Lec 23- inotropes Flashcards
Inotropes
- Increase cardiac force
- Inotropes are used to support failing heart
- The heart may fail in several circumstances and a variety of drugs may be used to support it
- HR is effected by chronotropes
HF
- HF is condition that develops when the hears muscle becomes weakened after injury
- This can be from high BP, and loses its ability to pump sufficient blood to supply the bodies needs
- On a frank-starling curve a failing heart will see decreased CO and more EDV
HF risk factors
- AMI
- High BP
- High ChE
- Damage to heart valves
- Diabetes
- Obesity
Mechanism responsible for HF
- Decreased energy production
- Increased energy utilisation
- Abnormal Ca homeostasis
- Altered gene expression
Compensatory mechanisms in HF
A) Frank-Starling
B) Neuroendocrine response: increase sympathetic output; increased RAAS activity; increased ADH (vasopressin)
C) Myocardial hypertrophy
Inotropes can be divided into the following classes
- Cardiac glycosides: digoxin
- Catecholamines: NA and adrenaline
- Phosphodiesterase inhibitors- sildenafil
- Calcium entry promoters- : opposite of CCB. Act on nitrendipine receptors
- Ca
- Ca sensitisers- increase affinity of troponin for calcium (depressed by hypoxia and acidosis). Potential future development (potential advantage that they wouldn’t increase myoplasmic Ca, therefore pherhaps less problems with arrhythmias)
Factors involved in cardiac contraction
- AP OR
- NA acts on B1-adrenoceptors (dobutamine act on these) resulting in phosphorylation (PKA pathway) of Ca2+ channels which increases opening times
- 1) Depolarisation allows Ca2+ influx through voltage gated Ca2+ channels
- 2) Ca2+ release from sarcoplasmic reticulum (SR) increases Ca2+ still further
3) Ca2+ plus troponin= contraction
Mechanism for decrease of Ca2+
1) Ca2+ is extruded in exchange for Na by Ca2+ exchanger (CE)
2) Na+ is exchanged with K+ by the Na/K/ATPase (Na pump;SP)
- Cardiac glycosides inhibit the Na pump leading to: slow removal of Ca2+ so increasing concentration –> increasing force of contraction
Muscle cell: cardiac or vascular
- AP
- Open Ca channels
- Influx of Ca2+
- These act on SR channels
- This causes further release of Ca2+
Inotrope action
- Inotrope action involves Ca2+ handling in the cardiac myocyte
- Rationale is to increase Ca2+ available of contractile proteins
- This is done by: increase Ca2+ influx; Decreasing Ca2+ efflux
Increasing Ca2+ influx
- B-adrenergic activation- dobutamine
- Phosphodiesterase inhibition- sildenafil
B-Aadrenergic activation
- Activation of B1 receptors, leads via adenylate cyclase which turns ATP to cAMP. cAMP activates Protein Kinase A (PKA)
- PKA phosphorylates L-type Ca2+ channels, which favours mode 2 gating (Opens them, also opens them for longer)
- Amount of Ca2+ entry during depolarisation is therefore increased
- Increased Ca2+ also means that more is stored in the sarcoplasmic reticulum for subsequent release
- Post synaptic B1-receptors are predominant adrenergic receptors in the heart
- Stimulation causes increased rate and force of cardiac contraction. mediated by cAMP
3 modes of Ca2+ channel opening
-Mode 0 opening probability is 0 Favoured by DHP antagonists % of time spent like this=<1% -Mode 1 Opening probability is low %of time spent like this=70% -Mode 2- This is the mode when opened by B-agonist Opening probability is high Favoured by DHP agonists %of time spent like this=30% -Weather or not a channel is open affects the binding of the drug
In addition to causing increased Ca2+ entry
- B1 adrenoceptors activation also leads to an increase of the sensitivity of the contractile machinery, probably via troponin C phosphorylation
- There is also more cytosolic Ca2+ for uptake into the SR, so that there is more Ca2+ for release during the AP
- Net result is to elevate and steepen the ventricular function curve
B-receptors
- Post synaptic B1 receptors are predominant adrenergic receptors in heart
- Stimulation causes increased rate and force of cardiac contraction
- Mediated by cAMP
- Post synaptic B2-receptors in vasculature mediate vasodilation
a1-receptors
- Post synaptic cardiac a1 receptors:
- Stimulation cause ssignificant increase in contractility without an increase in rate
- Mediated by IP3- Ca2+ release
- Effect more pronounced at low HR
- Slower onset and longer duration than B1-receptors mediated response
Dobutamine
- B1 agonist
- IV continuous infusion in acute severe HF; infarction; cardiac surgery; cardiomyopathy; septic shock; cariogenic shock and during positive expiratory pressure ventilation
Adrenaline/Epinephrine
- Agonist at a and B receptors, net effect is Inotropic
- Iv continuous infusion I cardiopulmonary resuscitation; anaphylaxis; acute hypotension
Phosphodiesterase inhibitors
- In cardiac muscle PDEIII catalyses breakdown of cAMP
- Inhibiting PDE III leads to increased levels of cAMP
- Increased activation of PKA
- Increased phosphorylation of L-type Ca2+ channels leads to more Ca2+ entry on depolarisation and so underlies the Inotropic effect
Phosphodiesterase inhibitors 2
-increased Ca2+ influx increases rate and force of myocardial contraction
-cAMP also affects diastolic heart function through enhanced Ca re-sequestration rate and hence improves diastolic relaxation
-Synergistic with beta agonists
-Also relax vascular smooth muscle resulting in vasodilation
-Myocardial O2 consumption and HR are not significantly increased
-Tolerance is not a feature
NB different variants of PDE
Enoximone and milrinoe
- USE: management of decompensated CHF
- Ademonstration: IV; (ITU or CCU)
- Monitoring: BP; ECG: platelets; K+; CVP
- Adverse effects: arrhythmias; hypersensitivity; hypotension
Decreasing Ca2+ efflux
- Na/K/ATPase inhibition
- Ca2+ is extruded in exchange for Na by the Na/Ca2+ exchanger
- Depends on Na gradient; Na is maintained low internally by Na/K/ATPase pump
- By maintaining high conc of Na inside the cell this means that the Na/Ca exchanger can’t work as effectively which means that Ca2+ stays inside the cell for longer
Cardiac glycosides
- Inhibit Na/K/ATPase
- Digoxin from digitalis purpurea (foxglove)
- Na gradient is maintained bt ATPase pump
- Na gradient drives Ca/Na
- Reduced Na gradient slows Ca removal (by inhibition of ATPase)
- NB due to the fact that we can’t pump out Ca2+ it is stored in sarcoplasmic reticulum
Digoxin mechanism
-Inhibits Na/K/ATPase and produces subtle changes in resting electrolyte status
-Increase [Na]i
Increased [Na]I reduces driving force for Ca efflux and thereby increased Ca2+ loading in the SR (positive inotropic effect)
-Decreases [K]i
-Lowers resting membrane potential (i.e. more +ve), makes them more excitable and more likely to depolarise
Digoxin
- Increases contractility: positive inotrope; used for HF treatment
- Decreased HR: Negative chronotrope; Used to control HR in AF
- Monitoring; ECG: pulse; renal function; K; symptoms of toxicity; TDM
Parasympathetic effects of cardiac glycosides
- Reduces HR
- Acts on Vagus nerve; the lowering of the resting membrane potential means the nerve is more excitable
- Therefore release more ACh (inhibitory effect)
- This acts on the SAN causing heart rate to slow down
Frank starling curve- failing heart
- A failing heart is unable to pump enough blood to meet the bodies demands
- Due to decrease in the contractility of the left ventricle heart mule
- Seen in the frank starling curve as a decrease in CO relative to ventricular filling
