Transcript CardiacDrugs

Drugs used in Heart Failure,
Angina, and Arrhythmia
But, first, some muscle review!
Regulation of cardiac myocyte Ca2+ flux
Regulation of cardiac contractility by β-adrenergic
receptors
Cellular Mechanisms
of Contractile
Pathophysiology
Drugs used in Heart Failure
• Heart failure: insufficient cardiac output to
adequately perfuse the tissues, despite
normal filling of the heart.
• Congestive heart failure: combined right and
left heart failure to produce pulmonary
congestion and peripheral edema.
• Causes: hypertension, valvular disease,
cardiomyopathy, and most commonly, coronay
artery disease.
Drugs used in Heart Failure (cont’d)
• Low cardiac output  incr sns activity 
stimulates the rate and force of the heart beat
and maintains bp by incr vascular resistance.
• In the failing heart, this afterload further decr
cardiac output.
• The resultant decr renal blood flow  renin
secretion and incr plasma and angiotensin and
aldosterone levels 
• Na+ and H2O retention incr the blood vol and bp
 incr P(edema).
Drugs used in Heart Failure (cont’d)
• These compensatory Δs at first help maintain
cardiac output, but in the long run,…
• Lead to Δs (e.g., abnormal ventricular dilation)
that incr morbidity and mortality.
• Only drugs that inhibit these neurohormones
involved in these compensatory Δs incr
patient survival with CHF (i.e., ACE inhibitors,
β-blockers).
Drugs used in Heart Failure (cont’d)
• Treatment of mild HF usually starts with an angiotensin
converting enzyme (ACE) inhibitor.
- decr load on the heart.
- decr symptoms.
- slow disease progression.
- prolong life.
- For more severe cases, add a diuretic (e.g.,
bendroflumethiazide, furosemide).
- For severe cases, in which a ACE inhibitor and diuretic fail,
then an inotropic drug (e.g., Digoxin), which incr the force
of cardiac muscle contraction by incr the rise of [Ca2+]cyto
that accompanies each AP (inhibit the Na+/K+-ATPase).
[See below]
- β-blockers may be added.
- Additional diuretics (next time) may be added.
ACE Inhibitors
• The most appropriate vasodilators used in HF, because
they decr both arterial and venous resistance.
• Preventing the incr in (vasoconstrictor) angiotensin II
that is often present in HF.
• Result: Incr cardiac output and because of the decr in
renovascular resistance, there is an incr in RBF…
• This, plus the decr in aldosterone, incr Na+ and H2O
excretion  decr blood vol and venous return to the
heart.
• Also decr direct growth action that angiotensin has on
the heart.
• [Angiotensin antagonists (e.g., losartan)may not have
the same benefits as ACE inhibitors].
β-Receptor Antagonists (β Blockers)
• Acutely, β-blockers can decrease myocardial
contractility and worsen HF.
• Long-term, however, administration has been
shown to improve the survival of stable patients
with HF (blocking the damaging effects of
overactive sympathetic activity).
• Start with a low dose and gradually incr over wksto-mos.
• Carvedilol, bisoprolol, and metaprolol, given with
an ACE inhibitor and diuretic for ~1 yr has been
shown to reduce mortality from 11-17% to 712%.
Inotropic Drugs
• Digoxin – a cardiac glycoside extracted from foxglove
leaves (Digitalis sp) is the most important inotrope.
• Increase the contractile force.
• Particularly indicated in patients with atrial fibrillation.
• Inhibits the Na+/K+-ATPase, which is responsible for
Na+/K+ exchange across the muscle cell membrane 
incr [Na+]in  incr [Ca2+]in  incr force of myocardial
contraction.
• Digoxin and K+ ions compete for a “receptor” (Na+/K+ATPase) on the ext membrane.
• So, the effects of digoxin may be dengerously incr by
hypokalemia, produced, for example, by diuretics.
Positive Inotropic Mechanism of Digoxin
Inotropic Drugs (cont’d)
• Direct Effects:
- AP and refractory period are shortened
because..
- The incr [Ca2+]in stimulates K+ channels.
- Toxic concentrations cause depol and oscillatory
depolarizing after pot appear after normal Aps
(caused by incr [Ca2+]in.
- If these delayed afterpot reach T0, Aps are
generated, causing ‘ectopic’ beats.
-With incr toxicity, the ectobic beat itself elicits
further beats, causing a self-sustaining
arrhythmia (vent tach), which may  vent
fibrillation.
Inotropic Drugs (cont’d)
• Indirect Effects:
– Digoxin incr vagal activity and faciliates muscarinic
transmission to the heart. This…
i. Slow HR
ii. Slows atrioventricular conductance.
iii. Prolongs the refractory period of the
atrioventrivular node.
Effects on Other Organs:
Digoxin may cause anorexia, nausea, vomiting or
diarrhea by affecting the smooth muscle of the gut.
Inotropic Drugs (cont’d)
• Toxicity:
-Digoxin toxicity is quite common because
arrhythmias can occur at concentrations that
are only 2-3 x that of the optimal therapeutic
dose.
- Treatment may entail K supplements,
antiarrhythmic drugs (lidocaine or phenytoin)
or even digoxin-specific Ab fragments (Fab).
Sympathomimetic Agents
• Activate cardiac β-receptors  AC  cAMP 
phosphorylation of L-type Ca2+ channels
(opens) incr [Ca2+]influx and the force of
myocardial contraction.
• Dobutamine used in acute severe HF.
• Dopamine incr renal perfusion by stimulates
dopamine receptors in the renal vasculature.
Drugs Used in Angina
Drugs Used in Angina – Pathogenesis of Acute Coronary Syndrome
Drugs Used in Angina
• Angina pectoris – ischemia of the heart
muscle as a result of coronary artery occlusion
or blockage.
• Drugs use to decr the work load of the heart
and hence, O2 demand.
• Nitrates are the 1st-line drugs  peripheral
vasodilation, especially in the veins by acting
on vascular smooth muscle that involves the
formation of NO and [cGMP]cyto.
Nitrates (cont’d)
• The cGMP  pooling of blood in the veins
decr venous return and the ventricular vol is
decr.
• Decr in the distension of the heart wall decr
O2 demand and the pain is quickly relieved.
Nitrates
• Short-acting nitrates: Glycerol trinitrate (sl, tablet,
or spray) acts for ~ 30 min.
-More useful in preventing attacks than in
stopping them once they have begun.
-Patches (transdermal) have longer duration of
action (~ 24 hr).
• Long-acting nitrates are more stable and effective
for several hr.
– Isosorbide dinitrate widely used, but metabolized
rapidly by liver.
– Isosorbide mononitrate (active metabolite) of
dinitrate avoids the variable absorption and
unpredictable 1st pass metabolism of the dinitrate.
Nitrates (cont’d)
• Adverse effects: Aterial dilation  headaches,
hypotension and fainting, and in severe cases,
reflex tachycardia.
- Can be counteracted with β-blockers.
- Prolonged high doses can 
methemaglobinemia.
Mechamism of action: Starts with formation of
nitrite ions (see figure).
Nitrates (cont’d)
• Tolerance to nitrates occurs regularly, but is
poorly understood.
• But, perhaps depletion of sulphydral group
donors may be involved, because tolerance to
nitrates in vitro can sometimes be reversed by
N-acetylcysteine.
-Peroxynitrite formed from NO inhibits cGMP
formation from GTP.
β-Adrenoceptor Antagonists
• Used as an angina prophylaxis.
• Better to use cardio-selective (e.g., atenolol,
metoprolol) β-blockers, rather than
nonspecific ones (propranolol).
• All β-blockers must be avoided in asthmatics
as they may ppt bronchospasms.
Calcium Antagonists
• Widely used for angina and with fewer sideeffects than with the β-Blockers.
• Ca antagonists block L-type VG Ca channels in
arterial smooth muscle  relaxation and
vasodilation.
• Ca channels in the myocardium and
conducting tissues of the heart are also
affected by Ca antagonists, which…
• Produce negative inotropic effects by decr
Ca2+ influx during the plateau phase of the AP.
Calcium Antagonists (cont’d)
• Dihydropyridines (e.g., nifidipine, amlopidine) have
relatively little effect on the heart because they have
much higher affinity for channels in the inactive state.
• Such channels are found more in vascular smooth
muscle because it is more depolarized than cardiac
muscle (50 vs. 80 mV).
• At clinical used doses, vasodilation  reflex increase in
sympathetic tone that  mild tach and counteracts the
mild inotropic effect.
• Alopidine < nifidipine, verapamil < diltiazem depress
the SA node  mild resting bradycardia.
• Verapamil binds preferentially to open channels and is
less affected by the RMP.
• Conduction at the AV node is slowed and slows the
ventricular rate of atrial arrhythmias.
Calcium Antagonists (cont’d)
• The negative inotropic effects of verapamil and
diltiazem are partially offset by the reflex incr in
adrenergic tone and the decr in afterload.
• Tobacco smoking: Smoking is prothromic and
atherogenic – it decr coronary blood flow and the
nicotine-induced rise in HR and bp incr O2
demand of the heart.
– Also, carboxyHb decr O2-carrying capacity of Hb.
– Some patients markedly improve on giving up
smoking.
Pharmacologic Management of Acute Coronary Syndrome
Drugs used in Arrhythmia
• Rhythm of the heart determined by pacemaker
cells in the SAN.
• Supraventrocular arrhythmias arise in the atrial
myocardium (AVN), whereas ventricular
arrhythmias arise in the ventricles.
• Ectopic focus: firing at a higher rate than the
normal SAN cells.
• Re-entry mechanism: Delayed APs (some
pathology) re-invade near-by muscle fibers,
which, no longer being refractory, again
depolarize, establishing a loop of depolarizaiton
(circus movement).
Drugs used in Arrhythmia (cont’d)
Three Classes:
1. Supraventricular arrhythmias
2. Ventricular arrythmias
3. Drugs used in both.
The Action Potential in Skeletal and Cardiac
Muscle
Figure 20.15
Drugs used in Arrhythmia (cont’d)
Drugs used in Supraventricular arrhythmias
• Adenosine stimulates A1-adenosine receptors and
opens Ach-sensitive K+ channels.
- This hyperpolarizes the cell membrabe in the AVN and
slows conduction in the AVN (by inhibiting Ca2+
channels).
• Digoxin stimulates vagal activity  Ach release which
slows conduction and prolongs the RP in the AVN and
Bundle of His.
- By delaying atrioventricular conductance, digoxin incr
the degree of block and slows and strengthens the
ventricular beat.
• Verapamil blocks L-type Ca channels, especially on the
AVN, where conduction is entirely dependent on Ca2+
spikes.
- Also inhibits Ca2+ influx during the plateau phase of
the AP and therefore, has negative inotropic action.
Drugs used in Arrhythmia (cont’d)
Drugs used in ventricular arrythmias
• Class 1B agents block VD Na+ channels.
• Lidocaine (iv) used after myocardial infarction.
- blocks inactivated Na+ channels.
- works in ischemic (anoxia causes depol and
antithrombogenic activity), but not healthy,
tissue.
Drugs used in Arrhythmia (cont’d)
Drugs used in supraventricular and ventricular
arrythmias
• Class IA agents block open VD Na+ channels.
• Slow Phase 0 and lengthen the RP
• Produce a freq (use)-dependent block.
• During diastole, when the Na+ channels are
closed, Class IA agents dissoc rel slowly; so, if
the freq is high, drug is still bound to the
channel, which, therefore, cannot contribute
to the AP.
Drugs used in Arrhythmia (cont’d)
Drugs used in supraventricular and ventricular
arrythmias
• Disopyramide (po) and quinidine to prevent
recurrent ventricular arrythmias.
- has negative inotropic effects.
- may cause hypotension and may aggravate
cardiac failure.
- Other side-effects: nausea, vomiting, marked
anticholinergic effect.
Drugs used in Arrhythmia (cont’d)
Drugs used in supraventricular and ventricular
arrythmias
• Class IC agents dissociate very slowly from Na+
channels and strongly depress myocardial
conduction.
- Flecainide – used mainly in prophylaxis of
paroxysmal atrial fibrillation.
- has negative inotropic effects.
Drugs used in Arrhythmia (cont’d)
Drugs used in supraventricular and ventricular arrythmias
• Class III agents slow the repolarization (Phase 3) and
prolong the AP and RP in all cardiac tissues.
• Amiodarone blocks several channels (e.g., K+ and
inactivated Na+ channels) and β-adrenoceptors.
- Often effective when other drugs have failed, but
should be used sparingly, as it causes serious sideeffects (e.g., photosensitivity, thyroid disorders,
neuropathy, and pulmonary alveolitis).
Sotalol has both Class III and Class II (β-blocking) actions,
but lacks the side-effects of amiodarone, but has the
side-effects of β-blockers.