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Drugsforthe heart
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
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)
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
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.
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
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
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
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