Drugs and the heart

Question 1

Describe what this graph shows in regards the SA node - mentioning the channels involved and also go into the full mechanism of myocardial contractility

Answer 1

1. At around - 60mV, there is spontaneous activation of the cardiac myocytes
2. I_f channel opens, allowing Na⁺ influx
3. This causes VGCC influx via I_{ca (T)} temporarily
4. Then VGCC influx major upstroke via I_{ca (L)} depolarisation
5. Once the potential reaches a threshold of 0mV, I_k channels open, repolarisation phase occurs after this until it goes back down to -60mV
6. Note that another action potential cannot be activated within the SAN during the repolarisation phase
7. Once its finished, the process repeats

Question 2

Describe the mechanisms of how the sympathetic and parasympathetic arms of the nervous system can impact the SAN activity and thus heart chronotropy

Answer 2

• Sympathetic: Increases cAMP → thus increases the I_f and I_ca (t and l - type) activity - thus promotes depolarisation
• Parasympathetic: Decreases cAMP → thus increases the I_K activity - thus promotes repolarisation - preventing another action potential arriving at that time

Question 3

Describe the step-wise mechanism of myocardial contraction

Answer 3

1. Action potential from SAN / adjacent cell enters, causing membrane depolarisation
2. This membrane depolarisation promotes gating of Ca2+ channels, which open and cause a small release of Ca2+ into the cytoplasm
3. Then there is Ca2+ induced Ca2+ release from sarcoplasmic reticulum via Ryr receptors
4. The Ca2+ then binds to troponin in the muscle fibres to initiate contraction……(skip over muscle contraction steps)
5. Eventually Ca2+ unbinds troponin, ending contraction
6. The Ca2+ then is stored in the sarcoplasmic reticulum again OR it is effluxed from the cardiac myocyte via Ca2+ / Na+ exchanger
7. The efflux of Ca2+ and influx of Na+ necessitates a constant high extracellular concentration of Na⁺, the Na+ / K+ ATPase maintains this balance by effluxing the Na⁺ influxed by the Ca²⁺ / Na⁺ exchanger
8. Another action potential (another depolarising phase) cannot occur during the repolarisation phase of the SAN, after which the cycle repeats

Question 4

Regarding the balance of myocardial oxygen demand and supply, what 4 factors will impact myocardial work and thus oxygen demand to the myocardial tissue, and how?

Answer 4

1. ↑ HR - obvious work increase
2. ↑ Contractility - obvious work increase
3. ↑ Afterload - requires a greater force of contraction to overcome - thus work increase
4. ↑ Preload - small increase in force of contraction thus work

Question 5

Give 3 drugs that influence heart rate and how they work to do this

Answer 5

1. ​Beta-blockers: Blocks the SNS action on I_f and I_ca via Beta-1 receptors which otherwise promotes depolarisation (so inhibits depolarisation) thereby lowering HR
2. Calcium antagonists: Decrease I_Ca (channel blocker → decreased Ca entry → decreased contractility)
3. Ivabradine: Targets I_f channels specifically to decrease opening → impacts spontaneous generation of APs → prolongs the distance between successive action potentials

Question 6

Give 2 drugs that decrease heart contractility and how they do this

Answer 6

1. ​Beta-blockers: Blocks the SNS action on I_f and I_ca via Beta-1 receptors which otherwise promotes depolarisation (so inhibits depolarisation) thereby lowering HR
2. Calcium antagonists: Decrease I_Ca (channel blocker → decreased Ca entry → decreased contractility)

Question 7

1) What are the 2 types of calcium antagonists and what do these classifications mean?
2) Give example drug types and specific drug names belonging to both categories

Answer 7

1)

1. Rate-slowing calcium antagonists - impact both cardiac and smooth muscle
2. Non-rate slowing calcium antagonists - impact only smooth muscle

2)

Rate-slowing calcium antagonists:

• Phenylalkylamines (e.g. Verapamil)
• Benzothiazepines (e.g. Diltiazem)

Non-rate slowing calcium antagonists:

• Dihydropyridines (e.g. amlodipine)

Question 8

How do organic nitrates work, and how do they impact myocardial demand and supply?

Answer 8

• Increase amount of organic NO available
• NO increases the amount of cGMP → promotion of smooth muscle relaxation → dilation and improved blood flow
• NO also acts as a K⁺ channel opener → induces hyperpolarisation via K⁺ channels
• Therefore they increase coronary blood flow
• Vasodilation thus lowers afterload
• Venodilation thus lowers preload
• Thereby increases myocardial supply and lowers myocardial demand

Question 9

How do K⁺ channel openers work, and how do they impact myocardial demand and supply?

Answer 9

• Direct K⁺ channel opening → potassium efflux → prolonged hyperpolarisation
• Increased coronary blood flow - greater myocardial oxygen supply
• Vasodilation → lowers afterload - less myocardial oxygen demand
• Venodilation → lowers preload - less myocardial oxygen demand

Question 10

What happens in angina - what are the 2 types and what happens in each of these, start with the common symptom of both?

Answer 10

• Chest pain
• Stable angina is a predictable pain on exertion and is due to a fixed narrowing of the coronary vessels by atheroma
• Unstable angina is characterised by pain following less and less exertion culminating in pain on resting. This is usually associated with a thrombus (derived from an atheromatous plaque) partially occluding the vessel(s)

Question 11

How is angina treated?

Answer 11

Main 3 given are:

1. Beta-blockers
2. Calcium antagonists
3. Ivabradine

For symptomatic treatment:

• Nitrate

IF intolerant to the other drugs:

• K⁺ channel openers

Question 12

What are the side effects of Beta-blockers and explain why these might occur where possible?

Answer 12

• Worsening of HF (heart failure) - if you have both angina and HF, be careful about giving beta-blockers because even though they relieve the angina, these reduce cardiac output so worsen the heart failure
• Bradycardia - due to less conduction through AVN
• Bronchoconstriction - due to partial Beta-2 selectivity - NEVER give to asthmatics
• Hypoglycaemia - by blocking sympathetic glycogenolysis and gluconeogenesis via beta receptors
• Cold extremities / worsening of peripheral arteries disease - due to blocking of Beta-2 mediated vasoconstriction in skeletal muscle vessels
• Fatigue
• Impotence
• Depression
• CNS effects

Question 13

What are the possible side effects of rate-limiting calcium channel blockers e.g. Verapamil?

Answer 13

• Bradycardia and AVN block
• Constipation - affects smooth muscle in gut

Question 14

What are the possible side effects of non-rate-limiting calcium channel blockers e.g. Dihydropiridines?

Answer 14

• Ankle oedema due to vasodilation
• Palpitation due to reflex tachycardia in response to vasodilation

Question 15

Give 3 different arrythmia classifications and for each give some drugs that may cause this

Answer 15

1. Supraventricular arrythmias (e.g. amiodarones and verapamil)
2. Ventricular arrythmias (e.g. flecainide, lidocaine)
3. Complex (supraventricular and ventricular) - (e.g. disopyramide)

Question 16

Describe the Vaughan-Williams Classifications of anti-arrythmics as shown by this graph and what the mechanisms of drugs within each class uses - class I, Ia, II, III, IV

Answer 16

• CLASS I: Sodium channel blockade
• CLASS II: Beta-adrenergic blockade
• CLASS III / Ia: prolongation of repolarisation (membrane stabilisation, mainly due to potassium channel blockade)
• CLASS IV: Calcium channel blockade

Question 17

Describe the mechanisms of how adenosine is useful as an anti-arrythmic, and mention what class of arrythmia it is useful in treating

Answer 17

• SVT (supra-ventricular tachycardia)
• Acts on A₂ receptors on VSM → Gs-linked receptor → increases cAMP via adenylate cyclase → activates PKA → opens K⁺ ATPase channels → more K⁺ efflux → more hyperpolarisation → relaxation of heart tissue
• Acts on A₁ receptors on nodal tissue → G_i-linked receptor → decreases cAMP via adenylate cyclase → inhibits calcium channel opening and prolonged K⁺ channel opening so less depolarisation and longer repolarisation (so takes longer to depolarise again) - thus normalises tachyarrythmia to sinus rhythm

Question 18

Discuss the use of Verapamil as an anti-arrythmic and the mechanism of how it carries out this function

Answer 18

• Use - reduction of ventricular responsiveness to atrial arrhythmias
• Depresses SA automaticity and subsequent AV node conduction (i.e. impair SAN activity and thus AVN conduction)
• Verapamil is a rate-limiting calcium channel blocker. They get into the nodal tissue, block calcium channels and therefore decrease depolarisation

Question 19

1) What type of arrythmias is amiodarone useful in treating, and in particular, which type?
2) What is the mechanism(s) by which amiodarone works, and describe how it works to combat the type of arrythmia mentioned in the first part of the question?

Answer 19

1) Both supraventricular and ventricular arrythmias, but in particular, re-entry arrythmias

2)

• Has many actions including beta-blocking / calcium channel blocking / K⁺ channel blockade
• Primary action is K⁺ channel blockade though
• By blocking the K⁺ channel, it prolongs the repolarisation phase of myocardial contraction, thereby prolonging the effective refractory period (another action potential upstroke can’t be initiated in this time)
• By both slowing myocardial contractility and by prolonging the effective refractory period, it is useful in abolishing re-entry arrythmias

Question 20

Outline what happens in a re-entry rhythm arrythmia

Answer 20

• Imagine a forking purkinje fibre with a common route in between them (see picture)
• As waves of depolarisation travel down they will travel apart or cancel each other out to prevent retrograde transport
• But if there is a uniderectional block, a retrograde current may occur which can then form a sort of loop which constitutes a re-entry arrythmia (see diagram below)
• So there will be constant depolarisation / maintained depolarisation yet an absence of a clear repolarisation phase - disrupted repolarisation

Question 21

1) What is the type of arrythmia that cardiac glycosides such as digoxin are useful in treating?
2) What is the mechanism by which digoxin is useful as an anti-arrythmic?

Answer 21

1)

Atrial fibrillation

2)

• IT BOTH DECREASES HR AND INCREASES F.O.C. by 2 methods:

1. Stimulates vagus → increases refractory period and reduced rate of conduction through the AVN - eases tachyarrythmia

2. Increases F.O.C. (force of contraction) by…

• Inhibits the Na⁺ / K⁺ ATPase channel in the cardiac myocyte
• Thus there is less K⁺ influx and, therefore more importantly, less Na⁺ efflux
• So there is more Na⁺ available within the cell to be effluxed in exchange for Ca²⁺ influx by the Ca²⁺ / Na⁺ exchanger
• So ULTIMATELY more Ca²⁺ available intracellularly so more can bind troponin and therefore the force of contraction increases

Question 22

Why must you be careful in prescribing digoxin to people who are hypokalaemic?

Answer 22

Because digoxin competes with K⁺ globally and so if you are hypokalaemic, the effects of digoxin will aggravate the hypokalaemia. So hypokalaemia lowers the toxicity threshold for digoxin

Question 23

How might non-rate limiting calcium channel blockers cause tachyarrythmias?

Answer 23

• Vasodilation causes baroreceptor mediated reflex tachycardia (to preserve CO)

Question 24

What type of beta-blocker is Pindolol, and what special property does it have?

Answer 24

• Non-selective beta-blocker
• Intrinsic sympathomimetic activity (ISA)

Question 25

What type of adrenergic antagonist is Carvedilol and what effects will it have?

Answer 25

• Mixed alpha and beta
• The alpha-1 antagonism will give it some vasodilatory properties