Pharmacology of Cardiac Contractility Flashcards
two ways drugs can effect cardiac contractility
directly- drugs that directly affect myocardial cells, usually by controlling intracellular calcium ions via voltage gated calcium channels o intracellular Na+, affecting sodium calcium exchange
indirect drugs drugs which effect heart contractility through changing vascular tone, determining cardiac contractility through changing preload and EDV
examples of direct acting drugs
catecholamines, cardiac glycosides
Examples of indirectly acting drugs
diuretics, ACE inhibitors
2 main cardiac glycosides + difference between them
digoxin and ouabain
ouabain is shorter acting
basic structure of cardiac glycosides
sugar moiety, a steroid and a lactone ring
key cardiac affects of cardiac glycosides
cardiac slowing, reducing rate of conduction through AVN
increased force of contraction
disturbances in rhythm, especially block of AV conduction and increased ectopic pacemaker activity
briefly, main mechanisms of action of cardiac glycosides
increased vagal activity and inhibition of sodium/potassium pump
explain stages of the positive inotropic effect
- glycosides binds to the extracellular alpha unit of the Na+/K+ ATPase
- binding inhibits the pump
- increased intracellular sodium concentration slows extrusion of calcium by reducing the inward directed sodium gradient for the sodium calcium exchanger
- increased intracellular calcium stored in the SR and thus an increased amount of calcium released with each action potential
explain use in treatment of atrial fibrillation
slows the AV conduction by increasing vagal activity
increases refractory period of the AVN, increasing the interval between impulses and the ventricular rate decreases, allowing time for diastolic filling
main conditions treated
congestive heart failure, by increasing inotropic activity, meaning enough blood can be pumped round the body
what are used alongside cardiac glycosides + why?
diuretics, which decrease extracellular potassium, which means there’s reduced competition at the binding site
example of a catecholamine drug
dobutamine
what is dobutamine used to treat?
acute but potentially reversible heart failure, such as after cardiac surgery
dobutamine results
increase chronotropy and ionotropy, increasing cardiac output and cardiac oxygen consumption
dobutamine mechanism
- activates Gs proteins of B1
- eventual activation of PKA, which phosphorylates the RAD subunit of the L type calcium channel increasing open state probability. This leads to an enhanced sarcoplasmic release of calcium, increasing contractility
- PKA may phosphorylate troponin C, increasing calcium sensitivity
- phosphorylates phospholamban, activates SERCA, more calcium taken up
increases heart rate by opening ion channels responsible for pacemaker currents in the SAN
what are the limitations of dobutamine and adrenaline?
leads to an increase need for oxygen for the heart to contract
can’t be used in haemorrhage
can’t be used in myocardial infarction, where coronary arteries are blocked
can only be used for shock
examples of adrenoreptor antagonists
propranolol and atenolol
actions of adrenoreceptor antagonists
have the opposite effect to agonists, mainly reducing contractility by blocking sympathetic stimulation of beta receptors
another name of adrenoreceptor antagonists
beta blockers
beta blocker uses
used to manage abnormal heart rhythms and to protect the heart from a secondary myocardial infarction
treat hypertension
explain propranolol and atenolol briefly
propanolol- blocks beta 1 and beta 2 equally, it has little effect on the heart rate at rest but reduces the effects of exercise and excitement
atenolol- beta 1 selective antagonists, used more commonly as it has fewer side effects, only targets the heart
heart effects explained
blocks Gs coupled receptor, less cAMP
reduced Ca2+ entry into myocytes
decreased contractility and heart rate
decreased SERCA and Ca2+ stores
overall decreases chrontropy, inotropy, lusitropy and conduction velocity
blood vessel effects explained
propranolol
inhibits Gs coupled receptor, less cAMP and PKA
PKA does not phosphorylate MLK so cannot cause smooth muscle relaxation, causing vasodilation
arrhythmia definition
a group of conditions in which the heart beat is irregular, too slow or too fast
examples of arrhythmias
tachycardia- heart rate is above 100 bpm
bradycardia- heart rate is below 60bpm
palpitations
four main groups of arrythmias + examples
extra beats- premature atrial contractions, premature ventricular contractions
supra ventricular tachycardias- atrial fibrillation, atrial flutter
ventricular arrhythmias- ventricular fibrillation and ventricular tachycardia
bradyarrthymias- bradycardia
what causes arrhythmias?
problems with the electrical conducting system of the heart
explain atrial fibrillation
an abnormal heart rhythm characterised by rapid and irregular beating which becomes longer or continuous over time
thought to be due to fibrosis of the atria due to atrial dilation
explain ventricular fibrillation
ventricles quiver rather then pumping normally due to disorganised electrical activity
hypoxic myocardium forms hyper irritable myocardial cells that then may act as pacemakers, stimulating the ventricles
explain ventricular tachycardia
monomorphic- increased automaticity of a single point
polymorphic- abnormalities of ventricular muscle depolarisation
what is heart block?
a disorder in the heart’s rhythm due to a fault in the pacemaker which causes an obstruction in the electrical conduction system of the heart
blockage normally occurs between the SAN and AVN or at or below the Bundle of His
three types of heart block
first degree AV block- where electrical impulses from the cardiac atria to the ventricles pass through the AVN more slowly than normal- slowed conduction
second degree- conduction block between the atria and ventricles, block of the AVN, where one or more atrial impulses fail to conduct
third degree- complete block, where nerve impulse generated in SAN cannot propagate to the ventricles
how does atrial fibrillation appear on an electrocardiogram?
absence of P wave
irregular R-R interval due to irregular conduction of impulses from the ventricles
ventricular fibrillation on ECG
irregular electrical activity with no discernible pattern
no visible P waves, QRS complexes or T waves
ventricular tachycardia on ECG
rate greater than 120 bpm
at least three wide QRS complexes in a row
different heart blocks on ECG
1st degree- regular rhythm, elongated PR
2nd degree- irregular rhythm/increasingly prolonged, more P waves than QRS
3rd degree- regular rhythm, lack of any apparent connection between P waves and QRS complexes
sinus rhythm definition
any cardiac rhythm in which depolarisation of the cardiac muscle begins at the sinus node
5 examples of anti dysrhythmics
lidocaine, propranolol, amiodarone, verapamil, adenosine
explain lidocaine use and mechanism of action
used for ventricular arrhythmias
binds to voltage gated sodium channels, acting as a competitive antagonist, preventing action potential generation
stabilise the excitability of over excitable cells, thus act as membrane stabilising agents
explain propranolol and mechanism of action
used to treat tachycardia
binds to beta 1 adrenoreceptors and act as an antagonist, inhibiting sympathetic stimulation of the heart
also thought to act similarly to lidocaine
explain amiodarone and mechanisms of action
used to treat ventricular tachycardia, ventricular fibrillation and atrial fibrillation
blocker of voltage gated potassium and calcium channels, this slows the conduction rate and prolongs the refectory period of SA and AV nodes
also acts by blocking voltage gated sodium channels and as a beta blocker
explain verapamil and mechanisms of action
treats supraventricular tachycardia
calcium channel blocker, decreasing impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias- only respond to the main impulses
also block calcium channels in smooth muscle found in blood vessels, causing them to dilate and thus can be used to treat high blood pressure and angina
explain adenosine and mechanisms of action
treats supraventricular tachycardia
causes transient heart block in the AVN, mediated by the A1 receptor, which inhibits adenyl cyclase, reducing cAMP and thus causing cell hyperpolarisation by increasing potassium efflux, subsequently inhibiting calcium current
angina definition
chest pain or pressure usually due to not enough blood flow to heart muscle, usually due to obstruction or spasm of coronary arteries
Vaughan Williams classification of drugs explained + examples
classification of cardiac drugs dependent on how they treat arrhythmias
Class I- interfere with sodium channels, lidocaine
class II- interfere with beta receptors, propranolol
class III- interfere with potassium channels, amiodarone
class IV- interfere with calcium channels, and affect AVN, verapamil, sotalol
Class V- agents work by other or unknown mechanisms, adenosine, digoxin
use of ouabain
blocks sodium potassium pump, which in turn prevents the movement of calcium due to the increase in intracellular sodium reducing the activity of sodium-calcium exchanger
used to treat reversible heart failure as it increases contractility and vagal tone
what anti muscarinic drug can also be used + explained?
atropine
used for bradycardia and 2nd and 3rd heart blocks
a competitive antagonist of nonselective muscarinic acetylcholine receptors, increasing firing of the SA and conduction through the AVN
oppose actions of the vagus nerve
secondary pacemaker explained
if the SAN is non functional, the AVN will take over pacemaker responsibility becoming the ectopic pacemaker of the heart
vagal tone definition
the continuous nature of baseline parasympathetic action that the vagus nerve exerts
