11. Drugs and the heart Flashcards
what is If?
hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel
“funny sodium channel”
what are Ica(T/L)?
Ica(T): transient T-type Ca2+ channel
Ica(L): long-lasting L-type Ca2+ channel
what is Ik?
potassium channels
describe how an AP is generated at the SA node
- at approx. -60mv there is spontaneous activation so the heart is constantly beating
- the If channel opens –> Na enters the cell –> kickstarts the depolarisation process
- this is propagated by the calcium channels (Ica(T)) first)
- the upstroke arm of the AP is driven by Ica(L)
- once the AP reaches above 0mv potassium channels (Ik) open –> repolarisation of the whole system
how does the sympathetic NS increase heart rate?
releases NA which acts on B1-receptors –> increases cAMP –> increases If and Ica (promoting depolarisation) so there is less time between APs generated
how does the parasympathetic NS decrease heart rate?
via the muscarinic M2 receptors –> decrease cAMP –> increases Ik (prolongs repolarisation) so there is more time between APs generated
what does electrical excitation of the cell from APs arising from the SA node induce?
membrane depolarisation that promotes gating of Ca2+ channels, which open and cause a small release of Ca2+ into 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 (ryanodine receptors, RyR2)
what proportions of free Ca2+ are contributed by different channels in cardiac contraction?
20-25%: depolarisation-induced influx of Ca2+ current through L-type channels (outside cell)
75-80%: release of calcium through RyRs (inside cell)
what does intracellular calcium allow?
formation of actin-myosin cross-bridges –> contraction
what impact do b-receptors have on cardiac contraction?
positive impact
increased cAMP –> increased PKA –> promotion of contractile machinery + reduction of Ca entry back into the SR
what mechanisms regulate myocardial oxygen supply and demand?
myocardial oxygen supply increases when:
- coronary blood flow increases
- arterial O2 content increases
myocardial oxygen demand increases when:
- HR increases
- preload increases
- afterload increases
- contractility increases
which drugs influence heart rate?
- beta-blockers: the SNS impacts the funny sodium channels (If) and calcium channels to promote depolarisation so b-blockers decrease HR (reduced effect of NA on b1-receptor)
- calcium antagonists: block Ca channels directly so influences Ca entry into nodal tissue, reducing depolarisation and decreasing HR
- ivabradine: targets funny sodium channels to decrease opening –> impacts spontaneous generation of APs and decreases HR
which drugs influence contractility?
- b-blockers: decrease contractility
- calcium-antagonists: decrease Ica (channel blocker –> decreases Ca entry –> decreases contractility)
what are the 2 classes of calcium antagonists? give examples
- rate slowing (cardiac and smooth muscle actions) e.g. phenylalkylamines, benzothiazepines
- non-rate slowing (smooth muscle actions - more potent) which have no effect on the heart
which drugs influence myocardial oxygen supply/demand?
- organic nitrates: increases amount of organic NO available. NO increases the amount of cGMP –> promotion of smooth muscle relaxation –> dilation and improved blood flow
- potassium channel openers: direct K channel opening –> potassium efflux –> prolonged hyperpolarisation
what 2 different effects of nitrates/potassium channel openers influence preload and afterload?
vasodilation = decreased afterload
venodilation = decreased preload
what is angina?
chest pain usually driven by atherosclerosis (narrowing of coronary arteries)
how is angina treated?
- start with a b-blocker or calcium antagonist as background anti-angina treatment
- ivabradine is a newer treatment with less side effects
- nitrate is given as symptomatic treatment (short-acting)
- potassium channel opener if intolerant to other drugs
what are the side effects of b-blockers?
- worsening of cardiac failure (reduced CO)
- bradycardia
- bronchoconstriction (blockade of b2 in airways)
- hypoglycaemia due to decreased glycogenolysis/gluconeogenesis - cold extremities
- worsening of peripheral arterial disease (b2 blockade in skeletal muscle vessels)
- fatigue
- impotence
- depression
- CNS effects (nightmares)
what are the side effects of calcium channel blockers?
verpamil:
- bradycardia and AV block
- constipation (gut ca2+ channels affected)
dihydropyridines:
- ankle oedema (due to vasodilation)
- headache
- palpitations
- flush
what types of rhythm disturbances are there?
arrhythmias:
- supraventricular arrhythmias can be atrial/nodal tissue
- ventricular arrhythmias
- complex (both)
arrhythmias either decrease (brady) or increase (tachy) HR
dysrhythmias
what are the aims of treatment of rhythm disturbances and what does management involve?
aims of treatment: reduce sudden death, prevent stroke, alleviate symptoms
management: cardioversion, pacemakers, catheter ablation therapy, implantable defibrillators, drug therapy
what is the vaughan-williams classification of anti-arrhythmic drugs?
class I: sodium channel blockade
class II: beta-adrenergic blockade
class III: prolongation of repolarisation (membrane stabilisation due to potassium channel blockade)
class IV: calcium channel blockade
what is the problem with the vaughan-williams classification?
there is too much crossover for drugs to be properly classified so there is limited clinical significance
what is adenosine?
a drug administered intravenously (fast effect) to terminate supraventricular tachyarrhythmias
it’s actions are short-lived
what are adenosine’s actions?
acts on multiple receptors:
- A2 on smooth muscle - stimulation of adenylate cyclase –> increased cAMP (relaxes smooth muscle)
- A1 on nodal tissue - decreases cAMP –> decreases Ca channel opening –> prolonged K channel opening –> prolonged depolarisation and slower repolarisation
what is verapamil and how does it work?
an anti-arrhythmic drug that is a rate-limiting calcium channel blocker
it gets into nodal tissue, blocks calcium channels and decreases depolarisation
what is amiodarone and what is it used to treat?
an anti-arrhythmic drug that has some beta-blocking effects and some calcium channel/potassium channel effect
used in supraventricular and ventricular tachyarrhythmias
what are the adverse effects of amiodarone?
amiodarone has a long half life so has many side effects:
- photosensitive skin rashes
- hypo/hyperthyroidism
- pulmonary fibrosis
what are re-entry rhythms?
in normal, healthy tissue APs pass down either side of the purkinje fibres, meet and cancel eachother out, ensuring the AP proceeds in 1 direction
tissue block can lead to re-entry rhythms where the AP returns upward and can reactivate the tissue if the repolarisation stage is finished, leading to tachyarrhythmia
how do we overcome re-entry rhythm?
try and prolong repolarisation so that the tissue hasn’t repolarised when the AP re-enters and just dies
this is done with a potassium channel blockers like amiodarone
what is digoxin and how does it work?
a drug used to treat arrhythmias that inhibits Na-K-ATPase (Na/K pump) and so increases intracellular Ca2+ via effects on Na+/Ca2+ exchange –> positive inotropic effect
central vagal stimulation by digoxin causes increased refractory period and reduced rate of conduction through the AV node so HR slows
what is a potential side effect of digoxin and why?
improved ventricular contraction - digoxin competes with potassium so sodium and potassium exchange is interfered with
there is a build up of sodium within the cell which leads to more sodium-calcium exchange so there is a powerful positive inotropic effect in the ventricles
what are the uses of digoxin?
AF and flutter (reduces conduction of electrical impulses within the AV node and fewer impulses reach the ventricles so ventricular rate falls)
what are the adverse effects of digoxin?
- dysrhythmias
- conduction block (if there is too much vagal stimulation)
why does hypokalaemia lower the threshold for digoxin toxicity?
diuretics are often given with digoxin and diuretics promote hypokalaemia
digoxin competes with potassium so if there is already little potassium in the blood, digoxin over-inhibits which can be dangerous
