Drugs and the heart Flashcards
What do the cardiovascular drugs tend to target
Drugs affecting heart rate, contractility and myocardial oxygen supply
What is important to remember about depolarisation of the SA node
Depolarisation of SAN is largely Ca2+ mediated, as opposed to Na+ mediated
There are, in fact, no fast Na+ channels and currents operating in SA nodal cells.
Ultimately, how is coordination of contraction achieved
Coordination of contraction is achieved by a specialised conducting system. Normal sinus rhythm is generated by pacemaker impulses that arise in the sinoatrial (SA) node and are conducted in sequence through the atria, the atrioventricular (AV) node, bundle of His, Purkinje fibres and ventricles.
What are the ion channels found in the SA node
If = hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels – “funny” channels.- open when cell is most hyperpolarisaed and use cAMP to drive Na+ entry
o Predominantly a sodium channel.
ICa (T or L) = Transient T-type Ca2+ channel or Long-lasting L-type.
o Mediates fast calcium influx.
IK = Potassium channels.
Describe the generation of an action potential in the SAN
If- uses cAMP to drive sodium ion entry to initiate depolarisation (this starts the process, but full depolarisation is not achieved)
The current rises leading to transient and long-lasting Ca2+ channels opening- action potential reached (mostly by long-acting calcium channels)
-60- 0mV
Ik channel open, K+ efflux, repolarisation (inward directing K+ channels).
What is phase four in the SAN
Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential
Mediated primarily by Ca2+ influx
Phase 0= Pacemaker potential — AP
Phase 3 – AP – hyperpolarisation
What is a key property of the SAN
Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials.
What are the effects of the SNS on the SAN
Increased cAMP which increases If opening and direct effect on Ica channels- more likely to see depolarisation.
What are the effects of the PSNS on the SAN
Decreased cAMP, increased Ik
Less likely to see depolarisation.
Extend the length of time between depolarisaitons.
Describe the depolaristion of cardiomyocytes
Electrical excitation of the cell from action potentials arising from the sino-atrial node induce membrane depolarization that promotes gating of Ca2+ channels, which open and cause a small release of Ca2+ into the cytoplasm. The small Ca2+ current induces a release of Ca2+ from the SR by a process called Ca-induced Ca-release. The release occurs through Ca2+ release channels commonly referred to as ryanodine receptors (RyR2). Depolarization-induced influx of Ca2+ current (ICa) through the L-type channels contributes approximately 20–25% of the free Ca2+ in a cardiac twitch. The release of Ca2+ through the RyRs contributes the remaining 75–80% of Ca2+ necessary for cardiac contraction.
What plasma membrane protein allows calcium to enter the cell following depolarisation
Dihydropyridine receptors
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 (mediated by adenylate cyclase)
How does the Ca2+ then initiate contraction
It binds to troponin on the thin filament - allowing the actin and myosin to bind together
(relaxation occurs when Ca2+ unbinds from troponin).
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 (Na+/K+ ATPase maintains Na+ gradient)
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
Essentially, what should there be a balance between in healthy heart function
Myocardial Oxygen supply and myocardial work (myocardial oyxgen demand)
Imbalance between supply and demand in angina
What are the determinants of myocaridal oxygen supply
Arterial oxygen content
Coronary blood flow (main determinant)
What are the determinants of myocardial oxygen demand
Heart rate
Contractility
Preload
Afterload
What is the primary determinant of myocardial oxygen demand
Myocyte contraction = primary determinant of myocardial oxygen demand
↑ H.R. = more contractions; ↑ afterload or contractility = greater force of
contraction; ↑ preload = small ↑ in force of contraction ( 100% ↑ ventricular
volume would only ↑ F.O.C. by 25%)
Why would an increase in preload and afterload increase myocarial contraction and thus myocardial work
Afterload- more resistance in vessels- heart needs to contract more forecefully to pump the blood into the vasculature.
Preload- Starling’s Law- more blood returned- heart needs to work harder to eject this volume (preload is linked to SV).
What are the main effects of the SNS on the heart
The main effects of the sympathetic nervous system on the heart are:
increased force of contraction (positive inotropic effect)
increased heart rate (positive chronotropic effect)
increased automaticity
repolarization and restoration of function following generalized cardiac depolarization
reduced cardiac efficiency (i.e. cardiac oxygen consumption is increased more than cardiac work)
How are the sympathetic effects on the heart achieved
These effects are largely due to activation of β1 adrenoceptors. Activation of β1 adrenoceptors stimulates adenyl cyclase resulting in production of cyclic AMP from ATP. This acts as an important intracellular messenger to increase intracellular Ca2+ (probably largely as a result of effects on L-type calcium channels and the sarcoplasmic reticulum) and stimulate Na-K ATPase in cardiac myocytes.
Describe the parasympathetic effects on the heart
Activation of the parasympathetic system results in:
Cardiac slowing and reduced automaticity
Inhibition of AV conduction
Cardiac work also depends on the load the heart experiences i.e. venous return (preload) or the impedance of the arterial circulation (after-load).
PSNS will reduce TPR, thus reducing afterload and thus cardiac work
What effect do beta blockers and calcium antagonists have on the channels responsible for SAN activation.
Beta-blockers decrease If and calcium channel activity
Calcium channel blockers only decrease calcium channel activity
Describe the effect of Ivabradine on heart rate
Blocks the If current
Less pronounced effect as only blocks Na+ entry, however it will still decrease the rate of depolarisation, thus increasing the ‘spacing’ between depolarisations, thus decreasing heart rate.
Which channels will calcium antagonists bind to
These agents act by binding to and inhibiting opening of L-type calcium channels.
What drugs affect contractility
β-blockers – Decrease contractility (reduced stimuli for calcium entry)- remember the effects of beta-1 adrenoreceptor stimulaiton
Calcium antagonists – Decrease Ica -less entry of Ca2+
What are the two classes of calcium antagonists
o Rate-slowing – cardiac + VSM:
§ Phenylalkylamines – Verapamil.
§ Benzothiazepines – Diltiazem.
o Non-rate slowing – VSM (more potent):
§ Dihydropyridines – Amlodipine
What is important to remember about non-rate slowing calcium antagonists
No effect on the heart. Profound vasodilation can lead to reflex tachycardia
This is due to the stimulation of arterial baroreceptors, which will decrease in firing rate- thus leading to increased HR to try and increase the BP
How do organic nitrates cause vasodiation
Organic nitrates are substrates for nitric oxide production
The NO then diffuses into the smooth muscle and causes smooth muscle relaxation by activating soluble guanylate cyclase (which converts GTP — cGMP)
This cGMP will lead to relaxation of the VSMC (dilation) and will also open K+ channels, leading to K+ efflux, hyperpolarising the cell, making it less favourable for Ca2+ to enter the VSMC and cause contraction.
Hence NO has direct and indirect effects to induce VSMC relaxation.
They are often in angina patients before they exercise