Block A - antiarrthymic drugs

Question 1

arrthmias ?

Answer 1

Arrhythmias are a group of conditions in which the heart beats irregularly, either too fast, or too slowly , they occur as a result of abnormal electrical activity. They arise due to an abnormality of the cardiac rhythm which is called a cardiac arrhythmia. Arrhythmias may arise from ischaemia, infarction, fibrosis or drugs

Question 2

irregular bradycardia ?

Answer 2

There are two main types of arrhythmia:

Irregular bradycardia in which the heart rate is too slow at less than 60 b.p.m.

Question 3

irregular tachycardia ?

Answer 3

Irregular tachycardia: the heart rate is fast at over 100 b.p.m

Question 4

symptoms of arrthmias ?

Answer 4

Palpitations – patient can feel their heartbeat

Heart failure symptoms (e.g. edema)

Fatigue

Dyspnea (breathing difficulties)

Dizziness

Angina

Syncope (fainting)

No symptoms at all

Question 5

why do arrthmias form ?

Answer 5

Cardiac arrythmias arise from altered formation of impulses in the heart or altered conduction of the impulse through the heart.

Question 6

ectopic beats ?

Answer 6

Ectopic beats arise from fibres or group of fibres outside normal pacemaker region (SA node). There is an area of the heart out with the SA node which develops pace maker qualities.

Question 7

heart block ?

Answer 7

Heart block is the obstruction in the electrical conduction system.

Question 8

reentry phenonenom ?

Answer 8

Reentry phenomenon is the return of the same impulse into a zone of heart muscle that it has previously been activated.

Question 9

treatment ?

Answer 9

Pharmacological therapy.

DC Cardioversion is a procedure to convert an abnormal heart rhythm to a normal heart rhythm.

Pacemaker therapy.

Surgical therapy e.g. aneurysmal excision.

Interventional therapy in which parts of the heart which give rise to these issues are ablated.

Question 10

what is pharmacology therapy ?

Answer 10

Pharmacological therapy is when drugs are used to alter the transmission of electrical signals in the heart.

Question 11

excitability ?

Answer 11

Excitability is the ability to respond to stimuli by producing and conducting action potentials. Any cells that poses the ability to conduct an action potential is said to have an excitatory membrane

Question 12

refractory period ?

Answer 12

Refractory period is the time following excitation during which a second action potential cannot be generates and conducted.

Question 13

membrane responsivness ?

Answer 13

Membrane responsiveness is the relationship between membrane activation voltage and the maximal rate of rise of the action potential , the upstroke of the action potential.

Question 14

antiarrytmic drugs effectiveness statement ?

Answer 14

Anti-arrhythmic drugs are a common theme and effective antiarrhythmic drugs increase the refractory period or slow upstroke of action potentials or both mechanisms.

These drugs work to control electrical signals by altering action potential generation or action potential propagation. It is important to understand how the membrane potentials arise and what various channels are doing.

Question 15

how are electrical impulses in our body carried ?

Answer 15

Electrical impulses in our bodies are carried by ions, and these ions require an access route across the membrane, ion channels allow this to occur.

Question 16

channels ?

Answer 16

Channels are large pores in a membrane that allow ions to flow from one side of the membrane to the other and carry the electrical signals.

Question 17

channels have gating , what is this ?

Answer 17

Gating is present and this can be opened or closed. The gating opens in response to a particular stimulus. A gating control mechanism is the membrane potential itself.

Question 18

channels have ion selectivity , what is this ?

Answer 18

Ion selectivity occurs in some channels and only allow Na+ ions to cross, while others only allow K+ or Ca2+ ions to flow through. If a channel only allows calcium ions to pass this is termed a Ca2+ ion channel, if a channel only allows Na+ ions to pass this is called a Sodium ion channel. Furthermore, if a channel only allows K+ ions to flow this is termed as a K+ ion channel.

Question 19

sodium and clcium ions concentration on a cell ?

Answer 19

Sodium and calcium ions are at a high concentration outside the membrane and cell,

Question 20

sodium ion concentration and anion ?

Answer 20

there is a low concentration of sodium on the inside of the cell. For every sodium ion, there is a balancing anion (negatively charged ion) present on both sides of the membrane. So even though there is a large concentration gradient present for sodium between the inside and outside of a cell, there is no membrane potential due to the cations (positively charged ion) and anions (negatively charged ion ) being balanced on both sides of the membrane.

Question 21

how does a membrane potential form ?

Answer 21

For a membrane potential to develop one side of the membrane must gain charge either positive or negative at the expense of the other which is achieved using channels. An example of this is a sodium channel, which is selective to sodium ions, this allows them to flow down their concentration gradient from a high concentration outside of the cell to a lower concentration inside the cell taking it’s positive charge with it, the anion is left behind as there is no channel for them. Therefore, the inside membrane is gaining an excess positive charge due to the influx of sodium ions , the anion is left behind and therefore the outside membrane gains an excess of negative charge. A membrane potential is developing as the inside is becoming positively charged with respect to the negatively charged outside membrane.

Question 22

run to equilibrium >

Answer 22

If you were to let this run to equilibrium, it would not become established as there are two competing forces acting on the sodium ion. There is the chemical concentration gradient which is driving sodium from the outside of the cell to the inside in one direction. As this is occurring, there is a build-up of negative charge on the outside of the cell, which tends to pull sodium back out of the cell. This is an equilibrium which has a positive charge on the inside of the cell with respect to the outside of the cell and there will no longer be a net movement of sodium ions as the concentration gradient remains and is completely stable. This is called an electrochemical equilibrium.

Question 23

potassium ions concentration ?

Answer 23

Potassium ions are at a high concentration inside the cells, and a low concentration on the outside of the cells which occur in normal cardiac cells. For every positive charge there is a balancing anion ( negatively charged ion) on each side of the membrane , even though there is a large concentration gradient there is no membrane potential as the charges are balanced.

Question 24

membrane potential potassium ?

Answer 24

For a membrane potential to develop one side of the membrane must gain charge either positive or negative at the expense of the other which is achieved using potassium channels. This allows potassium ions to flow down their concentration gradient from a high concentration inside of the cell to a lower concentration outside the cell taking it’s positive charge with it, the anion is left behind as there is no channel for them. Therefore, the outside of the membrane is gaining an excess positive charge due to the efflux of potassium ions , the anion is left behind and therefore the inside of the membrane gains an excess of a negative charge. A membrane potential is developing as the inside is becoming negatively charged with respect to the positively charged outside membrane

Question 25

what is a cardiac channel membrane like at rest ?

Answer 25

This is what happens to the cardiac cell at rest, the inside is negatively charged and the outside is positively charged as potassium is the most permeable ion across the membrane at rest so it tends to flow out taking it’s positive charge with it driving the membrane potential in a negative direction.

Question 26

death by lethal injection ?

Answer 26

this is altering the potassium levels

injections of potassium chloride. This was an ethical debate. Individuals were connected to an intravenous drip of harmless saline solution. To choose death the individuals switched the solution to one containing an anaesthetic solution followed automatically by potassium chloride. Therefore, it was the patient that switched the solution and caused their own death. The anaesthetic caused unconsciousness. Cardiac arrest and death were caused by the potassium chloride. The ionic basis of the resting membrane potential and its dependence on the external potassium concentration explains why the heart stopped beating , the membrane potential of the heart was depolarised as potassium chloride was injected.

Question 27

action potential phases >

Answer 27

During an action potential there are 2 main phases: sodium influx phase and potassium efflux phase. During an upstroke of an action potential the sodium channels start to open up in large numbers. The illustration on the left shows 3 sodium channels but there are thousands present on the membrane, the rapid depression is due to the rapid opening of and closing of sodium channels. As the channels open this allows sodium to flow into the cell taking it’s positive charge and the membrane potential moves positive.

One of the triggers for the opening of the sodium channels is the membrane potential itself. As the membrane potential moves positive, the sodium channels open allowing sodium to flow in and the membrane potential moves positive. The positive membrane potential is detected by the sodium channels , and more open in response. This is a positive feedback loop which drives the upstroke of the action potential.

Towards the peak of the upstroke , the sodium channels halt opening , and no more sodium ions flow into the cell. This is due to inactivation which blocks the sodium channels closed. It ensures action potentials can only move in one direction , to relieve the channels from inactivation , the membrane potential must be restored back down to resting level and once this occurs the sodium channels will be available to be reopened.

The process of inactivation is voltage dependent, like the opening of sodium channels.

At the peak of the action potential the potassium channels open in large numbers , illustrated in the lower left hand corner of the diagram the depressing are rapid opening and closing of the channels. As the channels open the potassium channels flow out of the axon down their concentration gradient from the higher concentration inside the cell to the lower concentration outside the axon. As it flows out, it takes it’s positive charge with it and the inside of the axon becomes negatively charged. The membrane potential undershoots the resting value after an action potential. This is because when potassium channels open , they remain open for a brief period of time so the membrane potential becomes even more negative than it was at resting value

Question 28

ventricular cells action potential ?

Answer 28

This illustrates ventricular cells, the bottom displays the sodium, potassium and calcium channels as well as the ATPase.

The sodium channel itself has 2 separate gates, an M and H gate. Something triggers an action potential to occur, and the membrane moves in a positive direction, when this occurs this results in a large number of sodium channels opening. The M gate of the channel moves out of the way, opening the channel up and sodium channels flow in , causing the membrane potential to move in a more positive direction as a result of a positive feedback loop. This is the upstroke of an action potential (Phase 0) called depolarisation that is driven by an influx of sodium ions.

At phase 1 the potassium channels open up and allow potassium ions to flow out and the membrane potential starts to move negative however it doesn’t completely recover because in addition to the potassium channels opening, the calcium channels open which allow calcium ions to flow in bringing their positive charge to maintain the membrane potential called the plateau phase (Phase 2).

Towards the end of the plateau phase the membrane potential starts to move negative again as calcium channels start to shut and at the same time large numbers of potassium channels open to allow a large efflux of potassium ions. This causes a rapid repolarisation of the membrane potential called phase 3.

As the membrane potential is restored back down to rest, any sodium ions that have flowed in during phase 0 are moved back out by the activity of Na/K ATPase or sodium pump and potassium ions flow back in. This restores the membrane potential back to resting, phase 4.

Question 29

pacemaker cells ?

Answer 29

In pacemaker cells there is a different type of action potential generated, during phase 4 the membrane potential spontaneously depolarises once again. This has a completely different shape to the ventricular action potential.

Question 30

what contains pacemaker regions ?

Answer 30

The pacemaker regions contain the Sinoatrial (SA) Node and Atrioventricular (AV) Node cells are ‘slow conductors’ that use calcium channels mainly in their action potential upstroke. They don’t use sodium ions to drive the upstroke. Therefore A.P is blocked by calcium channel blockers such as verapamil)

Question 31

fast condcuting cells that use sodium channels ?

Answer 31

atrium, Bundle of His, and ventricle cells are ‘fast conducting’ that use sodium channels mainly in their action potentials upstroke, thus blocked by sodium channel blockers (such as quinidine, lidocaine and propafenone).

Question 32

absolute reefractory period ?

Answer 32

Absolute Refractory Period – Na+ channels are completely inactivated and no matter what stimulus is applied they will not re-open to allow Na+ in and unable to depolarise the membrane to the threshold of generate an action potential.

Question 33

relative refractory period ?

Answer 33

Relative Refractory Period - Some of the Na+ channels have re-opened from inactivation but the threshold is higher than normal making it more difficult for the activated Na+ channels to raise the membrane potential to the threshold of excitation , but A.P can be generated.

Question 34

class I blockers ?

Answer 34

Class I blockers are Na+ channel blockers inhibit the upstroke of the A.P, because this inhibits action potential propagation in excitable cells, they are referred to as containing membrane stabilising activity.

Question 35

class II blockers ?

Answer 35

Class II blockers are beta blockers; they are not channel blockers. Instead, they are beta adrenergic blockers which have an effect on adrenaline and noradrenergic stimulation of electrical activity on the heart. The main effect of beta adrenergic stimulation on the heart will shorten the plateau phase and increase the pacemaker potential occurrence. Therefore, the effect of class II blockers is they affect the plateau (phase 2) and pacemaker potential ( phase 4 ) .

Question 36

class III blockers ?

Answer 36

Class III blockers operate on the phase 3 of the A.P they are potassium channel blockers. The potassium channels are important for the recovery of the membrane potential called repolarisation. By blocking this channel , the cardiac action potential is prolonged which affects the ability of other action potentials to be generated by a stimuli.

Question 37

Class IV blockers ?

Answer 37

Class IV blockers affect voltage sensitive calcium channels, which are important on the plateau phase ( phase 2) and pacemaker potential ( phase 4) of the action potential. Class IV drugs will slow conduction in the SA and AV nodes as the action potential relies on the inward current of calcium ions. Class IV drugs will shorten the plateau phase of the action potential and decrease the force of the contraction generated.

Question 38

procainamide ?

Answer 38

Class 1A blockers such as Procainamide will slow the upstroke of the A.P by decreasing membrane responsiveness, so it’s more difficult to generate an action potential. It requires a larger stimulus to generate the action potential and the duration takes longer for the A.P to occur. This drug is used to treat cardiac arrythmias and some side effects can include nausea and vomiting.

Question 39

Flecainide ?

Answer 39

Class IC such as flecainide are major inhibitors of membrane responsiveness. The class 1C drugs increase the stimuli required to evoke an A.P, so it slows the upstroke of the A.P by decreasing membrane responsiveness. This increases the duration of the A.P

Flecainide is a sodium channel inhibitor affecting phase 0, the upward stroke of the action potential. Therefore, it is a class one blocker, the upstroke is reduced subtly, and it slows the electrical propagation in the heart, as the sodium ions are affected by the blocker, this has an effect on the calcium ions, they also reduce as a consequence of the sodium ion decreasing. Flecainide is often used to treat paroxysmal supraventricular tachycardia and atrial flutter some side effects include dizziness and naseau.

Question 40

TTX ?

Answer 40

TTX is a highly potent and extremely selective blocker which affects phase 0 of the action potential , the upward stroke due to the influx of sodium ions, by using TTX this increases the stimuli threshold from approximately 2.5 to 5 needed to evoke an action potential , this decreases the amplitude ( height) of the action potential also.

Question 41

Propranolol ?

Answer 41

Propranolol is a beta-adrenergic antagonist, they are commonly used in rhythm disorders ,as they slow conduction in partially depolarised cells. However, propranolol also has some class I action in addition to the beta blocking effects. Some side effects can include worseing bronchospasms in patients with asthma.

Question 42

Amiodarone and sotalol ?

Answer 42

Amiodarone and sotalol is a ‘dirty drug’ which inhibits K channels, Class III (delays repolarization) to increase duration of A.P and increase the refractory period so that it affects ability of further stimuli to generate an A.P, as well as other channels like Na channels and Ca channels (slight), blocks beta-receptors non-competitively, blocks alpha receptors, potent suppressor of ectopic automaticity. Amiodarone is used clinically to treat tachycardia; however it contains a long half life so the drug is commonly found in tissues bound and it can accumulate in the body. Therefore, the dosing needs to be calculated carefully.

Question 43

Verpamil ?

Answer 43

Verapamil is a blocker which affects phase 2 of the action potential, the plateau due to the calcium ion influx. By using verapamil this causes the plateau to be hyperpolarized which in turn shortens the action potential. Verapamil is an unusual drug as it is not consistent with other anti-arrhythmic drugs which fit the common theme of effective antiarrhythmic drugs increase the refractory period or slow upstroke of action potentials or both mechanisms. Instead, verapamil shortens the action potential but does not slow the upstroke as it is not a sodium channel blocker. In addition to this, verapamil does not influence ventricular cells, instead it acts on pacemaker regions such as Sino atrial node (S.A node) and atrioventricular node (A.V node).

Question 44

Diltiazem ?

Answer 44

Diltiazem blocks mainly L-type calcium channels same as Verapamil resulting in a decrease in the SA and Purkinje fiber automaticity, slows conduction through and increases refractory period of AV node. Diltiazem has relativley more effect on smooth muscle than verapamil and produced ledd bradycardia , therefore said to be rate neutral.

Question 45

Digoxin

Answer 45

Digoxin slows the conduction in the A-V node

Digoxin is a cardiac glycoside extracted from foxglove leaves (Digitalis sp)and is the most important inotrope. It increases the contractile force and is particularly indicated in patients with atrial fibrillation.It does so by inhibiting the Na+/K+-ATPase, which is responsible for Na+/K+ exchange across the muscle cell membrane leading to an increase in Na+ ion concentration inside the cell and increase in Ca2+ ion concentration inside the cell causing an increase in the force of myocardial contraction.

Question 46

Digitoxin ?

Answer 46

Digitoxin does the same mechanism but is more powerful.

Question 47

positive ionotropic effects of digoxin ?

Answer 47

The sodium potassium ATPase moves sodium ions out and potassium ions in, digoxin inhibits this and increases sodium concentration inside the cell. The rise of sodium ions causes a rise in calcium ions as effects sodium calcium exchanger. The calcium sodium exchanger is normally responsible for pumping calcium out of a cell and bringing sodium ions into the cell. However, a large concentration of sodium will prevent the calcium from leaving the cell as the sodium can no longer flow into the cell and this halts the pump and calcium rises in the cell , it is stored in calcium stores and these lead to an increased myofibril contraction = increased myocardial contraction.

Question 48

Can inotropic drugs have indirect effects ?

Answer 48

Inotropic drugs can have indirect effects for example, Digoxin increases vagal activity and facilitates muscarinic transmission to the heart. This slows Heart rate and slows the atrioventricular conductance. In turn , this prolongs the refractory period of the atrioventricular node.