Flashcards in L65 – Positive Inotropic Drugs Deck (68):
Change in cardiac output during heart failure?
CO = SV x HR
Decrease in both SV (force of contraction decreases) and HR means CO is decreased
Compare acute and chronic heart failure in their compensation, time span and urgency/ danger?
Acute = decompensated, Develops rapidly (hours/days), Life-threatening
Chronic = Compensated, long-term condition (months/years), asymptotic due to adaptive changes
Compare acute and chronic heart failure in their management? Can they be managed?
Acute = can successfully manage by pharmacological or surgical intervention
Chronic = cannot manage successfully (reverse condition) but can alleviate
*adaptive changes of heart are irreversible*
Name the 5 drug classes in heart failure?
A Boy Visits Police Department
1) Angiotensin inhibitors
2) B-adrenergic receptor blocker
4) Positive Inotropic drug
What are the 2 Compensatory mechanisms to restore cardiac output in chronic heart failure?
1. Autonomic feedback – Increase sympathetic autonomic nervous activity
2. Hormonal feedback – stimulate renin-angiotensin aldosterone system
What is the consequence of increased sympathetic activity to restore CO in chronic heart failure?
Increase sympathetic activity > vasoconstriction, increase TPR > Increase Mean arterial pressure
> Increase cardiac workload, causing:
1) Myocardial hypertrophy
2) Ventricular remodeling (deposition of fibrotic tissue)
What is the consequence of increased RAAS activity to restore CO in chronic heart failure?
Activate RAAS > Increase water and salt retention in kidneys > Increase blood volume > Increase cardiac workload
1) Myocardial hypertrophy
2) Oedema of peripheral tissue, especially in ankles
3) Pulmonary oedema and SoB
How does the compensatory mechanisms of the heart in chronic heart failure only worse the situation?
Both compensatory mechanisms aim to increase CO,
but also increases mean arterial pressure and TPR (by activating a-adrenergic receptors)
>> ultimately lower CO
Compensatory mechanism becomes viscous cycle
What is the action of positive inotropic drugs?
Increase force of contraction of heart to restore CO
Which of the 5 heart failure drugs is for acute HF, which for Chronic HF?
For acute HF:
For long-term management of chronic HF:
-B-adrenergic receptor block
What are the 4 types of positive inotropic drugs?
Boy passes Crazy Criminal
B-Adrenergic receptor stimulant
Which of the positive inotropic drugs increases intracellular calcium concentration, which doesnt?
Calcium sensitizer= doesn't increase intracellular calcium concentration
The rest all increase intracellular calcium concentration
Name 2 common B-Adrenergic stimulants?"
Name 2 common Phosphodiesterase inhibitor?
Name 1 common Cardiac glycosides?
Name 1 common Calcium sensitizers?
What is the MoA of B-Adrenergic receptor stimulants?
Activate β1-adrenoceptor in cardiomyocyte:
- Increase intracellular cAMP
- Activation of PKA
- Increase intracellular [Ca2+] through L-type calcium channel
- Trigger larger release of Ca2+ from Sarcoplasmic Reticulum
Which of the B-Adrenergic receptor stimulants are enatiomer sensitive?
Explain the different enantiomers of Dobutamine and their respective effects?
(-) enantiomer = agonist of a-adrenergic receptors >> vasoconstriction
(+) enantiomer = partial agonist (or antagonist) of a-adrenergic receptors >> reduce vasoconstriction
What is the action of Dobutamine if both enantiomers are included? *in heart and in vessels*
non-selective agonists of
In heart: positive inotropic effect (activate B1 channel)
In vasculature: activation of B2 in vascular SM >> vasodilation, effect of (-) offset by (+) enantiomer
What does the pharmacological effect of Dopamine depend on?
Concentration of drug given
Compare the independent factors to the drug actions of Dopamine and Dobutamine
Dopine = dependent on concentration
Dobutamine = dependent on enantiomer
What is the difference in net effect between low dose vs Intermediate and high dose Dopamine?
Low dose = Decrease TPR
Int. to high dose = positive inotropic effect
Recall which drugs are used to treat asthma that belong to the same class as a positive inotropic drug?
B2 selective stimulants causes bronchodilation
Used for asthma and other obstructive lung diseases
e.g Salbutamol, formoterol...
What is the MoA for Dopamine at low dose?
=< 2 μg/kg/min
1) Activate D1 receptors in vascular smooth muscle >
2) Activate D2 receptors on sympathetic nerves at peripheral circulation:
a) Inhibit noradrenaline release
b) thus decrease in a-adrenergic receptor mediated vasoconstriction
Dopamine at low dose particularly targets D2 receptors where in the peripheral circulation?
(esp. at renal and splanchnic arterial beds)
What is the MoA for Dopamine at intermediate dose?
activate cardiac β1 adrenergic receptors
> positive inotrophy
What is the MoA for Dopamine at High dose?
activate vascular a- adrenergic receptors
>> Cause peripheral arterial and venous constriction
>> Increase afterload and further decrease CO
What are the clinical limitations of B-adrenergic receptor stimulants?
>> Decrease in efficacy after 4 days
What drug is added with B-adrenergic receptor stimulant to combat the tolerance development?
Phosphodiesterase III inhibitor
What drug contradicts B-adrenergic receptor stimulant ?
B-adrenergic receptor blockers
**e.g. hypertension drugs**
What are the advantages of B-adrenergic receptor stimulants?
Short duration of action
Why is the short duration of action of B-adrenergic receptor stimulant considered an advantage?
Not desirable to keep increasing force of contraction after relieving acute heart failure
What are the adverse effects of B-adrenergic receptor stimulants?
Why doe B-adrenergic receptor stimulant cause Pro-angina?
Increase in heart rate
> Decrease in diastolic time and heartbeat compresses on coronary artery
> Less time for coronary blood flow to meet demand
What is the route of admin. for B-adrenergic receptor stimulant ?
for acute HF
What is the MoA of phosphodiesterase inhibitors?
Phosphodiesterase is for breaking down cAMP to AMP
Inhibit phosphodiesterase III** > decrease breakdown of cAMP
> Increase activation of PKA
> increase Calcium entry, thus Ca release from SR
> Increase intracellular [Ca2+]
What drug works synergistically with phosphodiesterase inhibitor?
B-adrenergic receptor stimulant
Recall some other drugs that are also phosphodiesterase inhibitors ?
Methylxanthines: Theophylline, aminophylline: Non-specific PDEi
Viagra/ Sildenafil: PDE-5i
Daxas/ roflumilast: PDE-4i (for COPD)
Recall the action of increased intracellular Ca causing contraction of vascular SM?
increased Ca2+ influx activates myosin light-chain kinase (MLCK) to phosphorylate myosin
>> contraction of
vascular smooth cells
What is the net effect of phosphodiesterase inhibitors ?
List the advantages and disadvantages of phosphodiesterase inhibitors ?
Advantage = Vasodilating effect
Disadvantage = Pro-arrhythmic (due to increased Ca)
What are some adverse effects of PDE inhibitor at high doses?
What is the MoA of Cardiac glycosides?
Inhibit Na+/K+ ATPase (and SERCA) to pump out Na
Increase intracellular [Na+] > causing SHIFT in Na+/Ca2+ exchanger**
> Influx of Ca2+ and Efflux of Na+
> Increase Ca2+ storage in SR and intracellular [Ca2+]
What is the function of cardiac glyocsides?
What is the adverse effect of cardiac glycosides at high dose?
- Pro-arrhythmic and delayed afterdepolarizations (due to increased intracellular [Ca])
- GI disturbances (due to inhibition of Na+/K+ ATPase in GI tract)
- CNS disturbances (due to inhibition of Na+/K+ ATPase)
Is the therapeutic window for cardiac glycosides wide or narrow?
Why is cardiac glycosides not used as a first line therapy?
Effects are opposed by increased K+ and Mg2+
How can the adverse effects of cardiac glycosides be managed?
By increasing K+ and Mg2+ in body
Between the 4 positive inotropic drugs, which are used for acute heart failure and what adverse effects do they share?
Pro-arrhythmic effects caused by B-Adrenergic stimulator, PDE inhibitor, Cardiac glycosides
B-Adrenergic stimulator, PDE inhibitor are used for Acute HF
What is the MoA for Calcium sensitizers?
Stabilize binding between troponin C and calcium
> Increase affinity of troponin C for Ca
> Increase sensitivity to Ca
> Increase contractility without increase [Ca]
How come Calcium sensitizers are less prone to cause arrhythmia?
Increase contractility of heart without increase in intracellular Ca conc.
What is the major effect of Calcium sensitizers?
Drug causes huge efflux of K+ by activating several K channels
> Hyperpolarization of vascular smooth muscle
> nonselective coronary
and systemic vasodilator
What is the route of admin for Calcium sensitizers and what are the adverse effects?
Due to vasodilatation:
Headache (insufficient blood
supply to brain)
perfusion to peripheral
*adverse effects like PDEi*
Compare the extent of vasodilations between Levosimendan, Milrinone and Dobutamine?
Dobutamine = (non-selective) B-Adrenergic receptor stimulant = Mild systemic vasodilation
Milrinone = PDEi = Peripheral vasodilation
Levosimendan = Calcium sensitizer = CORONARY and Systemic vasodilation
Compare the side effects between Levosimendan, Milrinone and Dobutamine?
Dobutmaine = Pro-arrhythmic, Pro-angina
Milrinone = Pro-arrhythmic, Headache, Hypotension
Levosimendan = Headache and Hypotension
What are the 4 stages of chronic HF?
A, B (asymptomatic)
C (previous / current symptoms)
D (refractory symptoms)
Which drugs are used for stage A, B (asymptomatic)?
for Reduce risk factor (e.g. hypertension, hyperlipidemia, diabetes, obesity)
Which drugs are ROUTINELY (not selected) used for stage C (previous / current symptoms) and some stage D patients?
Diuretics (if fluid retention is present)
Angiotensin-converting enzyme inhibitors
Which drugs are selectively used in patients with some stage C and all stage D patients?
Angiotensin receptor blockers
Nitrates/hydralazine (additive to “drugs for routine use”)
Angiotensin receptor blockers are used for Stage D HF under what condition?
if patient is intolerant to ACE inhibitors >> switch to Angiotensin receptor blocker
Aldosterone antagonists are used for Stage D HF under what condition?
If patient has perserved renal function
Cardiac glycosides are used for Stage D HF under what condition?
If Atrial fibrillation is present
Nitrates/hydralazine are used for Stage D HF under what condition?
Used as additive drug to Routine drugs :
-Angiotensin converting enzyme inhibitor
What are the 3 effects of increased sympathetic activity on the heart?
1) Increase contractile force >> SV
2) Increase HR >> CO
3) Increase venous tone to increase venous return
All increases mean arterial pressure
What is the MoA of new drug Ivabradine?
Decrease HR by inhibiting HCN channels
What is the MoA of Valsartan +sacubitril combo therapy?
**optional, not in exam**
Valsartan = angiotensin receptor blocker
Sacubitril = prevent ventricular remodelling, bradykinin breakdown, diuresis and anti-fibrosis