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Flashcards in L65 – Positive Inotropic Drugs Deck (68):
1

Change in cardiac output during heart failure?

CO = SV x HR

Decrease in both SV (force of contraction decreases) and HR means CO is decreased

2

Compare acute and chronic heart failure in their compensation, time span and urgency/ danger?

Acute = decompensated, Develops rapidly (hours/days), Life-threatening

Chronic = Compensated, long-term condition (months/years), asymptotic due to adaptive changes

3

Compare acute and chronic heart failure in their management? Can they be managed?

Acute = can successfully manage by pharmacological or surgical intervention

Chronic = cannot manage successfully (reverse condition) but can alleviate
*adaptive changes of heart are irreversible*

4

Name the 5 drug classes in heart failure?

A Boy Visits Police Department

1) Angiotensin inhibitors
2) B-adrenergic receptor blocker
3) Vasodilators
4) Positive Inotropic drug
5) Diuretics

5

What are the 2 Compensatory mechanisms to restore cardiac output in chronic heart failure?

1. Autonomic feedback – Increase sympathetic autonomic nervous activity

2. Hormonal feedback – stimulate renin-angiotensin aldosterone system

6

What is the consequence of increased sympathetic activity to restore CO in chronic heart failure?

Increase sympathetic activity > vasoconstriction, increase TPR > Increase Mean arterial pressure

> Increase cardiac workload, causing:
1) Myocardial hypertrophy
2) Ventricular remodeling (deposition of fibrotic tissue)

7

What is the consequence of increased RAAS activity to restore CO in chronic heart failure?

Activate RAAS > Increase water and salt retention in kidneys > Increase blood volume > Increase cardiac workload

Consequences:
1) Myocardial hypertrophy
2) Oedema of peripheral tissue, especially in ankles
3) Pulmonary oedema and SoB

8

How does the compensatory mechanisms of the heart in chronic heart failure only worse the situation?

Both compensatory mechanisms aim to increase CO,

but also increases mean arterial pressure and TPR (by activating a-adrenergic receptors)

>> ultimately lower CO

Compensatory mechanism becomes viscous cycle

9

What is the action of positive inotropic drugs?

Increase force of contraction of heart to restore CO

10

Which of the 5 heart failure drugs is for acute HF, which for Chronic HF?

For acute HF:
-Positive Inotropic

For long-term management of chronic HF:
-Angiotensin inhibitor
-B-adrenergic receptor block
-Vasodilator
-Diuretics

11

What are the 4 types of positive inotropic drugs?

Boy passes Crazy Criminal

B-Adrenergic receptor stimulant
Phosphodiesterase inhibitor
Cardiac glycosides
Calcium sensitizers

12

Which of the positive inotropic drugs increases intracellular calcium concentration, which doesnt?

Calcium sensitizer= doesn't increase intracellular calcium concentration

The rest all increase intracellular calcium concentration

13

Name 2 common B-Adrenergic stimulants?"

Dopamine
Dobutamine

14

Name 2 common Phosphodiesterase inhibitor?

Amrinone
Milrinone

15

Name 1 common Cardiac glycosides?

Digoxin

16

Name 1 common Calcium sensitizers?

Levosimendan

17

What is the MoA of B-Adrenergic receptor stimulants?

Activate β1-adrenoceptor in cardiomyocyte:
- Increase intracellular cAMP
- Activation of PKA
- Increase intracellular [Ca2+] through L-type calcium channel
- Trigger larger release of Ca2+ from Sarcoplasmic Reticulum

18

Which of the B-Adrenergic receptor stimulants are enatiomer sensitive?

Dobutamine

19

Explain the different enantiomers of Dobutamine and their respective effects?

(-) enantiomer = agonist of a-adrenergic receptors >> vasoconstriction

(+) enantiomer = partial agonist (or antagonist) of a-adrenergic receptors >> reduce vasoconstriction

20

What is the action of Dobutamine if both enantiomers are included? *in heart and in vessels*

non-selective agonists of
β-adrenergic receptors

In heart: positive inotropic effect (activate B1 channel)

In vasculature: activation of B2 in vascular SM >> vasodilation, effect of (-) offset by (+) enantiomer

21

What does the pharmacological effect of Dopamine depend on?

Concentration of drug given

22

Compare the independent factors to the drug actions of Dopamine and Dobutamine

Dopine = dependent on concentration

Dobutamine = dependent on enantiomer

23

What is the difference in net effect between low dose vs Intermediate and high dose Dopamine?

Low dose = Decrease TPR

Int. to high dose = positive inotropic effect

24

Recall which drugs are used to treat asthma that belong to the same class as a positive inotropic drug?

B2 selective stimulants causes bronchodilation
Used for asthma and other obstructive lung diseases

e.g Salbutamol, formoterol...

25

What is the MoA for Dopamine at low dose?

=< 2 μg/kg/min

1) Activate D1 receptors in vascular smooth muscle >
cAMP-dependent vasodilatation

2) Activate D2 receptors on sympathetic nerves at peripheral circulation:
a) Inhibit noradrenaline release
b) thus decrease in a-adrenergic receptor mediated vasoconstriction

26

Dopamine at low dose particularly targets D2 receptors where in the peripheral circulation?

(esp. at renal and splanchnic arterial beds)

27

What is the MoA for Dopamine at intermediate dose?

2-5 μg/kg/min

activate cardiac β1 adrenergic receptors
> positive inotrophy

28

What is the MoA for Dopamine at High dose?

5-15 μg/kg/min

activate vascular a- adrenergic receptors
>> Cause peripheral arterial and venous constriction

>> Increase afterload and further decrease CO

29

What are the clinical limitations of B-adrenergic receptor stimulants?

Tolerance development

>> Decrease in efficacy after 4 days

30

What drug is added with B-adrenergic receptor stimulant to combat the tolerance development?

Phosphodiesterase III inhibitor

31

What drug contradicts B-adrenergic receptor stimulant ?

B-adrenergic receptor blockers

**e.g. hypertension drugs**

32

What are the advantages of B-adrenergic receptor stimulants?

Fast onset
Short duration of action

33

Why is the short duration of action of B-adrenergic receptor stimulant considered an advantage?

Not desirable to keep increasing force of contraction after relieving acute heart failure

34

What are the adverse effects of B-adrenergic receptor stimulants?

Pro-arrhythmic
Pro-angina
Tachyphylaxis (tolerance)

35

Why doe B-adrenergic receptor stimulant cause Pro-angina?

Increase in heart rate

> Decrease in diastolic time and heartbeat compresses on coronary artery

> Less time for coronary blood flow to meet demand

36

What is the route of admin. for B-adrenergic receptor stimulant ?

IV
for acute HF

37

What is the MoA of phosphodiesterase inhibitors?

Phosphodiesterase is for breaking down cAMP to AMP

Inhibit phosphodiesterase III** > decrease breakdown of cAMP

> Increase activation of PKA
> increase Calcium entry, thus Ca release from SR
> Increase intracellular [Ca2+]

38

What drug works synergistically with phosphodiesterase inhibitor?

B-adrenergic receptor stimulant

39

Recall some other drugs that are also phosphodiesterase inhibitors ?

Methylxanthines: Theophylline, aminophylline: Non-specific PDEi

Viagra/ Sildenafil: PDE-5i

Daxas/ roflumilast: PDE-4i (for COPD)

40

Recall the action of increased intracellular Ca causing contraction of vascular SM?

increased Ca2+ influx activates myosin light-chain kinase (MLCK) to phosphorylate myosin


>> contraction of
vascular smooth cells

41

What is the net effect of phosphodiesterase inhibitors ?

Peripheral vasodilating
action

42

List the advantages and disadvantages of phosphodiesterase inhibitors ?

Advantage = Vasodilating effect
Disadvantage = Pro-arrhythmic (due to increased Ca)
GI disturbances

43

What are some adverse effects of PDE inhibitor at high doses?

Hypotension
Headache

44

What is the MoA of Cardiac glycosides?

Inhibit Na+/K+ ATPase (and SERCA) to pump out Na

Increase intracellular [Na+] > causing SHIFT in Na+/Ca2+ exchanger**

> Influx of Ca2+ and Efflux of Na+
> Increase Ca2+ storage in SR and intracellular [Ca2+]

45

What is the function of cardiac glyocsides?

Anti-arrhythmic

46

What is the adverse effect of cardiac glycosides at high dose?

- Pro-arrhythmic and delayed afterdepolarizations (due to increased intracellular [Ca])

- GI disturbances (due to inhibition of Na+/K+ ATPase in GI tract)

- CNS disturbances (due to inhibition of Na+/K+ ATPase)

47

Is the therapeutic window for cardiac glycosides wide or narrow?

Narrow

48

Why is cardiac glycosides not used as a first line therapy?

Effects are opposed by increased K+ and Mg2+

49

How can the adverse effects of cardiac glycosides be managed?

By increasing K+ and Mg2+ in body

50

Between the 4 positive inotropic drugs, which are used for acute heart failure and what adverse effects do they share?

Pro-arrhythmic effects caused by B-Adrenergic stimulator, PDE inhibitor, Cardiac glycosides

B-Adrenergic stimulator, PDE inhibitor are used for Acute HF

51

What is the MoA for Calcium sensitizers?

Stabilize binding between troponin C and calcium

> Increase affinity of troponin C for Ca
> Increase sensitivity to Ca
> Increase contractility without increase [Ca]

52

How come Calcium sensitizers are less prone to cause arrhythmia?

Increase contractility of heart without increase in intracellular Ca conc.

53

What is the major effect of Calcium sensitizers?

Drug causes huge efflux of K+ by activating several K channels

> Hyperpolarization of vascular smooth muscle

> nonselective coronary
and systemic vasodilator

54

What is the route of admin for Calcium sensitizers and what are the adverse effects?

IV

Due to vasodilatation:
 Headache (insufficient blood
supply to brain)
 Hypotension (decreased
perfusion to peripheral
organs)
*adverse effects like PDEi*

55

Compare the extent of vasodilations between Levosimendan, Milrinone and Dobutamine?

Dobutamine = (non-selective) B-Adrenergic receptor stimulant = Mild systemic vasodilation

Milrinone = PDEi = Peripheral vasodilation

Levosimendan = Calcium sensitizer = CORONARY and Systemic vasodilation

56

Compare the side effects between Levosimendan, Milrinone and Dobutamine?

Dobutmaine = Pro-arrhythmic, Pro-angina

Milrinone = Pro-arrhythmic, Headache, Hypotension

Levosimendan = Headache and Hypotension

57

What are the 4 stages of chronic HF?

A, B (asymptomatic)

C (previous / current symptoms)

D (refractory symptoms)

58

Which drugs are used for stage A, B (asymptomatic)?

 Angiotensin inhibitors
 β-blocker

for Reduce risk factor (e.g. hypertension, hyperlipidemia, diabetes, obesity)

59

Which drugs are ROUTINELY (not selected) used for stage C (previous / current symptoms) and some stage D patients?

 Diuretics (if fluid retention is present)
 Angiotensin-converting enzyme inhibitors
 β-blocker

60

Which drugs are selectively used in patients with some stage C and all stage D patients?

 Aldosterone antagonist

 Angiotensin receptor blockers

 Cardiac glycosides

 Nitrates/hydralazine (additive to “drugs for routine use”)

61

Angiotensin receptor blockers are used for Stage D HF under what condition?

if patient is intolerant to ACE inhibitors >> switch to Angiotensin receptor blocker

62

Aldosterone antagonists are used for Stage D HF under what condition?

If patient has perserved renal function

63

Cardiac glycosides are used for Stage D HF under what condition?

If Atrial fibrillation is present

64

Nitrates/hydralazine are used for Stage D HF under what condition?

Used as additive drug to Routine drugs :
-Diuretics
-Angiotensin converting enzyme inhibitor
-B-blockers

65

What are the 3 effects of increased sympathetic activity on the heart?

1) Increase contractile force >> SV
2) Increase HR >> CO
3) Increase venous tone to increase venous return

All increases mean arterial pressure

66

What is the MoA of new drug Ivabradine?

Decrease HR by inhibiting HCN channels

67

What is the MoA of Valsartan +sacubitril combo therapy?

LCZ696

**optional, not in exam**

Valsartan = angiotensin receptor blocker

Sacubitril = prevent ventricular remodelling, bradykinin breakdown, diuresis and anti-fibrosis

68

What drug prevents bradykinin breakdown?

ACEi

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