Pharmacological Options in Heart Failure 1 & 2

M.10, W.2, L.8+9

List the 4 different drug classes used for heart failure

• Sympathomimetics

• Diuretics

• Vasodilators

• Inodilators

Define Sympathomimetics

drugs that stimulate the sympathetic nervous system, mainly through B1-adrenoreceptors in the heart

Describe the MOA for Sympathomimetics

B1 receptor stimulation activates adenylate cyclase through a G-protein:

B1 receptor activation → ↑ cAMP → ↑Ca2+ → ↑cardiaccontractility

This leads to:

• increased intracellular Ca2+

• increased force of contraction (positive inotropy)

• Increased heart rate (positive chronotropy)

Describe the G-protein-coupled receptor and cAMP pathway and how that leads to increased intracellular Ca2+ for sympathomimetics

• Drug or hormone binds to B1-adrenoreceptor on cardiac muscle cells

  • B1-adrenoreceptors activated by sympathetic neurotransmitters

    • Adrenaline (epinephrine)

    • Noradrenaline (norepinephrine)

• Binding activates g-protein dissociation

• G-protein binds to adenylate cyclase and activates it

• adenylate cyclase converts ATP to cAMP

• cAMP acts as secondary messenger inside the cell and activates protein kinase A (PKA)

• PKA causes calcium channels to open and Ca2+ enters the cardiac cell

  • Sarcoplasmic reticulum also releases calcium

• More Ca2+ = Increase force of contraction

• Final result: Increased cardiac contractility

List an example of a synthetic B1-agonist and when it’s used

• Dobutamine

  • used short term in severe acute heart failure with poor systolic function

List limitations and adverse effects of Sympathomimetics

• Catecholamines can also stimulate a-receptors causing:

  • vasoconstriction

  • tachycardia

  • arrhythmias

• Long-term use may down-regulate B-receptors, reducing effectiveness

What do diuretics do?

• Increase:

  • urine production (diuresis)

  • sodium excretion (natriuresis)

• reduce fluid overload and edema in heart failure

List the 5 types of diuretics

• Loop Diuretics

• Thiazide Diuretics

• Potassium-sparing Diuretics

• Other Diuretics:

  • Osmotic Diuretics

  • Carbonic Anhydrase Inhibitors

List examples, MOA and adverse effects of Loop Diuretics

Examples

• furosemide

• torasemide

MOA

• Act in the thick ascending limb of the loop of Henle by inhibiting the Na+/K+/2Cl- cotransporter:

  • Na+/K+/2Cl- transporter inhibition → Increased Na+, K+, Cl- excretion → Increased waterloss

  • This decreases medullary osmolarity and reduces water reabsorption

Adverse Effects

• dehydration

• electrolyte loss

• pre-renal azotemia

• ototoxicity at high doses

List two examples of Potassium-sparing diuretics

• Amiloride

• Spironolactone

Define Amiloride (type of diuretic, MOA)

• weak diuretic

• MOA

  • reduces epithelial Na+ channels in collecting tubule

  • reduces K+ loss

Define Spironolactone (type of medication, MOA)

• competitive aldosterone antagonist

  • (reduces action of aldosterone)

• prevents Na+ and water retention

• helps prevent “aldosterone escape”

What is the clinical importance of potassium-sparing diuretics?

combined with loop diuretics to reduce hypokalemia and improve survivial

What do vasodilators do?

Reduce:

• preload

• afterload

• cardiac workload (“unloading the failing heart”)

List the 5 types of Vasodilators

• Calcium channel blockers

• a1-adrenoreceptor antagonists

• Nitrates

• ACE Inhibitors

• Angiotensin II Receptor Blockers (ARBs)

Describe Calcium Channel Blockers (Classes and MOA)

Classes

• Verapamil → mainly cardiac effects

• Amlodipine → mainly vascular dilation

• Diltiazem → intermediate effects

MOA

• Block L-type calcium channels

  • relaxes blood vessels

  • decreases heart contractility

  • slows heart rate

Describe a1-adrenoreceptor antagonists (example, MOA, adverse effects)

Example

• Prazosin

MOA

• block a1-receptors

  • causing vasodilation and reduced peripheral resistance

Adverse Effects

• hypotension

• syncope

Describe Nitrates (example, MOA, adverse effects)

Example

• Glyceryl trinitrate

MOA

• Donate nitric oxide (NO), producing vasodilation:

  • NO → Increased cGMP → vascular smooth muscle relaxation

Adverse Effects

• hypotension

• syncope

Describe ACE Inhibitors (example, MOA + effects, adverse effects)

Example

• Enalapril

• Benazepril

• Ramipril

MOA

• Block conversion of angiotensin I to angiotensin II:

  • ACE inhibition → Decreased Angiotensin II → vasodilation + decreased aldosterone

    • arteriolar and venous dilation

    • reduced aldosterone

    • increased Na+ and water excretion

    • reduced edema

    • increased bradykinin-mediated vasodilation

Adverse Effects

• hypotension

• hyperkalemia

• renal impairment