Pharmacological control of contractility

Question 1

What are 2 main uses of positive inotropes?

Answer 1

Cardiac failure (chronic/ischaemic and acute)

Hypovolaemia (actual and functional e.g. vasodilation so lose effective circulating volume)

Question 2

What 3 main factors affect cardiac output?

Answer 2

Cardiac input (i.e. venous return) and thus SV
Contractility
Peripheral resistance

Question 3

What are the priorities for inotropes treating ischaemic heart disease?

Answer 3

Increase contractility but not oxygen demand
Vasodilation to reduce afterload
Increase cardiac output

Question 4

What are the focuses of inotropes in treating cardiogenic shock?

Answer 4

Vasoconstriction (avoid vasodilation)

Must increase cardiac output

Question 5

What is a risk of using inotropes to treat acute cardiac failure?

Answer 5

Increasing contractility may enhance ischaemia due to reduced coronary perfusion

Question 6

What are 2 main types of positive inotropes?

Answer 6

Sympathomiemetics

Non sympathomimetic positive inotropes

Question 7

What are the 3 types of inotropes needed for exams?

Answer 7

Sympathomimetics
Cardiac glycosides
Calcium sensitising agents

Question 8

When are sympathomimetics used?

Answer 8

Acute shock/hypotension to increase cardiac contractility

Question 9

What is the risk of sympathomimetics?

Answer 9

Myocardial ischaemia (due to increased oxygen supply) and arrhythmias

Question 10

What are the direct and indirect effects of sympathomimetics?

Answer 10

Direct: affect symp receptors
Indirect: effect intracellular messengers

Question 11

What are 2 broad examples of sympathomimetics?

Answer 11

Phosphodiesterase inhibitor

Catecholamines

Question 12

What are examples of PDE inhibitors?

Answer 12

Milrinone, methyl xanthines

Question 13

What are the actions of indirect sympathomimetics?

Answer 13

Inhibit phosphodiesterase 3 so amplify effects of beta adrenergic stimulation, prolong effects of cAMP

Question 14

When are phosphodiesterase inhibitors not effective?

Answer 14

When beta blockers taken

Question 15

What are examples of catehcolamines?

Answer 15

Noradrenaline, adrenaline, dopamine, dobutamine

Question 16

What are the effects of catecholamines (+ve and -ve), what do they act on?

Answer 16

Beta 1 receptors
Increase heart rate and contractility
Increased myocardial oxygen consumption

Question 17

What is the benefit of catecholamines increasing vascular tone?

Answer 17

Reduce blood supply to vascular beds of gut, kidney etc so more fluid available in circulating volume

Question 18

What is the effect of high levels of adrenaline on bp, why is this useful?

Answer 18

Increased blood pressure so can be used for hypotension

Question 19

Why does moderate adrenaline cause vasodilation in skeletal muscle but elevated amounts cause vasoconstriction?

Answer 19

At moderate levels: mostly bound to beta receptor

Higher doses: beta receptors saturated so adrenaline binds alpha receptors

Question 20

How can adrenaline and dopamine cause myocardial ischaemia?

Answer 20

Increase cardiac workload, insufficient perfusion to cornary arteries so not enough oxygen.

Question 21

What are the solutions to the problems of dopamine and adrenaline, how come?

Answer 21

Dobutamine (b1 agonist):
reduces risk from myocardial infarction but increases cardiac output.
Does not act on dopamine receptors so less prone to hypertension

Question 22

What is a problem with dobutamine?

Answer 22

Not as effective as dopamine at vasoconstriction and also causes mesenteric vasodilation so lose blood volume to gut

Question 23

Why is dobutamine not used for ischaemic heart disease?

Answer 23

Increases heart rate and thus myocardial oxygen demand, though note, better than adrenaline

Question 24

Describe action of propanolol

Answer 24

Adrenoceptor antagonist so have negative effect on contractility and inotropy

Question 25

Examples of calcium sensitisers?

Answer 25

Levosimendan, omecamtiv

Question 26

What do calcium sensitisers do, why are they good?

Answer 26

Increase sensetivity of contractile mechanism to calcium so increase force of contraction without extra ion pumping (i.e. doesn't increase oxygen demand much)

Question 27

What does omecamtiv do?

Answer 27

Myosin activator: prolong contractile phase of actin myosin cycling so increase contractility

Question 28

What are examples of cardiac glycosides?

Answer 28

Digoxin, ouabain and digitoxin

Question 29

What are the benefits of cardiac glycosides?

Answer 29

Increase contractility Little increase in oxygen demand Have diuretic effect so reduce effect of circulating volume so reduced ventricular dilation

Question 30

What are some side effects of cardiac glycosides?

Answer 30

Risk of arrhythmia as delayed after depolarisations

Question 31

How come cardiac glycosides don't increase oxygen demand?

Answer 31

Heart does not have to exert as much force to pump the blood, or they directly increasing the heart's contractile force, so that the heart can overcome the higher blood pressure.

Question 32

What are good treatments for ischaemic heart failure?

Answer 32

Calcium sensitiser | Cardiac glycosides

Question 33

What is a possible mechaism for cardiac glycosides?

Answer 33

Inhibition of Na+ K+ ATPase So build up of sodium within cell This reduces Na+ gradient to drive NCX So less Ca2+ extruded, Ca builds up and increase contractility.

Question 34

How do after depolarisations arise?

Answer 34

Excessive increase in Ca2+ inside cells during depolarisation causes delayed after depolarisations due to activation of Na+ Ca2+ exchange (which brings in more Na+ so cell depolarises) and opening of Ca2+ sensitive non selective ion channels

Question 35

Why can after depolarisations be problematic?

Answer 35

As heart rate increases, after depolaristation increases until it is high enough to trigger an AP - self perpertuating effect leading to tachycardia.

Question 36

What is the initial therapy you would give?

Answer 36

NICE Beta blockers ACE inhibitors Diuretics

Question 37

Why do ACE inhibitors treat cardiac failure?

Answer 37

ACE inhibitors Reduce reabsorption of sodium and water at the kidneys Reduces after-load

Question 38

What are some examples of ACE inhibitors?

Answer 38

Ramipril Enalapril Captopril

Question 39

What use do beta blockers give in treating heart disease?

Answer 39

Reduce risk of arrythmias Reduce the oxygen demand of tissue proportionally more than they reduce contraction – tissue more efficient Reduce heart rate, improved mortality

Question 40

What is an example of a negative inotrope?

Answer 40

Beta blocker

Question 41

Why are beta blockers good for treating ischaemic heart disease?

Answer 41

Reduce oxygen demand of tissue

Question 42

Why are diuretics effective at treating heart disease?

Answer 42

Reduce after load by lowering blood volume (normal starling range), lowers oedema

Question 43

How does NO act as a good first line treatment for CHD?

Answer 43

Causes smooth muscle relaxation Improves blood flow to cardiac tissue itself (e.g. used for angina) Reduces the pressure against which the heart has to work

Question 44

When is ivabradine used?

Answer 44

As a second line of treatment (if beta blockers ineffective), reduce heart rate (CHD)

Question 45

What does ivabradine act on and what is its effect?

Answer 45

HCN4 (If) inhibitor, reduces the rate of pacemaker potential decay and slows heart rate

Question 46

After blockade of both sympathetic and parasympathetic neural influence on the heart, the heart rate would typically be...

Answer 46

Higher than the control rate