Lecture 9: Inotropic mechanisms Flashcards
Describe the RAA pathway and how it attempts to combat heart failure;
Angiotensinogen - Renin ANG 1 - ACE ANG 2
= Vasoconstriction, Aldosterone, sympathetic drive
What does reduced renal perfusion pressure lead to?
Renin release
Catecholamines
ADH
Prostaglandins
What are the aims of treatment for heart failure?
1) To improve symptoms
2) Improve survival of the patient
What drugs aim to improve symptoms?
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)
What drugs are used to improve the survival of the patient?
- ACE inhibitors
- Beta blockers
- Spirinolactone (weak diuretic, long term)
All exist to remodel chamber size to improve EF and assist HF
What are some non-inotropic agents used in heart failure? (think of what they do)
Diuretics
Vasodilators (nitrates)
ACE inhibitors
ANG receptor agtagonists
What are some examples of ACE inhibitors?
Captoprolol
Enalprolol
Whats some examples of ANG 2 receptors antagonists?
Losartan
Whats some examples of inotropes?
- Cardiac glycosides (digoxin)
- Sympathomimetics (dobutamine)
- PDE inhibitors
What does contractile force depend on?
The number of cross bridge cycles activated (inotropy)
Learn the cross birdge cycle
now
What is the rate limiting step in the cross bridge cycle?
ATP hydrolyses
In theory what does a drug want to do to increase inotropic state?
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
What is inotropy dependant on?
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)
How can inotropy be increased endogenously?
1) LD activation (LT-FS relationship)
2) Force frequency relationship
3) Catecholamines
Affected by ion concentration gradient
Describe Ca uptake in HF;
- 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
Whats a Na/K ATPase inhibitor?
Digoxin
Whats an PDE inhibitor?
Enoximone
What is a beta adernergic agonist?
- Dobutamine
- Dopamine
What increases troponin Ca sensitivity?
Levosimendon
What a non-cardiac glycoside Na/K ATPase inhibitor?
Istaroxmine
- Also activates SERCA and Reverses NCX
How can SERCA levels be increased?
Via gene transfer SERCA insertion virus vector
What is a problem with using some of these drugs?
Their receptors are through the body = side effects, not just in the heart
Whats a cardiac myosin activator?
omecamtiv mecarbil accelerates the release actin dependant phosphate release. (rate limiting step)
What is a drug that activates SERCA and a Vasodilator?
HNO
NO
Nitrates
Whats a drug that is an energetic modulator?
Etomoxir or pyruvate
Changes from FA oxidation to glycolysis
How do beta receptors agonists work to increase inotropic state?
Beta agonists
- Increase cAMP levels
- Increase PKA activity
- Increase Ca
Describe how istaroxime functions
- 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
Describe how omecamtiv mecarbil works:
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)
Describe how nitroxyl donors work?
- Vasodilator, affects coronary beds (good) and other large arteries
- Increased SERCA activity
How does gene therapy work?
Upregulation of SERCa via gene insertion is suggested to improve systolic and diastolic function in animal models.
How do RYR stabilizers work?
- 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
What hormone does the failing myocardium release?
Relaxin like factor.
Increases eNOS and iNOS expression
What could be targeted in the heart not previously mentioned to protect it from HF?
ANP release
- Natriuretic (na)
- Diuretic
- Kaliuretic (k)
Antagonizes RAAS
What are the two forms of digoxin?
- Digoxin
- Digitalis
Give an overview of digoxin function
- Rapid onset
- Low oral activity
- Hydrophile
- Low affinity for serum proteins
Give an overview of digitalis function;
- LONG duration
- Slow onset
- Lipophile
- Good absorption
- Strong binding to serum proteins
- OH group
What does the strong binding to serum proteins mean for patients on digitalis?
They must be monitored at the serum level for toxicity (narrow window) especially if the patient has raised serum protein levels.
Discribe how digoxin functions;
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
Describe the actions of digoxin
F - increased force
E - Increased excitability
A - Decreased AV conduction (prolonged plateau)
R - Decreased rate (HR)
Whats the side effects of digoxin?
GI effects
- Anorexia
- Abd pain
- Vommiting
- Diarrhoea
Arrhythmias (increased cytosol Ca, DADs)
- Premature ventricular contractions
- Atrial tachycardias
- AV dissociation
What is the use of digitalis?
- Potent drug
- Long half life, careful patient titration needed
- Clearly indicated in failure when atrail flatter/ fibrillation is present
