13. Cardiac arrhythmias and CVS drugs Flashcards
What is an arrhythmia?
An arrhythmia is an a abnormally/ irregular heart rate/rhythm.
Give 5 examples of types of arrhythmias
- Sinus Bradycardia
- sinus tachycardia
- atrial flutter
- atrial fibrillation
- tachycardia (ventricular tachycardia and supraventricular tachycardia)
- ventricular fibrillation
List 4 causes of tachycardia
Arrhythmias arise due to a disturbance of impulse generation, impulse conduction or both.
- Ectopic pacemaker activity
- After-depolarisations
- This is when you have abnormal depolarisations following the action potential. - Atrial flutter/ atrial fibrillation
- This is an abnormal heart rhythm which is characterised by rapid and irregular beating of the atrial chambers of the heart. - Re-entry loop
– conduction delay
– accessory pathway
What may lead to ectopic pacemaker activity?
This is when another (damaged) area of the myocardium becomes spontaneously active and it’s depolarisations dominate over the SA node. This leads to random and irregular depolarisations and heartbeats.
- latent pacemaker region activated due to ischaemia (dominates over SA node)
List and describe 2 causes of bradycardia
- Sinus bradycardia
This can be caused by a condition known as sick sinus syndrome. Here the SA node is malfunctioning and isn’t depolarising properly. This is a type of arrhythmia.
Another cause would be extrinsic factors such as drugs (e.g beta blockers, some Ca2+ channel blockers). These work to slow down conduction at the AV node.
- Conduction block:
Here there are problems at the AV node or the bundle of His, this means that there’s a block in conduction between the atria and the ventricles.
Another cause would be extrinsic factors (e.g beta blockers and some Ca2+ channel blockers). These cause slow conduction at the AV node.
Explain what a delayed after-depolarisation (DAD) is
DADs begin after repolarisation of the ventricles is completed but before another action potential would normally occur via the normal conduction systems of the heart.
They’re due to increased levels of intracellular calcium concentrations.
The overload in the SR of the cell causes spontaneous release of Ca2+ after repolarisation.
- thought to activate NCX channels
- sodium in causes slight depolarisation
- If threshold is reached an action potential is triggered before it should.
You get triggered activity.
If this happens routinely it can result in ventricular tachycardia.
Explain what an early after-depolarisation (EAD) is
This is when you get abnormal action potentials occurring before normal repolarisation is completed.
This can be due to random openings of sodium or calcium ion channels.
You’re more likely to get this if the action potential is prolonged.
If the AP is prolonged you get a longer QT interval.
This can suggest that the patient is more prone to arrhythmia.
Why are early after-depolarisations more likely to occur when there is prolonged AP?
If action potential is prolonged (e.g. in hypokalaemia)
- Ca++ channels recover from inactivation
- can lead to calcium spikes
- depolarising the membrane leading to oscillation
When does reentry occur?
When a propagating impulse fails to die out after normal activation of the heart and persists to re-excite the heart after expiration of the refractory period
Describe the reentrant mechanism in a unidirectional block.
A re-entry loop occurs when the normal spread of excitation across the heart is disrupted due to a damaged area.
In a normal spread of excitation without damage, the impulses will spread out from the point of diversion in opposite directions and impulses will also meet at a point and cancel out as all cells are in the refractory period.
If there’s an area of damage that blocks conduction through one diversion, it means that the impulse will spread the opposite way and continue as normal. This doesn’t create a problem.
However, where there’s an incomplete conduction damage, the damaged tissue will only conduct in one direction (unidirectional block)(but normally not in the right direction)
The excitation can’t get through the area of damage through one route so it’ll take the long route and spread the wrong way through the damaged area. This sets up a circuit of excitation where there is rapid depolarisation - setting up tachycardia
What effect can a reentry loop have on the atria?
Multiple small reentry loops can form in the atria, leading to atrial fibrillation. - tachycardia, irregular rhythm, wavy baseline
Explain what happens in AV nodal re-entry
AV nodal reentry is a type of tachycardia (supraventricular tachycardia).
It occurs when a re-entrant circuit forms within or next to the AVN, this causes the heart to beat prematurely as there is a circuit of depolarisation .
You get fast and slow pathways in the AVN to create a re-entry loop.
Explain what happens in ventricular pre-excitation
In ventricular pre-excitation part of the cardiac ventricles are activated too early.
Its caused by an abnormal electrical connection known as an accessory pathway between the atria and the ventricles - not the normal route.
This creates a re-entry loop such as in Wolff-Parkinson-White syndrome.
List the 4 basic classes of anti-arrhythmic drugs
I. Drugs that block voltage-sensitive sodium channels
II. Antagonists of β-adrenoreceptors
III. Drugs that block potassium channels
IV. Drugs that block calcium channels
Give an examples of a class I anti-arrhythmic drug?
Lidocaine (local anaethetic)
In which state of the Na+ channel does lidocaine block it?
Only blocks voltage gated Na+ channels in open or inactive state - therefore preferentially blocks damaged depolarised tissue.
Why does lidocaine have little effect in normal cardiac tissue?
Lidocaine has a rapid dissociation time meaning that it’ll block during depolarisation but dissociated in time for the next AP.
This means that it has little effect in normal tissue.
When and how might lidocaine be given following an MI?
Lidocaine is sometimes administered intravenously following an MI but only if the patient is showing signs of a ventricular tachycardia.
Why does lidocaine have a greater effect on damaged myocardium than normal myocardium?
• Damaged areas of myocardium may be depolarised and fire automatically
• More Na+ channels are open in depolarised tissue
- lidocaine blocks these Na+ channels (use-dependent)
- prevents automatic firing of depolarised ventricular tissue
What can lead to atrial fibrillation or flutter?
Atrial flutter or fibrillation may occur following conditions which put extra stretch and pressure on the atria (eg mitral valve stenosis)
Is lidocaine used prophylactically?
Not used prophylactically following MI
– Even in patients showing VT generally use other drugs
Give example of class II (Antagonists of β-adrenoreceptors) anti-arrhythmic drugs
propranolol, atenolol(Beta blockers)
What are the effects of class II anti-arrhythmic drugs?
They work by blocking sympathetic action and act on the β 1 -adrenoreceptors in the heart.
They carry out this action by decreasing the slope of the pacemaker potential in the SAN and slowing down conduction at the AV node.
What type of arrhythmias can beta blockers prevent and how?
Supraventricular arrhythmias
- β-blockers slow conduction in AV node
- Slows ventricular rate in patients with AF
Why are beta blockers (Antagonists of β-adrenoreceptors) given after a MI?
- MI often causes increased sympathetic activity (β-blockers block this activity - reduce the workload of the heart)
- Arrhythmias may be partly due to increased sympathetic activity
- β-blockers prevent ventricular arrhythmias
What effect do beta blockers have on oxygen demand for the heart and why is this important?
reduces O2 demand
- Reduces myocardial ischaemia
- Beneficial following MI
What is the main mechanism of Drugs that block K+ channels (class III)?
• Prolong the action potential
- mainly by blocking K+ channels
• This lengthens the absolute refractory period
Why are drugs that block K+ channels (class III) generally bad?
In theory would prevent another AP occurring too soon
- In reality can be pro-arrhythmic as it can prolong the QT interval.
What is the exception in the class III drugs and why?
Amiodarone
- has other actions in addition to blocking K+ channels
- non specific drug, blocks other types of ion channels also
What conditions is amiodarone used to treat?
- Used to treat tachycardia associated with Wolff-Parkinson-White syndrome (re-entry loop due to an extra conduction pathway)
- Effective for supressing ventricular arrhythmias post MI
Give examples of drugs that block Ca2+ channels (class IV).
verapamil, diltiazem (non-dihydropyridine types)
What are the effects of drugs that block Ca2+ channels (class IV).?
- Decreases slope of action potential at SA node
- Decreases AV nodal conduction
- Decreases force of contraction (negative inotropy)
- Also some coronary and peripheral vasodilation
What do dihydropyridine Ca2+ channel blockers act on? give examples.
Dihydropyridine Ca2+ channel blockers are NOT effective in preventing arrhythmias, but do act on Vascular smooth muscle causing vasiodilation:
Amlodipine, nifedipine, nicardipine
Describe the features, functions and the mechanism of action of Adenosine
Adenosine is a drug that’s produced endogenously at physiological levels but it can also be administer intravenously.
Whilst it has arrhythmic properties it doesn’t fit into any of the 4 categories of arrhythmic drugs.
It acts on a1 receptors at the AVN but has a very short half life.
It works to enhance K+ conductance, this means that it helps to hyperpolarise cells of conducting tissue.
It’s also anti-arrhythmic, Useful for terminating re-entrant supra ventricular tachycardia and to decrease the slope of the pacemaker potential(o decreases intracellular CAMP to reduce If).
Give an example of an ACEi.
Perindopril, Lisinopril
What do ACEi do?
Prevents conversion of angiotensin I to angiotensin II by blocking the angiotensin converting enzyme.
What are ACEi important in the treatment of?
Hypertension AND heart failure
How do ACEi help treat heart failure?
• Prevents 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
– both of which cause an increase in blood pressure
– ACEi prevents Angiotensin II formation so reduces the increase in blood pressure
• decrease vasomotor tone (↓blood pressure)
• Reduce afterload of the heart
• ALSO Decrease fluid retention (↓blood volume)
• Reduce preload of the heart
• BOTH effects reduce work load of the heart
What can be used alternatively to ACEi? give an example.
Angiotensin II receptor blockers (ARBs)
- work at AT1 receptor
e.g. Losartan, Valsartan
It’s used on patients who can’t use ACE-inhibitors due to side effects.
It can be used in treatment of heart failure and hypertension
What is a side effect of ACEi?
ACEi can cause a dry cough (excess bradykinin)
Describe the features, functions and the mechanism of action of Diuretics
Diuretics are drugs that can be used in the treatment of heart failure and hypertension.
These type of drug promote an increased production of urine.
They work to reduce the volume of fluid present in blood and increase the excretion off this fluid in the kidneys
What are loop diuretics? How do they work? Give an example.
A type of diuretic are loop diuretics which are useful in congestive heart failure.
An example is durosemide.
This reduces pulmonary and peripheral oedema.
Loop diuretics, such as furosemide, inhibit the body’s ability to reabsorb sodium at the ascending loop in the nephron, which leads to an excretion of water in the urine, whereas water normally follows sodium back into the extracellular fluid.
Describe the features, functions and the mechanism of action of Ca2+ channel blockers🚩
Ca2+ channel blockers useful in hypertension, angina, coronary artery spasm, SVTs.
Whilst Dihydropyridine Ca2+ channel blockers are not effective in preventing arrhythmias, they are able to act on vascular smooth muscle to reduce contraction.
Examples of these include amlopidine and nicardipine.
These work to decrease peripheral resistance, decrease arterial BP and then reduce the workload of the heart by reducing afterload.
There are other types of calcium channel blockers e.g verapamil and diltiazem, these act on the heart.
They reduce workload of the heart by reducing the force of contraction
Define the term ‘inotropic drugs’, give the function of positive inotropes, provide 2 examples of these
Inotropic drugs are drugs that affect the force of contraction.
Positive inotropes increase contractility and therefore cardiac output.
Examples include cardiac glycosides (e.g digoxin) and β-adrenergic agonists (e.g dobutamine)
What effects do cardiac glycosides have on the heart?
- increases contractility
- can decrease heart rate
How do cardiac glycosides cause increase contractility?
Block Na+/K+ ATPase
- Na+ builds up intracellularly
- reduced Na+ gradient
- decreased NCX activity
- increase Ca++ intracellularly
- stored in SR
- increased force of contraction
How do cardiac glycosides cause decrease heart rate?
- Action via central nervous system to increase vagal activity (parasympathetic)
- slows AV conduction
- slows the heart rate
Acts as an anti-arrhythmic agent
What type of arrhythmias might cardiac glycosides be useful in treating?
Used in heart failure when there is an arrhythmia such asAF
Give an example of a cardiac glycoside.
Digoxin
Why aren’t cardiac glycosides now used in the treatment of heart failure?
Makes heart work harder so don’t improve long term survival, so now used for it anti-arrhythmic effects in treating heart failure with AF
What may lead to atrial flutter or fibrillation?
Atrial flutter or fibrillation may occur following conditions which put extra stretch and pressure on the atria (eg mitral valve stenosis). Damage to the atria may cause several short re-entrant loops to develop or may be as the result of an ectopic focal point of excitation. Such points of excitation are frequently in the large veins entering the atria. With atrial flutter and atrial fibrillation, the actual heart rate depends on the frequency of impulses passing through the AV node. A major concern with atrial fibrillation is the risk of thrombus formation.
When might β - adrenoceptor agonists be used?
- cardiogenic shock
* acute but reversible heart failure (eg following cardiac surgery)
How can selective B1-adrenoceptor agonists be used on the CVS
Dobutamine is an example of a selective β1 - adrenoceptor agonist. It works by stimulating the β1 receptors present at the SA node, AV node and on ventricular myocytes. increase the force of contraction and heart rate by activating β1-adrenoreceptors
Explain how heart failure can be treated
There are many options that can used when treating heart failure.
Cardiac glycosdies can be used to relieve symptoms by making the heart contract harder.
However there’s no long term benefit in making the heart contract harder long term so it’s not used often for treatment.
The aim in treating heart failure would be to reduce workload, this is why ACEinhibitors or ARBs and diuretics are argued to be better for treatment of heart failure.
Beta blockers can also reduce workload of the heart.
What are nitrates used to treat?
angina
Explain the role organic nitrates play in the CVS
- Reaction of organic nitrates with thiols (-SH groups) in vascular smooth muscle causes NO2- to be released
- NO2- is reduced to NO (Nitric Oxide)
- Nitric oxide is released endogenously from endothelial cells
- NO is a powerful vasodilator
What effect does NO have and how is this caused?
vasodilation
• NO activates guanylate cyclase
• Increases cGMP by converting GTP to cGMP, activates PKG
• Lowers intracellular [Ca2+]
• Causes relaxation of vascular smooth muscle
Give examples of organic nitrates used to treat angina.
- GTN spay (quick, short acting)
- Isosorbide dinitrate (longer acting)
What causes angina?
- Angina occurs when O2 supply to the heart does not meet its need – But of limited duration and does not result in death of myocytes
- Ischaemia of heart tissue – Chest pain
- Usually pain with exertion
Which blood vessels do organic nitrate preferentially act on and why?
At normal therapeutic doses it is most effective on veins
- less of an effect on arteries, very little effect on arterioles
Maybe because there is less endogenous nitric oxide in veins
How do the actions of nitrates alleviate angina?
PRIMARY ACTION
• action on venous system -venodilation lowers preload
– reduces work load of the heart
– heart fills less therefore force of contraction reduced (Starling’s Law)
– this lowers O2 demand
SECONDARY ACTION
• action on coronary collateral arteries improves O2
delivery to the ischaemic myocardium
– acts on collateral arteries NOT arterioles
It’s emphasised that organic nitrates don’t work by dilating arterioles. Explain why this is
This is because patients with cardiovascular disease will already have their arterioles dilated in order to maximise cardiac blood flow.
This is due to flow-limiting stenosis.
This means thatit’s diffcult to dilate coronary vessels further this is why there’s limited effect of nitrates on arterioles.
Overall how can you treat a patient with angina?
There are 2 main aims; to reduce the work load of the heart and to improve the blood supply to the heart.
• Reduce the work load of the heart
- Organic nitrates (via venodilation)
- β-adrenoreceptor blockers
- Ca2+ channel antagonists
• Improve the blood supply to the heart
- Ca2+ channel antagonists
- Minor effect of organic nitrates
What are the vasodilator drugs?
• ACE-inhibitors
• Ca2+ channel blockers
• α1adrenoreceptor antagonists
•
What effect does vasodilation have on the heart?
Arteriolar vasodilation reduces peripheral resistance, lowering arterial blood pressure and reducing the afterload against which the heart must pump
What are the inotropic drugs?
Drugs that affect the force of contraction are referred to as inotropic drugs
• Cardiac glycosides such as digoxin - increase force of contraction
• Adrenaline and dobutamine (selective β1 agonist) - increase force of contraction
• β-adrenoreceptors blockers - reduce force of contraction and thus lower the workload of the heart - In addition to reducing the force of contraction β-blockers also reduce heart rate and can help to prevent arrhythmias following MI
Give examples of conditions that have increased risk of thrombus formation.
- Atrial fibrillation
- Acute myocardial infarction
- Mechanical prosthetic heart valves
What is the function of anticoagulants ?
Prevention of venous thromboembolism
– Heparin (given intravenously)
• inhibits thrombin
• used acutely for short term action
– Fractionated heparin (subcutaneous injection)
– Warfarin (given orally)
• antagonises action of vitamin K
– Direct acting oral thrombin inhibitors such as dabigatran
What is the function of anti platelet drugs?
These are used to prevent the formation of platelet rich blood clots from forming. It can be used on an individual who’s already had an MI or someone who’s at risk of an MI.
– Aspirin
– Clopidogrel
