Drugs and the cardiovascular system: The heart

Question 1

what are the mechanisms regulating the heart?

Answer 1

Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials. Unlike non-pacemaker action potentials in the heart, and most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried into the cell primarily by relatively slow Ca++ currents instead of by fast Na+ currents. There are, in fact, no fast Na+ channels and currents operating in SA nodal cells.
Graph shows: funny current, influx of calcium, potassium channel opening.
Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential

Question 2

What effect does sympathetic and parasympathetic have on cAMP? and other current?

Answer 2

Sympathetic - ↑ cAMP, ↑ If & Ica

Parasympathetic - ↓ cAMP, ↑ IK

Question 3

describe the process of the mechanisms regulating contractility

Answer 3

action potential enters from adjacent cell
voltage-gated calcium channels open, calcium enters cell
calcium induces calcium release through ryanodine receptor-channels
local release causes calcium spark
summed calcium sparks create a calcium signal
calcium binds to troponin to initiate contraction
relaxation occurs when calcium unbinds from troponin
calcium is pumped back into the sarcoplasmic reticulum for storage
calcium is exchanged with sodium
sodium gradient is maintained by the na/k atpase

Question 4

what is the mechanism regulating myocardial oxygen supply and demand?

Answer 4

myocardial oxygen supply vs work -> myocardial oxygen demand

Question 5

what determines the work done

Answer 5

increase: 
HR
preload
afterload
contractility

Question 6

what determines myocardial oxygen supply?

Answer 6

increase:
coronary blood flow
arterial oxygen content

Question 7

what does myocyte contraction effect

Answer 7

Myocyte contraction = primary determinant of myocardial oxygen demand
↑ 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

what drugs influence HR?

and what do they affect

Answer 8

β-blockers – Decrease If and Ica. decrease contractility

Calcium antagonists – Decrease Ica

Ivabradine – Decrease If

Question 9

what are the two classes of calcium antagonists

Answer 9

TWO CLASSES:
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)

Question 10

what can non-rate slowing calcium antagonists lead to?

Answer 10

No effect on the heart. Profound vasodilation can lead to reflex tachycardia

Question 11

mechanism of organic nitrates

Answer 11

stimulates sGC which increases production of cGMP leading to muscle relaxation

Question 12

mechanism of potassium channel opener

Answer 12

K out, leading to hyperpolarisation, which leads to less influx of calcium ions leading to relaxation

Question 13

what do Organic nitrates & Potassium Channel Openers do?

Answer 13

increase coronary blood flow

Question 14

What two different effects of nitrates/potassium channel openers influence preload and afterload?

Answer 14

Vasodilation = ↓ afterload
Venodilation = ↓ preload

Question 15

drugs for treating stable angina?

Answer 15

1. beta blocker or calcium channel blocker
2. cannot tolerate one, give the other
3. combination of both
4. both not tolerated then long acting nitrate, ivabradine or nicorandil

Question 16

what is pindolol?

Answer 16

Non-selective beta blocker
‘Equal’ affinity for 1 & 2 receptors

With intrinsic sympathetic activity

Question 17

what is carvedilol?

Answer 17

Mixed - alpha and beta blockers
alpa blockade gives additional vasodilator properties
E.g. Carvedilol

Question 18

why doe alpha blocking help alongside beta blocking?

Answer 18

Beta 2 receptor blockade will reduce vasodilation and increase TPR which can worsen heart failure.

Pindolol will have some beta 2 stimulating effects due to ISA or carvedilol with alpha 1 blocking effects can decrease TPR and alleviate this problem.

Question 19

why do beta blockers lead to cold extremities?

Answer 19

Loss of β2 receptor mediated cutaneous vasodilation in

extremities

Question 20

beta blocker side effects

Answer 20

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

Question 21

name two calcium channel blockers and their side effects

Answer 21

Verapamil
Bradycardia and AV block (Ca2+ channel block)
Constipation (Gut Ca2+ channels) – 25 % patients

Dihydropyridines – 10-20% patients
Ankle Oedema – vasodilation means more pressure on capillary vessels
Headache / Flushing – vasodilation
Palpitations
Vasodilation/reflex adrenergic activation

Question 22

what are the aims of treatment of abnormalities of cardiac rhythm

Answer 22

Reduce sudden death
Prevent stroke
Alleviate symptoms

Question 23

what might rhythm disturbances be associated with?

Answer 23

May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias).

Question 24

classification of arrhythmias:

Answer 24

A simple classification of arrhythmias is based on site of origin:
Supraventricular arrhythmias (e.g. amiodarone, verapamil)
Ventricular arrhythmias (e.g. flecainide, lidocaine).
Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).

Question 25

what is Vaughan-William classification of anti-arrhythmic drugs

Answer 25

classifies drugs according to their effect on cardiac action potential and their mechanism of action This includes:
I = sodium channel blockers
II beta adrenergic blockers
III = potassium channel blockers (which prolongs repolarisation)
IV calcium channel blockers
good for research, not in clinical setting

Question 26

what is used for supraventricular tachyarrhythmias?

Answer 26

Adenosine
In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein. Activation of this G-protein stimulates adenylyl cyclase (AC in figure), increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force. There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels.
In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins. Activation of this pathway opens potassium channels, which hyperpolarizes the cell. Activation of the Gi-protein also decreases cAMP, which inhibits L-type calcium channels and therefore calcium entry into the cell. In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy).

Question 27

uses of verapamil and mechanism of action

Answer 27

Uses:
Reduction of ventricular responsiveness to atrial arrythmias

Mechanism of action:
Depresses SA automaticity and subsequent AV node conduction

Question 28

uses of amiodarone

Answer 28

supraventricular and ventricular arrhythmias

-particularly when other drugs are ineffective

Question 29

how does digoxine work?

Answer 29

Inhibition of Na-K-ATPase (Na/K pump). This results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange → positive inotropic effect
central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node

Question 30

uses of digoxin

Answer 30

Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output.

Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls.

Question 31

adverse effect of digoxin

Answer 31

dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)

Note: Hypokalaemia (usually a consequence of diuretic use) lowers the threshold for digoxin toxicity