Drugs affecting cardiac rate and force

Question 1

How does NA cause increased HR?

Answer 1

Coupling through Gs protein activates adenylyl cyclase to increase [cAMP]i;

(i) an increase in the slope of phase 4 depolarization (‘the pacemaker potential’) caused by enhanced If and ICa
(ii) reduction in the threshold for AP initiation caused by enhanced ICa

Question 2

Describe the sympathetic effects on the heart?

Answer 2

increased HR

increased contractililty

increased conduction velocity

increased automaticity
decreased duration of systole

increased activity of Na/K-ATPase

increased mass of cardiac muscle

Question 3

describe the parasympathetic effects on the heart?

Answer 3

decreased HR
decreased contractility
decreased conduction in AV node
parasympathetic stimulation

Question 4

How does ivabradine work?

Answer 4

Selective blocker of HCN channels, used to flow heart rate in angina

Question 5

Describe the steps in excitation contraction coupling in cardiac muscle

Answer 5

1. ventricular action potential
2. opening of voltage activated Ca channels during phase 2
3. ca influx into cytoplasm
4. CICR caused by ryanodine type 2 channel
5. Ca binds to troponin C ans shift tropomyosin out of the actin cleft
6. cross bridge forms resulting in contraction

Question 6

Describe the steps in muscle relaxation

Answer 6

1. depolarise in phase 3 to phase 4
2. voltage activated L type channels close
3. Ca influx ceases Ca efflux occurs via the Na.Ca exchanger (NCX1) a plasma membrane ATPase
4. Ca release from sarcoplasmic reticulum ceases. active sequestration of Ca via SERCA
5. ca dissociated from troponin C
6. cross bridge between actin and myosin break

Question 7

How does B1 adrenoreceptor activation modulate cardiac contractility?

Answer 7

formation of cAMP and activation of protein kinase A

Question 8

Name some B agonist ligands used on the heart

Answer 8

Dobutamine
Adrenaline
Catecholamines

Question 9

What do B agonist ligands do to the heart

Answer 9

increased force, rate and cardiac output

decreased cardiac efficiency

Question 10

Clinical uses of adrenaline

Answer 10

cardiac arrest (IV), as part of the Advanced Life Support (ALS) treatment algorithm.

anaphylactic shock (IM, not IV unless cardiac arrest occurs), very important in immediate management

Question 11

Clinical uses of dobutamine

Answer 11

acute, but potentially reversible, heart failure (e.g. following cardiac surgery, or cardiogenic, or septic, shock).

For reasons unknown, causes less tachycardia than other β1 agonists

Question 12

Effect of b adrenoreceptor antagonists on the heart

Answer 12

depend upon the degree to which the sympathetic nervous system is activated

At rest (normal subjects) - little effect on rate, force, CO, or MABP (agents with partial agonist activity increase rate at rest, but reduce

During exercise, or stress, rate, force and CO are significantly depressed – reduction in maximal exercise tolerance

Coronary vessel diameter marginally reduced, but myocardial O2 requirement falls, thus better oxygenation of the myocardium

Question 13

non-selective b blockers

Answer 13

β1 and β2, e.g. propranolol

Question 14

selective b blockers

Answer 14

β1, e.g. atenolol, bisoprolol, metoprolol

Question 15

Uses of B adrenereceptor antagonists

Answer 15

Treatment of disturbances of cardiac rhythm (arrhythmias)

Treatment angina

Treatment of heart failure (compensated)

Treatment of hypertension (HT)

Question 16

Adverse effects of B blockers

Answer 16

Bronchospasm
Aggravation of cardiac failure
Bradycardia
Hypoglycaemia
Fatigue
Cold extremities

Question 17

pharmacodynamic effect of atropine

Answer 17

> Increase in HR in normal subjects (at all but low doses) – more pronounced effect in highly trained athletes (who have increased vagal tone)
No effect upon arterial BP (resistance vessels lack a parasympathetic innervation)
No effect upon the response to exercise

Question 18

effect of atropine on heart

Answer 18

First line in management of severe, or symptomatic bradycardia, particularly following myocardial infarction (in which vagal tone is elevated). In MI given IV (with caution) in incremental doses*. Monitoring is required. Glycopyrronium is an alternative

In anticholinesterase poisoning (to reduce excessive parasympathetic activity, e.g. bradycardia

Question 19

Use of digoxin

Answer 19

Heart failure – a CO insufficient to provide adequate tissue perfusion

Inotropes cause an upward and leftward shift of the ventricular function curve, such that SV increases at any given EDP

Question 20

How does digoxin work?

Answer 20

Block sarcolemma ATPase

Question 21

Indirect effects of digoxin

Answer 21

Slows SA node discharge

Slows AV node conduction; increases refractory period

Question 22

Direct effect of digoxin

Answer 22

Shortens the action potential and refractory period in atrial and ventricular myocytes (which is pro-arrhythmic); toxic concentration cause membrane depolarization and oscillatory afterpotentials- likely due to Ca2+ overload

Question 23

Clinical use of digoxin

Answer 23

IV in acute heart failure, or orally in chronic heart failure, in patients remaining symptomatic despite optimal use of other drugs (e.g. ACE inhibitors, diuretics)
Particularly indicated in heart failure with atrial fibrillation (AF)

Question 24

Levosinedan function

Answer 24

Binds to troponin C in cardiac muscle sensitizing it to the action of Ca2+

Additionally opens KATP channels in vascular smooth muscle causing vasodilation (reduces afterload and cardiac work)

Question 25

Use of levosimedan

Answer 25

in treatment of acute decompensated heart failure (IV)

Question 26

Inodilators

Answer 26

Amrinone

Milrinone

Question 27

How do inodilators work?

Answer 27

Inhibit phosphodiesterase (PDE) in cardiac and smooth muscle cells and hence increase [cAMP]i

Increase myocardial contractility, decrease peripheral resistance (haemodynamic indices are improved), but worsen survival – perhaps due to increased incidence of arrhythmias