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Cardiovascular Biology 311 > Lecture 9: Inotropic mechanisms > Flashcards

Lecture 9: Inotropic mechanisms Flashcards

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1
Q

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

A 
Angiotensinogen 
- Renin
ANG 1
- ACE
ANG 2

= Vasoconstriction, Aldosterone, sympathetic drive

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2
Q

What does reduced renal perfusion pressure lead to?

A

Renin release
Catecholamines
ADH
Prostaglandins

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3
Q

What are the aims of treatment for heart failure?

A

1) To improve symptoms

2) Improve survival of the patient

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4
Q

What drugs aim to improve symptoms?

A

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)

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5
Q

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

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

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

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6
Q

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

A

Diuretics
Vasodilators (nitrates)
ACE inhibitors
ANG receptor agtagonists

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7
Q

What are some examples of ACE inhibitors?

A

Captoprolol

Enalprolol

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8
Q

Whats some examples of ANG 2 receptors antagonists?

A

Losartan

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9
Q

Whats some examples of inotropes?

A
  • Cardiac glycosides (digoxin)
  • Sympathomimetics (dobutamine)
  • PDE inhibitors
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10
Q

What does contractile force depend on?

A

The number of cross bridge cycles activated (inotropy)

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11
Q

Learn the cross birdge cycle

A

now

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12
Q

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

A

ATP hydrolyses

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13
Q

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

A

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

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14
Q

What is inotropy dependant on?

A

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)

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15
Q

How can inotropy be increased endogenously?

A

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

Affected by ion concentration gradient

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16
Q

Describe Ca uptake in HF;

A
  • 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
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17
Q

Whats a Na/K ATPase inhibitor?

A

Digoxin

18
Q

Whats an PDE inhibitor?

A

Enoximone

19
Q

What is a beta adernergic agonist?

A
  • Dobutamine

- Dopamine

20
Q

What increases troponin Ca sensitivity?

A

Levosimendon

21
Q

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

A

Istaroxmine

  • Also activates SERCA and Reverses NCX
22
Q

How can SERCA levels be increased?

A

Via gene transfer SERCA insertion virus vector

23
Q

What is a problem with using some of these drugs?

A

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

24
Q

Whats a cardiac myosin activator?

A

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

25
Q

What is a drug that activates SERCA and a Vasodilator?

A

HNO
NO

Nitrates

26
Q

Whats a drug that is an energetic modulator?

A

Etomoxir or pyruvate

Changes from FA oxidation to glycolysis

27
Q

How do beta receptors agonists work to increase inotropic state?

A

Beta agonists

  • Increase cAMP levels
  • Increase PKA activity
  • Increase Ca
28
Q

Describe how istaroxime functions

A
  • 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
29
Q

Describe how omecamtiv mecarbil works:

A

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)

30
Q

Describe how nitroxyl donors work?

A
  • Vasodilator, affects coronary beds (good) and other large arteries
  • Increased SERCA activity
31
Q

How does gene therapy work?

A

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

32
Q

How do RYR stabilizers work?

A
  • 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

33
Q

What hormone does the failing myocardium release?

A

Relaxin like factor.

Increases eNOS and iNOS expression

34
Q

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

A

ANP release

  • Natriuretic (na)
  • Diuretic
  • Kaliuretic (k)

Antagonizes RAAS

35
Q

What are the two forms of digoxin?

A
  • Digoxin

- Digitalis

36
Q

Give an overview of digoxin function

A
  • Rapid onset
  • Low oral activity
  • Hydrophile
  • Low affinity for serum proteins
37
Q

Give an overview of digitalis function;

A
  • LONG duration
  • Slow onset
  • Lipophile
  • Good absorption
  • Strong binding to serum proteins
  • OH group
38
Q

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

A

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

39
Q

Discribe how digoxin functions;

A

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
40
Q

Describe the actions of digoxin

A

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

41
Q

Whats the side effects of digoxin?

A

GI effects

  • Anorexia
  • Abd pain
  • Vommiting
  • Diarrhoea

Arrhythmias (increased cytosol Ca, DADs)

  • Premature ventricular contractions
  • Atrial tachycardias
  • AV dissociation
42
Q

What is the use of digitalis?

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

Cardiovascular Biology 311 (18 decks)

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