Drugs and the Cardiovascular System – The Heart Flashcards
What is the major store of calcium within the cardiomyocyte?
Sarcoplasmic reticulum
The heart has two signalling pathways that are involved in elevating the level of two intracellular second messengers. What are these second messengers?
Ca2+ and cAMP
Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?
Dihydropyridine receptors
What happens to the calcium once it has passes into the cell in response to depolarisation?
It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR Also contributes 20-30% of the free calcium binding to troponin
How does the calcium stimulate contraction?
It binds to troponin on the thin filament This causes a conformational change in tropomyosin so it unblocks the myosin-actin binding site
What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction? Which method is responsible for the majority of calcium removal?
Plasma membrane calcium ATPase Na+/Ca2+ exchanger SERCA2a (sarcoendoplasmic reticulum calcium ATPase) –responsible for >70% of calcium removal
What features of contraction is SERCA2a responsible for and why?
Rate of calcium removal and so it’s responsible for the rate of cardiac muscle relaxation Size of calcium store, which affects the contractility of the subsequent beat
What regulates the action of SERCA2a and how does it do this?
Phospholamban (PLN) Phospholamban phosphorylation is stimulated by beta-adrenergic activity When dephosphorylated it is an inhibitor of SERCA2a When phosphorylated it dissociates from SERCA2a and activates the Ca2+ pump As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is in proportion to the elevation in the size of the SR calcium store
What is phospholamban phosphorylated and dephosphorylated by?
Phosphorylated by by protein kinase A dephosphorylated by Protein phosphatase 1
What are the three main channels that are responsible for the action potential in the sinoatrial node?
If channel:
- hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel.
- Sodium
Ica (T or L):
- Transient T-type Ca++ channel
- or Long Lasting L-type Ca++ channel
IK – Potassium K+ channels
Describe how these channels are responsible for the action potential of the sinoatrial node.
If channel is a slow release sodium channel that opens at the most negative membrane potential Opening of the sodium channel causes sodium influx, which begins to depolarise the membrane and stimulates the opening of calcium channels, which further depolarises the membrane Potassium channels are responsible for repolarisation
Describe the intracellular pathway that beta adrenoceptors are coupled with in the heart
Adenylate cyclase:
- it increases cAMP.
- cAMP upregulates PKA production which in turn activates (through phosphorylation) Ica channels, RyRs and If channels
How does the parasympathetic nervous system affect heart rate and contractility?
It is negatively coupled with adenylate cyclase
Inhibition of adenylate cyclase causes decreased cAMP levels
This causes decreased opening of If and Ica channels
Decreased rate and strength of cardiac contraction
What are the determinants of myocardial oxygen supply?
Arterial oxygen content Coronary blood flow
What are the determinents of myocardial oxygen demand?
Heart rate Contractility Preload (least powerful determinate) Afterload
What effect do beta-blockers and calcium channel blockers have on the channels responsible for the SA node action potential?
Beta-blockers decrease If and calcium channel activity by blocking an increase in cAMP Calcium channel blockers decrease L-type calcium channel activity
Name a drug that decreases If activity, what effect does it have on contracility?
Ivabradine (blocks the If channel) It has no effect on contractility because it doesn’t affect the calcium channels
What are the two types of calcium channel blocker? Name the drugs in each category including their drug class.
Rate slowing Phenylalkylamines – verapamil Benzothiazepines – diltiazem Non-rate slowing Dihydropyridines – amlodipine
What is a consequence of non-rate slowing calcium channel blockers?
Reflex tachycardia (baroreceptor reflex)
How do organic nitrates cause vasodilation?
Organic nitrates are substrates for nitric oxide production
The NO then diffuses into the smooth muscle and activating guanylate cyclase
Guanylate cyclase converts GTP to cGMP
cGMP actiavtes the plasma membrane potassium channel - efflux of potassium from the cell causes hyperpolarization
Hyperpolarization inhibits the membrane calcium channel causes relaxtion
cGMP also causes direct relaxtion of the cell by an unknown mechanism
How do potassium channel openers work?
They open the potassium channels and hyperpolarise the vascular smooth muscle This causes a closure of voltage-gated calcium (Ca2+) channels so the cell is less likely to contract
How do vasodilation and venodilation reduce myocardial oxygen demand?
Vasodilation reduced TPR, so reduce the pressure against which the heart is pumping (reduce afterload) Venodilation increases the reservoir capacity of the venous system, reducing venous return to the heart (reduced preload) Decreases the work-load of the heart so decreased strength of contractility
As these drugs reduce the myocardial oxygen demand, what condition can they all be used to treat?
Angina pectoris
State some unwanted effects of beta-blockers.
Bradycardia Hypotension Hypoglycaemia in diabetics on insulin Cold extremities (because of beta-2 blockade) Bronchoconstriction Fatigue Impotence Depression CNS effects
When treating what condition must caution be taken when giving beta-blockers?
In the treatment of heart failure b blockers slow the heart to allow time to fill effectively but because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients if the dose is too high Can also be used to treat heart failure
What are the side effects of verapamil?
Bradycardia
AV block
Constipation
What are the side effects of dihydropyridines?
Ankle oedema Headaches/flushing Palpitations
What is a simple classification of arrhythmias?
Based on its point of origin:
Supraventricular, Ventricular and Complex
What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?
Vaughan-Williams classification
I – sodium channel blockers
II – beta-blockers
III – prolongation of repolarisation (mainly due to potassium channelblockade)
IV – calcium channel blockers
What is adenosine used to treat?
It is used to terminate supraventricular tachycardia
How does adenosine work in coronary vascular smooth muscle?
- In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein.
- Activation of this G-protein stimulates adenylyl cyclase (AC in figure),
- this increases cAMP and causes protein kinase activation.
- PKA activates K+ATP channels, which hyperpolarizes the smooth muscle, causing relaxation.
- Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force.
- There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels.
What is verapamil used to treat?
Supraventricular tachycardia Atrial fibrillation
What is the target of verapamil and how does it work?
L-type calcium channel Reducing calcium entry means that the speed with which the tissue is depolarise is reduced
What is amiodarone used to treat?
Supraventricular tachyarrhythmia Ventricular tachyarrhythmia - often due to re-entry
How does amiodarone work?
It works by blocking many ion channels Its main effect seems to be through potassium channel blockade This prolongs repolarisation, so you’re prolonging the time during which the tissue can’t depolarise This reduces the chances of re-entry
Describe re-entry.
Some damaged cardiac tissue will make it difficult for depolarisation to pass through it in one direction, but it will allow the action potential to propagate in the opposite direction This could mean that you get a miniature circuit set up within the tissueand you get re-entry of action potentials
What is the target of cardiac glycosides like digoxin?
Na+/K+ ATPase
How does digoxin work and what are its effects on the heart?
By blocking Na+/K+ ATPase it causes an accumulation of Na+ in the cell The excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular calcium concentration This has a positive inotropic effect
It also causes vagal stimulation, which has a negative chronotropic effect so reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls.
What is an important factor to consider before starting treatment with digoxin?
Hypokalaemia Digoxin binds to the potassium binding site on the extracellular component of Na+/K+ ATPase so it competes with potassium for the binding site If hypokalaemic, there is less competition for digoxin and so the effects of digoxin are exaggerated
What is digoxin used to treat?
Atrial fibrillation Atrial flutter
What is an adverse effect of digoxin?
Dysrrhythmia e.g. AV conduction block, ectopic pacemaker activity
What are cardiac inotropes? Name two.
They increase the contractility of the heart (it is used in acute heart failure in some cases) Dobutamine (beta-1 agonist) Milrinone (phosphodiesterase inhibitor)
What are the ion currents responsible for the SA node depolarization?
If channel - slow leak sodium current to initiate depolarization Ica(t) - transient T-type calcium channel Ica(L) - Long lasting L-type calcium channel These channels generate a calcium current that is mainly responsible for depolarizion of the cell
Whats the difference between the classes of calcium antagonist?
Rate slowing = effects primarily on the heart and some smooth muscle action Non-rate slowing = no effect on heart and stronger effect on vascular smooth muscle than rate slowing types
When are organic nitrates often used?
They are often in angina patients before they exercise
How does adenosine work in cardiac tissue?
- In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins.
- Activation of this pathway opens potassium channels, which hyperpolarizes the cell.
- Activation of the Gi-protein also decreases cAMP,
- which inhibits L-type calcium channels and therefore calcium entry into the cell. (negative ionotropy)
- In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If),
- which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy).
