Drugs and the Cardiovascular System – The Heart

Question 1

What is the major store of calcium within the cardiomyocyte?

Answer 1

Sarcoplasmic reticulum

Question 2

Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?

Answer 2

Dihydropyridine receptors

Question 3

What happens to calcium once it has passed into the cell via dihydropyridine receptor channels?

Answer 3

It binds to ryanodine receptors on the SR + causes Ca2+ release from the SR

Question 4

How does calcium stimulate contraction?

Answer 4

It binds to troponin on Actin

Question 5

What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction?

Answer 5

Na+/Ca2+ exchanger

SERCA2a (sarcoendoplasmic reticulum calcium ATPase)

Question 6

What features of contraction is SERCA2a responsible for and why?

Answer 6

Rate of calcium removal: thus rate of cardiac muscle relaxation
Size of calcium store: thus affects contractility of the subsequent beat

Question 7

What are the 3 main channels that are responsible for the action potential in the sinoatrial node?

Answer 7

If channel: hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel (funny channel)
Ca2+ channel (Transient + Long-lasting)
K+ channel

Question 8

Describe how channels are responsible for the action potential of the sinoatrial node.

Answer 8

If channels open in hyperpolarised state, utilising cAMP, drive in Na+ to initiate depolarisation
Current starts to rise, stimulating the opening of Ca2+ channels (T then L), which further depolarises the membrane.
K+ channels are responsible for repolarisation

Question 9

What are beta adrenoceptors coupled with?

Answer 9

Adenylate cyclase: it increases cAMP, which is important in the opening of the If channel to begin depolarisation

Question 10

How does the parasympathetic nervous system affect heart rate and contractility?

Answer 10

It is negatively coupled with adenylate cyclase, thus decreases cAMP + interferes with funny currents, slows HR
Promotes K+ channel opening

Question 11

What are the determinants of myocardial oxygen supply?

Answer 11

Arterial oxygen content

Coronary blood flow

Question 12

What are the determinants of myocardial oxygen demand (work)?

Answer 12

Heart rate
Contractility
Preload
Afterload

Question 13

What effect do beta-blockers and calcium channel blockers have on the channels responsible for the SA node action potential?

Answer 13

B-blockers decrease If + Ca2+ channel activity
Ca2+ channel blockers decrease Ca2+ channel activity
Thus both decrease HR + contractility

Question 14

Name a drug that decreases If activity.

Answer 14

Ivabradine (blocks the If channel)

Question 15

What effect does Ivabradine have on contractility?

Answer 15

No effect on contractility because it doesn’t affect the Ca2+ channels

Question 16

What are the 2 types of calcium channel blocker? Name the drugs in each category including their drug class.

Answer 16

Rate slowing  
Phenylalkylamines– Verapamil 
Benzothiazepines– Diltiazem 
Non-rate slowing  
Dihydropyridines– Amlodipine

Question 17

What is a consequence of non-rate slowing calcium channel blockers?

Answer 17

Reflex tachycardia due to profound vasodilation

Question 18

How do organic nitrates cause vasodilation?

Answer 18

Organic nitrates are substrates for NO production
NO diffuses into smooth muscle + causes relaxation by activating guanylate cyclase that produces cGMP
cGMP also causes opening of K+ channels + K+ efflux, resulting in hyperpolarisation

Question 19

How do potassium channel openers work?

Answer 19

They open K+ channels + hyperpolarise the smooth muscle so it is less likely to contract

Question 20

How do vasodilation and venodilation reduce myocardial oxygen demand?

Answer 20

Reduce pressure against which the heart is pumping (reduce afterload)
Reduce venous return to the heart (reduce preload)

Question 21

State 5 unwanted effects of beta-blockers.

Answer 21

Bradycardia  
Hypotension  
Hypoglycaemia in diabetics on insulin  
Cold extremities (loss of beta-2 receptor mediated cutaneous vasodilation) 
Bronchoconstriction

Question 22

Under what circumstance must caution be taken when giving beta-blockers?

Answer 22

Heart failure (CO already reduced)
B-Blockers further reduce CO + increase vascular resistance (B2 receptors are dilating receptors, so less vasodilation occurs)
Asthmatics: B2 blockade in lungs worsens attacks
Diabetics: Hypoglycaemia masked

Question 23

What are the side effects of verapamil?

Answer 23

Bradycardia + AV block (Ca2+ channel block)

Constipation (Gut Ca2+ channel block)

Question 24

What are the side effects of dihydropyridines?

Answer 24

Ankle oedema (vasodilation increases pressure on capillary vessels)
Headaches/flushing (vasodilation)
Palpitations (reflex sympathetic response)

Question 25

What is a simple classification of arrhythmias based on?

Answer 25

Point of origin | Supraventricular, Ventricular + Complex

Question 26

What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?

Answer 26

``` Vaughan-Williams classification I: Na+ channel blockers II: B-blockers III: prolongation of repolarisation (mainly due to K+ channel blockade) IV: Ca2+ channel blockers ```

Question 27

What is adenosine used to treat?

Answer 27

``` To terminate supraventricular tachyarrhythmias Short lived (20-30s), thus quite safe ```

Question 28

How does adenosine work?

Answer 28

Binds to A1 receptors on nodal cells Inhibitory effect on adenylate cyclase, inhibits cAMP production + funny currents, reduces depolarisation (tissue has longer time to repolarise) Binds to A2 receptors on vascular smooth muscle Increases cAMP, promotes relaxation + vasodilation

Question 29

What is verapamil used to treat?

Answer 29

Supraventricular arrythmias

Question 30

What is the target of verapamil and how does it work?

Answer 30

L-type calcium channel | Reducing Ca2+ entry means speed with which the tissue depolarises is reduced

Question 31

What is amiodarone used to treat?

Answer 31

Supraventricular tachyarrhythmia | Ventricular tachyarrhythmia

Question 32

How does amiodarone work?

Answer 32

By blocking many ion channels Main effect through K+ channel blockade This prolongs repolarisation, thus prolonging the time during which the tissue can’t depolarise

Question 33

Describe re-entry.

Answer 33

In damaged cardiac tissue signal passes down 1 branch of conductive tissue, but can't pass down another. When signal passes through a third branch (usually the 2 signals would meet + cancel out) the signal goes back up 2nd branch + reactivates the tissue Causes premature contraction (if muscle in ready state)

Question 34

What is the target of cardiac glycosides like digoxin?

Answer 34

Na+/K+ ATPase

Question 35

How does digoxin work and what are its effects on the heart?

Answer 35

Blockage of Na+/K+ ATPase causes accumulation of Na+ in the cell Excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular Ca2+ concentration Causes inotropic effect (increases force of contraction) Also causes vagal stimulation which increases refractory period + reduces rate of contraction through AVN

Question 36

What is an important factor to consider before starting treatment with digoxin?

Answer 36

Hypokalaemia Digoxin binds to the K+ binding site on the extracellular component of Na+/K+ ATPase so it competes with K+ for the binding site If hypokalaemic, there is less competition for digoxin + so the effects of digoxin are exaggerated

Question 37

What is digoxin used to treat?

Answer 37

Atrial fibrillation | Atrial flutter

Question 38

What is an adverse effect of digoxin?

Answer 38

Dysrrhythmia

Question 39

What effect does the sympathetic system have on SA nodal cells?

Answer 39

Increases cAMP, increases opening of If + Ca2+ channels Increased chance of depolarisation Increased HR

Question 40

Why is afterload a determinant of myocardial oxygen demand?

Answer 40

The higher the afterload, the harder the heart has to contract to eject blood from the heart

Question 41

Why is preload a determinant of myocardial oxygen demand?

Answer 41

Due to Starlings law | If increased volume returned to heart, heart will have higher stroke volume + have to work harder

Question 42

How do B blockers help decrease heart rate in angina?

Answer 42

Sympathetic nervous system exerts its effects via B1 receptors in heart Blockade stops sympathetic stimulation, so stops the opening of If + Ca2+ channels

Question 43

What B blocker may be appropriate to use in heart failure patients with angina and why?

Answer 43

Pindolol Has intrinsic sympathetic activity at low sympathetic levels Thus in normal daily life it helps HF B blockade prevents pain during exercise

Question 44

Why should B-blocker usage in heart block patients or those with conduction problems be avoided?

Answer 44

B-blockers cause bradycardia, exacerbating decreased conduction through AVN

Question 45

Which B blocker drugs can be used to attempt to prevent increased vascular resistance?

Answer 45

Mixed A-B- Blockers | Alpha blockade causes more dilation than constriction

Question 46

Name 2 types of arrhythmia

Answer 46

Bradyarrthmia (decreased HR) | Tachyarrythmia (increased HR)

Question 47

Why must Amiodarone be used with caution?

Answer 47

It accumulates in the body | Serious side effects (photosensitive skin rashes, hypo/ hyperthyroidism, pulmonary fibrosis)

Question 48

Why must potassium levels be monitored after digoxin administration?

Answer 48

Hypokalaemia lowers threshold for digoxin toxicity Digoxin binds to same site as K+ So if blood K+ falls, digoxin has easier access to target + more powerful effect Side effects increase