Lecture 9.2: Action of Drugs on the CVS Flashcards
What Conditions are Cardiovascular Drugs used to Treat? (5)
- Arrhythmias
- Heart Failure
- Angina
- Hypertension
- Risk of Thrombus Formation
What Factors are Cardiovascular Drugs able to alter? (4)
- The rate and rhythm of the heart
- The force of myocardial contraction
- Peripheral resistance and blood flow
- Blood volume
Drugs influence the Heart in different ways: Inotropy
- Contractility
Drugs influence the Heart in different ways: Chronotropy
- Heart Rate
Drugs influence the Heart in different ways: Dromotropy
- Electrical Conduction
Drugs influence the Heart in different ways: Lusitropy
- Relaxation
What is the key cellular event in muscle contraction?
An increase in intracellular Calcium (Ca2+)!!
Cardiac Muscle Contraction and Relaxation (8 Steps)
1) Rapid depolarisation occurs when fast‐.
opening Na + channels in the sarcolemma
open and allow an influx of Na + ions into the
cardiac muscle cell (Na + channels close)
2) A plateau phase occurs during which Ca 2+
enters the cytosol of the muscle cell from
sarcoplasmic reticulum and also from outside
the cell through slow‐opening Ca2+ channels
in the sarcolemma
3) Within the cell, Ca2+ binds to troponin
4) This triggers the cross‐bridge binding that
leads to the sliding of actin filaments past
myosin filaments
5) The sliding of the filaments produces cell
contraction
6) At the same time that the Ca2+ channels
open, K+ channels, which normally leak small
amounts of K+ out of the cell, become more
impermeable to K+ leakage
7) Re-polarisation occurs as K + channels open
and K + diffuses out of the cell. At the same
time, Ca 2+ channels close
8) A refractory period follows, during which.
concentration of K + and Na + are actively
restored to their appropriate sides of the.
sarcolemma by Na +/K + pumps
Bradycardia
Abnormally Slow Heart Rate
Tachycardia
Abnormally Fast Heart Rate
Atrial Flutter
It occurs when a short circuit in the heart causes the upper chambers (atria) to pump very rapidly
Atrial Fibrillation
The atria beat irregularly
Ventricular Tachycardia
It occurs when the lower chamber of the heart beats too fast to pump well and the body doesn’t receive enough oxygenated blood
Supraventricular Tachycardias
Supraventricular tachycardia (SVT) is as an irregularly fast or erratic heartbeat (arrhythmia) that affects the heart’s upper chambers (atria)
Ventricular Fibrillation
The ventricles beat irregularly
Inappropriate Sinus Tachycardia
Characterised by a sinus heart rate inexplicably higher than one hundred beats per minute (bpm) at rest
Ectopic Pacemaker Activity
An excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart
Afterdepolarisations
- Abnormal depolarisations following the action
potential - Anything which prolongs the duration of the
action potential can allow afterdepolarisations
to occur - Can cause a premature AP to fire
Re-Entry Loop
- Reentry describes a self-sustaining cardiac
rhythm abnormality (several of these can lead
to AF) - In reentry, the action potential propagates in a
circus-like closed loop manner - Conduction Delay
- Accessory Pathway
What is Wolff-Parkinson-White Syndrome?
- A relatively common heart condition that
causes the heart to beat abnormally fast for
periods of time - The cause is an extra electrical connection in
the heart
Pathophysiology of Wolff-Parkinson-White Syndrome
An extra electrical pathway between your heart’s upper chambers (atria) and lower chambers (ventricles) causes a rapid heartbeat (tachycardia)
What are the basic classes of anti-arrhythmic
drugs? (4/5 Classes)
- Class I: Drugs that block voltage-sensitive
sodium channels - Class II: Antagonists of β-adrenoceptors
- Class III: Drugs that block potassium channels
- Class IV: Drugs that block calcium channels
- Class V: Drugs that don’t fit the first 4 classes
Class I Anti-Arrhythmic Drugs: Mechanism? Examples?
- Only blocks voltage gated Na+ channels in
open or inactive state - Dissociates rapidly in time for next AP
- Typical example is the local anaesthetic
lidocaine
When is Lidocaine Used? Why does it work?
- Sometimes used following MI if patient shows
signs of ventricular tachycardia - Damaged areas of myocardium may be
depolarised and fire automatically - More Na+ channels are open in depolarised
tissue - Lidocaine blocks these Na+ channels
- Prevents automatic firing of depolarised
ventricular tissue
Class II Anti-Arrhythmic Drugs: Mechanism? Examples?
- Block sympathetic action
- Act at β1-adrenoreceptors in the heart
- Decrease slope of pacemaker potential in SA
- Examples: propranolol, atenolol (β-blockers)
When is β-blockers Used? Why does it work?
- Used following an MI
- MI causes increased sympathetic activity,
arrhythmias may be partly due to increased
sympathetic activity - β-blockers prevent ventricular arrhythmias
- Also reduces O2 demand (thus reduces
myocardial ischaemia) - β-blockers slow conduction in AV node (thus
prevent supraventricular tachycardias)
Class III Anti-Arrhythmic Drugs: Mechanism? Examples?
- Prolong the action potential, mainly by blocking
K+ channels - This lengthens the absolute refractory period
- Prevents another AP occurring too soon (in
theory) - Amiodarone, sotalol, dofetilide, and ibutilide
Why are Class III Anti-Arrhythmic Drugs often not used?
- Not generally used because they can be also
be pro-arrhythmic
What is the Class III Anti-Arrhythmic Drug that is NOT pro-arrhythmic?
Amiodarone
What is Amiodarone used to treat?
Used to treat tachycardia associated with
Wolff-Parkinson-White syndrome (re-entry loop
due to an extra conduction pathway)
Class IV Anti-Arrhythmic Drugs: Mechanism? Examples?
- Drugs that block Ca2+ channels
- Decreases slope of pacemaker action potential
at SA node - Decreases AV nodal conduction
- Decreases force of contraction (negative
inotropy) - Also cause some coronary and peripheral
vasodilation
Dihydropyridine vs Non-Dihydropyridine Ca2+ Channel Blockers?
- Dihydropyridine: predominantly peripheral
vasodilatory actions, block calcium channels
located in the muscle cells of the heart and
arterial blood vessels, thereby reducing the
entry of calcium ions into the cell - Non-Dihydropyridine: significant SA and AV
node depressant effects and possible
myocardial depressant effects with lesser
amounts of peripheral vasodilation
Adenosine as an Anti-Arrhythmic Drug: Where is it produced?
Produced Endogenously
Adenosine as an Anti-Arrhythmic Drug: How does it work?
- Acts on A1 receptors at AV node
- Enhances K+ conductance
- Hyperpolarises cells of conducting tissue
- Stops heart momentarily & resets the
rhythm
What is Heart Failure?
Chronic failure of the heart to provide sufficient output to meet the body’s requirements
What are some Common Features of Heart Failure? (4)
- Reduced force of contraction
- Reduced cardiac output
- Reduced tissue perfusion
- Oedema – from back pressure
What does the Frank–Starling Law state?
The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction, when all other factors remain constant
What are the 3 Types of Drugs used to Treat Heart Failure?
- β-Adrenergic Agonists (+ve inotropes increase
cardiac output) - Cardiac Glycosides (+ve inotropes increase
cardiac output) - ACE Inhibitors (reduce work of heart)
How do ACE Inhibitors work?
- Inhibit the action of angiotensin converting
enzyme (prevent conversion of angiotensin I to
angiotensin II) - Aldosterone acts on the kidneys to increase
Na+ and water reabsorption - Decrease vasomotor tone (↓ blood
pressure) - Reduce after-load of the heart
- Decrease fluid retention (↓ blood volume)
- Reduce preload of the heart
- Reduce work load of the heart
Why is is important that ACE-Inhibitors prevent the conversion of angiotensin I to angiotensin II?
- Angiotensin II is also a vasoconstrictor
- Thus increases vasomotor tone (increased BP)
What other type of drugs have a similar effect as ACE-Inhibitors?
Angiotensin II Receptor Blockers (ARBs)
E.g. Losartan
Examples of ACE-Inhibitors (3)
- Benazepril
- Ramipril
- Lisinopril
How do β–adrenoceptor antagonists (β-blockers) work?
- Beta blockers work by blocking the effects of
the hormone epinephrine, also known as
adrenaline - Act as Diuretics (as adrenaline increased water
reabsorption, blocking it means more urine
output) - Reduce blood volume
- Cause the heart to beat more slowly and with
less force, which lowers blood pressure
How do Cardiac Glycosides work?
- They increase myocardial contractility
(ionotropy) and output force of the heart - They do this by acting on the cellular sodium-
potassium ATPase pump - Block Na+/K+ ATPase
- Increase in Na+ concentration inside the
cells leads to an inhibition of the Na+/ Ca2+
exchanger - Increase Ca2+ concentration inside cardiac
myocytes - Positive inotropic effect
- Increased force of contraction
What else are Cardiac Glycosides used to treat?
Atrial Fibrillation
Examples of Cardiac Glycosides
Digitoxin (derivatives of foxglove)
What is the Action of Cardiac Glycosides on Heart Rate?
- Chronotropy
- Cardiac glycosides also cause increased vagal
activity - Action via central nervous system
- Slows AV conduction
- Slows the heart rate
How do β–adrenoreceptor agonists work? What are they used to treat?
increase myocardial
contractility and speed of relaxation
What is Angina (Myocardial Ischaemia)?
- Occurs when O2 supply to the heart does not
meet its need - Chest Pain
- Usually pain with exertion
- Due to narrowing of the coronary arteries,
atheromatous disease
Treating Angina: What Drugs work to reduce the work load of the heart?
- ACE inhibitor / ARB
- β-adrenoceptor blockers
- Ca2+ channel antagonists
- Organic nitrates
- If channel blockers (slow pacemaker)
Treating Angina: What Drugs work to improve the blood supply to the heart?
Ca2+ channel antagonists
Treating Angina: What Drugs reduce Cholesterol?
Statins
Treating Angina: Surgery
- Angiography
- +/- stents
- Revascularise
Action of Organic Nitrates
- Reaction of organic nitrates with thiols (-SH
groups) in vascular smooth muscle causes
nitrite (NO2-) to be released - NO2- is reduced to NO
- NO is a powerful vasodilator
- Venodilation reduces venous pressure and
the return of blood to the heart - This reduces the work of the heart
Examples of Organic Nitrates (3)
- Glyceryl Trinitrate (GTN)
- Isosorbide Mononitrate (ISMN)
- Isosorbide Dinitrate
How does NO cause Vasodilation?
- NO activates guanylate cyclase
- Increases cGMP
- Lowers intracellular [Ca2+]
- Causes relaxation of vascular smooth muscle
How does this vasodilation (due to NO) help alleviate symptoms of Heart Failure?: 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
What is Preload?
Preload is the amount of sarcomere stretch experienced by cardiac muscle cells, called cardiomyocytes, at the end of ventricular filling during diastole
How does this vasodilation (due to NO) help alleviate symptoms of Heart Failure?: Secondary Action
- Action on coronary arteries improves O2
delivery to the ischaemic myocardium - Acts on collateral arteries rather than arterioles
What conditions carry an increased risk
of thrombus formation? (3)
- Atrial Fibrillation
- Acute Myocardial Infarction
- Mechanical Prosthetic Heart Valves
Antithrombotic Drugs: Anticoagulants (target clotting cascade) Examples (4)
- Heparin (given intravenously)
- Fractionated Heparin (subcutaneous injection)
- Fondaparinux
- Warfarin (given orally)
How does Heparin work?
- Inhibits thrombin
- Used acutely for short term action
How does Warfarin work?
- Blocks activation/recycling of vitamin K (vitamin
K epoxide reductase complex 1 inhibitor) - This Inhibits synthesis of hepatic clotting
factors II, VII, IX and X - Can be used long term
Antithrombotic Drugs: Novel Oral Anticoagulants (NOAC) Examples (2)
- Thrombin Inhibitor (Dabigatran)
- Factor Xa Inhibitors (Apixaban, Rivaroxaban)
Antithrombotic Drugs: Antiplatelet Drugs Examples (3)
- Aspirin (following acute MI/high risk of MI)
- Dipyridamol (phosphodiesterase inhibition)
- Clopidogrel (inhibits ADP dependant platelet
aggregation)
Mineralocorticoid Receptor Antagonists MoA
- Decrease the aldosterone effect by binding to
the mineralocorticoid receptor inhibiting
aldosterone - This leads to higher levels of potassium in
serum and increased sodium excretion - Resulting in decreased body fluid and lower
blood pressure
Examples of Mineralocorticoid Receptor Antagonists
Spironolactone and Eplerenone
I(f) Channel Blockers MoA
