Pharmacological control of contractility Flashcards
What are 2 main uses of positive inotropes?
Cardiac failure (chronic/ischaemic and acute)
Hypovolaemia (actual and functional e.g. vasodilation so lose effective circulating volume)
What 3 main factors affect cardiac output?
Cardiac input (i.e. venous return) and thus SV
Contractility
Peripheral resistance
What are the priorities for inotropes treating ischaemic heart disease?
Increase contractility but not oxygen demand
Vasodilation to reduce afterload
Increase cardiac output
What are the focuses of inotropes in treating cardiogenic shock?
Vasoconstriction (avoid vasodilation)
Must increase cardiac output
What is a risk of using inotropes to treat acute cardiac failure?
Increasing contractility may enhance ischaemia due to reduced coronary perfusion
What are 2 main types of positive inotropes?
Sympathomiemetics
Non sympathomimetic positive inotropes
What are the 3 types of inotropes needed for exams?
Sympathomimetics
Cardiac glycosides
Calcium sensitising agents
When are sympathomimetics used?
Acute shock/hypotension to increase cardiac contractility
What is the risk of sympathomimetics?
Myocardial ischaemia (due to increased oxygen supply) and arrhythmias
What are the direct and indirect effects of sympathomimetics?
Direct: affect symp receptors
Indirect: effect intracellular messengers
What are 2 broad examples of sympathomimetics?
Phosphodiesterase inhibitor
Catecholamines
What are examples of PDE inhibitors?
Milrinone, methyl xanthines
What are the actions of indirect sympathomimetics?
Inhibit phosphodiesterase 3 so amplify effects of beta adrenergic stimulation, prolong effects of cAMP
When are phosphodiesterase inhibitors not effective?
When beta blockers taken
What are examples of catehcolamines?
Noradrenaline, adrenaline, dopamine, dobutamine
What are the effects of catecholamines (+ve and -ve), what do they act on?
Beta 1 receptors
Increase heart rate and contractility
Increased myocardial oxygen consumption
What is the benefit of catecholamines increasing vascular tone?
Reduce blood supply to vascular beds of gut, kidney etc so more fluid available in circulating volume
What is the effect of high levels of adrenaline on bp, why is this useful?
Increased blood pressure so can be used for hypotension
Why does moderate adrenaline cause vasodilation in skeletal muscle but elevated amounts cause vasoconstriction?
At moderate levels: mostly bound to beta receptor
Higher doses: beta receptors saturated so adrenaline binds alpha receptors
How can adrenaline and dopamine cause myocardial ischaemia?
Increase cardiac workload, insufficient perfusion to cornary arteries so not enough oxygen.
What are the solutions to the problems of dopamine and adrenaline, how come?
Dobutamine (b1 agonist):
reduces risk from myocardial infarction but increases cardiac output.
Does not act on dopamine receptors so less prone to hypertension
What is a problem with dobutamine?
Not as effective as dopamine at vasoconstriction and also causes mesenteric vasodilation so lose blood volume to gut
Why is dobutamine not used for ischaemic heart disease?
Increases heart rate and thus myocardial oxygen demand, though note, better than adrenaline
Describe action of propanolol
Adrenoceptor antagonist so have negative effect on contractility and inotropy
Examples of calcium sensitisers?
Levosimendan, omecamtiv
What do calcium sensitisers do, why are they good?
Increase sensetivity of contractile mechanism to calcium so increase force of contraction without extra ion pumping (i.e. doesn’t increase oxygen demand much)
What does omecamtiv do?
Myosin activator: prolong contractile phase of actin myosin cycling so increase contractility
What are examples of cardiac glycosides?
Digoxin, ouabain and digitoxin
What are the benefits of cardiac glycosides?
Increase contractility
Little increase in oxygen demand
Have diuretic effect so reduce effect of circulating volume so reduced ventricular dilation
What are some side effects of cardiac glycosides?
Risk of arrhythmia as delayed after depolarisations
How come cardiac glycosides don’t increase oxygen demand?
Heart does not have to exert as much force to pump the blood, or they directly increasing the heart’s contractile force, so that the heart can overcome the higher blood pressure.
What are good treatments for ischaemic heart failure?
Calcium sensitiser
Cardiac glycosides
What is a possible mechaism for cardiac glycosides?
Inhibition of Na+ K+ ATPase
So build up of sodium within cell
This reduces Na+ gradient to drive NCX
So less Ca2+ extruded, Ca builds up and increase contractility.
How do after depolarisations arise?
Excessive increase in Ca2+ inside cells during depolarisation causes delayed after depolarisations due to activation of Na+ Ca2+ exchange (which brings in more Na+ so cell depolarises) and opening of Ca2+ sensitive non selective ion channels
Why can after depolarisations be problematic?
As heart rate increases, after depolaristation increases until it is high enough to trigger an AP - self perpertuating effect leading to tachycardia.
What is the initial therapy you would give?
NICE
Beta blockers
ACE inhibitors
Diuretics
Why do ACE inhibitors treat cardiac failure?
ACE inhibitors
Reduce reabsorption of sodium and water at the kidneys
Reduces after-load
What are some examples of ACE inhibitors?
Ramipril
Enalapril
Captopril
What use do beta blockers give in treating heart disease?
Reduce risk of arrythmias
Reduce the oxygen demand of tissue proportionally more than they reduce contraction – tissue more efficient
Reduce heart rate, improved mortality
What is an example of a negative inotrope?
Beta blocker
Why are beta blockers good for treating ischaemic heart disease?
Reduce oxygen demand of tissue
Why are diuretics effective at treating heart disease?
Reduce after load by lowering blood volume (normal starling range), lowers oedema
How does NO act as a good first line treatment for CHD?
Causes smooth muscle relaxation
Improves blood flow to cardiac tissue itself (e.g. used for angina)
Reduces the pressure against which the heart has to work
When is ivabradine used?
As a second line of treatment (if beta blockers ineffective), reduce heart rate (CHD)
What does ivabradine act on and what is its effect?
HCN4 (If) inhibitor, reduces the rate of pacemaker potential decay and slows heart rate
After blockade of both sympathetic and parasympathetic neural influence on the heart, the heart rate would typically be…
Higher than the control rate
