Drugs for the heart Flashcards
What could drugs control with the heart
regulating heart rate, contractility and myocardial oxygen supply
T/f SA node cells have a stable resting potetnial
F: no true resting potential, but instead generate regular, spontaneous action potentials
How does depolarisation occur in SA node
Driven by calcium
What is the If channel
Funny sodium channel…. activated by hyperpolarisation (whereas calcium channels inactivated by this)
Sodium comes in
Happens at sub-threshold levels.
Slow sodium leak, initiating depolarisation but not allowing the reaching of threshold potential
What happens in response to the small amount of depolarisation due to the opening of If channels
Opening of transient calcium channels, then Long Lasting calcium channels
The calcium channels won’t open if the cell is hyperpolarised. A small amount of depolarisation in the form of If channel is required.
When do Ik channels open
In response to depolarisation, they then activate, allowing repolarisation
T/f there are fast Na currents in the SA node
F: ), the depolarizing current is carried into the cell primarily by relatively SLOW Ca++ currents instead of by fast Na+ currents. There are, in fact, no fast Na+ channels and currents operating in SA nodal cells.
What is the effect of SNS?
It increases cAMP, increasing If and Ica, increasing steepness of depolarisation,
(in contrast to adenosine, which reduces cAMP in cardiomyocytes, but not VSMC, and this reduces If and Ica, i.e. basically does what PNS does in the heart)
What is the effect of PNS
Reduces cAMP, and increases Ik. This prolongs repolarisation
How does contraction occur in the heart
Action potential –> opening of L type calcium channels (NOTE THESE ARE THE SAME AS THE LONG-LASTING CHANNELS THAT OPEN IN RESPONSE TO THE SMALL AMOUNT OF DEPOLARISATION FROM SODIUM THEN CALCIUM!)–> calcium influx (only 20% of what is needed)
THEN calcium binds to SR via ryanodine receptors , which causes more calcium release (the remaining 70%)
Ca2+ binds troponin and this exposes binding sites and allows contraction
How does relaxation occur
ATP mediated Calcium reuptake into the SR
AND
Na+/Ca2+ exchange protein on the membrane removing calcium at the same rate that it comes in
How is myocardial oxygen supply and demand mediated
- What increases MO demand. What is the most important
- What increases MO oxygen supply
demand: Increase HR, preload, aferload or contractility (most important)
supply: increased coronary blood flow, and increased arterial O2 content
What has smallest effect on force of contraction, and thus MO demand
preload….
100% ↑ ventricular
volume would only ↑ F.O.C. by 25%
Which drugs can affect HR
β-blockers – Decrease If and Ica due to less cAMP (prolong time taken to reach threshold)
Direct channel blockers:
Calcium antagonists – Decrease Ica
Ivabradine – Decrease If
Which drugs can affect contractility
β-blockers – Decrease contractility
Calcium antagonists – Decrease Ica
State the 2 classes of calcium antagonists and where each type acts.
Give examples
Rate slowing (Cardiac and smooth muscle actions)
Phenylalkylamines (e.g. Verapamil)
Benzothiazepines (e.g. Diltiazem)
Non-rate slowing (smooth muscle actions – more potent)
Dihydropyridines (e.g. amlodipine)
Which type of calcium channel blocker causes reflex tachycardia
Non rate slowing….
No effect on the heart. Profound vasodilation can lead to reflex tachycardia due to baroreceptors…. nothing to slow the heart
Which other drug types can influence MO supply or demand
Organic nitrates
and
Potassium channel openers
How do organic nitrates work and to what effect
How do potassiun channel openers work and to what effect
NOTE THESE ARE AFFECTING CHANNELS IN THE CORONARY ARTERIES TO INCREASE SUPPLY AND REDUCE DEMAND, NOT ON THE SAN
Organic nitrates:
They form NO
Increase action of sGC, which converts GTP–>cGMP.
cGMP opens potassium channels, leading to hyperpolarisation. This reduces calcium entry becuse hyperpolarisation prevents Ca2+ opening (both here add in the heart, leading to relaxation)
cGMP also directly cases relaxation
This INCREASES MO supply due to the vasodilation
BUT
Also impacts on MO DEMAND (look in next box)
Potassium channel openers:
Potassium-channel openers are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains
What is the effect of nitrates/potassium channel openers on preload and afterload
Vasodilation of vessels generally (they don’t just affect coronary vessels!) –. REDUCED AFTERLOAD
Venodilation –> reduced venous return –> reduced preload
SO IN ADDITION TO CAUSING VASODILATION TO CORONARY VESSELS THEY REDUCE AMOUNT OF BLOOD REACHING HEART, AND THE RESISTANCE AGAINST WHICH HEART PUMPS
What of the following aspects do the following drugs have:
Coronary blood flow Arterial O2 content HR Preload Afterload Contractility
Nitrates, K+ channel opener, ivabradine, betabocker, CCB
Coronary blood flow: organic nitrates, K channel openers
Arterial O2 content: none in this one
HR: beta blocker, CCB, ivabradine
Preload: Organic nitrates/ K channel openers
Afterload: Organic nitrates/ K channel openers
Contractility: beta blocker, CCB
Outline the treatment of angina using drugs affecting the heart
Beta blocker or calcium antagonist as background anti-angina treatment.
Ivabradine is a newer treatment
Nitrate as symptomatic treatment (short acting)– e..g GTN sublingual spray. For quick dilation of coronary vessels
Other agents e.g. potassium channel opener if intolerant to other drugs
What are the principles of angina treatment
Reduce MO demand or increase MO supply
Side effects of betal blockers
Worse heart failure (due to CO reduction and increased vascular resistance, due to b receptors)
Bradycardia (leads to heart block–> decreased conduction through the AV node)
What is the effect of BLOCKADE of beta receptors on the vasculature
Beta 2 receptor blockade will reduce vasodilation and increase TPR which can worsen heart failure.
How can the beta blocker side effects be mitigated in HF
You want to reduce vascular resistance….
give something with ISA (pindolol)
give mixed beta and alpha blocker as the a blockade gives vasodilatory properties e.g. carvedilol
Other beta blocker effects, and contraindications
Reduces bronchodilation –> NOT FOR ASTHMATICS!
and reduces glucuneogenesis and glycogenolysis (and mask the effects) –> NOT FOR DIABETICS
Which types of vascualature have B2 receptors and why
Peripheral vessels (they can dilate for temperature regulation!) and skeletal muscle vasculature (to allow for runnign during stress)
Why do beta blockers cause cold extremeties. What causes this. What condition would this be bad for
Loss of β2 receptor mediated cutaneous vasodilation in extremities
Worsening peripheral artery disease
i. e. beta blockers contraindicated in:
- diabetes, asthmatics, peripheral artery disease
Other side effects of beta blockers, perhaps
Impotence (sexual dysfunction)
Depression
Fatigue
CNS effects (lipophilic agents) e.g. nightmares
Side effects of calcium channel blockers
Verapamil (rate limiting):
- Bradycardia and AV block (Ca2+ channel block)
- Constipation (Gut Ca2+ channels) – 25 % patients
Dihydropyridines (non-rate blocking)
- Ankle oedema (vasodilation means more pressure on capillary vessels)
- Headache/flushing (vasodilation)
- Palpitations (due to reflex tachy?)
- Vasodilation/reflex adrenergic activation
What drugs could have same side effects as dihydropyridines?
K+ channel openers and nitrates as they are also causing vasodilation of VSMC
(-Ankle oedema (vasodilation means more pressure on capillary vessels)
- Headache/flushing (vasodilation)
- Palpitations
- Vasodilation/reflex adrenergic activation)
What are the aims of treatment in arrhythmias
Reduce sudden death
Prevent stroke
Alleviate symptoms
t/f arryhtmias always refers to increased rate of rhythm
F May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias).
Classify arrythmas and the treatment
Supraventricular arrhythmias (e.g. amiodarone, verapamil)
Ventricular arrhythmias (e.g. flecainide, lidocaine).
Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).
What is the MAO of each each class of vaughan-williams classification of anti-rhythmic drugs
- Sodium channel blockade
- Beta adrenergic blockade
- Prolong repolarisation (membrane ‘stabilisation’, mainly due to postassium channel blockade, reduce K+ efflux)
- Calcium channel blockade
How does adenosine work on vascular smooth muscle
In coronary vascular smooth muscle:
- binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein.
- this stimulates adenylyl cyclase (AC in figure), increases cAMP and causes protein kinase activation.
- this stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation.
- increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, leading to decreased myosin phosphorylation and a decrease in contractile force.
- adenosine may inhibit calcium entry into the cell through L-type calcium channels.
(Note the difference that in cardiac tissue, reducing cAMP will increase Ik due to PNS,
here, increasing cAMP will increase KATP, which are different types of channels to Ik)
How does adenosine work on AV/SA nodal tissue
In cardiac tissue:
- adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins.
- this opens potassium channels, which hyperpolarizes the cell.
- Activation of the Gi-protein also decreases cAMP, inhibiting L-type calcium channels and therefore calcium entry into the cell.
- 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).
When is adenosine used
why is it safer than verapamil
Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil.
Which proteins are adenosine receptors coupled to in VSMC and in nodal cells
VSMC- Gs
Nodal cells -Gi
How does verapamil work
Depress SA automaticity and subsequent AV node conduction
In addition will prolong the plateau phase of the ventricular action potential too
Outline uses of verapamil
Reduction of ventricular responsiveness to atrial arrythmias
MAO of amiodarone
Complex action probably involving multiple ion channel block
What is reentry
Normal: purkinje fibre splits in 2. These 2 branches are connected distally by a third, common branch. The action potential will travel down both branches, and then cancel each other out when they meet in the distal branch.
A UNIDIRECTIONAL BLOCK can occur in a branch in which depolarisation cannot travel through, but repolarisation can. Therefore, the AP travelling down the second branch will not travel to the distal common branch and cancel out the depolarisation from the 1st branch.
The AP from the 1 branch will travel along the common distal branch, and then up the 2nd branch (depolarisation is not affected in this direction as the block is unidirectional)… in this case the AP can then cause excitation in the 1st branch again and can recircle (depending on whether the 1st branch has refractory period… check the notes on the slide)
How does amiodarone work to help in reentry
Affect on the ventricular cells, not on SA node
So there is never enough repolarisation becuase of the reentrant AP, so no full relaxation, reduced cardiac output.
But the tissue cannot be depolarisaed again if it is in a state of hyperpolarisation, so the amiodarone works by blocking potassium channel (and other channels), to delay the repolarisation step and thus hyperpolarisation and less likely for reentrant rhythms.
What is digoxin
cardiac glycoside….
it inhibits Na/K+ ATPase
Effect is on the SA nodal cells
What is the effect of digoxin on inotropy
Positive effect
Build up of sodium inthe cell
Increases Na+/Ca2+ exchanger so more Ca2+ in so more positively inotropic
What are the 2 effects of digoxin
Increases contraction due to inhibition of Na-K-ATPase (Na/K pump). This results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange → positive inotropic effect
but SLOWS heart too (good) because
central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node
Uses of digoxin
Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output.
Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls.
What are the adverse effects of digoxin
dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
Why does hypokalaemia lower threshold of digoxin toxicity
Digoxin is in competition with K+ for the K+ binding site on the Na+/K+ ATPase.
If there is less K+ then digoxin has greater access to the pump so it can block it more effectively
