Lecture 17: Heart failure and angina

Question 1

HFrEF

Answer 1

HF with reduced EF (ejection fraction)

weakened or impaired contractility

cannot overcome afterload (the pressure heart have to push against)

CARDIOMYOCYTE LOSS

Question 2

EFpEF

Answer 2

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

Question 3

2 compensatory mechanism to early heart failure

Answer 3

1. Activation of SNS (increase cardiac output)

2. Activation of RAAS through B1 receptor (increase blood pressure)

Question 4

4 modulation to effective treatment of heart failure

Answer 4

1. decrease preload
2. decrease afterload
3. increase contractility (short term), decrease contractility (long term)
4. decrease heart rate

Question 5

1st line treatment for Heart failure

Answer 5

Diuretics and ACE inhibitors

Question 6

2nd or 3rd line treatment for heart failure

Answer 6

Beta blockers and vasodilators

Question 7

Digitalis Glycosides (Digoxin)

Answer 7

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)

Question 8

Electrical effects of digoxin

Answer 8

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

Question 9

Autonomic effects of digoxin

Answer 9

domination of parasympathetic tone due to sensitization of baroreceptors and vagal stimulation

less SNS activation

decrease heart rate and ventricular contraction

Question 10

Digoxin drug interactions

Answer 10

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)

Question 11

How to treat digoxin intoxication

Answer 11

increase serum K by supplements

pacemaker

digitalis antibody to mop up excessive digoxin

Question 12

Dobutamine

Answer 12

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

Question 13

Paradoxical pharmacology of Beta adrenergic drug

Answer 13

Congestive heart failure

acute: B agonist
chronic: B blocker

Asthma

acute: B agonist
chronic: ?

Question 14

Bipyrimidines

Answer 14

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

Question 15

Levosimendan

Answer 15

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

Question 16

Ivabradine

Answer 16

inhibit funny current of pacemaker cell

reduce heart rate

decrease O2 demand

only used for stable CHF

Question 17

Entresto

Answer 17

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

Question 18

Dapagliflozin

Answer 18

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

Question 19

Organic Nitrates (GTN, ISDN and ISMN)

Answer 19

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

Question 20

Adverse effect of organic nitrate

Answer 20

headache through vasodilation

hypotension

syncope (temporary loss of consious)

skin rash and inflammation with transdermal formulation

HIGH DOSES reduce TPR increase baroR (SNS)

Question 21

Sodium Nitroprusside (SNP)

Answer 21

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

Question 22

Nesiritide

Answer 22

recombinant hBNP

only decrease preload

very rapid

adverse effect: hypotension, headache, nausea

RENAL TOXICITY

did not reduce mortality

Question 23

Hydralazine

Answer 23

decrease afterload only

unknown mechanism

activates baroreceptor reflex due to a1 stimulation and release of NE

increase heart rate, contractility and SNS stimulation

Question 24

Dihydropyridines (Nifedipine and amlodipine)

Answer 24

work at L-type calcium channel

only reduce afterload

Question 25

Non-dihydropyridines

Answer 25

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

Question 26

Difference between DHP and non-DHP

Answer 26

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