Drugs and the CVS: The Heart

Question 1

Describe the process of AP generation in a the SAN.

Answer 1

SAN = primary pacemaker site within the heart

• These cells are characterized as having no true resting potential
• They instead generate regular, spontaneous action potentials

Three phases (phase 4, phase 0, phase 3):

PHASE 4 = the spontaneous depolarization (pacemaker potential) that triggers the AP once the membrane potential reaches the threshold

• At the end of repolarisation, when the membrane is hyperpolarised (very negative: -60mV), you get the opening of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels
  
  • This results in the slow movement of Na⁺ into the cell so the cells begins to spontaneously depolarise, thereby initiating phase 4
  • This inward Na⁺ current is known as the funny current (I_f)
• As the membrane potential reaches about -50mV, this stimulates another type of ion channel to open - transient T-type Ca²⁺ channel
  
  • This inward Ca²⁺ current is known as I_{Ca (T)}
  • ​​The influx of Ca²⁺ causes further depolarisation
• As the membrane potential reaches about -40mV, this stimulates another type of ion channel to open - long lasting L-type Ca²⁺ channel
  
  • This inward Ca²⁺ current is known as I_{Ca (L)}
  • The influx of Ca²⁺ through these channels as well causes even more depolarisation until the threshold to generate an AP is reached
    
    • The threshold is usually between -40 and -30mV

PHASE 0 = depolarization phase of the action potential

• Once the threshold potential is reached, an AP is generated
• The depolarisation part of the AP is primarily due to I_{Ca (L)}
• ICa (T) and I_f decline during this phase as their respective channels close
• NOTE:
  
  • The Ca²⁺ currents are relatively slow (i.e. Ca²⁺ movement though the ion channels is relatively slow)
  • There are no fast Na+ channels and currents operating in SA nodal cells

PHASE 3 = repolarisation

• K⁺ channels open so you get outward K⁺ currents known as I
• At the same time, the L-type Ca²⁺ channels become inactivated and close so you get decline in I_{Ca (L)}
• This results in repolarisation and as the K⁺ efflux continues you get hyperpolarisation

Question 2

Describe how the sympathetic nervous system impacts the electrical activity of the SAN.

Answer 2

Sympathetic stimulation:

• Increases cAMP to increase I_f
• Directly increases I_Ca
  
  • The ion channels involved in these currents open faster due to sympathetic stimulation
  • Therefore, threshold is reached quicker so you get a greater frequency of AP generation = faster HR

EXPLANATION (extra) - increase in I_f:

• The Na⁺ ion channels responsible for I_f open in response to both voltage (i.e. hyperpolarisation) and cAMP
• cAMP can directly bind to those ion channels, stimuating them to open at more +ve voltages
  
  • The SAN cells do not need to be as hyperpolarised, for the channels to open
• The beta 1 adrenoceptors on the SA nodal cells are GPCRs (G_s) so they stimulate adenylyl cyclase which catalyses the conversion of ATP to cAMP
• So stimulation of adrenoceptrors (GPCRs) would increase cAMP production inside the SAN cells

EXPLANATION (extra) - increase in I_Ca:

• The increase in I_Ca is also mediated by activation of the GPCRs which cause phosphorylation of the Ca²⁺ ion channels, stimulating them to open

Question 3

Describe how the parasympathetic nervous system impacts the electrical activity of the SAN.

Answer 3

Parasympathetic stimulation:

• Decreases cAMP to decrease I_f
  
  • _​This means that I_f can only be activated at more -ve voltages
  • So they can’t be activated as quickly as you have to wait for the more negative voltages to be reached
• Directly increases the I_K​
  
  • This leads to further hyperpolarisation

Therefore, threshold is reached more slowly so you get a decreased frequency of AP generation = slower HR

EXPLANATION (extra):

• Parasympathetic stimulation leads to release of ACh
• ACh binds to the M2 muscarinic receptors on the SA nodal cells which are also GPCRs but G_i
• Therefore, they inhibit adenylyl cylase and cAMP production which impacts I_f
• The GPCR activation also directly activates the K⁺ channels
  
  • NOTE: This I_K is not the same current you see in phase 3 of the normal SAN electrical activity

Question 4

Describe the process of excitation-contraction coupling in a cardiomyocyte.

Answer 4

• APs can spread from pacemaker cells to cardiomyocytes and from cardiomycyte to cardiomycocyte due to gap junctions
• Ions can travel through the gap junctions to the neighbouring cell resulting in depolarisation
• If that cell becomes depolarised enough for the threshold potential to be reached, it generates its own AP
• This is what it means by step 1

NOTE:

• 70% of the Ca²⁺ which binds to the tr

Question 5

What two things should be in balance in a normal individual?

Answer 5

Myocardial oxygen supply

Myocardial oxygen demand - determined by how much WORK is being done by the myocardium

Question 6

Which factors influence myocardial oxygen supply and demand?

Answer 6

Question 7

Explain the factors influencing myocardial oxygen demand.

Answer 7

Myocyte contraction = primary determinant of myocardial oxygen demand (i.e. how much work they are doing)

• ↑ H.R. = more contractions
• ↑ afterload or contractility = greater force of contraction
• ↑ preload = small ↑ in force of contraction
  
  • 100% ↑ ventricular volume would only ↑ F.O.C. by 25%

Question 8

State 3 drugs which influence heart rate and explain how they work.

Answer 8

• β-blockers – decrease I_f and I_Ca
  
  • Activation of the beta 1 adrenoceptor (GPCR) increases cAMP to increase I_f and directly increases I_Ca
• Calcium antagonists – decrease I_Ca
  
  • _​Calcium antagonists = calcium channel blockers
  • They work by binding to and blocking the calcium channels, thereby preventing Ca²⁺ entry into the cell
• Ivabradine – decrease I_f
  
  • Binds to the HCN channels to prevent the influx of Na⁺ into the cell that initiates the spontaneous depolarisation (pacemaker potential)

EXPLANATION (extra):

• Each of these drugs inhibit flow of ions into the cell
• Obviously you still get some ion inflow but this will be reduced
  
  • The drug won’t work on every single receptor/ion channel but will block enough to slow down the currents
• Therefore:
  
  • Depolarisation is slower
  • Threshold is reached more slowly
  • Decreased frequency of AP generation = slower HR

Reduced HR = reduced myocardial oxygen demand

Question 9

State two drugs influencing contractility.

Answer 9

• β-blockers – decrease contractility
  
  • Activation of the beta 1 adrenoceptor (GPCR) directly increases ICa
  • So with beta blockers you get reduced influx of Ca into the cell (reduced I_Ca)
• Calcium antagonists – decrease I_Ca

EXPLANATION (extra):

• Reduction of I_Ca reduces intracellular (cytoplasmic) Ca²⁺ concentration
  
  • This is because you need extracellular Ca²⁺ to stimulate Ca²⁺ release from SR - calcium-induced calcium release
• More Ca²⁺ that is available to bind to troponin so more actin-myosin cross bridges can form
  
  • More cross bridges = greater contractility (FOC)

Question 10

What are the two classes of calcium antagonists?

Answer 10

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)

The slight difference in structure between cardiac muscle and vascular smooth muscle Ca²⁺ channels means drugs can be more selective for one type than the other

• Non-rate slowing calcium antagonists are selective for the vascular Ca²⁺ channels so don’t have much of an effect on the heart

Question 11

What is a problem with using non-rate slowing calcium antagonists?

Answer 11

Due to their action on blocking vascular smooth muscle Ca²⁺ channels they can cause profound vasodilation

This could lead to a drop in blood pressure (↓ TPR) which can be detected by baroreceptors which in response trigger a REFLEX TACHYCARDIA

Question 12

State two drugs which influence the coronary blood flow and describe how they work.

Answer 12

• Organic nitrates
  
  • Organic nitrates are substrates for nitric oxide production
  • They enter the endothelial cells and promote NO production
  • The NO then diffuses into the vascular smooth muscle and causes VSMC relaxation → vasodilation
    
    • NO activates guanylyl cyclase
    • Gynaylyl cyclase catalyses the conversion of GTP to cGMP
    • cGMP upregulates (activates) protein kinase G
    • PKG activates K⁺ channels
    • K+ efflux → VSMC hyperpolarizes
• Potassium channel opener
  
  • ​Results in K⁺ efflux so the VSMCs become hyperpolarised
  • Therefore, the VSMCs relax → vasodilation

Vasodilation = increased coronary blood flow

Question 13

What effect do organic nitrates and potassium channel openers have on myocardial oxygen demand?

Answer 13

Both these drugs result in vasodilation

Vasodilation = ↓ TPR

↓ TPR reduces:

• Afterload
  
  • ​If the arteries near the heart are dilated, this means the blood pressure in them is reduced
  • Therefore, the heart does not have to work as hard to overcome that pressure (resistance)
• Preload
  
  • ​↓ TPR → ↓ EDV → ↓ preload
  • ↓ preload = reduced force of contraction - heart is not working as hard

Question 14

What can these drugs be used to treat?

Answer 14

Stable angina

• Angina is when you get chest pain due to myocardial oxygen demand exceeding supply
• The stable part refers to the pain coming on with exertion (e.g. exercise)
• This is generally due to atherosclerosis (narrowing of the arteries)

Treatment:

• Reduce myocardial oxygen demand by using drugs to reduce HR, contractility etc
• Increase myocardial oxygen supply by using drugs to dilate the coronary vessels to increase coronary blood flow
• NOTE: First line treatment - beta blockers or calcium antagonists

Question 15

What is heart failure?

Answer 15

The inability to match cardiac output with tissue perfusion demand

Question 16

Which conditions are beta blockers generally not suitable for?

Answer 16

Beta blockers would worsen these conditions

Heart failure

• Beta blockers reduce HR and contractility which would reduce CO
  
  • In patients with HF, CO is already insufficient, so reducing it even further would just exacerbate the problem
• Blockade of beta 2 receptors would lead to increased vascular resistance (vasoconstriction → ↑ TPR)
  
  • Beta 2 receptors more prominent in skeletal muscle and cutaneous blood vessels
  • Increased TPR is bad for patients with HF because the heart is already failing and having to work harder against the increased resistance would make the problem worse

Bradycardia

• Blockade of the beta 1 receptor slows down HR which could exacerbate the bradycardia
• You could get a heart block due to reduced atrioventricular conduction
  
  • Reduced conduction through AVN
  • AV nodal cells also have beta 1 receptors which stimulate electrical conduction through the heart
• ​NOTE: Bradycardia and AV block can also be side effects of beta blockers

Question 17

Which two beta blockers may be suitable for patients with heart failure? Explain why.

Answer 17

Both of these prevent a major increase in vascular resistance

• Pindolol
  
  • ​Pindolol is a non-selective beta blocker
    
    • So it has equal affinity for beta 1 and beta 2 receptors
  • However, pindol has intrinsic sympathomimetic activity (i.e. it is a partial agonist)
  • Therefore, it would result in some stimulation of beta 2 receptors so it would prevent a major increase in vascular resistance
• Carvediolol
  
  • ​Carvedilol is a mixed beta and alpha blocker
    
    • Blocks: beta 1, beta 2, alpha 1
  • Alpha 1 → vasoconstriction
    
    • Mainly present in mucous membranes, sphlancnic area
  • Blocking of alpha 1 receptors would prevent this vasoconstriction and hence prevent a major increase in vascular resistance

NOTE:

• Pindolol would have ISA on beta 1 receptors too
• But in HF the sympathetic drive to the heart would be high anyway to try and maximise CO
• So it would probably be having more of an antagonistic effect by blocking adrenaline/NA binding to those receptors

Question 18

What are some important side effects of beta blockers?

Answer 18

• Cold extremities
  
  • Due to blockade of beta 2 mediated cutaenous vasodilation in extremities
• Bronchoconstriction
  
  • Due to blockade of beta 2 receptors in airways which cause bronchodilation when stimulated
• Hypoglycaemia
  
  • Due to blockade of beta 2 receptors in the liver which cause glycogenesis and gluconeogenesis when stimulated

Question 19

What are some less important side effects of beta blockers?

Answer 19

• Fatigue
• Impotence (sexual dysfunction)
• Depression
• CNS effects (lipophilic agents) e.g. nightmares

Less important because RCTs question the validity of these side effects

Question 20

What are some side effects of calcium channel blockers?

Answer 20

Verapamil (rate slowing)

• Bradycardia and AV block
  
  • Due to reduction of I_Ca in the heart in both SAN (bradycardia) and AVN (AV block)
• Constipation
  
  • Seen in 25% of the patients
  • This is due to blocking of the Ca²⁺ channels in the smooth muscle of the gut → reduced gut motility

Dihydropyridine (non-rate slowing)

• These side effects are seen in 10-20% of the patients
• Ankle oedema
  
  • Vasodilation results in more blood flow towards ankles due to gravity
  • Therefore, you have a higher hydrostatic pressure in the capillaries there so more fluid leaks out of the capillaries → oedema
• Headache/flushing
  
  • Flushing = going red
  • Due to vasodilation
• Palpitations
  
  • Vasodilation results in reflex adrenergic activation (via baroreceptor pathway)
  • Palpitations = a noticeably rapid, strong, or irregular heartbeat
• NOTE: The ankle oedema and headache/flushing are also side effects of organic nitrates or K⁺ channel openers as these also cause vasodilation

Question 21

What are arrythmias? Describe how they are classified.

Answer 21

Arrythmia = abnormal heart rhythm

• May be associated with:
  
  • Decreased heart rate - bradyarrhythmias
  • Increased heart rate - tachyarrhythmias

Simple classification - based on site of origin:

• Supraventricular arrythmias
  
  • Usually occur in the atria
• Ventricular arrythmias
• Complex (supraventricular AND ventricular) arrythmias

Question 22

Explain the Vaughan-Williams classification and its limitations.

Question 23

Explain what re-entry is

Question 24

What type of arrythmia is adenosine used to treat? Explain its mechanism of action and its pharamkokinetics.

Answer 24

Used to terminate paroxysmal supraventricular tachycardia

• Paroxysmal = episodic condition with an abrupt onset and termination
• Usually due to re-entry current

Pharamokinetics:

• Administered IV
• Half-life: 20-30s
  
  • Therefore its actions are short-lived which makes it safer than verapamil

How it works:

Relevant to supraventricular tachycardia

• Adenosine binds to A1 receptors on SAN and AVN cells
  
  • These are GPCRs (G_i)
• Activation of the G_i protein decreases cAMP, which decreases I_f
• Activation of the GPCR pathway also directly activates the K⁺ channels so it hyperpolarises the cells
• This means it takes longer for the cells to reach threshold and generate an AP
• Reduced AP frequency = reduced firing rate by SAN and reduced conduction velocity by AVN
  
  • Essentially reduced HR
  • Explain re-entry then explain this
  • This gives the tissue longer to depolarise and leaves it in the repolarised state for longer

Also does this

• Adenosine binds to A2 receptors on vascular smooth muscle
  *