This slide set provides an introduction at new learner to intermediate level to some of the most common drugs that are used clinically to modulate the rate and force of contraction of the heart. Created by Prof. JA Peters, University of Dundee School of Medicine.

1. Professor John A. Peters
E-mail j.a.peters@dundee.ac.uk
Drugs Modifying Cardiac Rate
and Force

2. Following this session and additional reading students should be able to:
 Describe the effects of the autonomic transmitters acetylcholine and noradrenaline
(norepinephrine) and the hormone adrenaline (epinephrine) upon heart rate, heart force
and electrical conduction within the heart
 Describe the mechanisms by which the autonomic transmitters modulate heart rate
 Discuss the mechanism by which the anti-anginal drug, ivabradine, reduces heart rate
 State the process of excitation contraction coupling in cardiac muscle
 Explain the mechanism by which 1-adrenoceptor activation increases the force of
contraction of the heart
 Outline the clinical uses of the adrenoceptor agonists adrenaline and dobutamine
 Outline the effects of β-adrenoceptor antagonists on the heart and circulatory system
and be aware of their clinical applications and adverse effects
 Describe the effects of the muscarinic receptor antagonist atropine upon the heart and
list its clinical uses in relation to the cardiovascular system
 Comment upon the use of cardiac glycosides and other inotropic agents in the therapy
of heart failure
Recommended reading
• Aaronson, Ward, Connolly (2013). ‘The Cardiovascular System at a Glance’ (4th. ed.),
Chapters 11 and 12.
• Boron, Boulpaep (2016). ‘Medical Physiology’ (3rd. ed.), Chapter 21 pp. 483-493.
• Rang, Ritter, Flower, Henderson (2016). 'Rang and Dale's Pharmacology’ (8th. ed.),
Chapter 14 pp. 187-192, Chapter 21 pp. 247-264 and all relevant sections of Chapter 22.

3. The Action Potential in Nodal (SA and AV) Tissue of the Heart
Background to the effect of autonomic transmitters and drugs on rate
Phase 4
(pacemaker
potential)
Ib, ↑If, ICaT, ↓IK
Phase 0
↑ICaL
Phase 3
↑IK
~+10 mV
~-60 mV
Threshold
If,‘funny’ current (mediated by hyperpolarization-activated and cyclic nucleotide gated (HCN)
channels that conduct Na+ and K+) (inward)
Ib, background sodium current (inward)
ICaT, transient calcium current (inward)
ICaL, long calcium current (inward)
IK, delayed rectifier potassium current (outward)
Regulatory influences
• Balance of autonomic
input (sympathetic
vs. parasympathetic)
• Stretch
• Temperature
• Hypoxia
• Blood pH
• Thyroid hormones
Modified and redrawn from Kumar and Clark (2012)
‘Clinical Medicine’ (8th. ed.)
200 ms

4. The Action Potential in Atrial and Ventricular Myocytes of the Heart
Background to the effect of autonomic transmitters and drugs on force
IK1, inward rectifier potassium current (outward)
INa, sodium current (inward)
Ito, transient outward potassium current (outward)
ICaL, long calcium current (inward)
IK, delayed rectifier potassium current (outward)
Phase 4
(diastolic
potential)
IK1
Phase 0
↑INa
~+20
mV
~-90 mV
Phase 1
Ito Phase 2 (plateau)
↑ICaL (+ INaL
*)
Phase 3
↑IK + ↑IK1 in terminal
repolarization
Note: Plateau is
largely a fine
balance of inward
Ca2+ current that
slowly inactivates
and outward K+
current that slowly
activates
*INaL, a late (or persistent),
sodium current (inward)
200 ms

5. Autonomic Regulation of Cardiac Rate and Force (1)
SYMPATHETIC SYSTEM Noradrenaline (post-ganglionic transmitter) and
adrenaline (adrenomedullary hormone) activate 1 -
adrenoceptors in: (i) nodal cells, (ii) myocardial
cells
 Coupling through Gs protein activates
adenylyl cyclase to increase [cAMP]I
and causes:
1-adrenoceptor
ATP cAMP
Adenylyl cyclase
Gs
NA
•  heart rate (positive chronotropic effect) – mediated by SA node and due to (i)
an increase in the slope of phase 4 depolarization (‘the pacemaker potential’)
caused by enhanced If and ICa, (ii) reduction in the threshold for AP initiation
caused by enhanced ICa noradrenaline
SA node
↑ If and ICa increases
slope
↑ ICa decreases
threshold

6. • contractility (positive
inotropic response) – due to (i)
increase in phase 2 of the cardiac
action potential in atrial and
ventricular myocytes and
enhanced Ca2+ influx and (ii)
sensitisation of contractile
proteins to Ca2+ (see later)
• conduction velocity in AV
node (positive dromotropic
response) – due to enhancement
of If and ICa (as in the SA node)
•  automaticity (i.e. tendency for non-
nodal regions to acquire spontaneous
activity)
•  duration of systole (positive lusitropic action) – due to increased uptake
of Ca2+ into the sarcoplasmic reticulum
•  activity of the Na+/K+-ATPase (Na+-pump) (important for repolarization and
restoration of function following generalised myocardial depolarization)
•  mass of cardiac muscle (cardiac hypertrophy, long term effect)
0
0 10
150
Strokevolume(SV)(ml)
End diastolic pressure (EDP) (mmHg)
Ventricular function curves
Sympathetic
stimulation
↑contractility
Normal
Effect of ↑EDP→
Note: sympathetic
stimulation increases
SV without an
increase in EDP

7. PARASYMPATHETIC SYSTEM Acetylcholine (post-ganglionic transmitter) –
activates M2 muscarinic cholinoceptors,
largely in nodal cells
 Coupling through Gi protein: (i)
decreases activity of adenylate
cyclase and reduces [cAMP]I and
(ii) opens potassium channels
(GIRK) to cause hyperpolarization
of SA node (mediated by Gi βγ
subunits)
Autonomic Regulation of Cardiac Rate and Force (2)
Muscarinic M2 receptor Adenylyl cyclase
Gi
_
ACh
ATP cAMP
•  heart rate (negative chronotropic effect) – mediated by the SA node and due to
(i) decreased slope of the pacemaker potential caused by reduced If and ICa, (ii)
hyperpolarization caused by the opening of GIRK channels, (iii) increase in
threshold for AP initiation caused by reduced ICa
acetylcholine
SA node
↓ ICa increases
threshold
hyperpolarization
by GIRK
↓ If and ICa reduces
slope

8. •  contractility (negative inotropic effect; atria only) – due to decrease in
phase 2 of cardiac action potential and decreased Ca2+ entry
•  conduction in AV node (negative dromotropic effect) – due to
decreased activity of voltage-dependent Ca2+ channels and
hyperpolarization via opening of K+ channels
• parasympathetic stimulation may cause arrhythmias to occur in the
atria (AP duration is reduced and correspondingly the refractory period – predisposes to
re-entrant arrhythmias)
Vagal manoeuvres
• Increase parasympathetic output and may be employed
in atrial tachycardia, atrial flutter, or atrial fibrillation to
suppress impulse conduction through the AV node
o Valsalva manoeuvre – activates aortic baroreceptors
o massage of the bifurcation of the carotid artery –
stimulates baroreceptors in the carotid sinus – not
recommended

9. • Ivabradine is a selective blocker
of HCN channels that is used to
slow heart rate (HR) in angina (a
condition in which coronary
artery disease (CAD) reduces
the blood supply to cardiac
muscle). Slower HR reduces O2
consumption
• Block of HCN channels
decreases the slope of the
pacemaker potential and reduces
heart rate
Pacemaking Involves a ‘Funny Current’ (If)
Action potentials recorded from a single SA node cell in the
presence and absence of ivabradine. Modified from DeFrancesco
(2005). Curr. Med. Res. Opin.21:1115-1122
The pacemaker potential is modulated by a depolarizing current the ‘funny
current’ (If) mediated by channels that are activated by (i) hyperpolarization
and (ii) 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 a
slow, phase 4, depolarization
(the pacemaker potential)
HCN
channels
activate
cAMP
increases
the
activation
of HCN
channels
HCN Channels
blocked

10. Review of Excitation Contraction Coupling in Cardiac
Muscle (1) Contraction
1.Ventricular action potential
5. Ca2+ binds to
troponin C and shifts
tropomyosin out of
the actin cleft
6. Cross bridge formation
between actin and myosin
resulting in contraction via
the sliding filament
mechanism
Sarcoplasmic reticulum
Ca2+
Ca2+
Ca2+
4.Ca2+ release from the
sarcoplasmic reticulum (Calcium-
Induced Calcium Release – CICR).
Caused by Ca2+ activating the
ryanodine type 2 channel (RyR2)
Amplification
of Ca2+ signal
3.Ca2+ influx into cytoplasm
2.Opening of voltage-
activated Ca2+ channels
(mainly L-type) during
phase 2 of action potential
Ca2+
Ca2+
Ca2+ activates RyR2
Ca2+

11. 1.Repolarization in phase 3 to
phase 4
5. Ca2+ dissociates
from troponin C
6. Cross bridges between
actin and myosin break
resulting in relaxation
Sarcoplasmic reticulum
4.Ca2+ release from the sarcoplasmic
reticulum ceases. Active sequestration via
Ca2+-ATPase (SERCA) of Ca2+ from the
cytoplasm now dominates
3.Ca2+ influx ceases. Ca2+
efflux occurs by the Na+/Ca2+
exchanger 1 (NCX1) a plasma
membrane ATPase (not illustrated) is
less important
2.Voltage-activated L-type
Ca2+ channels close
Ca2+
Ca2+ATPase
NCX1
1 Ca2+ 3 Na+
Review of Excitation Contraction Coupling in Cardiac
Muscle (2) Relaxation
Ca2+

12. How Does 1-Adrenoceptor Activation Modulate Cardiac Contractility?
ATP*cAMP
Protein kinase
A
Phosphorylation
PO4
1-adrenoceptor
Adenylyl cyclase
Voltage-activated
Ca2+ channel
(L-type)
Ca2+
Gs
Sarcoplasmic reticulum
Ca2+ influx due to
phosphorylation
Ca2+
CICR via
RyR2
Sarcoplasmic reticulum
Ca2+
Ca2+ ATPase
Enhanced contractilitySensitivity to Ca2+
Phosphorylation of
phospholamban
pumping of Ca2+
rate of relaxation
Ca2+
Ca2+
Ca2+
Ca2+
*Note: cAMP is converted to inactive 5‘AMP by a phosphodiesterase enzyme (PDE) (not illustrated).
Inhibition of PDE results in a positive ionotropic effect that can be achieved with drugs such as milrinone
that are now seldom used, except IV in acute heart failure

13. The Effect of -Adrenoceptor Ligands Upon the HeartThe Effect of -Adrenoceptor Ligands Upon the Heart
Agonists
Dobutamine, adrenaline and noradrenaline (catecholamines)
Pharmacodynamic effects
•  force, rate and cardiac output (i.e. HR x SV) and O2 consumption
•  cardiac efficiency (O2 consumption  more than cardiac work)
• can cause disturbances in cardiac rhythm
Dobutamine Adrenaline Noradrenaline

14. The Effect of -Adrenoceptor Agonists Upon the Heart
Clinical uses (including those involving the vasculature)
 Adrenaline (epinephrine) (α/β agonist). Given IM, SC, IV, or as IV
infusion in intensive care. Short plasma t1/2 (~ 2 min) due to
uptake/metabolism
o cardiac arrest (IV), as part of the Advanced Life Support (ALS)
treatment algorithm.
• positive inotropic and chronotropic actions (β1)
• redistribution of blood flow to the heart [constricts blood vessels in the
skin, mucosa and abdomen (α1)]
• dilation of coronary arteries (β2)
o anaphylactic shock (IM, not IV unless cardiac arrest occurs), very
important in immediate management
 Dobutamine (selective for -adrenoceptors – via the (+)-isomer) – given as
IV infusion. Short plasma t1/2 (~ 2 min)
o acute, but potentially reversible, heart failure (e.g. following cardiac
surgery, or cardiogenic, or septic, shock). For reasons unknown,
causes less tachycardia than other β1 agonists

15. 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)
 Coronary vessel diameter marginally reduced, but myocardial O2 requirement
falls, thus better oxygenation of the myocardium
 During exercise, or stress, rate, force and CO are significantly depressed –
reduction in maximal exercise tolerance
The Effect of -Adrenoceptor Ligands Upon the Heart
Antagonists
 The physiological effects of
-adrenoceptor blockade
depend upon the degree to
which the sympathetic
nervous system is activated
 May block -adrenoceptors
non-selectively (β1 and β2,
e.g. propranolol), or
selectively (1, e.g. atenolol,
bisoprolol, metoprolol) in a
competitive manner
 May be non-selective and a
partial agonist (e.g. alprenolol)
Heart rate of a spectator at a live football match showing the
effect of the β-blocker, oxprenolol. From Rang et al. (2016)
Heartrate(bpm)
Time (min)

16. Clinical Uses of -Adrenoceptor Antagonists (CVS actions only)
 Treatment angina
o First line as an alternative to calcium entry blockers
 Treatment of disturbances of cardiac rhythm (arrhythmias)
o 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
• -blockers decrease excessive sympathetic drive and help restore normal
sinus rhythm
o Atrial fibrillation (AF) and supraventricular tachycardia (SVT)
• β-blockers delay conduction through the AV node and help restore sinus
rhythm
 Treatment of hypertension (HT)
o No longer first-line unless co-morbidities (e.g. angina) are present
 Treatment of heart failure (compensated)
o 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’

17. Adverse Effects of -Blockers (as a class)
Adverse effects relate logically to mechanism of action
*Less risk associated with 1-selective agents (e.g.
atenolol, bisoprolol, metoprolol
! Bronchospasm* (block of airway smooth muscle 2-
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 -blockers are used in compensated
heart failure
! Bradycardia (heart block – in patients with coronary
disease; -adrenoceptors facilitate nodal conduction)
! Hypoglycaemia* (in patients with poorly controlled
diabetes – the release of glucose from the liver is
controlled by 2-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 2-adrenoceptor mediated
vasodilatation in cutaneous vessels

18. The Effect of Non-Selective Muscarinic ACh Receptor
Antagonists Upon The Heart
Atropine (competitive antagonist)
Clinical uses in relation to the heart
 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*. Monitoring is required. Glycopyrronium
is an alternative
 In anticholinesterase poisoning (to reduce excessive parasympathetic activity,
e.g. bradycardia)
* 300 – 600 micrograms. Some practitioners recommend no less than 600 micrograms as
low-dose atropine may paradoxically transiently slow heart rate (see figure)
Pharmacodynamic effects
 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
Increased HR
Effect of atropine on heart rate (HR) in young and older
volunteers. Atropine was intravenously injected in six
graded doses from 0.03- to 0.96-mg bolus each over 5 min.
From Poller et al. (1979). J. Am. Coll. Cardiol. 29:187-193
Decreased HR

19. Digoxin – A 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
End diastolic Pressure (EDP)
Strokevolume(SV) Normal
Heart failure
Heart failure + inotrope
 Inotropes cause an
upward and
leftward shift of the
ventricular
function curve,
such that SV
increases at any
given EDP

20. Digoxin Increases Contractility by Blocking the
Sarcolemma ATPase (‘Na+- Pump’)
In the presence of digoxin
•Na+/K+ATPase blocked
•[Na]i and  Vm (i.e. depolarizes)
•Na+/Ca2+ exchange and  [Ca2+]i
•storage of Ca2+ in SR
•CICR; contractility
Ca2+
ATPase
2K+ 3Na+
3Na+
1Ca2+
Na+/K+ATPase
actively maintains ion
gradients; contributes
to resting potential
(Vm)
Na+/Ca2+exchanger
couples the chemical and
electrical gradient driving
Na+ influx to Ca2+ efflux
L-type Ca2+
Channel
(dihydropyridine
sensitive)
Ca2+
Ca2+
CICR
Sarcoplasmic reticulum
Ca2+

21. Pharmacodynamics of Digoxin
Binds to the -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)
Has complex direct and indirect actions on electrical activity
o Indirect –
increased vagal
activity
• Slows SA node
discharge
o Direct
Shortens the action potential and
refractory period in atrial and
ventricular myocytes (which is pro-
arrhythmic); toxic concentration
cause membrane depolarization
and delayed after depolarizations
(DADs)- likely due to Ca2+
overload. DADs may trigger ectopic
beats if they reach threshold for action
potential (AP) generation
• Slows AV node
conduction;
increases
refractory period
DAD
AP evoked by SA node (i.e.
sinus rhythm)
Triggered AP when
DAD reaches
threshold

22.  Digoxin has many unwanted effects, the most serious cardiac effects
are:
• excessive depression of AV node conduction (causing heart block)
• propensity to cause arrhythmias
Clinical Use and Adverse Effects of Digoxin
 Orally or 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, low dose β-blockers)
 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)
 Extracardiac effects are numerous:
• nausea
• vomiting
• diarrhoea
• disturbances of colour vision

23. Other Inotropic Drugs (1)
Calcium-sensitizers
Levosimendan
 Binds to troponin C in cardiac muscle sensitizing it to the action of Ca2+
Ca2+ bound to
troponin C
Cross bridge formation
between actin and myosin
resulting in contraction
Sarcoplasmic reticulum
Ca2+
Ca2+
Ca2+
Ca2+ release from the
sarcoplasmic reticulum (Calcium-
Induced Calcium Release – CICR)
Levosimendan
sensitizes
 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 (IV)

24. Other Inotropic Drugs (2)
‘Inodilators’ amrinone and milrinone
 Inhibit phosphodiesterase (PDE) in cardiac and smooth muscle cells and
hence increase [cAMP]i
 Increase myocardial contractility, decrease peripheral resistance by
vasodilation (haemodynamic indices are improved), but worsen survival –
perhaps due to increased incidence of arrhythmias
 Use limited to IV administration in acute heart failure