49 - Drugs Influencing Cardiac Structure and Function Flashcards
What determines preload?
Input into the heart
What determines afterload?
Resistance to flow of blood vessels after heart
Old name for heart failure
Dropsy
How was symptomatic relief of dropsy achieved?
Digitalis extracts from Foxglove plant
Active component of digitalis
Digoxin, a cardiac glycoside
Effect of cardiac glycosides on myocytes
Increases Ca2+ release in cardiac myocytes after depolarisation.
At lower doses increases contractility.
At higher doses have dysrhythmias
Mechanism of digoxin action 1) 2) 3) 4)
1) Inhibit Na+/K+ ATPase.
2) Increased intracellular [Na+] decreases Ca2+ extrusion from cell.
3) This increases [Ca2+] in sarcoplasmic reticulum
4) This increases amount of Ca2+ released on action potential
Margin of safety of cardiac glycosides
Narrow margin of safety.
Side effects of cardiac glycosides
1)
2)
3)
Affects all excitable tissues
1) GIT - anorexia, nausea, diarrhoea
2) CNS - drowsiness, confusion, psychosis
3) Cardiac - ventricular dysrhythmias
What are cardiac glycosides used to treat?
Atrial dysrhythmias
What increases cardiac glycoside toxicity?
1)
2)
3)
1) Low K+
2) High Ca2+
3) Renal impairment
Why does low K+ increase cardiac glycoside toxicity?
K+ normally competes with digoxin for binding to Na+/K+ATPase. If there is less K+ competing, more of administered digoxin binds ATPase, increasing potency.
Half life of digoxin
T1/2+~40 hours
Volume of distribution of digoxin
Vd + ~400L.
Due to high-affinity binding to skeletal and cardiac muscle
Why is digoxin used to treat atrial dysrhythmia?
Increases parasympathetic activity on heart, which is good for dysrhythmias from sympathetic overstimulation.
Mechanism is not well understood
Use of beta-adrenoceptor agonists in treating heart failure
Intravenous, short-term treatment for acute heart failure.
Short-term treatments for acute cardiac failure
Beta-adrenoceptor agonists, phosphodiesterase inhibitors
Example of a selective beta1 adrR agonist
Dobutamine
Why can’t beta1 adrR agonists be used as a long-term treatment for cardiac failure?
1)
2)
3)
1) Chronic activation of beta1 adrR
2) With overstimulation of beta1 from sympathetic compensation for cardiac failure, plus beta1 agonist stimulation reduced beta1 expression and coupling to signal transducers in cell.
3) Reduced sensitivity of heart to beta1 agonists or sympathetic drive
Phosphodiesterase inhibitor use
Phosphodiesterase breaks down cAMP.
cAMP formed as a result of adrenoceptor stimulation, so stopping cAMP breakdown increases effects of adrenoceptor stimulation.
Used to treat heart failure (short-term treatment)
Side effects of phosphodiesterase inhibitors
Same as adrenoceptor agonists
Example of a phosphodiesterase inhibitor
Amrinone
Side effects of phosphodiesterase inhibitors, adrenoceptor agonists
Increased cardiac work, leading to increased O2 demand
Risk of arrhythmias
Inotrope use in treating cardiac failure
Can increase contractility of cardiomyocytes.
Symptomatic relief.
Side effects of inotropes
Progression of symptoms (doesn’t stop underlying cause of cardiac failure)
Cardiac remodelling is sped up (hypertrophy)
Cause of death from heart failure
Insufficient CO to meet tissue needs
Causes of acute and chronic heart failure
1)
2)
3)
1) Loss of contractility (loss of myocardial muscle)
2) Increased afterload (pressure overload)
3) Increased preload (increased volume)
Potential causes of loss of myocardial muscle, leading to CF
Ischaemic heart disease
Cardiomyopathy
Potential causes of increased afterload, leading to CF
Pressure overload from aortic stenosis, hypertension
Potential causes of increased preload, leading to CF
Volume overload from valve regurgitation, shunts (septal defects)
How can compensatory mechanisms for low CO lead to worsening CF?
Vasoconstriction from alpha1 adrR stimulation increases afterload (pressure)
Increased blood volume from aldosterone leads to increased preload (volume)
Potential treatments for excessive afterload 1) 2) 3) 4)
1) Vasodilators (to decrease MAP)
2) ACE inhibitors
3) AT1 antagonists (alternative to ACE inhibitors)
4) Beta-adrR antagonists
Potential treatments for excessive preload 1) 2) 3) 4)
1) Venodilators (to decrease volume of blood that heart has to pump).
2) Diuretics
3) Aldosterone receptor antagonists
4) Aquaretics (vasopressin receptor antagonists)
Diuretics that are stronger than thiazides
Frusemide. Works on loop of Henle
Example of venodilators
Nitrates.
Effect of aldosterone receptor antagonists
Inhibits aldosterone action on cortical and distal tubules.
What is spirolactone?
A K+-sparing diuretic.
Aldosterone receptor antagonist
Monitoring required for aldosterone receptor antagonists
Monitor for hyperkalaemia, renal failure
First-line therapy for afterload reduction
ACE inhibitors
Effect on disease progression of ACE inhibitors
Delay progression
Why do beta-adrR help in cardiac failure?
Counter-intuitive
Beta1 blockade used in early disease to protect against receptor downregulation.
Alpha1, beta1 blockade reduces afterload, cardiac work
Effect of beta1 adrR in cardiac failure
1)
2)
3)
1) Reduces tachycardia, cardiac work
2) Inhibits renin release, therefore preload (volume)
3) Protects against adrenoceptor downregulation
When do you use beta adrR in heart failure?
Early mild to moderate chronic heart failure
Aims of cardiac failure treatment
1)
2)
3)
1) Decrease cardiac work, improve function
2) Reduce signs and symptoms
3) Increase survival (one-year survival)
Drugs affecting contractility
1)
2)
Inotropes
1) Acute - beta adrR antagonists, phosphodiesterase inhibitors
2) Chronic - Cardiac glycosides (EG: digoxin)
Drugs affecting preload
Diuretics, venodilators, aldosterone agonists
Drugs providing symptomatic relief
Inotropes (beta adrR agonists, PDE inhibitors, glycosides), diuretics, venodilators
Drugs that reduce mortality
Angiotensin inhibitors, beta adrR antagonists, aldosterone antagonists
Drugs affecting afterload
Angiotensin inhibitors, beta adrR antagonists
