Also, expression of the sodium/calcium exchanger increases, so that cytoplasmic
calcium is removed from the myocyte, instead of being stored in the SR
o Things that increase cytoplasmic calcium and deplete SR stores include decreased SR
calcium reuptake and increased # of sodium-calcium exchangers in the sarcolemma
 The ability to store calcium in the SR is essential to end contraction
 So since there’s no calcium getting stored, you can’t do relaxation or future
contraction
Dysfunctional contractile proteins are made by changes in the transcription of genes in failing
heart myocytes
o In normal myocardium, phosphorylation of troponin I exposes the actin-myosin
interaction site, and myosin hydrolyzes ATP during each contraction cycle
 In failing myocardium, there is decreased phosphorylation of troponin I, cuasing
less efficient actin-myosin cross-linking
 Myosin doesn’t hydrolyze ATP as well, further reducing the
effectiveness of each contraction cycle
o There’s also increased expression of fetal isoform of troponin T
 When there’s a problem with myocyte growth, it reverts to making fetal
isoforms of some proteins
 Ex: failing myocytes increase expression of fetal troponin T, which is a more
efficient contractile protein
 Other reversions to fetal forms include less phosphorylation of troponin I, and
decreased ATP breakdown by myosin, each of which slows rate of cross-bridge
cycling
Desensitizing the β-adrenergic pathways is also seen in failing myocytes leading to systolic
heart failure
o Failing myocytes down-regulate the # of β-adrenergic receptors expressed at the cell
surface
o Symp stimulation of the remaining receptors results in a smaller increase in cAMP than
normal
o There’s also more β-adrenergic receptor kinase, which phosphorylates and inhibits βadrenergic receptors, and inhibitory G protein (Gαi)
o Heart failure also increases expression of inducible NO synthase (iNOS), which can
reduce β-adrenergic signaling
o
o
o
β-arrestin also binds and inhibits the β-adrenergic receptors
The decreased response of failing myocytes to adrenergic stimulation causes
decreased phosphorylation of phospholamban, which impairs SR calcium uptake ability
Decreased cAMP levels also decrease the ability to make and use ATP
Cardiac glycosides – drugs that raise intracellular calcium levels, by inhibiting the sarcolemma
sodium/potassium ATPase (sodium pump)
-
Cardiac glycosides include digoxin (aka digitalis), digitoxin, and ouabain
Digoxin is the most commonly used cardiac glycoside and inotropic agent (↑ contractility)
o Digoxin – selective inhibitor of the plasma membrane sodium pump – page 429
o Heart myocytes exposed to digoxin remove less sodium, leading to an increase in
sodium in the cell
 This messes up sodium-calcium exchanger
 Calcium efflux is decreased because the gradient for sodium entry is
decreased
 Calcium influx is increased, because the gradient for sodium efflux is
increased
 So digoxin increases intracellular calcium, triggering the SR to store more
calcium
 When digoxin-treated cells depolarize in response to an action potential, there
is more calcium available to bind troponin C, and so there’s increased
contractility
 So during each contraction, the increased calcium released from the SR
leads to increased myofibril contraction, and therefore increased heart
inotropy (increased contractility)
o Digoxin also has an autonomic effect by binding to sodium pumps in the plasma
membranes of neurons int eh CNS and PNS
 Digoxin inhibits symp outflow, sensitizes baroreceptors, and increases
parasymp (vagal) tone
o Digoxin also directly acts on the heart conduction system
 Digoxin decrease automaticity at the atrioventricular (AV) node, prolonging the
refractory period of AV node tissue, and slowing conduction velocity through
the AV node
o Digoxin is used for atrial fibrillation and rapid ventricular response rates
 Rapid ventricular response is a common result of afib
 The decreased automaticity of the AV nodal tissue, prolongs the wait to conduct
the signal to the ventricles, which decreases ventricular response rates
o Unlike at the AV node though, digoxin increases automaticity of the bundle of His and
purkinje fibers (His-Purkinje system)

o
o
This is why a side effect of using digoxin for afib is complete heart block with
accelerated junctional or idioventricular escape rhythm (so increased ventricle
escape rhythm), called “regularized” afib
Digoxin has a narrow therapeutic window, so you need to know how it works to prevent
toxicity
 Oral digoxin has a bioavailability of about 75%
 A minority of people have gut flora that metabolize digoxin into an
inactive metabolite, so you would give them an antibiotic to get rid of
the bacteria so that you can absorb the digoxin
 Digoxin binds to lots of stuff, but the main ones are sodium/potassium ATPase
in skeletal muscle
 Digoxin works within 30 minutes by IV, and then reaches peak effect in 1-5
hours, and has a half life of 36 hours
 The kidney excretes about 70% of the digoxin, while the rest is excreted in the
gut or by the liver
 Chronic kidney disease decreases the volume of distribution of digoxin
(because the digoxin doesn’t bind stuff as well), and its clearance
o So people with chronic kidney disease need smaller doses
 Hypokalemia increases digoxin localization to the heart
 Decreases in ECF potassium increase phosphorylation of
phospholemman at the sodium pump
 Digoxin has a higher binding affinity for the phosphorylated forms of
these proteins
 For the same reasons, increasing plasma potassium can relieve
symptoms of digoxin toxicity by promoting dephosphorylation
Digoxin also interacts with many drugs
 These interactions are divided into pharmacodynamics & pharmacokinetic rxns
 Pharmacodynamics interactions include with β-blocerks, calcium channel
blockers, and potassium-wasting diuretics (normal diuretics!)
 β-adrenergic antagonists, just like digoxin, decrease AV node
conduction, so using both a β-adrenergic antagonist and digoxin
increase the risk for developing a high grade AV block
 Both β-adrenergic antagonists & calcium channel blockers can decrease
heart contractility, and so attenuate (decrease) the effect of digoxin
 Potassium wasting diuretics decrease plasma potassium, which
increases affinity of digoxin for the sodium/potassium ATPase
 Pharmacokinetic interactions happen from changes in absorption, volume of
distribution, or renal clearance of digoxin
 Many antibiotics, like erythromycin, can increase digoxin absorption
by killing the gut bacteria that would normally metabolize some of the
digoxin before absorption

-
Taking digoxin with verapamil (calcium channel blocker) or quinidine or
amiodarone (antiarrhythmics), can increase digoxin levels because of
you’re competing for P450’s
o To treat digoxin toxicity, you want to normalize plasma potassium levels, and minimize
the potential for ventricular arrhythmias
 Life-threatening digoxin toxicity can be treated with anti-digoxin antibodies
 The antibody form complexes with digoxin, so that it’s quickly cleared
from the body
 Using just the Fab fragment of the Ig (part that binds the antigen)
instead of the whole IgG, works better because it’s less immunogenic,
has a larger volume of distribution, more rapid onset of action, and
higher clearance
o Digoxin can be taken with β-antagonists like carvedilol for heart failure
 Not sure why, but we think it’s cause digoxin promotes contractile function
o Digoxin has been shown to improve symptoms of heart failure, improve functional
status, and reduce hospital visits
 Digoxin has not been shown to improve survival rate from heart failure
 So although digoxin won’t make you live longer, it improves quality of life for
people with heart failure
Digitoxin – identical to digoxin, except it’s missing a an OH, which makes it less hydrophilic than
digoxin
o So digitoxin is metabolized and excreted mainly by the liver, and it’s clearance doesn’t
depend on the kidneys
o So digitoxin is preferred when they have both heart failure and chronic kidney disease
o Digitoxin has a much longer half life of about 7 days
β-agonists and phosphodiesterase inhibitors increase intracellular cAMP levels
-
β-adrenergic receptor agonists:
o Inhaled β adrenergic agonists are used for asthma
o The effect of a β adrenergic agonist depends on the dose, and different doses do
different things
 Ex: dopamine – at low doses will stimulate the heart, while higher doses have α1
adrenergic effects
 Page 431 – table of the different effects each β agonist has
o Sympathomimetc inotropes (increase contractility) are not used until you need them
for failing circulation, due to their adverse effects
 Sympathomimetic agents that stimulate heart β adrenergics have the adverse
effects of tachycardia, arrhythmia, and increased heart oxygen use
 They also induce tolerance by rapid down-regulation of the adrenergic receptors
 Sympathomimetics also have low oral bioavailability, so you give them by IV
o
o
o
Dopamine – endogenous sympathomimetic amine that acts as a neurotransmitter and
precursor to norepinephrine and epinephrine
 At low doses – dopamine vasodilates in the periphery by stimulating
dopaminergic D1 receptors
 This decreases resistance to left ventricle ejection (aka it decreases
afterload)
 At intermediate doses – dopamine vasodilates by stimulating β2 adrenergic
receptors, and also activates β1 receptors to increase contractility and heart rate
 At high doses – dopamine activates α1 adrenergics in the periphery, causing
vasoconstriction and an increase in afterload
 Dopamine must be given IV
 Dopamine is metabolized rapidly by monoamine oxidase (MAO) and dopamine
β hydroxylase into inactive metabolites that are excreted by the kidney
 People taking both dopamine and an MAO inhibitor don’t metabolize
the dopamine, so there’s more dopamine, which can cause
tachycardia, arrhythmia, and increased myocardial oxygen use
 Dopamine is used in septic and anaphylactic shock, to reverse the vasodilation
they cause
 At low or medium doses, dopamine is used in cardiogenic shock or heart failure
 Since dopamine is more unpredictable, more predictable drugs like
dobutamine and phosphodiesterase inhibitors are more often used and
are less likely to cause tachycardia or arrhythmia
Dobutamine – synthetic sympathomimetic amine that is a racemic mixture of
enantiomers that acts as a β1 agonist with a little β2 vasodilator effect
 Dobutamine is given by IV
 Dobutamine is metabolized rapidly by catechol-O-methyl transferase
 It’s half life is less than 3 minutes
 Dobutamine can cause arrhythmias, like all sympathomimetic amines that work
as β agonists
 Supraventricular tachycardia and ventricular arrhythmia happen less
often with dobutamine than with dopamine
 This is why dobutamine is the sympathomimetic inotrope (increased
contractility) of choice for acute cardiogenic circulatory failure
Epinephrine – nonselective adrenergic agonist released by the adrenal medulla
 Exogenous epinephrine stimulates α1 and 2 receptors, and β1 and 2 receptors
 The effect of exogenous epinephrine depends on the dose
 At all dose levels, epinephrine is a strong β1 agonist with inotropic,
chronotropic,a dn lusitropic effects (increases HR, SV, and filling)
 Low dose epinephrine – stimulates β2 receptors to cause vasodilation
 High dose epinephrine – stimulates α1 receptors to cause vasoconstriction and
increased afterload
-
 Not good for heart failure
 Epinephrine is given IV, and can be inhaled for asthma, or given subcutaneously
for anaphylaxis
 Epinephrine is rapidly metabolized to metabolites excreted by the kidney
 At high doses epinephrine can cause tachycardia and life-threatening
ventricular arrhythmias
 The main use for epinephrine is to resuscitate from cardiac arrest
 The goal is to rapidly resuscitate spontaneous circulatory function
 You really don’t care about adverse effects in this case
 Other uses for epinephrine:
 Relief of bronchospasm – β2’s cause bronchorelaxation
 Enhancing the effect of local anesthetics – α1 vasoconstriction
 Treating allergic hypersensitivity rxns
o Norepinephrine – endogenous neurotransmitter released at symp nerve terminals
 Norepinephrine is a potent β1 agonist to improve heart systolic and diastolic
performance, and a potent α1 agonist in peripheral vessels to increase vascular
resistance
 During exercise, release of norep increases heart rate and contractility, and
enhances diastolic relaxation, and vasoconstrict (α1)
 IV norep is rapidly metabolized by the liver into inactive metabolites
 Norepinephrine can cause tachycardia, arrhythmia, and increased heart oxygen
use
 When given to patients with contractile dysfunction, norep tends to cause
tachycardias involved the SA node and ectopic sites int eh atria and ventricles
 The peripheral vasoconstriction norep causes increases resistance, limiting the
inotropic benefit of norep
 Increased afterload is usually seen in patients who already are trying to
vasoconstrict, like with renin-angiotensin, etc.
 Norepinephrine is used in shock when there’s no underlying heart disease
o Isoproterenol – synthetic selective β1 agonist that mainly increases heart rate
 Has minor β2 effects that can cause peripheral vasodilation and hypotension
 Isoproterenol shouldn’t be given to patients with active coronary artery disease,
because it can worsen ischemia (increased heart demand)
 Isoproterenol is used for refractory bradycardia not responding to atropine, and
for a β-antagonist overdose
Phosphodiesterase (PDE) inhibitors – increase heart contractility by raising intracellular cAMP
levels
o cAMP is converted to AMP by phosphodiesterase, ending the β1 effect
o PDE inhibitors inhibit the enzyme that breaks down cAMP, which increases CAMP and
indirectly increases intracellular calcium
o
o
o
o
There are many isoforms of phosphodiesterase, each of which has its own signal
transduction pathway
Theophylline – nonspecific PDE inhibitor
Inhibiting PDE3 in heart muscle can have cardiovascular benefits
 PDE3 inhibitors include inamrinone (aka amrinone) and milrinone
 Inamrinone and milrinone increase contractility and enhance the rate and
extent of diastolic relaxation
 PDE3 inhibitors also vasodilate, through cAMP regulating calcium and vascular
smooth muscle
 In arteries, vasodilation decreases vascular resistance (afterload)
 In veins, vasodilation increases capacitance, which decreases venous
return to the heart (so decreases preload)
 So PDE3 inhibitors have positive inotropic effects (increase contractility) and
artery and vein dilatory effects
PDE inhibitors are used for severely failing circulation
 Widespread use of inamrinone is limited by adverse effects of
thrombocytopenia in 1/10 of patients
Alpha 1 – vasoconstriction from phospholipase C
Alpha 2 – vasodilation from inhibiting adenylyl cyclase
Beta 1 – symps at heart (↑HR and SV) and kidney from activating adenylyl cyclase
-
Contractility is increased by letting more calcium into the myocyte
Beta 2 – muscle relaxation (including vessels and lungs) from protein kinase A inhibiting myosin