lecture 4&5: drugs affecting the heart

Question 1

How is cardiac cross bridge cycling initiated?

Answer 1

Action potential propagates down the T tubules causing voltage gated sodium and calcium channels to open.

This causes Ca release from the SR allowing Ca to be available for cross bridge cycling.

For the heart to relax, the Ca concentration must be suddenly reduced to its resting state

Question 2

What regulates calcium levels in the heart?

Answer 2

L type calcium channels
ATPases on the membrane
Na/Ca exchanger
Mitochondria

Question 3

How is sodium maintained in the heart?

Answer 3

sodium potassium pumps

Question 4

What are the three main groups of drugs affecting cardiac function?

Answer 4

Drugs affecting myocardial cells directly
drugs affecting myocardial cells indirectly

calcium antagonists (which affect calcium cycling directly)

Question 5

Which drugs affect myocardial cells directly?

Answer 5

autonomic neurotransmitters and related drugs
antidysarrhthmic drugs
cardiac glcosides and aother inotropic drugs
miscellaneous drugs and endogenous substances such as doxorubicin.

Question 6

What drugs affect myocardial cells indirectly?

Answer 6

some antianginal drugs like nitrates
diuretics
ACE inhibitors
hormones, autocrine and paracrine

Question 7

What are calcium antagonists?

Answer 7

drugs which affect cardiac function by direct action on mycardial cells as well as indirectly by relaxing the arterioles

Question 8

What are the main electrophysical properties of the heart?

Answer 8

Opening of V gated Na channels preceding the Ca current.

Cardiac myocytes have a pace maker activity assoc with the SA node. This pacemaker current is associated with a slow inward flux of Ca responsible for the initiation of the AP

The cardiac action potential is much longer in comparison to neurons as the heart must have enough time to relax to fill with blood to pump.

Question 9

Why is the SA node the pacemaker potential?

Answer 9

the rate these cells depolarise is faster than any other cell in the heart

Question 10

How do arrhythmias occur?

Answer 10

when, for some reason the SA node does not depolarise or initiate myogenic activity, other cells will take over

Question 11

What is the conduction pathway of the heart?

Answer 11

SA node cells branch in to the AV node. The AP is then propagated by the bundle of his and then to the left and right atrium via the purkinje fibres which allow the AP to spread sequentially through the heart, crucial for proper function of the heart

Question 12

What are the main phases of the pacemaker potential?

Answer 12

first phase (actually termed phase 4:) 
gradual depolarisation during systole

t type Ca channels open at slightly lower voltage than l type Ca channels (these are also opened but are overtaken by the t type channels until a threshold is reached.)

Potassium currents open during repolarisation.

Question 13

What affects the initiation of the pacemaker potential?

Answer 13

sympathetic nervous system,
autonomic nervous system,
hormones
drugs

Question 14

What are the differences of the ventricular action potential compared to the pacemaker action potential?

Answer 14

Ventricular: massive Na current on depolarisation. followed by slight repolarisation before a long plateau phase is reached,

Question 15

What are the main phases of the ventricular action potential?

Answer 15

Phase 0: rapid Na influx once pacemaker potential reaches 60mV. After a few seconds, Na channels inactivate and remain closed

Phase 1: partial repolarisation as Na current is inactivated

Phase 2: plateau phase due to the slow inward Ca current. K channels stay closed so there is no rectifying outward K channel opening.

Phase 3: repolarisation due to a slow delayed potassium channel opening. Other potassium channels also open and the membrane potential returns to resting levels

Phase 4: Pace maker potential occurs. This is most rapid in the SA node. Slow Na and Ca inward currents and reduced outward currents cause a gradual depolarisation until the firing threshold of 60mV is reached

Question 16

What is an etopic pacemaker activity?

Answer 16

disturbances in the cardiac rhythm where, if it occurs in the SA node, other cardiac tissues can take over. This provides a safety mechanism in case the SA node fails but can also contribute to tachyarrhthmias

Question 17

What are possible causes of etopic pacemaker activity?

Answer 17

SNS and partial depolarisation occurring with ischaemia.

If there are ventricular arrhythmias they are pretty lethal except for etopic beats.

Question 18

How are arrhythmias categorised?

Answer 18

rate, mechanism, and site of origin

Question 19

What is rate?

Answer 19

whether the heart beat is increased e.g. tachycardia or bradycardia

Question 20

What is mechanism?

Answer 20

whether or not ther eare automatic changes in the rate of the heart, renetry of the action potential or fibrillation.

Question 21

What is site or origin?

Answer 21

where the arrhythmia is occurring e.g. atrial, junctional or ventricular portions of the heart

Question 22

What causes arrhythmias?

Answer 22

congenital (e.g. long QT syndrome)
external factors like drug and stress
diseases e.g. in fever, high blood pressure,

Question 23

how do class I drugs work?

Answer 23

Affect rapid depolarisation phase and block the voltage sensitive sodium channels via a use dependent block.

The drugs bind most strongly when the subunits are in an open or refractory state.

Question 24

What is a use dependent block?

Answer 24

Where the block occurs at a phase which slows the heart rate due to channels being unavailable for excitation when the drug is bound

Question 25

What are the three groups of class 1 drugs?

Answer 25

class 1a: quinidine
class 1b: lidocaine
class 1c: flecainide

Question 26

What is the mechanism of class 1a drugs?

Answer 26

Moderate sodium channel blockade which increases duration of the action potential and decreases the rate of the rapid depolarisation phase.

Also increases early refractive period

Question 27

What is the mechanism of 1b drugs?

Answer 27

Blocks the sodium channels weakly causing a reduced QT duration and decreases early refractive period

Question 28

What is the mechanism of 1c drugs?

Answer 28

blocks the sodium channels strongly to slow the rate of depolarisation, increase QRS complex with no real effect on the early refractory period

Question 29

When are class 1b drugs used?

Answer 29

1b = fast dissociation so is used to prevent premature heart beats e.g. in early after depolarisation where you have some ischaemic tissue causing influx or depolarisation during the AP

Question 30

When are class 1c drugs used?

Answer 30

its slow dissociation nature is good for preventing the delay after depolarisations and for prevnting the diastolic interval between the beats.

Question 31

What are class 2 drugs?

Answer 31

beta blockers

Increases calcium current and the plateau phase as well as affecting pacemaker currents e.g. metoprolol, propanolol

Question 32

What is the mechanism of class II drugs?

Answer 32

blocks the beat agonist effects as sympathetic activity is essential for conduction of the action potential through the AV node.

Inhibits cAMP and intracellular calcium levels

Question 33

What is the role of beta adrenoreceptors?

Answer 33

Beta adrenoreceptors increase the refractive period of the AV node to slow the depolarisation as it passes from the atria, through AV node and to the ventricles, thus effectively slowing the heart rate.

Question 34

When are class 2 drugs used?

Answer 34

preventing etopic beats or etopic pacemaker activity where there is a full AP occurring outside the pacemaker rhythm

Question 35

What are class 3 drugs?

Answer 35

potassium channel blockers e.g. amiodarone and sotalol

Question 36

What is the mechanism of class 3 drugs?

Answer 36

they block repolarisation, prolonging the action potential and can have more than one mechanism of action.

They prolong the QT interval by blocking the repolarisation (or the K channels involved in this)

Question 37

When are class 3 drugs used?

Answer 37

in dysarrhythmias however they can slow and prolong the action potential to a point where you get drug induced QT syndrome

Question 38

What are class 4 drugs?

Answer 38

calcium channel blockers which affect the plateau phase of the action potentials e.g. verapamil and diltiazem.

Question 39

What is the mechanism of class 4 drugs?

Answer 39

These block the l type Ca channels during the plateau phase.
Drugs slow the induction of the sinoatrial and atrioventricular node. Blocking the Ca channels shortens the plateau phase.

Question 40

What are dihydropyrridine channels?

Answer 40

calcium channels ( l-type) which are mostly found in the vasculature.

Question 41

What are the unclassified drugs?

Answer 41

adenosine and digoxin.

Question 42

How does adenosine work?

Answer 42

Adenosine is produced endogenously and acts on an A1 receptor which linked to the KACh channel on the AV node.
It hyperpolarises conducting tissues and slows the rate of the pacemaker potential so it is used via IV to treat supraventricular tachycardia.

Question 43

What is digoxin and how does it work?

Answer 43

Digoxin is a cardiac glycoside. These increase vagal activity and inhibit the Na/K Pump. They bind to the extracellular aspect of the α subunit to slow AV conduction which can thus terminate supra ventricular tachycardia.

Question 44

How does glucagon increase myocardial contractility?

Answer 44

It increases cAMP synthesis.

It has been used in patients with acute cardiac dysfunction due to beta blocker overdose.

Question 45

Why do phosphodiesterase type III inhibitors increase myocardial contractility?

Answer 45

Phosphodiesterase is the enzyme responsible for degrading cAMP. Thus inhibiting its degradation increases cAMP levels and increases contractility. E.g. Amrinone, milrinone.

Question 46

What are the two main classes of angina drugs?

Answer 46

Organic nitrates
Calcium antagonists

These are vasodilators and either improve perfusion of the myocardium or reduce its metabolic demand.

Question 47

Why are organic nitrates used to treat angina?

Answer 47

They relax vasculature and some other smooth muscles and reduce central venous pressure which in return reduces the stroke volume (in health individuals). The reduced preload and after load of the heart results in reduced CO and redistribution of coronary flow towards ischaemic areas of the heart.

It also promotes relief of coronary spasm.

Question 48

What is the mechanism of action of Organic nitrates?

Answer 48

Organic nitrates such as glyceryl trinitrate, sodium natriprusside, isosorbide mononitrate etc. are metabolised in the body by nitrate synthase to release nitric oxide.
NO activates soluble guanylate Cyclase leading to a cascade of events in smooth muscle resulting in dephosphorylation of the MLCs, sequestering of intracellular calcium levels leading to smooth muscle relaxation.