Drugs influencing cardiac structure and function Flashcards
Digoxin
- cardiac glycoside
- oral administration, long half-life
- ionotropic agent
- improves contractility by inhibiting the Na+/K+ ATPase (less Na+ pumped out means less Ca2+ pumped out), increasing intracellular Ca2+ that moves into the SR
- tf more Ca2+ is released in subsequent APs
- narrow margin of safetey, low therapeutic index (desired and undesired effects very close)
- widely distributed and non-specific
- affects all excitable tissues (gut, CNS, cardiac)
- used to treat atrial dysrhythmia by increasing PSNS activity through the vagus nerve
What are the adverse effects of digoxin and other cardiac glycosides?
- continuous administration shortens ventricular AP
- leads to LADs from Ca2+ overload
- promotes ventricular dysrhythmias
- leads to LADs from Ca2+ overload
- affects all exciteable tissues:
- gut - anorexia, nausea, diarrhoea
- CNS - drowsiness, confusion, psychosis
- cardiac - ventricular dysrhythmias
- increased toxicity with:
- low K+ (decreased competition for binding at the Na/KATPase)
- high Ca2+ (decreased gradient for Ca2+ efflux)
- renal impairment
By what mechanism does SNS stimulation increase contractility and rate?
- @ SA node
- @ B1-aRs on myocytes
- agonist binding activates adenyly cyclase via G protein
- +cAMP
- activates PKA
- PKA phosphorylates Ca++ channel –> opens
- cAMP is degraded to AMP by phosphodiesterase
Amrinone
phosphodiesterase inhibitor
What is the use of beta agonists and phosphodiesterase inhibitors in heart failure?
- IV administration
- acute, short term support for acute heart failure and cardiogenic shock
- beta agonists:
- noreadrenaline, adrenaline
- activate both alpha and beta-aRs
- dobutamine
- selective b1-aR agonist
- noreadrenaline, adrenaline
- PDE inhibitors:
- amrinone
- inhbitis cAMP –> AMP
- amrinone
What are the adverse effects of beta agonists and PDE inhibitors in heart failure?
- increased cardiac work
- increased O2 demand
- risk of arrhythmias
Dobutamine
- selective b1-aR agonist
- replaced prenalterol as it is a stronger agonist and will still work if the receptor becomes desensitized
What is the consequence of chronic heart failure on b1-aRs?
- chronic overactivation by sympathetic compensation for reduced CO causes:
- reduced b1-aR expression
- tf -cAMP activation and contraction
- impaired b1-aR coupling with adenyly cyclase and cAMP
- reduced b1-aR expression
- leading to an overall reduced sensitivity to b1-aR agonists or sympathetic drive
What is the role of ionotropes in heart failure?
- +contractile force of myocytes
- this can increase work on the heart, negating symptomatic relief it overused
- symptomatic relief of:
- chest pain
- fainting
- death
- excessive use can lead to cardiac remodelling (hypertrophy, -compliance), altering cardiac pump function
What are the types of drugs used to combat increased afterload and increased preload in heart failure?
- beta blockers
- ACE inhibitors
- aldosterone antagonists
- diuretics
- venodilators
- vasodilators
How are nitrates used in heart failure?
- to reduce preload by venodilation
- undergo first-pass metabolism tf admin under tongue or by patch
- primarily for angina (symptomatic relief in cardiac failure)
- can develop tolerance, tf useful in intermittent conditions
How is furosemide/frusemide used in heart failure?
- to reduce preload as a diuretic
- acts at loop of henle
What is the function of aquaretics?
- vasopressin (ADH) receptor antagonists
What types of drugs reduce preload?
- venodilators (nitrates)
- diuretics (furosemide/frusemide)
- aldosterone receptor antagonists
- aquaretics (vasporessin/ADH receptor antagonists)
Spironolactone
- aldosterone receptor antagonist
- inhibits aldosterone action on the cortical and distal tubules
- K+ sparing, tf can cause hyperkalaemia - must be monitored
- can interfere with renal function
- improves survival w/combo therapy in severe heart failure
What types of drugs reduce afterload?
- arterial vasodilators
- ACE inhibitors
- AT1 antagonists (alternative to ACE inhibitors)
- b-aR antagonists
What is the risk of using arterial vasodilators to reduce afterload in heart failure?
- the vasodilation causes a drop in BP triggering a baroreflex tachycardia
- this causes the heart to work harder
- tf not used as front-line therapy
What are the first line therapy drugs in heart failure?
- ACE inhibitors
- decrease angiotensin II production
- this decreases vasoconstriction (-afterload)
- and decreases fluid retention (-preload)
- tf limiting progression of hypertrophy
- RAS involved in remodelling
How do ACE inhibitors function in heart failure?
- first-line therapy
- decrease angiotensin II
- decreases vasoconstriction (-afterload)
- decreases fluid retention (-preload)
- slows cardiac hypertrophy
How are angiotensin I antagonists used in heart failure?
- afterload reduction
- used when ACE inhibitors do not work
How do beta blockers function in heart failure?
- adjuncts to ACE inhibitors and diuretics
- reduce HR
- decrease renin secretion
- lowers O2 demand at heart by lowering the extracellular volume and increasing the O2 carrying capacity of blood
What are the benefits of using ACE inhibitors and agiotensin receptor blockers (ARBs) in heart failure?
- nb: also used in hypertension
- effective at all grades of HF
- improve symptoms, delay progression of remodelling
- reduce mortality up to 30-40%, reduce morbidity
What are the adverse effects of ACE inhibitors and ARBs in treating heart failure?
- first-dose hypotension - titrate dosage
- dry cough
- loss of taste
- hyperkalaemia (rx: thiazide diuretic)
- acute renal failure
- itching, rash, angioedema
- foetal malformations (contratx in pregnancy)
In what patients with heart failure are ACE inhibitors and ARBs contraindicated?
- bilateral renal stenosis
- angioneurotic oedema
- pregnancy
When treating heart failure, ACE inhibitors and ARBs should be used in adjunct with
- diuretics
- thiazide for hyperkalaemia
- glycosides
- b-aR antagonists
What are the side effects of beta blockers?
- hypotension, fatigue (cadiac & b2 mediated)
- bronchoconstriction (b2 block)
- cold extremities (a1 mediated)
- cause or mask signs of hypoglycemia
therefore, contraindicated in:
- asthma
- PVD (peripheral vascular disease)
- diabetes
How do beta blockers cause increased stroke volume if they block b1 receptors?
- b1 blockade removes NA influence, decreasing cardiac output
- stroke volume increases because working at a high CO is inefficient (frank-starling)
- tf reducing CO with beta blockers increases efficiency which increases SV
Why is the use of beta blockers in heart failure considered counter-intuitive?
- some side effects actually worsen the symptoms
- often used to inhibit the early stages of the disease process
Metoprolol
- cardiac b1 blockade in heart failure:
- reduces tachycardia and cardiac work (inhibits compensation)
- inhibits renin release and subsewuent AII effects
- protects against receptor downregulation
- used in early and mild to moderate CHF
Carvedilol
- b1 and a1 vascular blockade in heart failure
- vasodilation reduces afterload, cardiac work
- can improve ejection fraction (SV)
- can reduce mortality
- can reduce chance of fatal stroke or MI
- used in early and mild to moderate CHF
What are the aims of heart failure treatment?
- decrease cardiac work and improve cardiac function
- preload, afterload, contractility
- reduce signs and symptoms
- oedema, fatigue, arrhythmias, ventricular remodelling
- increase survival
- one-year mortality rate is ~10% for mild and moderate CHF
Symptomatic relief in heart failure is achieved by
- ionotropes to improve contractility
- diuretics and venodilators to decrease preload
Mortality in heart failure is reduced by
- angtiotensin inhibitors, beta blockers, and aldosterone antagonists decreasing afterload and preload
What are the alternatives to pharmacological treatment of heart failure?
- surgical:
- pacemaker, defib, valve replacement, transplant
- complements to pharm and surgical approaches:
- reduce salt, dluid, alcohol intake
- stop smoking
- exercise
- consider risk factors and attenuate them with lifestyle changes
