Drugs and the Cardiovascular System – The Heart Flashcards
What is the major store of calcium within the cardiomyocyte?
Sarcoplasmic reticulum
Channels associated with initiating a heart rate
If
ICa Transient
ICa Long lasting
Ik
Chemical associations of If channels
Associated with cAMP
Are hyperpolarisation activated cyclic nucleotide gated channels which tend to let in sodium during hyperpolarised times
Role of 2 calcium channels
Main drivers behind depolarisation
Role of Ik
Initiate repolarisation
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 via the dihydropyridine channel?
It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR
How does the calcium stimulate contraction?
It binds to troponin on the thin filament
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 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
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
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
Calcium channel blockers only decrease calcium channel activity
These 2 affect both HR and contractility
Name a drug that decreases If activity.
Ivabradine (blocks the If channel)
What effect does Ivabradine have on contractility?
It has no effect on contractility because it doesn’t affect the calcium channels
What are the two types of calcium channel blocker?
Rate slowing - cardiac and smooth muscle effects
Non-rate slowing - only really potent in smooth muscle
What is a consequence of non-rate slowing calcium channel blockers?
Reflex tachycardia (baroreceptor reflex)
How do organic nitrates cause vasodilation in coronary vasculature?
Organic nitrates are substrates for nitric oxide production
The NO then diffuses into the smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase
They are often given in angina patients before they exercise
How do potassium channel openers work?
They open the potassium channels and hyperpolarise the vascular smooth muscle so that it is less likely to contract
How do vasodilation and venodilation of nitrates and potassium channel openers reduce myocardial oxygen demand?
They reduce the pressure against which the heart is pumping (reduce afterload) and it also causes reduce venous return to the heart (reduced preload) meaning that contractility is decreased
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
Under what circumstance must caution be taken when giving beta-blockers?
Cardiac failure – because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients
Reduced CO and increased vascular resistance
What are the side effects of verapamil?
Bradycardia and AV block
Constipation
What are the side effects of dihydropyridines?
Ankle oedema - due to vasodilation
Headaches/flushing - due to vasodilation in brain
Palpitations- reflex tachycardia
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?
Adenosine binds to adenosine receptors in the cardiac muscle and vascular smooth muscle
Adenosine receptors are negatively coupled with adenylate cyclase in the heart (A1 receptor) and positively in the vasculature (a2)
Results in relaxation in VSMC and reduced HR and contractility in the nodes
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
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
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 so an early contraction
How does amioadarone prevent reentry
By prolonging the length of repolarisation you decrease the likelihood of tissue in affected area being able to depolarise
Adverse affects of amiodarine
Remains in body for long time
Thyroid disease
Photosensitive rashes
What is the target of cardiac glycosides like digoxin?
Na+/K+ ATPase
How does digoxin work and what are its effects on the heart and the PSNS?
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 an inotropic effect
It also causes vagal stimulation which increases refractory period, which has a chronotropic effect
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
Driver behind initial depolarisation in phase 4
Pacemaker potential
What does SNS affect in heart rate
Increase cAMP
If
ICa
What does PNS do to affect heart rate
Decrease cAMP and increase K
Percentage of Ca responsible for binding to troponin
EC 25%
SR 75%
How is Na conc gradient maintained in myocyte
Plasma Na/K pump
Drugs influencing heart rate
Beta blockers- decrease If and ICa
Calcium antagonists- decrease ICa
Ivabradine- decrease If
2 types of rate slowing Ca channels
Phenylalkylamines
Benzothiazepines
Example of non rate slowing Ca channel antagonist
Dihydropyridines- amplodine
Example of phenylalkylamines
Verapamil
Example of benzothiazepine
Diltiazem
What is an adverse effect of digoxin?
Dysrrhythmia
Overall effects of digoxin
Decreases heart rate to aid with any arrhythmia and increase contractility to improve CO
Selectivity of pindolol
Equal affinity for b1 and b2 receptors
ISA
Selectivity of carvedilol
Affinity for both beta adrenoceptors and a1
