Lecture 17: Heart failure and angina Flashcards
HFrEF
HF with reduced EF (ejection fraction)
weakened or impaired contractility
cannot overcome afterload (the pressure heart have to push against)
CARDIOMYOCYTE LOSS
EFpEF
HF preserved ventricular EF with diastolic dysfunction failing to relax in diastole and ventricle cannot fill with blood
ventricle cannot relax
due to INFLAMMATION and REMODELLING
2 compensatory mechanism to early heart failure
- Activation of SNS (increase cardiac output)
2. Activation of RAAS through B1 receptor (increase blood pressure)
4 modulation to effective treatment of heart failure
- decrease preload
- decrease afterload
- increase contractility (short term), decrease contractility (long term)
- decrease heart rate
1st line treatment for Heart failure
Diuretics and ACE inhibitors
2nd or 3rd line treatment for heart failure
Beta blockers and vasodilators
Digitalis Glycosides (Digoxin)
positive inotropy in healthy and failing heart
increase contraction of cardiac sarcomere by increasing free Ca
increase cardiac contractility and cardiac output (decrease end diastolic volume)
Electrical effects of digoxin
inhibit Na/K ATPase pump
decrease action potential due to increase intracellular calcium and increase K conductance (decrease intracellular K)
toxic effect: dose dependent arrhythmias
Autonomic effects of digoxin
domination of parasympathetic tone due to sensitization of baroreceptors and vagal stimulation
less SNS activation
decrease heart rate and ventricular contraction
Digoxin drug interactions
enhanced by slow GI motility, change in electrolytes level, renal clearance and stimulation of B Adr receptor
reduced by reduced GI absorption, increased GI motility and enhanced biotransformation (phenytoin and ASA)
How to treat digoxin intoxication
increase serum K by supplements
pacemaker
digitalis antibody to mop up excessive digoxin
Dobutamine
B adrenergic agonist
only for ACUTE measures
increase CO and decrease filling pressure
increase cAMP and PKA phosphorylation of L-type calcium channel to increase Ca influx
also increase blood pressure
increase O2 demand and angina
Paradoxical pharmacology of Beta adrenergic drug
Congestive heart failure
acute: B agonist
chronic: B blocker
Asthma
acute: B agonist
chronic: ?
Bipyrimidines
Inamrinone and milrinone
inhibits PDE-3
increase cAMP increase intracellular Calcium during cardiac AP
increase contractility and vasodilation (due to decrease extracellular Ca in vsm)
LONG TERM TREATMENT CAN LEAD TO INCREASE MORBIDITY due to increase Ca lead to increase O2 demand
Levosimendan
calcium sensitizers
increase affinity for troponin C for Calcium
make Ca more effective without increase cAMP in intracellular calcium
inotropic effect as well as vasodilator (decrease in K leads to efflux of Ca leads to hyperpolarization)
shown to inhibit PDE3 at therapeutic conditions
NO INCREASE IN MORBIDITY
Ivabradine
inhibit funny current of pacemaker cell
reduce heart rate
decrease O2 demand
only used for stable CHF
Entresto
Angiotensin-receptor Neprilysin inhibitor (ARNI)
used for HFrEF
Valsartan (Angiotensin receptor blocker) + Sacubitril (Neprilysin inhibitor)
NP promote diuresis natriuresis and vasodilation
NP reduce cardiac remodeling
counteracts RAAS
Dapagliflozin
SGLT2 inhibitor
used for T2D to reduce glucose reabsorption to blood glucose
decrease risk of hospitalization for HF and CV death in HFrEF and 30% reduction in HFpEF
reduce preload and afterload
Organic Nitrates (GTN, ISDN and ISMN)
PRODRUGS which act as source for nitric oxide
rapid angina pain relief
increase cGMP
increase dephosphorylation of MLCK
inhibit Ca influx at calcium channel
lead to less intracellular calcium, vasodilation and muscle relaxation
Adverse effect of organic nitrate
headache through vasodilation
hypotension
syncope (temporary loss of consious)
skin rash and inflammation with transdermal formulation
HIGH DOSES reduce TPR increase baroR (SNS)
Sodium Nitroprusside (SNP)
decrease both preload and afterload
increase cardiac output
delivered through IV
TREAT HYPERTENSIVE EMERGENCY (acute)
no increase in O2 demand
mimic activation of endogenous NO
effect apparent in 30 seconds, disappear in 3 min
Nesiritide
recombinant hBNP
only decrease preload
very rapid
adverse effect: hypotension, headache, nausea
RENAL TOXICITY
did not reduce mortality
Hydralazine
decrease afterload only
unknown mechanism
activates baroreceptor reflex due to a1 stimulation and release of NE
increase heart rate, contractility and SNS stimulation
Dihydropyridines (Nifedipine and amlodipine)
work at L-type calcium channel
only reduce afterload
Non-dihydropyridines
verapamil and diltiazem
act at periphery and heart
decrease contractility worsen heart failure
decrease vascular resistance
decrease afterload
use for hypertension: reduce TPR, slow heart rate
DO NOT USE WITH HEART FAILURE and BRADYCARDIA
Difference between DHP and non-DHP
DNP: lower affinity for channels in heart, little effect on HR and contraction, preferred in heart failure and vasodilator
non-DNP: similar affinity for heart and vsm, reduce strength and rate of heart contraction
cause reduction of TPR
used in treating arrhythmias and vasodilators