1.
Drugs for the Heart
A brief run down of cardiac physiology and how to treat common conditions
Brooke Sachs 2017
This presentation summarises key points featured in Drugs for the Heart
https://www.elsevierhealth.com.au/drugs-for-the-heart-9781455733224.html

2.
Purposeofthe
heart
 Pump blood round and round (to systemic and
pulmonary vasculatures – 25/5mmHg in pulmonary
and 120/80 in systemic, capillary pressure ~ 1mmHg)
 Hormone balance (fluid balance, sodium balance)
 Responding to bodily need (sympathetic and
parasympathetic input) through exercise, stress,
positional changes

3.
Electricfunction
oftheheart
 SA node at junction of SVC and RA (embryologically R
heart – R vagus n supply)
 AV node at right posterior portion of the interatrial
septum (embryologically L heart – L vagus n supply)
 Three bundles of atrial fibres that contain purkinge-
type fibres connecting the SA to AV nodes (tract of
Wenckebach, tract of Thorel and anterior tract)
 AV node continuous with bundle of His (L branch and
R branch)

4.
Pacemakercells
 Lower resting membrane potential than
cardiomyocytes
 Primarily dependent on opening of calcium channels
 Noradrenaline release activates B1-adrenoceptors in
the SA, AV node, His-Purkinje conductive tissue and
atrial and ventricular contractile tissue
 Sympathetic activation causes chronotropy,
dromotropy, iontropy
 Acetylcholine from postganglionic parasympathetic
fibres (vagus) activates nicotinic receptors on SA and
AV nodes, as well as atrial muscle  reduces rate of
transmission through AV node and atrial contractility.

5.
Heartrate
 Balance of sympathetic and parasympathetic input
leads to a HR of about 70
 Up to 150-180 bpm with unopposed sympathetic tone
(e.g. atropine (nicotinic receptor antagonist), intense
exercise)
 In no sympathetic OR parasympathetic input, HR
about 100 bpm

6.
Beta-blockers

7.
Beta-
adrenoceptors
 B1-r situated on cardiac sarcolemma, part of the G-protein
coupled receptors
 Linked to Gs (stimulates adenylyl cyclase) vs Gi
(muscarinic stimulation following vagal activation)
 Intracellular second messenger of B1-r is cAMP which
opens calcium channels to increase the rate and force of
myocardial contraction (+ve inotropy) and increased
reuptake of cytosolic calcium into the SR.
 SA node pacemaker current is increased (+ve
chronotropy), rate of conduction accelerated (+ve
dromotropy)
 20-30% B-receptors in the heart are B2, this is
upregulated with B1-blockade and in heart failure
 B3-r endothelial receptors mediate vasodilation induced
by NO in response to nebivolol

8.
Beta-activation
hasnatural
limits
 B-receptor stimulation has a negative feedback loop
through activating B-adrenergic receptor kinase (B-ARK,
aka GRK2)  phosphorylates the receptor that leads to
recruitment of B-arrestin, which desensitises the
stimulated receptor.
 B-arrestin mediates desensitisation in heart failure
 B-arrestin also acts physiologically as a signal transduce
to induce anti-apoptotic signalling
 Prolonged and excess B-adrenergic stimulation causes
receptor internalisation and downregulation, which
diminishes the inotropic response
 Dobutamine (b-agonist) therapy had progressive loss of
therapeutic efficacy (tachyphylaxis)
 In sustained beta-blockade, there is resultant increase in
B-receptors (? Explains improved systolic function with
time)

9.
How dobeta-
blockerswork?
 Improves coronary flow and myocardial perfusion by
increasing the diastolic filling time, because of it’s -ve
chronotropy
 Unclear mechanisms for anti-hypertensive effects,
however thought to be due to
 inhibition of B-receptors on terminal neurons facilitating
release of norad
 CNS effects with decreased adrenergic outflow
 Decreased activity of RAS system due to B-r mediated
renin release
 Because of the increased B-r density with blockade,
any cessation of B-blockers should be slow as otherwise
it will exaccerbate angina and may cause MI in at-risk
patients

10.
BetaBlockers
 Can be B1-selective (for heart) or act on B1- and B2-
adrenoceptors
 The closest to an “all purpose” cardiovascular therapy,
no lipid problems induced but be aware of
hypoglycaemic unawareness, interactions in asthmatic
patients. Can also induce diabetes (particularly in
combination with diuretics e.g. thiazides)
 Very good post-infarct protectiveness and mortality
reduction in CHF
 Early use of B-blockade in stable systolic heart failure
will counter excessive adrenergic drive (best evidence
for carvedilol, metoprolol and bisoprolol). Nebivolol is
good in old patients for improving EF in systolic but
not diastolic failure

11.
Beta-blockers
 B-blockade is very effective symptomatic treatment in
CAD/angina however does not appear to slow
progression of disease
 Very effective ventricular antiarrhythmics (particularly
sotalol as it also has class III anti-arrhythmic
properties)

12.
Don’tuseB-
blockerswhen…
 The patient is at high risk of CAD – has DM, chronic
renal disease – as an anti-hypertensive
 In prinzmetal’s angina
 In older black adults
 Not the best to combine with ACEI/ARB because both
reduce renin levels (so no real gain)

13.
Nitrates and anti-
anginals

14.
Whydowe get
angina?
 Imbalance between oxygen suppy and demand 
inadequate myocardial blood flow
 Deficiency of ATP leads to loss of K, gain of Na and Ca,
with rapid onset of diastolic dysfunction

15.
Fourclassesof
anti-anginals
 B-blockers (covered just prior)
 CCBs
 Nitrates
 Metabolic agents (ivabradine, allopurinol, ranolazine)

16.
Actby
 Reducing HR
 Reducing afterload
 Reducing venous return and pre-load
 Negatively inotropic
 Vasodilating

17.
Nitrates
 Nitrates enter vessel wall, converted to NO, which
stimulates guanylate cyclase to produce GMP
 NO acts directly via S-nitrosylation of proteins and
may be scavenged by superoxide (contributes to nitrate
toxicity and tolerance)
 NO causes coronary vasodilation and peripheral
vasodilation
 Reduce preload and afterload
 Increase venous capacitance  pooling of blood in ther
peripheries  less mechanical stress on the myocardial
wall and therefore reduced myocardial oxygen demand
 Beneficial to combine with hydralazine in heart failure
(likely lessens tolerance)

18.
Metabolic
agents
 Ranolazine – for chronic effort angina, may be
combined with amlodipine, B-blockers or nitrates. It
inhibits oxygen-wasting fatty acid metabolism and
increases metabolism of protective glucose. Can
prolong QTi. Metabolised by CYP3A – be aware of drug
interactions
 Trimetazidine – patial inhibitor of fatty acid oxidation
without haemodynamic effects. Worsens Parkinson’s,
improves chronic systolic heart failure.
 Perhexiline – inhibits fatty acid oxidation at CPT-1
(enzyme that transports activated lon—chain fatty
acids into the mitochondria). Beware hepatotoxicity,
and peripheral neuropathy

19.
Metabolic
agents
 Ivabradine – blocker of pacemaker current If – does not
act directly on metabolism but indirectly by decreasing
HR and therefore metabolic demand. No –ve inotropy
nor BP reduction, nor rebound. Beware transient
impaired night vision.
 Nicorandil – both potassium channel activator and
nitrate-like effect. Dilates large coronary arteries and
reduces pre- and afterload.
 Allopurinol – reduces myocardial oxygen consumption
via inhibition of xanthine oxidase.

20.
Calcium channel
blockers

21.
CCBactions
 Vasodilation and reduction of peripheral vascular
resistance
 Selective inhibition of L-type channel opening in
vascular smooth muscle and in the myocardium
(prevents inward flow of calcium)
 Non-DHP CCBs act at the nodes, reducing heart rate
 DHP CCBs act more on vasculature, reducing blood
pressure
 CCBs are contraindicated in heart failure
 CCBs give endothelial protecting and promote
formation of NO, inhibitory effects on carotid
atheromatous disease
 S/E: headache, facial flushing, dizziness, constipation

22.
Dihydropyridine
s
 Bind to the alpha1 subunit of the calcium channel
 Side effect of headache (arteriolar dilation), ankle
oedema (precapillary dilation)

23.
Non-
dydropyridines
 Bind to alpha1-subunit of the calcium channel
 Act on nodal tissue (tend to decrease the sinus rate)
 Less vascularly selective
 Better access to the binding site of the AV node when
the calcium channel pore is open, which is in
SVT/tachycardia
 Verapamil inhibits one limb of the reentry circuit
believed to underlie most pSVT.
 HR drops only modestly at rest – big effect is during
exertion
 Negatively inotropic
 Reduce proteinuria

24.
Diuretics

25.
Loopdiuretics
 Frusemide/bumetanide/torsemide/ethacrynic acid
 Lose more water than sodium
 Small doses can be effective as monotherapy in
hypertension
 In AMI, high IV doses can be beneficial for
haemodynamics
 Frusemide is the diuretic of choice in severe heart
failure and APO
 Ethacrynic acid is the only non-sulfur diuretic
 Torsemide and bumetanide have more reliable
absorption orally (80-100%) vs frusemide (10-100%) but
all have similar total duration of action, with varying
peaks of diuresis
 Diuretic-induced glucose intolerance is likely related to
hypokalaemia, or total body K depletion. This can be
minimised with concommitant ACEI/ARB therapy
 Frusemide IV can be used to Rx hypercalcaemia

26.
Thiazides
 Most widely recommended first-line therapy for
hypertension
 Chlorthalidone is preferred for hypertension
 Inhibit reabsorption of sodium and chloride in the more
distal part of the nephron
 Rapidly absorbed by the GIT to produce diuresis within 1-
2h, lasting 16-24 h with HCTZ
 Maximal effect of thiazides is reached with relatively low
doses
 Much decreased capacity to work in renal failure (GFR
<15-20)
 HCTZ dose >25mg may precipitate hyperglycaemia
 Thiazides block the nephron sites at which hypertrophy
occurs during long term loop diuretic therapy  reduces
resistance
 Beware co-therapy with sotalol (induction of arrhythmias),
aminoglycosides (nephrotoxicity potentiation), probenicid
and lithium (block thiazide transport into the tubule)
 Beware hypercalcaemia
 Can be used to Rx nephrogenic diabetes inspidus

27.
Potassium
sparingagents
 Amiloride (ENaC) and triamterene (Na-H exchanger) -
reduced K loss. Side effects – hyperkalaemia, acidosis.
Do not have risk of hyperglycaemia and gout.
Amiloride is particularly useful in black patients with
low-renin, low-aldosterone hypertension and genetic
defect in the ENaC channel.
 Spironolactone and eplerenone – aldosterone blockers
that spare K by blocking mineralocorticoid receptor
that binds aldo/cortisol/deoxycorticosterone.
Eplerenone is more specific and prevents
gynaecomastia and sexual dysfunction (seen in 10%
Rxd with spiro). No reflex sympathetic activation.
 Eplerenone as effective as enalapril in regressing LVH
and lowering BP

28.
Aquaretics
 Antagonists of AVP-2 receptors in the kidney – promote
solute-free water clearance to correct hyponatraemia
 Tolvaptan, conivaptan, satavaptan, lixivaptan
 Evidence is still pending as to improved mortality in
heart failure patients

29.
RAA-system inhibitors

30.
RAAS
 Angiotensin I originates in the liver from
angiotensinogen
 Its production is influenced by renin (protease) formed
in renal JG cells
 ACE activity chiefly in vascular endothelium of lungs
(but occurs in all vascular beds)
 ACE converts Angiotensin I to Angiotensin II
 Angiotensin II can be formed by other pathways
(chymase activity)
 Angiotensin II receptor stimulus causes
phosphodiesterase to activate protein kinase C, which
in turn activates inositol trisphosphate signalling in
blood vessels, which liberates calcium which causes
vasoconstriction. Phosphodiesterase activation also
stimulates ventricular remodelling pathways.

31.
RAAScontinued
 Two Angiotensin II receptors – AT-1 and AT-2
 ARBs are AT-1 blockers
 AT-1 activation in the diseased heart causes
stimulation of contraction, vasoconstriction, myocyte
hypertrophy, fibrosis, antinaturiesis
 AT-2 role involves inhibition of growth in the late fetal
phase and otherwise is unclear

32.
RAAScontinued
 Stimulation for release is caused by hypotension,
decreased sodium reabsorption in the DT, decreased
blood volume, increased beta1sympathetic activity
 Aldosterone stimulation means release of sodium-
retaining aldosterone from renal cortex

33.
Bradykinin
 Acts on receptors in the vascular endothelium and
promotes the release of two vasodilators (NO and
vasodilatory PGs – prostacyclin and PGE2)
 Indomethacin can therefore reduce the hypotensive
effect of ACEIs by inhibiting PGE synthesis that would
be released by bradykinin
 Bradykinin is inactivated by two kinases, kininase II is
identical to ACE
 ARBs may not be quite as good at ACEIs as a result,
though they do lack the adverse effects of cough and
angioedema

34.
ACEIs
 Good because:
 Prolong life
 Reduce maladaptive LV remodelling
 Less new DM
 Reduce proteinuria in T1DM, delays onset of
microalbuminuria
 Beware:
 Angioedema – 0.3-1.6% - can be fatal
 Teratogenic
 Can cause neutropaenia (usually with high-dose captopril)
 Contraindicated in:
 Bilateral renal artery stenosis
 Pregnancy
 Hyperkalaemia
 Serum Cr >220-265

35.
Antiarrhythmics

36.
Class1A
Quinidineand
similar
 Quinidine, procaiamide, disopyramide
 Inhibit fast Na channel
 Depress phase 0 of the action potential
 Prolong duration of the AP (mild class III effect)
 Proarrhythmic in prolonging the QTi
 May increase mortality, or at least be neutral

37.
ClassIB
Lignocaine
 Inhibit fast sodium current while shortening the action
potential duration in non-diseased tissue
 No QT prolongation
 Interrupt reentry circuits
 Hypokalaemia must be corrected for maximal efficacy
 Only used in sustained VT
 Phenytoin is an alternative Class IB but is rarely used,
except in patients who have concurrent epilepsy

38.
ClassIC
 Powerful inhibitors of the fast sodium channel
 Marked inhibitory effect on His-Purkinje conduction
with QRS widening
 May variably prolong the action potential duration by
delyaing inactivation of the slow sodiu, channel and
inhibition of the rapid repolarising current
 Good in paroxysmal supraventricular
tachyarrhythmias (AF, Vas)
 Should not be used in patients with structural heart
disease

39.
ClassII
B-blockers
 See section on B-blockers
 At present, B-blockers are the closest to an ideal class
of anti-arrhythmic because of their broad spectrum of
activity and established safety record

40.
ClassIII
Amiodarone
andsotalol
 Lengthen the APD and hence lengthen the effective
refractory period
 Prolong the QTi
 Amiodarone is a significant sodium and calcium
channel inhibitor
 Sotalol is a B-blocker

41.
ClassIV  Verapamil and diltiazem (see earlier descriptions)