11. Drugs and the heart

Question 1

what is If?

Answer 1

hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel

“funny sodium channel”

Question 2

what are Ica(T/L)?

Answer 2

Ica(T): transient T-type Ca2+ channel

Ica(L): long-lasting L-type Ca2+ channel

Question 3

what is Ik?

Answer 3

potassium channels

Question 4

describe how an AP is generated at the SA node

Answer 4

1. at approx. -60mv there is spontaneous activation so the heart is constantly beating
2. the If channel opens –> Na enters the cell –> kickstarts the depolarisation process
3. this is propagated by the calcium channels (Ica(T)) first)
4. the upstroke arm of the AP is driven by Ica(L)
5. once the AP reaches above 0mv potassium channels (Ik) open –> repolarisation of the whole system

Question 5

how does the sympathetic NS increase heart rate?

Answer 5

releases NA which acts on B1-receptors –> increases cAMP –> increases If and Ica (promoting depolarisation) so there is less time between APs generated

Question 6

how does the parasympathetic NS decrease heart rate?

Answer 6

via the muscarinic M2 receptors –> decrease cAMP –> increases Ik (prolongs repolarisation) so there is more time between APs generated

Question 7

what does electrical excitation of the cell from APs arising from the SA node induce?

Answer 7

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)

Question 8

what proportions of free Ca2+ are contributed by different channels in cardiac contraction?

Answer 8

20-25%: depolarisation-induced influx of Ca2+ current through L-type channels (outside cell)

75-80%: release of calcium through RyRs (inside cell)

Question 9

what does intracellular calcium allow?

Answer 9

formation of actin-myosin cross-bridges –> contraction

Question 10

what impact do b-receptors have on cardiac contraction?

Answer 10

positive impact

increased cAMP –> increased PKA –> promotion of contractile machinery + reduction of Ca entry back into the SR

Question 11

what mechanisms regulate myocardial oxygen supply and demand?

Answer 11

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

Question 12

which drugs influence heart rate?

Answer 12

• 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

Question 13

which drugs influence contractility?

Answer 13

• b-blockers: decrease contractility

- calcium-antagonists: decrease Ica (channel blocker –> decreases Ca entry –> decreases contractility)

Question 14

what are the 2 classes of calcium antagonists? give examples

Answer 14

• 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

Question 15

which drugs influence myocardial oxygen supply/demand?

Answer 15

• 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

Question 16

what 2 different effects of nitrates/potassium channel openers influence preload and afterload?

Answer 16

vasodilation = decreased afterload

venodilation = decreased preload

Question 17

what is angina?

Answer 17

chest pain usually driven by atherosclerosis (narrowing of coronary arteries)

Question 18

how is angina treated?

Answer 18

• 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

Question 19

what are the side effects of b-blockers?

Answer 19

• 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)

Question 20

what are the side effects of calcium channel blockers?

Answer 20

verpamil:

• bradycardia and AV block
• constipation (gut ca2+ channels affected)

dihydropyridines:

• ankle oedema (due to vasodilation)
• headache
• palpitations
• flush

Question 21

what types of rhythm disturbances are there?

Answer 21

arrhythmias:

• supraventricular arrhythmias can be atrial/nodal tissue
• ventricular arrhythmias
• complex (both)

arrhythmias either decrease (brady) or increase (tachy) HR

dysrhythmias

Question 22

what are the aims of treatment of rhythm disturbances and what does management involve?

Answer 22

aims of treatment: reduce sudden death, prevent stroke, alleviate symptoms

management: cardioversion, pacemakers, catheter ablation therapy, implantable defibrillators, drug therapy

Question 23

what is the vaughan-williams classification of anti-arrhythmic drugs?

Answer 23

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

Question 24

what is the problem with the vaughan-williams classification?

Answer 24

there is too much crossover for drugs to be properly classified so there is limited clinical significance

Question 25

what is adenosine?

Answer 25

a drug administered intravenously (fast effect) to terminate supraventricular tachyarrhythmias

it’s actions are short-lived

Question 26

what are adenosine’s actions?

Answer 26

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

Question 27

what is verapamil and how does it work?

Answer 27

an anti-arrhythmic drug that is a rate-limiting calcium channel blocker

it gets into nodal tissue, blocks calcium channels and decreases depolarisation

Question 28

what is amiodarone and what is it used to treat?

Answer 28

an anti-arrhythmic drug that has some beta-blocking effects and some calcium channel/potassium channel effect

used in supraventricular and ventricular tachyarrhythmias

Question 29

what are the adverse effects of amiodarone?

Answer 29

amiodarone has a long half life so has many side effects:

• photosensitive skin rashes
• hypo/hyperthyroidism
• pulmonary fibrosis

Question 30

what are re-entry rhythms?

Answer 30

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

Question 31

how do we overcome re-entry rhythm?

Answer 31

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

Question 32

what is digoxin and how does it work?

Answer 32

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

Question 33

what is a potential side effect of digoxin and why?

Answer 33

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

Question 34

what are the uses of digoxin?

Answer 34

AF and flutter (reduces conduction of electrical impulses within the AV node and fewer impulses reach the ventricles so ventricular rate falls)

Question 35

what are the adverse effects of digoxin?

Answer 35

• dysrhythmias

- conduction block (if there is too much vagal stimulation)

Question 36

why does hypokalaemia lower the threshold for digoxin toxicity?

Answer 36

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