Drugs of the Cardiovascular system: the Heart

Question 1

What channels are important in regulation of sinoatrial potential?

Answer 1

If - hyperpolarization-activated cyclic nucleotide-gated (HCN) channels

Ica - Transient T-type Ca++ channel or Long lasting L-type Ca ++ channel

Ik - Potassium K+ channels

Question 2

What are the cells within the SA node?

Answer 2

• primary pacemaker site within the heart

- no true resting potential

Question 3

What is different about SA node cells compare to other non-pacemaker action potentials in the heart?

Answer 3

• there are no fast Na+ channels and currrents operating in the SA node
• only HCN channels

Question 4

What is the job of the If channel?

Answer 4

• it is a sodium channel
• allows the action potential to propagate
• opens at the most negative potential and causes a certain amount of depolarisation before calcium channels open

Question 5

What two forms do calcium channels come in?

Answer 5

• transient

- long-lasting

Question 6

What is the role of potassium channels?

Answer 6

-initiate repolarisation

Question 7

What mechanism is important in opening if channels?

Answer 7

-beta adrenoceptors are linked to adenyl cyclase and lead to an increase in cAMP

Question 8

What does sympathetic activity do?

Answer 8

-increases cAMP and therefore Increased activation of If and Ica channels - increase of Ca

Question 9

What does parasympathetic activity do?

Answer 9

• negatively coupled with adenyl cyclase
• promotes the opening of potassium channels
• prolonged repolarisation

Question 10

What is stage 4 of the SA node potential responsible for?

Answer 10

-spontaneous depolarization that triggers the action potential

Question 11

What is the mechanism of contracting heart muscle?

Answer 11

• action potential enters from adjacent cells
• voltage-gated Ca++ channels open, Ca++ enters cells
• Ca++ induces Ca++ release through ryanodine receptor channels
• -local release causes a ca++ spark
• summed ca++ sparks creates a Ca++ signal
• Ca++ ions bind to troponin to initiate contraction

Question 12

What is the mechanism for relaxation of heart muscle?

Answer 12

• relaxation occurs when Ca++ unbinds from troponin
• Ca++ is pumped back into the SR for storage
• Ca++ is exchanged with Na+
• Na+ gradient maintained with Na-K+-ATPase pump

Question 13

What factors determine the myocardial oxygen supply to the heart?

Answer 13

• coronary blood flow

- arterial O2 content

Question 14

What 4 factors determine the myocardial oxygen demand from the heart?

Answer 14

• HR
• contractility
• afterload
• preload

Question 15

What is the primary determinant of myocardial oxygen demand?

Answer 15

-myocyte contraction

• increased HR leads to increased contractility
• increased afterload or contractility = greater force of contraction
• increased preload = small increase in force of contraction

ALL THESE CONTRIBUTE TO INCREASED WORK

Question 16

Which drugs decrease HR?

Answer 16

• beta blockers ( decreases If and Ica)
• calcium antagonists (decrease Ica)
• Ivabradine (decrease If)

Question 17

Which drugs decrease contractility?

Answer 17

• beta blockers (decrease contractility)

- calcium antagonists (decrease Ica)

Question 18

What are the two classes of calcium antagonists?

Answer 18

• rate slowing (cardiac and smooth muscle actions)

- non-rate slowing (smooth muscle actions - more potent)

Question 19

What are the examples of calcium antagonists?

Answer 19

-rate slowing

Phenylalkylamines e.g. Verapamil
Benzothiazepines e.g. Diltiazem

-Non-rate slowing

Dihydropyridines e.g. amlodipine

Question 20

What can non-rate slowing drugs lead to?

Answer 20

• no direct effect on the heart
• profound dilation can lead to reflex tachycardia
• reduced peripheral pressure triggers baroreceptors to speed up HR

Question 21

What types of drugs influence myocardial oxygen supply/demand?

Answer 21

• organic nitrates

- potassium channel openers

Question 22

What effects do the organic nitrates and potassium channels openers have?

Answer 22

• increase coronary blood flow
• vasodilation =decreased afterload
• venodilation =decreased preload

LESS WORK

Question 23

How does NO work on vascular smooth muscle?

Answer 23

-diffuses into vascular smooth muscle and causes relaxation by activating guanylate cyclase

Question 24

What is the treatment plan for angina?

Answer 24

• offer either a beta blocker or calcium channel blocker as first line treatment
• switch to the other option if the person cannot tolerate the first
• if the person’s symptoms are not controlled by one try a combination of the two
• if this is still not working try monotherapy with one of the following : long acting nitrate, ivabradine, nicorandil

Question 25

What are the side effects of beta blockers?

Answer 25

- worsening heart failure ( CO reduction and increased vascular resistance) - Bradycardia ( heart block and decreased conduction through AV node) - cold extremities (loss of B2 receptor mediated cutaneous vasodilation in extremities) - fatigue - impotence - depression - CNS effects e.g. nightmares

Question 26

What other conditions do you have to be careful about before giving beta blockers?

Answer 26

- asthmatic- inhibits B2 action of bronchodilation | - diabetes - they interfere with actions of the liver masking hypoglycaemia

Question 27

What are the side effects of verapamil?

Answer 27

- bradycardia and AV block | - constipation

Question 28

What are the side effects of dihydropyridines?

Answer 28

- ankle oedema - headache/ flushing - palpitations due to vasodilation/reflex adrenergic activation

Question 29

What are the aims of rhythm disturbance treatment?

Answer 29

- reduce sudden death - prevent stroke - alleviate symptoms

Question 30

How are arrhythmias classed?

Answer 30

based on location - supraventricular - ventricular - complex (combination of the two)

Question 31

What is the Vaughan-Williams classification of anti-arrhythmic drugs?

Answer 31

``` class I - sodium channel blockade class II - beta adrenergic blockade class III - prolongation of repolarisation (membrane stabilisation mainly due to potassium channel blockade) class IV - calcium channel blockade ```

Question 32

What are the limitations of Vaughan -Williams classification?

Answer 32

- rare that a drug only fits into one category | - clinical significance is limites

Question 33

What are the uses and mechanism of action of adenosine?

Answer 33

- IV to terminate supraventricular tachyarrhythmias - short lived - safer than verapamil binds to A1 receptors, cAMP reduces and so reduced contraction

Question 34

What are the uses and mechanism of action of verapamil?

Answer 34

- reduction of ventricular responsiveness to atrial arrhythmias - depresses SA automaticity and subsequent AV node conduction

Question 35

What are the uses, mechanism of action and side effects of amiodarone?

Answer 35

- superventricular and ventricular tachyarrhythmias, often due to re-entry - complex action involving multiple ion channel block it accumulates in the body and leads to photosensitive skin rashes, hypo/hyperthyroidism, pulmonary fibrosis

Question 36

What are the uses and mechanism of action of digoxin?

Answer 36

-atrial fibrillation and flutter - inhibition of the Na-K-ATPase pump, results in increased intracellular Ca++ and causes a positive inotrophic effects - central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node - side effects - dysrhythmias

Question 37

why does hypokalaemia lower the threshold for digoxin toxicity?

Answer 37

-digoxin binding site is the same as the potassium binding site, if potassium falls digoxin is more likely and available to bind to that target