Lecture 9: Inotropic mechanisms

Question 1

Describe the RAA pathway and how it attempts to combat heart failure;

Answer 1

Angiotensinogen 
- Renin
ANG 1
- ACE
ANG 2

= Vasoconstriction, Aldosterone, sympathetic drive

Question 2

What does reduced renal perfusion pressure lead to?

Answer 2

Renin release
Catecholamines
ADH
Prostaglandins

Question 3

What are the aims of treatment for heart failure?

Answer 3

1) To improve symptoms

2) Improve survival of the patient

Question 4

What drugs aim to improve symptoms?

Answer 4

1) Diuretics = decrease BV, VR, Preload, (lower volume overload) Ventricle dilation or decrease BP and (decrease pressure overload) decrease ventricle hypertrophy
2) digoxin = inotropic agent, inc CO (preserve EF)
3) ACE inhibitors (lower fluid retention)

Question 5

What drugs are used to improve the survival of the patient?

Answer 5

• ACE inhibitors
• Beta blockers
• Spirinolactone (weak diuretic, long term)

All exist to remodel chamber size to improve EF and assist HF

Question 6

What are some non-inotropic agents used in heart failure? (think of what they do)

Answer 6

Diuretics
Vasodilators (nitrates)
ACE inhibitors
ANG receptor agtagonists

Question 7

What are some examples of ACE inhibitors?

Answer 7

Captoprolol

Enalprolol

Question 8

Whats some examples of ANG 2 receptors antagonists?

Answer 8

Losartan

Question 9

Whats some examples of inotropes?

Answer 9

• Cardiac glycosides (digoxin)
• Sympathomimetics (dobutamine)
• PDE inhibitors

Question 10

What does contractile force depend on?

Answer 10

The number of cross bridge cycles activated (inotropy)

Question 11

Learn the cross birdge cycle

Answer 11

now

Question 12

What is the rate limiting step in the cross bridge cycle?

Answer 12

ATP hydrolyses

Question 13

In theory what does a drug want to do to increase inotropic state?

Answer 13

Increase SERCA activity or inhibit/reverse NCX to increase cytosolic Ca and increase Ca uptake into the SR for the next Ca spark and cross bridge cycle

Question 14

What is inotropy dependant on?

Answer 14

1) The amount of Ca available to bind troponin C
2) The affinity of Ca for troponin C
3) Alterations at the level of the cross bridge cycle (time)

Question 15

How can inotropy be increased endogenously?

Answer 15

1) LD activation (LT-FS relationship)
2) Force frequency relationship
3) Catecholamines

Affected by ion concentration gradient

Question 16

Describe Ca uptake in HF;

Answer 16

• SR Ca uptake is abnormal due to SR leak through RYR channels (leads to arrhythmias)
• Decreased SERCA levels (downregulated)
• NCX upregulation thus increased Ca elimination

Question 17

Whats a Na/K ATPase inhibitor?

Answer 17

Digoxin

Question 18

Whats an PDE inhibitor?

Answer 18

Enoximone

Question 19

What is a beta adernergic agonist?

Answer 19

• Dobutamine

- Dopamine

Question 20

What increases troponin Ca sensitivity?

Answer 20

Levosimendon

Question 21

What a non-cardiac glycoside Na/K ATPase inhibitor?

Answer 21

Istaroxmine

• Also activates SERCA and Reverses NCX

Question 22

How can SERCA levels be increased?

Answer 22

Via gene transfer SERCA insertion virus vector

Question 23

What is a problem with using some of these drugs?

Answer 23

Their receptors are through the body = side effects, not just in the heart

Question 24

Whats a cardiac myosin activator?

Answer 24

omecamtiv mecarbil accelerates the release actin dependant phosphate release. (rate limiting step)

Question 25

What is a drug that activates SERCA and a Vasodilator?

Answer 25

HNO NO Nitrates

Question 26

Whats a drug that is an energetic modulator?

Answer 26

Etomoxir or pyruvate Changes from FA oxidation to glycolysis

Question 27

How do beta receptors agonists work to increase inotropic state?

Answer 27

Beta agonists - Increase cAMP levels - Increase PKA activity - Increase Ca

Question 28

Describe how istaroxime functions

Answer 28

- Inhibits Na/K ATPase, deminished Na gradient, NCX slows, Ca accumulates, increased SERCA uptake - It also activates SERCA - Increased Na may stimulate NCX to reverse

Question 29

Describe how omecamtiv mecarbil works:

Answer 29

Increases the rate of actin dependant phosphate release. (rate limiting step). Transition to the force producing on state. More cross bridge units are activated per unit time. = increased contractile force and inotropy Doesnt alter Ca levels (less likely for arrhythmia) Doesnt increase O2 consumption of cells (important as other drugs do and if CAD then could cause infarct)

Question 30

Describe how nitroxyl donors work?

Answer 30

- Vasodilator, affects coronary beds (good) and other large arteries - Increased SERCA activity

Question 31

How does gene therapy work?

Answer 31

Upregulation of SERCa via gene insertion is suggested to improve systolic and diastolic function in animal models.

Question 32

How do RYR stabilizers work?

Answer 32

- Leak of Ca from the SR reduces Ca availability for contraction (lower inotropy) and may promote diastolic dysfunction due to diastolic activation of contractile proteins (leaking) Therefore using drugs to stabilize these may prevent Ca release

Question 33

What hormone does the failing myocardium release?

Answer 33

Relaxin like factor. Increases eNOS and iNOS expression

Question 34

What could be targeted in the heart not previously mentioned to protect it from HF?

Answer 34

ANP release - Natriuretic (na) - Diuretic - Kaliuretic (k) Antagonizes RAAS

Question 35

What are the two forms of digoxin?

Answer 35

- Digoxin | - Digitalis

Question 36

Give an overview of digoxin function

Answer 36

- Rapid onset - Low oral activity - Hydrophile - Low affinity for serum proteins

Question 37

Give an overview of digitalis function;

Answer 37

- LONG duration - Slow onset - Lipophile - Good absorption - Strong binding to serum proteins - OH group

Question 38

What does the strong binding to serum proteins mean for patients on digitalis?

Answer 38

They must be monitored at the serum level for toxicity (narrow window) especially if the patient has raised serum protein levels.

Question 39

Discribe how digoxin functions;

Answer 39

Blocks Na/K ATPase - Increased iNa, some depolarisation - NCX slowed (eNa drops) - Increased iNa leads to increased iCa via NCX reversal - Increased Ca = Ca spark and increased inotropic state

Question 40

Describe the actions of digoxin

Answer 40

F - increased force E - Increased excitability A - Decreased AV conduction (prolonged plateau) R - Decreased rate (HR)

Question 41

Whats the side effects of digoxin?

Answer 41

GI effects - Anorexia - Abd pain - Vommiting - Diarrhoea Arrhythmias (increased cytosol Ca, DADs) - Premature ventricular contractions - Atrial tachycardias - AV dissociation

Question 42

What is the use of digitalis?

Answer 42

- Potent drug - Long half life, careful patient titration needed - Clearly indicated in failure when atrail flatter/ fibrillation is present