Drugs Affecting Cardiac Rate and Force

Question 1

describe fast response of action potential in the heart

Answer 1

present in atrial and ventricular muscle cells - purkinje fibres
mediated by voltage activated Na+ channels
ventricular myocyte action potentials

Question 2

describe slow response of action potential in the heart

Answer 2

present in SA node - normal pacemaker and AV node - normal route of action potential conduction between atria and ventricles
mediated by voltage gated K+ channels

Question 3

describe what the significant changes that occur to the duration and phases of action potential are due to

Answer 3

normal, physiological, influences such as autonomic transmitters and some hormones - phase 2 in particular
cardiac disease - ischaemia
pH of blood and electrolyte abnormalities
drugs, either intentionally - treat heart failure or disturbances of cardiac rhythm (arrhythmias, dysrhythmias), or unintentionally as adverse effects

Question 4

describe the action potential in ventricular cardiac muscle cells - phase 4

Answer 4

outward flux of K+ is dominant
resting potential
membrane potential between action potentials (resting, diastolic potential) is steady = ~90mV
resting Vm is close to equilibrium potential for K+ (Ek=~-94mV) due to a K+ conductance (gk) via specific voltage gated K+ channels - inward rectifier K+ channels - conducting an outward, hyperpolarising, current called Ik1
Vm is not exactly Ek due to a small inward, depolarising, leak conductance to Na+ (gNa)
ion concentration gradients across the membrane are maintained by Na/K-ATPase - if this inhibited (by digoxin) the cell depolarises slightly

Question 5

describe the action potential in ventricular cardiac muscle cells - phase 0

Answer 5

inward flux of Na+ is dominant
upstroke
ventricular (and preceding atrial) action potential is triggered by impulses initiated by SA node
involves rapid activation (~0.1-0.2 ms) of voltage activated Na+ channels at a threshold potential (~65mV) generating a Na+ conductance (gNa) and an inward, depolarising, Na+ current (INa) that drives Vm towards the Na+ equilibrium potential (Ena ~74mV)
vey brief, voltage activated Na+ channels rapidly inactivate (half time ~1 ms) during depolarisation to a non conducting state from which they only recover upon (partial) depolarisation of the membrane

Question 6

describe the action potential in ventricular cardiac muscle cells - phase 1

Answer 6

outward flux of K+ is dominant
early repolarisation
brief and most evident in cardiac cells that have a prominent phase 2 (plateau) such as Purkinje fibres and epicardial ventricular fibres
is due to;
rapid inactivation of Ina
activation of transient outward K+ current, called Ito, mediated by a specific class of voltage activated potassium channel distinct from the inward rectifier K+ channels

Question 7

describe the action potential in ventricular cardiac muscle cells - phase 2

Answer 7

inward flux of Ca2+ is roughly balanced by outward flux of K+ . Plateau persists for as long as the charge carried by the inward flux of Ca2+ ions is balanced by that carried by the outward flux of K+ ions

plateau (flat phase)
due to balance of conductances; namely an inward, depolarising, flow of Ca2+ ions occurring simultaneously with an outward, repolarising, flow of K+ ions
inward flux of Ca2+ constituting the current ICa,L, is via voltage-activated Ca2+ channels (L type channels) that activate relatively slowly during the upstroke of the action potential (~30mV) these channels inactivate (to be non-conducting) even more slowly producing a long lasting Ca2+ current crucial to cardiac muscle contraction

during plateau, several changes in potassium conductance occur:
IK1 (active in phase 4) decreases, facilitating the depolarising effect of ICa,L
Ito continues to exert a repolarizing effect initially but reduces with time
voltage activated delayed rectifier potassium channels slowly open, generating the repolarizing current IK [that has both relatively rapid (IKr) and slow (IKs) components] that gradually increase with time (over several hundreds of milliseconds) – their influence increases as phase 2 continues

drugs that reduce ICa,L (i.e. calcium channel blockers) thus reduce the duration of plateau (and force of cardiac contraction) whereas drugs that block certain potassium channels (e.g. delayed rectifiers) increase the duration of the ventricular action potential producing an acquired long QT syndrome (drug induce long QT is a major concern in the development of new therapeutic agents)

Question 8

describe the action potential in ventricular cardiac muscle cells - phase 3

Answer 8

outward flux of K+ is dominant
final repolarisation
commences at the end of phase 2 when outward K+ currents exceed inward Ica,l - during plateau Ica,l, slowly decreases due to the inactivation of L-type Ca2+ channels, whereas Ikr and Iks, slowly activate in succession
3 K+ currents contribute to rapid repolarisation;
Ikr - initially
Iks - more slowly
Ik1 - although this current is minimal during plateau, it contributes substantially to the late period of rapid repolarisation and subsequently reassumes dominance in phase 4

Question 9

describe action potential in atrial cardiac muscle cells

Answer 9

the ionic conductances mediating the action potential in atrial muscle cells are similar to those in ventricular cells, one notable difference is;
an additional ultrarapid delayed rectifier outward K+ current, Ikur, that is absent from ventricular cells which has the effect of initiating final repolarisation more rapidly, hence phase 2 is less evident

Question 10

describe action potential in nodal (SA and AV) tissue of the heart

Answer 10

slow response differs from the fast response;
Vm between action potentials (phase 4) is unsteady gradually shifting with a slope in the depolarising direction (pacemaker potential) . Slope steepness in the SA node, in part, sets action potential interval and thus heart rate
upstroke (phase 0) is far less steep and is due to the opening of L-type Ca2+ channels that mediate ICa,L, not voltage-activated Na+ channels
there is no distinct steady plateau (phase 2), but instead a more gradual repolarisation (phase 3) caused by the opening of delayed rectifier K+ channels mediating Ik

in phase 4, outward flux of K+ is reduced and inward flux of Ca2+ and Na+ is increased generating the pacemaker potential
The pacemaker potential underlies the automaticity of nodal tissue. It is determined by at least three time-dependent and voltage-regulated conductances that interact with each other. During phase 4:
the repolarizing outward current IK that mediates phase 3 gradually decreases facilitating depolarization
the inward current ICa,L (plus one other distinct Ca2+ current) that mediates a depolarizing effect gradually increases. At threshold ICa,L increases sharply, generating upstroke (phase 0)
at the end of phase 3 a cation conductance mediated by HCN channels develops in response to hyperpolarization (!) triggering the ‘funny current’ (If). HCN channels conduct Na+ ions inwardly causing depolarization

Question 11

describe autonomic regulation of cardiac rate and force - sympathetic system

Answer 11

refer to PP
noradrenaline (post-ganglionic trnasmitter) and adrenaline (adrenomedullary hormone) activate beta1 adrenoceptors in (i) nodal cells, (ii) myocardial cells
coupling through Gs protein alpha subunit stimulates adenylyl cyclase to increase the intracellular concentration of cyclic AMP [cAMP]I

by signalling through Gs, beta1-adrenoceptor activation causes;
increased SA node action potential frequency and heart rate (positive chronotropic effect) due to;
an increase in the sope of phase 4 depolarisation (pacemaker potential) by enhanced If and ICa,l
a reduction in the threshold for AP initiation by enhanced ICa,l

increased contractility (positive inotropic response);
due to increase in phase 2 of cardiac action potential in atrial and ventricular myocytes and enhanced Ca2+ influx
sensitisation of contractile proteins to Ca2+
increased conduction velcoty in AV node (positive dromotropic response) - due to enhancement of If and ICa (SA node)
increase automaticity (tendency for non-nodal regions to acquire spontaneous activity)
decreased duration of systole (positive lusitropic action) - due to increased uptake of Ca2+ into Sacroplasmic reticulum
increased activity of the Na+/K+-ATPase (Na+-pump) - important for repolarisation and restoration of function following generalised myocardial depolarisation
increased mass of cardiac muscle (cardiac hypertrophy, long term effect)

Question 12

describe autonomic regulation of cardiac rate and force - parasympathetic system

Answer 12

Ach (post-ganglionic transmitter) - activates M2 muscarinic cholinoceptors
coupling through Gi protein;
via alpha subunit inhibits adenylyl cyclase and reduced [cAMP]I
via beta/gamma subunit dimer opens specific potassium channels (G protein coupled inward rectifiers; GIRKs) in SA node

by signalling through Gi, M2 muscarinic receptor activation causes;
decreased SA node action potential frequency and heart rate (negative chronotropic effect) due to;
decrease in the slope of phase 4 depolarisation (pacemaker potential) by reduced If and ICa,l
an increase in the threshold of AP initiation by reduced ICa,l
hyperpolarisation during phase 4 via GIRKs

decreased contractility (negative inotropic effect; atria only) – due to decrease in phase 2 of cardiac action potential and decreased Ca2+ entry
decreased conduction in AV node (negative dromotropic effect) – due to decreased activity of voltage-dependent Ca2+ channels and hyperpolarization via opening of GIRK K+ channels
parasympathetic stimulation may cause arrhythmias to occur in the atria (AP duration is reduced and correspondingly the refractory period – predisposes the re-entrant arrhythmias)

Question 13

describe vagal manoeuvres

Answer 13

Increase parasympathetic output may be evoked in atrial tachycardia, atrial flutter, or atrial fibrillation to suppress impulse conduction through the AV node
Valsalva manoeuvre - activates aortic baroreceptors
massage of the bifurcation of the carotid artery – stimulates baroreceptors in the carotid sinus – not recommended

Question 14

describe funny current of pacemaker

Answer 14

The pacemaker potential is modulated by a depolarizing current the ‘funny current’ (If) mediated by channels that are activated by;
hyperpolarization
cyclic AMP [called hyperpolarization-activated cyclic nucleotide gated (HCN) channels

hyperpolarization following the action potential activates cation selective HCN channels in the SA node facilitating the slow, phase 4, depolarization (the pacemaker potential)
block of HCN channels decreases the slope of the pacemaker potential and reduces heart rate
ivabradine is a selective blocker of HCN channels that is used to slow heart rate in angina (a condition in which coronary artery disease (CAD) reduces the blood supply to cardiac muscle). Slower heart rate reduces O2 consumption

Question 15

describe excitation contraction coupling in cardiac muscle relaxation

Answer 15

1. repolarisation in phase 3 to 4
2. voltage activated L-type Ca2+ channels return to losed state
3. Ca2+ influx ceases. Ca2+ efflux occurs by the Na+/Ca2+ exchnager 1 (NCX1) a plasma membrane Ca2+ ATPase is less important
4. Ca2+ release from sarcoplasmic reticulum ceases. Active sequestration via Ca2+-ATPase (SERCA) of Ca2+ from the cytoplasm now dominates
5. Ca2+ dissociates from troponin C
6. cross bridges between actin and myosin break resulting in relaxation

Question 16

describe how beta1-adrenoceptor activation modulates cardiac contractility

Answer 16

refer PP

Question 17

describe the effect of beta-adrenoceptor ligands upon the heart - agonists

Answer 17

catecholamines - dobutamine, adrenaline and noradrenaline

pharmacodynamic effects;
increased force, rate and cardiac output and oxygen consumption
decrease in cardiac efficiency (oxygen consumption increases more than cardiac work)
can cause disturbances in cardiac rhythm (arrhythmias)

Question 18

describe the effect of beta-adrenoceptor ligands upon the heart - adrenaline (epinephrine)

Answer 18

alpha/beta agonist
given IM, SC, IV or as IV infusion in intensive way
short plasma half life due to uptake/metabolism;
cardiac arrest (IV) as part of advanced life support treatment algorithm;
positive inotropic and chronotropic action (beta1)
redistribution of blood flow to heart (vasoconstriction in the skin, mucosa and abdomen (aplha1)
dilation of coronary arteries (beta2) => relaxation

anaphylactic shock (IM, not IV unless cardiac arrest occurs), important in immediate management

Question 19

describe the effect of beta-adrenoceptor ligands upon the heart - dobutamine

Answer 19

selective for beta1-adrenoceptors via the (+) isomer - given as IV infusion
short plasma half life
acute but potentially reversible, heart failure (following cardiac surgery or cariogenic or septic, shock)
causes less tachycardia than other beta1 agonist
increases rate rather than force

Question 20

describe the effect of beta-adrenoceptor ligands upon the heart - antagonists

Answer 20

physiological effects of beta-adrenoceptors blockade depend upon the degree to which the sympathetic nervous system is activated
may block beta-adrenoceptors non-selectively (beta1 and beta 2 e.g. propranolol) or selectively (beta 1 e.g. atenolol, bisoprolol, metoprolol) in a competitive manner
may be non-seletive and a partial agonist (e.g. alprenolol)

pharmacodynamic effects (of non selective blockers);
at rest (normal subjects) - little effect on rate, force, CO, or MABP (agents with partial agonist activity increase rate at rest, but reduce it during exercise)
during exercise or stress, rate, force and CO are significantly depressed - reduction in maximal exercise tolerance
coronary vessel diameter marginally reduced, but myocardial oxygen requirement falls, thus better oxygenation of the myocardium

Question 21

describe clinical uses of beta-adrenoceptor antagonists - treatment of disturbance of cardiac rhythm

Answer 21

excessive sympathetic activity associated with stress, emotion, or disease (e.g. heart failure, myocardial infarction) can lead to tachycardia, or spontaneous activation of ‘latent cardiac pacemakers’ outside nodal tissue - beta blockers decrease excessive sympathetic drive and help restore normal sinus rhythm

atrial fibrillation and supra-ventricular tachycardia - beta blockers delay conduction through AV node and help restore sinus rhythm

Question 22

describe clinical uses of beta-adrenoceptor antagonists - angina

Answer 22

first line as an alternative to calcium entry blockers

Question 23

describe clinical uses of beta-adrenoceptor antagonists - heart failure

Answer 23

appears paradoxical – however numerous studies indicate that low-dose β-blockers improve morbidity and mortality, presumably by reducing excessive sympathetic drive. Carvedilol (which has additional α1 antagonist activity causing vasodilation) is often used, ‘starting low, increasing slow’

Question 24

describe clinical uses of beta-adrenoceptor antagonists - hypertension

Answer 24

no longer first line treatment unless co-morbidities (e.g. angina) are present

Question 25

describe adverse effects of beta-blockers

Answer 25

relate logically to mechanism of action

Bronchospasm (less risk associated with beta1-selective agents) (block of airway smooth muscle beta2-adrenoceptors) – not troublesome in normal subjects, but can be severe in asthmatics

Aggravation of cardiac failure (patients with heart disease may rely on sympathetic drive to maintain an adequate CO) – but low dose beta-blockers are used in compensated heart failure

Bradycardia (heart block – in patients with coronary disease; beta-adrenoceptors facilitate nodal conduction)

Hypoglycaemia* (in patients with poorly controlled diabetes – the release of glucose from the liver is controlled by beta2-adrenoceptors). Also tachycardia in response to hypoglycaemia is a warning mechanism.

Fatigue – CO (β1) and skeletal muscle perfusion (β2) in exercise are regulated by adrenoceptors

Cold extremities – loss of beta2-adrenoceptor mediated vasodilatation in cutaneous vessels

Question 26

describe the effect of non-selective muscarinic ACh receptor antagonists upon the heart

Answer 26

atropine (competitive antagonists);
Increase in HR in normal subjects (at all but low doses) – more pronounced effect in highly trained athletes (who have increased vagal tone)
No effect upon arterial BP (resistance vessels lack a parasympathetic innervation)
No effect upon the response to exercise

clinical uses;
First line in management of severe, or symptomatic bradycardia, particularly following myocardial infarction (in which vagal tone is elevated). In MI given IV (with caution) in incremental doses (300-600 micrograms). Monitoring is required. Glycopyrronium is an alternative
In anticholinesterase poisoning (to reduce excessive parasympathetic activity, e.g. bradycardia)

Question 27

describe digoxin

Answer 27

cardiac glycoside that increases contractility of the heart;
Heart failure – a CO insufficient to provide adequate tissue perfusion
Many causes (any structural, or functional disorder, that impairs the ability of the heart to function as a pump) - ultimately the ventricular function curve is depressed
Inotropic drugs (e.g. digoxin, dobutamine) enhance contractility by inhibiting the sarcolemma ATPase (refer PP)
Inotropes cause an upward and leftward shift of the ventricular function curve, such that SV increases at any given EDP

Question 28

describe the pharmodynamics of digoxin

Answer 28

Binds to the alpha-subunit of Na+/K+ ATPase in competition with K+ - effects can be dangerously enhanced by low plasma [K+] (hypokalaemia).
Particularly important because digoxin has a very low T.R. (plasma therapeutic concentration within 1.0 to 2.6 nmol/L)
complex direct and indirect actions on electrical activity;
direct - Shortens the action potential and refractory period in atrial and ventricular myocytes (which is pro-arrhythmic); toxic concentration cause membrane depolarization and oscillatory afterpotentials- likely due to Ca2+ overload
indirect - increases vagal activity, slows SA node discharge and slows AV conduction (increasing refractory period)

Question 29

describe clinical use and adverse effects of digoxin

Answer 29

IV in acute heart failure, or orally in chronic heart failure, in patients remaining symptomatic despite optimal use of other drugs (e.g. ACE inhibitors, diuretics)

Particularly indicated in heart failure with atrial fibrillation (AF) - increase in AV node refractory period is beneficial, helps to prevent spreading of the arrhythmia to the ventricles)

many unwanted effects, most serious cardiac effects include;
excessive depression of AV node conduction (heart block)
propensity to cause arrhythmias

Extracardiac effects are numerous:
nausea
vomiting
diarrhoea
disturbances of colour vision

Question 30

describe calcium sensitizers

Answer 30

inotropic drug
e.g. levosimendan

binds to troponin C in cardiac muscle sensitising it to the action of Ca2+ - cross bridge formation between . actin and myosin resulting in contraction, Ca2+ release from SR (calcium induced calcium release)
additionally opens KATP channels in vascular smooth muscle causing vasodilation (reduces afterload and cardiac work)
relatively new agent, used in treatment of acute decompensated heart failure

Question 31

describe inodilators

Answer 31

e.g. amrinone and milrinone

inhibit phosphodiesterase (PDE) in cardiac and smooth muscle cells and hence increase [cAMP]l
increase myocardial contractility, decrease peripheral resistance (hemodynamic indices are improved), but worsen survival - due to increased incidence f arrhythmias
use limited to IV administration in acute heart failure