What conditions are Cardiovascular drugs used to treat?
Arrhythmias (abnormal rhythm)
Risk of thrombus formation
NB: some drugs can act at more than one site and are used to treat more than one condition
What can drugs alter?
The rate and rhythm of the heart
The force of myocardial contraction
Peripheral resistance and blood flow - acting on peripheral resistance vessels to alter after-load and blood pressure.
What abnormalities of heart or rhythm may there be?
Explain what is Atrial Flutter and Atrial Fibrillation
Atrial flutter: the impulse travels along a pathway within the RA, moving in an organised circular motion or circuit, causing the atria to beat faster than the ventricles - the heart beats fast but in a regular pattern.
Atrial fibrillation: many random electrical impulses firing off in the atria - atrial depolarisation is uncontrolled. The atria then fibrillate - only partially contract but very rapidly. Only some of these impulses pass through to the ventricles in a haphazard way. Therefore the ventricles contract in an irregular way and with varying force.
When could be the cause of Atrial Flutter or Atrial Fibrillation
May occur following conditions which put extra stretch and pressure on the atria (e.g. Mitral valve stenosis) and therefore damage the atria.
Damage to the atria may cause several short re-entrant loops to develop or may be as a result of an ectopic focal point of excitation.
Such points of excitation are frequently in the large veins entering the atria.
The actual heart rate depends on the frequency of impulse passing through the AV node.
A major concern with atrial fibrillation is the risk of thrombus formation.
Where could Tachycardia originate?
Ventricular tachycardia originates at ventricles (the bundle of His, Purkinje fibres or ventricular myoctes)
Supraventricular tachycardias originate at the atria or AV node.
Ventricular tachycardia may occur following MI as a result of ectopic pacemaker activity from damaged myocardium.
This could lead to ventricular fibrillation.
What is Ventricular Fibrillation?
Ventricles contract randomly causing a complete failure of ventricular function
- cardiac output cannot be maintained
- immediately life threatening.
List the causes of arrhythmia
Arrhythmias arise due to a disturbance of impulse generation, impulse conduction or both:
Ectopic pacemaker activity
How can ectopic pacemaker activity cause an arrhythmia?
Damaged area of myocardium becomes depolarised and spontaneous activity is being generated (due to leakage of K+ ions).
Latent pacemaker region is activated due to ischaemia - which dominates over SA node.
How can afterdepolarisations cause an arrhythmia?
Abnormal depolarisations following the action potential (triggered activity --> premature action potentials).
Early after- depolarisations can lead to oscillations - more likely if AP is prolonged (Q-T period is long)
Delayed after/depolarisations can trigger premature APs if it reaches threshold - more likely to happen if intracellular Ca2+ is high.
How can re-entry loop(s) cause an arrhythmia?
Conduction delay (e.g. Due to damaged area of myocardium)
Or accessory pathway (anatomical; there is a conduction problem at one of more points).
Incomplete conduction damage (unidirectional block) - excitation can take a long route to spread the wrong way through the damaged area, setting up a circuit of excitation.
What are the 4 basic classes of anti-arrhythmic drugs?
I. Drugs that block voltage-sensitive N+ channels
II. Antagonists of B-adrenoceptors
III. Drugs that block K+ channels
IV. Drugs that block Ca2+ channels
Note: anti-arrhythmic drugs can be pro-arrhythmic drugs as well - can aggravate or cause Arrhythmias under certain conditions so must be used with great care.
Describe the Mechanism of Action of Class I: Drugs that block Voltage-Dependent Na+ Channels
E.g. Local anaesthetic lidocaine (Class Ib)
Only blocks voltage-gated Na+ channels in open or inactive state (not in closed state).
Dissociates rapidly in time for next AP - doesn't stop normal AP but might stop extra activity - stops another AP from being generated prematurely.
Lidocaine is sometimes used following MI if a patient shows signs of ventricular tachycardia - given intravenously.
This is because damaged areas of myocardium may be depolarised and fire automatically which could lead to ventricular fibrillation.
More Na+ channels are open in depolarised tissue so lidocaine blocks these Na+ channels (use-dependent)- prevents automatic firing of depolarised ventricular tissue - the ventricular action potential can still take place but the local anaesthetic would block the Na+ channels once open.
Not used prophylactically following MI - overall benefit is not convincing.
Describe the Mechanism of Action of Class II: beta-adrenoceptor antagonists
Examples: Propranolol, atenolol (beta blockers).
Block sympathetic action - act at B1-adrenoceptors in the heart.
Decrease slope of pacemaker potential in sinoatrial node - slows down heart rate.
B-blockers are used following an MI; MI causes increased sympathetic activity and B-blockers prevent ventricular Arrhythmias which may be partly due to increased sympathetic activity.
B-blockers also reduce O2 demand - reduce myocardial ischaemia and this is beneficial following MI.
B-blockers slow conduction in AV node (slow down ventricular depolarisation) and can prevent supra ventricular tachycardias.
Describe the Mechanism of Action of Class III: Drugs that block K+ Channels
They prolong the action potential mainly by blocking voltage-gated K+ channels.
This lengthens the absolute refractory period.
In theory, the drugs should prevent another AP occurring too soon but in reality can be pro-arrhythmic therefore not generously used.
One EXCEPTION is Amiodarone but this drug has other actions in addition to blocking K+ channels. Used to treat tachycardia associated with Wolff-Parkinson-White syndrome (re-entry loop due to an extra conduction pathway). Amiodarone is an important anti-arrhythmic agent which acts on Na+, K+ and Ca2+ channels as well as B-adrenoceptors.
Describe the Mechanism of Action of Class IV: Drugs that block Ca2+ Channels
Decreases slope of pacemaker potential at SA node.
Decreases AV nodal conduction.
Decreases force of contraction (negative inotropy).
Also causes some coronary and peripheral vasodilation.
The Dihydropyridine Ca2+ channel blockers are not effective in preventing Arrhythmias but do act on vascular smooth muscle.
Describe the action of Adenosine
Produced endogenously but can also be administered pharmacologically - doesn't belong in any of the four classes:
Acts on A1 receptors on AV node.
Enhances K+ conductance - hyperpolarises cells of conducting tissue.
Decreases cAMP levels.
Anti-arrhythmic - administered intravenously and very short acting.
Chronic Failure of the heart to produce sufficient output to meet the body's requirements has what features?
Reduced force of contraction
Reduced cardiac output
Reduced tissue perfusion
What are drugs used in the treatment of heart failure?
Positive inotropes increase cardiac output: cardiac glycosides and B-Adrenergic agonists (e.g. Dobutamine), as they increase the force of cotraction.
Drugs which reduce the workload of the heart -reduce afterload and preload.
What are Cardiac Glycosides?
They increase myocardial contractility and therefore increase symptoms but NOT long term outcome.
Digoxin is the prototype cardiac glycoside.
It blocks Na+/K+-ATPase and increases the force of contraction.
It can, in some limited circumstances be used to increase cardiac output in heart failure.
NB: cardiac glycosides are not usually used in the treatment of heart failure as they do not improve long term survival; however they also have an anti-arrhythmic action by enhancing the Vagal input to the heart and can sometimes be used where heart failure is accompanied by atrial fibrillation.
Describe the action of Cardiac Glycosides
Ca2+ is extruded via the Na+-Ca2+ Exchanger, driven by Na+ moving down the concentration gradient.
Cardiac glycosides block Na+/K+-ATPase so [Na+]in increases.
The rise in [Na+]in leads to decrease in activity (inhibition) of Na+-Ca2+ exchanger.
This causes increase in [Ca2+]in which causes more Ca2+ to be stored in SR.
This has a positive inotropic effect - increased force of contraction.
What are B-adrenoceptor agonists?
They are used in heart failure as they increase myocardial contractility e..g dobutamine acts on B1 receptors and is used in cardiogenic shock and acute but reversible heat failure (e.g. Following cardiac surgery).
What is the action of Cardiac Glycosides on Heart Rate?
Cardiac glycosides cause increased Vagal activity - action via the central nervous system to increase Vagal activity - slows AV conduction, slows the heart rate.
Making the heart work harder when treating heart failure is not good in the long run. It is better to reduce workload. What may be used?
Pharmacological agents may be used to reduce force of contraction and thus lower the workload of the heart.
How do Beta-adrenoceptor blockers (antagonists) reduce the workload of the heart?
Prevent the action of sympathetically released NA and can be used to reduce the workload of the heart following MI when there is often and increased sympathetic response - have effect when stressed or excited as sympathetic effects are dominant. At rest there is little sympathetic activity and so B receptors have little effect.
In addition to reducing the force of contraction, B-blockers also reduce heart rate and can help to prevent Arrhythmias following MI.
B-blockers can be helpful in the treatment of angina (and even with care, in clinically stable heart failure.
How do ACE inhibitors reduce the workload of the heart?
They inhibit the action of angiotensin converting enzyme - prevent the conversion of angiotensin I to angiotensin II.
Angiotensin II acts on the kidneys to increase Na+ and water reabsorption.
Angiotensin II is also a vasoconstrictor.
ACE inhibitors decrease vasomotor (cause vasodilation) which leads to a decrease in total peripheral resistance and a decrease in blood pressure.
This reduces the afterload of the heart.
ACE-inhibitors also have a diuretic action since angiotensin II promotes aldosterone release from adrenal cortex.
The renin-angiotensin-aldosterone system is up-regulated in heart failure and is an important pharmacological target for improving long term outcome.
ACE-inhibitors decrease fluid retention (decrease blood volume) and thereby reduce the preload of the heart (heart filling reduces) thus reducing workload of the heart.
What is Angina? And how can it be treated?
Occurs when O2 supply to the heart does not meet its need.
Major symptom is chest pain - usually brought on by exertion.
Due to narrowing of the coronary arteries - atheromatous disease.
Angina can be treated by reducing the workload of the heart e.g. By using B-adrenoceptor antagonists, Ca2+ channel antagonists (causing peripheral dilation of blood vessels) or Organic Nitrates
Angina could also be treated by improving the blood supply to the heart - using Ca2+ channel antagonists or Organic Nitrates.
How do organic nitrates produce NO?
Reaction of organic nitrates with thiols (-SH groups) in vascular smooth muscle causes NO2- to be released.
NO2- is reduced to NO (nitric oxide).
NO is a powerful vasodilator, produced by endothelial cells lining the blood vessels.
NO activates guanylate cyclase which increases cGMP which lowers intracellular [Ca2+] which causes relaxation of vascular smooth muscle.
This dilatation of the collateral coronary arteries improves blood supply to the heart but it is only the SECONDARY effect. Organic nitrates do not alleviate angina by dilating arterioles.
What is the Primary Action of Organic Nitrates?
Main action: Venodilation
Venodilation lowers preload (central venous pressure) therefore reducing workload of the heart.
Heart fills less therefore force of contraction is reduced (Starling's law) which lowers O2 demand.
What is the Secondary Action of Organic Nitrates?
Action on coronary arteries improves O2 delivery to the ischaemic myocardium - acts on collateral (end) arteries rather than arterioles - causing dilation.
NOTE: organic nitrates do not alleviate angina by dilating arterioles.
What are some examples of Organic Nitrates?
Give some examples of Antithrombotic Drugs
Certain heart conditions carry an increased risk of thrombus formation; atrial fibrillation, MI and mechanical prosthetic heart valves.
heparin (given intravenously, inhibits thrombin and is used acutely for short terminal action), fractionated heparin (subcutaneous injection)
warfarin (given orally: antagonises action of Vitamin K and can be used long term).
Anti platelet drugs: given to reduce the risk of platelet rich arterial clots forming - Aspirin following acute MI or high risk of MI.
Discuss the possible treatments for Hypertension
Associated with increases in blood volume - Na+ and water retention by the kidneys of an increase in total peripheral resistance.
Hypertension is an important cardiovascular condition since it carries a risk of developing cardiovascular disease or stroke
Possible targets: (to reduce the workload of the heart) - Lower blood volume; lower cardiac output via Starling's law, lower cardiac output directly, lower peripheral resistance.
Diuretics decrease Na+ and water retention by kidney --> decrease in blood volume.
ACE inhibitors decrease Na+ and water retention by kidney and decrease total peripheral resistance (via vasodilation).
B-blockers decrease cardiac output.
Ca2+ channel blockers selective for vascular smooth muscle cause vasodilation.
Alpha-1 adrenoceptor antagonists cause vasodilation.
What effect would administration of an Alpha1-adrenoreceptor antagonist have on the cardiovascular system?
Alpha1-adrenoceptors are present on peripheral resistance vessels.
Activation of these receptors by noradrenaline leads to vasoconstriction.
The action of Alpha1 adrenoceptor antagonists reduce vasoconstriction (i.e. they have a vasodilator effect) and reduce peripheral resistance.
How does the binding of Noradrenaline to B1 adrenoceptors increase the force of contraction of cardiac myocytes?
Noradrenaline increases the opening of Ca2+ channels in the plateau of the action potnetial.
More Ca2+ enters, having a positive inotropic effect.
More importantly noradrenaline increases the affinity of the pumps in the SR for Ca2+.
More Ca2+ is stored in the SR therefore more is available for release during an action potential.
NOTE: binding of Na to B1-adrenoreceptors in heart activates adenylate cyclase thus increasing cAMP levels and activating Protein Kinase A (PKA).
PKA phosphorylates Ca2+ channels to increase opening and phosphorylates a protein involved in SR Pump Regulation allowing more Ca2+ to be stored.
What might be the effect of atropine upon an individual with an abnormally low heart rate? ('bradycardia')
The heart rate is normally slowed by vagal input i.e. is under parasympathetic control.
The neurotransmitter released from post-ganglionic sympathetic neurones is acetylcholine which acts on muscarinic receptors in the heart.
Atropine blocks muscarinic receptors, removing the slowing effect of the vagal input.
Thus atropine would cause an increase in heart rate.