Drugs and the Cardiovascular System – The Heart Flashcards
What is the major store of calcium within the cardiomyocyte?
Sarcoplasmic reticulum
Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?
Dihydropyridine receptors
What happens to calcium once it has passed into the cell via dihydropyridine receptor channels?
It binds to ryanodine receptors on the SR + causes Ca2+ release from the SR
How does calcium stimulate contraction?
It binds to troponin on Actin
What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction?
Na+/Ca2+ exchanger
SERCA2a (sarcoendoplasmic reticulum calcium ATPase)
What features of contraction is SERCA2a responsible for and why?
Rate of calcium removal: thus rate of cardiac muscle relaxation
Size of calcium store: thus affects contractility of the subsequent beat
What are the 3 main channels that are responsible for the action potential in the sinoatrial node?
If channel: hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel (funny channel)
Ca2+ channel (Transient + Long-lasting)
K+ channel
Describe how channels are responsible for the action potential of the sinoatrial node.
If channels open in hyperpolarised state, utilising cAMP, drive in Na+ to initiate depolarisation
Current starts to rise, stimulating the opening of Ca2+ channels (T then L), which further depolarises the membrane.
K+ channels are responsible for repolarisation
What are beta adrenoceptors coupled with?
Adenylate cyclase: it increases cAMP, which is important in the opening of the If channel to begin depolarisation
How does the parasympathetic nervous system affect heart rate and contractility?
It is negatively coupled with adenylate cyclase, thus decreases cAMP + interferes with funny currents, slows HR
Promotes K+ channel opening
What are the determinants of myocardial oxygen supply?
Arterial oxygen content
Coronary blood flow
What are the determinants of myocardial oxygen demand (work)?
Heart rate
Contractility
Preload
Afterload
What effect do beta-blockers and calcium channel blockers have on the channels responsible for the SA node action potential?
B-blockers decrease If + Ca2+ channel activity
Ca2+ channel blockers decrease Ca2+ channel activity
Thus both decrease HR + contractility
Name a drug that decreases If activity.
Ivabradine (blocks the If channel)
What effect does Ivabradine have on contractility?
No effect on contractility because it doesn’t affect the Ca2+ channels
What are the 2 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 due to profound vasodilation
How do organic nitrates cause vasodilation?
Organic nitrates are substrates for NO production
NO diffuses into smooth muscle + causes relaxation by activating guanylate cyclase that produces cGMP
cGMP also causes opening of K+ channels + K+ efflux, resulting in hyperpolarisation
How do potassium channel openers work?
They open K+ channels + hyperpolarise the smooth muscle so it is less likely to contract
How do vasodilation and venodilation reduce myocardial oxygen demand?
Reduce pressure against which the heart is pumping (reduce afterload)
Reduce venous return to the heart (reduce preload)
State 5 unwanted effects of beta-blockers.
Bradycardia Hypotension Hypoglycaemia in diabetics on insulin Cold extremities (loss of beta-2 receptor mediated cutaneous vasodilation) Bronchoconstriction
Under what circumstance must caution be taken when giving beta-blockers?
Heart failure (CO already reduced)
B-Blockers further reduce CO + increase vascular resistance (B2 receptors are dilating receptors, so less vasodilation occurs)
Asthmatics: B2 blockade in lungs worsens attacks
Diabetics: Hypoglycaemia masked
What are the side effects of verapamil?
Bradycardia + AV block (Ca2+ channel block)
Constipation (Gut Ca2+ channel block)
What are the side effects of dihydropyridines?
Ankle oedema (vasodilation increases pressure on capillary vessels)
Headaches/flushing (vasodilation)
Palpitations (reflex sympathetic response)
What is a simple classification of arrhythmias based on?
Point of origin
Supraventricular, Ventricular + Complex
What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?
Vaughan-Williams classification I: Na+ channel blockers II: B-blockers III: prolongation of repolarisation (mainly due to K+ channel blockade) IV: Ca2+ channel blockers
What is adenosine used to treat?
To terminate supraventricular tachyarrhythmias Short lived (20-30s), thus quite safe
How does adenosine work?
Binds to A1 receptors on nodal cells
Inhibitory effect on adenylate cyclase, inhibits cAMP production + funny currents, reduces depolarisation (tissue has longer time to repolarise)
Binds to A2 receptors on vascular smooth muscle
Increases cAMP, promotes relaxation + vasodilation
What is verapamil used to treat?
Supraventricular arrythmias
What is the target of verapamil and how does it work?
L-type calcium channel
Reducing Ca2+ entry means speed with which the tissue depolarises is reduced
What is amiodarone used to treat?
Supraventricular tachyarrhythmia
Ventricular tachyarrhythmia
How does amiodarone work?
By blocking many ion channels
Main effect through K+ channel blockade
This prolongs repolarisation, thus prolonging the time during which the tissue can’t depolarise
Describe re-entry.
In damaged cardiac tissue signal passes down 1 branch of conductive tissue, but can’t pass down another. When signal passes through a third branch (usually the 2 signals would meet + cancel out) the signal goes back up 2nd branch + reactivates the tissue
Causes premature contraction (if muscle in ready state)
What is the target of cardiac glycosides like digoxin?
Na+/K+ ATPase
How does digoxin work and what are its effects on the heart?
Blockage of Na+/K+ ATPase causes accumulation of Na+ in the cell
Excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular Ca2+ concentration
Causes inotropic effect (increases force of contraction)
Also causes vagal stimulation which increases refractory period + reduces rate of contraction through AVN
What is an important factor to consider before starting treatment with digoxin?
Hypokalaemia
Digoxin binds to the K+ binding site on the extracellular component of Na+/K+ ATPase so it competes with K+ for the binding site
If hypokalaemic, there is less competition for digoxin + 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
What effect does the sympathetic system have on SA nodal cells?
Increases cAMP, increases opening of If + Ca2+ channels
Increased chance of depolarisation
Increased HR
Why is afterload a determinant of myocardial oxygen demand?
The higher the afterload, the harder the heart has to contract to eject blood from the heart
Why is preload a determinant of myocardial oxygen demand?
Due to Starlings law
If increased volume returned to heart, heart will have higher stroke volume + have to work harder
How do B blockers help decrease heart rate in angina?
Sympathetic nervous system exerts its effects via B1 receptors in heart
Blockade stops sympathetic stimulation, so stops the opening of If + Ca2+ channels
What B blocker may be appropriate to use in heart failure patients with angina and why?
Pindolol
Has intrinsic sympathetic activity at low sympathetic levels
Thus in normal daily life it helps HF
B blockade prevents pain during exercise
Why should B-blocker usage in heart block patients or those with conduction problems be avoided?
B-blockers cause bradycardia, exacerbating decreased conduction through AVN
Which B blocker drugs can be used to attempt to prevent increased vascular resistance?
Mixed A-B- Blockers
Alpha blockade causes more dilation than constriction
Name 2 types of arrhythmia
Bradyarrthmia (decreased HR)
Tachyarrythmia (increased HR)
Why must Amiodarone be used with caution?
It accumulates in the body
Serious side effects (photosensitive skin rashes, hypo/ hyperthyroidism, pulmonary fibrosis)
Why must potassium levels be monitored after digoxin administration?
Hypokalaemia lowers threshold for digoxin toxicity
Digoxin binds to same site as K+
So if blood K+ falls, digoxin has easier access to target + more powerful effect
Side effects increase
