cardiac failure drug treatment

Question 0

disease progression of heart failure -
heart failure - chronic or acute state resulting from failure of heart to meat 02 demand of the body
what are the primary and LT effects of cardiac failure?

Answer 0

primary effects:
- reduce CO, excessive SNS discharge, Na and water retention

LT effects:
- remodelling, cardiac hypertrophy and cardiac apoptosis

Question 1

explain the pathophysiology of cardiac failure and what the general treatment method used

Answer 1

preload - atrial pressure – increase in blood volume and venous tone <– inotropic drugs

HR – increased through SNS compensation

Question 2

what are the 7 classes of drugs used as for cardiac failure drug treatment?

Answer 2

digitalis/digoxin - antagonist of Na/K ATPase pump 
nitrates - prodrug of NO
ACE-I
angiotensin receptor antagonist 
aldosterone antagonist 
beta blockers
diuretics

Question 3

drug --> digitalis/digoxin 
nature 
MOA
consequence
uses
pharmacokinetics
SEs

Answer 3

antagonist of Na/K ATPase pump
works on heart and vascular SM
heart:
- digoxin blocks Na/K ATPase which is connected to 2nd transporter that sends Ca out – hence when blocked –> less expulsion of cystolic Ca by Na/Ca exchanger
- this will increase intracellular Ca –> which would increase cystolic Ca released from sarcoplasmic reticulum
- more Ca available to bind to troponin –> increase contractility

vascular smooth muscle
- inhibition of Na/K ATPase cause depolarisation which causes SM contraction and vasoconstriction

effects:

• primary effect of CHF is reduced cardiac output hence digoxin aim is to INCREASE CARDIAC OUTPUT
• increase force of contraction
• increase CO and SV - clear the heart to reduce ventricular/atrial pressure
• decrease HR - dont pump as much due to more efficient clearance
• decrease BV
• decrease heart size and wall tension
• increase cardiac efficiency

uses: beneficial effect in heart failure - partial return to normal.

PK:

• orally active w 60-80% bioavailability
• renal elimination
• half life 36 hours damn long
• loading w maintenance dose
• useful at 1-2.6nM
• toxicity hence use at lower range; toxicity is patient specific hence requires monitoring (read more on notes)

SEs

• antiarrhythmic at low doses but pro-arrhythmic at higher doses
• GI
• visual effects – orange hue in eyes
• neurological and neuromuscular effects

Question 4

cardiac failure
drugs - nitrates
example
general MOA etc (drug used in treatment of angina pectoralis)

Answer 4

nitroglycerin
isosorbide mononitrate

nature: prodrug when metabolised will release NO which will activate guanyl cyclase cascade so on

1) maintain platelet at resting/inactivated state
2) vasodilation - main target SMC
- PK-G work on myosin light chain and dephosphorylate it - inactivate - reduce uptake of Ca - inhibit vasoconstriction.

relax large arteries – reduce aortic pressure
relax smc - esp vascular
coronary vasodilation - collaterals – coronary BF
venorelaxation and reduce central venous pressure - reduce preload - hene reduce SB
relief coronary spams

• good for stable and unstable angina + acute cardiac failure

Question 5

cardiac failure 
drug: ACE-I 
example 
MOA
consequence
uses
SEs

Answer 5

captopril, elanopril
RAAS inappropriately activated in heart failure (through low BP)
hence inhibit AGI–>AGII
AGII – 1) salt retention through aldosterone and Na reabsorption 2) activate SNS via adrenaline to increase BP

abnormal vasoconstriction, increase ald, vasopressin and endothelin, platelet aggregation and remodelling – vascular growth and hypertrophy hyperplasia

effects: reduce vascular resistance and improve tissue perfusion and reduce cardiac afterload

• vasodilation - reduce afterload improve perfusion
• natriuresis - excretion of large amt Na in urine
• reduction of aldosterone

SE:
persistant cough
risk of angioedema - swelling of deeper layers of skin caused by buildup of fluid

Question 6

cardiac failure
drug - angiotensin receptor antagonist 
examples
MOA
use
SE

Answer 6

losartan, valsartan

block AT1 receptor
AT1 receptor allows for:
1) vascular growth - hypertrophy and hyperplasia
2) vasoconstriction - direct or via SNS adrenaline
3) salt retention - ald secretion and tubular Na reabsorption

–> reduce vascular resistance and improve tissue perfusion and reduce cardiac afterload

SE:
no cough!

Question 7

cardiac failure
drug – aldosterone antagonist
example
SE

Answer 7

spironlactone, eplerenone

• competitive antagonist of ald receptor
• block ald binding at minerocorticoid receptor in kidney heart brain and BV
  -blockage in distal renal tubule increase NaCl secretion and water too, w K retention (hyperkalemia)
• ald - is grossly elevated in cardiac failure - Na retention (edema) and Mg/K retention (arrhythmias), SNS activation, PNS inhibition and fibrosis
  SE:
  serious hyperkalemia
  renal insufficiency
  breast pain
  rash

Question 8

cardiac failure
drug - beta blockers
examples
nature
MOA
consequences
uses

Answer 8

bisopolol, metoprolol, carvediol…
beta adrenergic receptor antagonist
cardiac myocyte protection of receptor from catecholamine
prevent binding of autoantibodies to adrenoreceptor – anyhow activation of signalling pathway

consequences:
- heart rate reduction - improve diastolic BF and oxygenation - more time for diastole <- where coronary blood flows!!!

uses:
-use along w ACEI - major drug therapy associated w LV systolic dysfunction

Question 9

cardiac failure
drug - diuretics
consequences

Answer 9

ST: reduce pulmonary congestion (reduce BV), peripheral edema and body weight
intermediate: improve cardiac function, symptoms and exercise tolerance
LT: currently - incomplete studies on mortality