Cardiovascular: Pharmacology - Heart failure Flashcards
List 7 classes of treatments used in the management of chronic systolic HF. Which of these confer a mortality benefit and reduction in hospitalisations?
- Diuretics
- Aldosterone receptor antagonists*
- ACEIs/ARBs
- B-blockers*
- Cardiac glycosides
- Vasodilators
- Resynchronisation, cardioversion
- mortality benefit and reduction in hospitalisations (certain B-blockers only)
List 6 classes of treatments used in the management of acute HF
- Diuretics
- Vasodilators
- B-agonists
- Bipyridines
- Natriuretic peptide
- LVAD
What is the effect of B-agonists in acute vs chronic HF?
Used in treatment of acute HF but reduce survival in chronic HF
What’s the most common cause of HF?
CAD
What are the three types of HF? Describe each briefly
- Systolic failure: decreased contractility, HFrEF
- Diastolic failure: stiffening and decreased relaxation leading to reduced filling and reduced SV/CO, often HFpEF, more common with increasing age and in women
- High-output failure
List 4 causes of high-output HF
- Hyperthyroidism
- Anaemia
- Beriberi
- AV shunts
What are four main pathophysiological features of HF? What causes each
- Increased preload: due to increased Na+/H2O retention, venous tone
- Increased afterload: due to increased TPR
- Reduce contractility: due to remodelling, cell apoptosis
- Increased HR: due to B-adrenergic stimulation
What are the effects of tachycardia in HF?
Reduced filling time and coronary blood flow
Describe the pathophysiology of HF
- Reduced CO results in reduced carotid sinus firing and reduced renal blood flow
- Reduced carotid sinus firing causes increased sympathetic discharge: increased contractility, HR and preload
- Reduced renal blood flow activates RAAS: angiotensin II increases afterload and further increases sympathetic discharge
What is the effect of HF on the baroreceptor reflex?
Baroreceptor reflex is reset with lower sensitivity to arterial pressure
Decreased stimulation of vasomotor centre increases sympathetic outflow and decreases parasympathetic outflow
What class of drug is digitalis/digoxin?
Cardiac glycoside
Describe the pharmacokinetics of digitalis in terms of its chemical structure and ADME
Chemical structure: steroid nucleus, lacks easily ionisable group so solubility is not pH-dependent
Absorption: bioavailability 65-80%
Distribution: widely distributed (including CNS) with 20-30% protein binding
Metabolism: 2/3 excreted unchanged by kidneys, t1/2 = 36-40hrs with normal renal function
Elimination: proportional to CrCl
List four drugs which inhibit excretion of digitalis
Amiodarone
Verapamil
Quinidine
Spironolactone
What is the mechanism of action of digitalis?
Inhibits Na+/K+ ATPase
Causes increased intracellular Na+, which produces decrease Ca2+ efflux via Na+/Ca2+ antiport
Increased cytosolic Ca2+ increases contractility
Describe the effects of digitalis on intracellular K+
Initially: increased K+ conductance due to increased Ca2+ causes reduced action potential duration
At higher doses: decreased K+ due to Na+/K+/ATPase pump inhibition causes resting membrane potential to become less negative, can get delayed after-depolarisations which cause ectopics if they reach thresholds -> further increase in dose produces tachyarrhythmias
Describe the autonomic effects of digitalis
Low therapeutic doses increase parasympathetic effects (predominantly in SA and AV nodes as there is less cholinergic innervation in ventricles)
At toxic doses increases sympathetic outflow
What are the three cardiac effects of digitalis?
- Positive inotropy
- Negative chronotropy (decreased SA node firing and conduction velocity)
- Negative dromotropy (increased AV block)
What are two extra-cardiac effects of digitalis?
GI: increased motility (N+V, diarrohoea), anorexia
CNS: vagal and chemoreceptor trigger zone stimulation, disorientation, hallucination, visual disturbance
What is the effect of K+, Ca2+ and Mg2+ on risk of digoxin toxicity?
Decreased K+, decreased Mg2+ and increased Ca2+ all increase digoxin toxicity
What arrhythmias can be induced by digoxin?
AV junctional rhythm
PVCs
Bigeminy
VT
2nd degree AVB
How is digoxin toxicity treated?
Digibind (sheep Ab)
What is the clinical application for digoxin?
Used in patients with HF and AF
What is the mechanism of action of bipyridines?
Inhibits PDE-3
Increased contractility by increased Ca2+ influx during action potential
Also vasodilates
Give an example of a bipyridine
Milrinone
