Pharmacological Options in Heart Failure

Summarize the Autonomic control of the heart.

Autonomic Nervous system - governs control of the cardiovascular system

• Sympathetic - adrenergic

• Parasympathetic - cholinergic

Heart - primarily concerned with B-receptors (Increase in rate, force, automaticity) and M receptors (reduction in rate, force, velocity)

Vasculature - autonomic control via sympathetic (a and B receptors), little influence by parasympathetic nervous system on the smooth muscle

• a receptors - constrict

• B receptors - dilate

• **All tissues have both receptors, dominant type is shown in the table

Summarize the divisions of the Autonomic Nervous System and the receptor division used by each.

1⃣ Sympathetic Nervous System (SNS)

“Fight or flight”

• Main neurotransmitter at target organ: Norepinephrine (NE)

• Receptors used: Adrenergic receptors (α and β types)

🔹 Adrenergic Receptors (Sympathetic)

Receptor	Location (examples)	Effect	Excitatory or Inhibitory?
α1	Blood vessels	Vasoconstriction	✅ Excitatory
α2	Presynaptic nerve terminals	↓ NE release	❌ Inhibitory
β1	Heart	↑ HR & contractility	✅ Excitatory
β2	Bronchi, skeletal muscle vessels	Bronchodilation, vasodilation	❌ Inhibitory (relaxes smooth muscle)
β3	Adipose tissue	Lipolysis	✅ Excitatory

2⃣ Parasympathetic Nervous System (PNS)

“Rest and digest”

• Main neurotransmitter at target organ: Acetylcholine (ACh)

• Receptors used: Muscarinic receptors (M1–M5)

🔹 Muscarinic Receptors (Parasympathetic)

Receptor	Location (examples)	Effect	Excitatory or Inhibitory?
M1	CNS, gastric glands	↑ gastric secretion	✅ Excitatory
M2	Heart	↓ HR	❌ Inhibitory
M3	Smooth muscle, glands	Contraction, secretion

⚡ Important Extra Point

Both systems use:

• Nicotinic (Nn) receptors at autonomic ganglia
  → Always excitatory

These are found in both sympathetic and parasympathetic ganglia.

Describe the following image.

More intracellular Ca²⁺ → Contraction

Less intracellular Ca²⁺ → Relaxation

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LEFT SIDE: CONTRACTION

1⃣ Excitatory GPCRs (Gq-coupled)

Examples: Noradrenaline (α1), Histamine (H1), Angiotensin II

• In vascular smooth muscle - receptors are typically α1 adrenoreceptors

• Activate PLC

• PLC → IP₃

• IP₃ → releases Ca²⁺ from sarcoplasmic reticulum

• ↑ intracellular Ca²⁺

• → Smooth muscle contracts

So:
Gq → IP₃ → Ca²⁺ ↑ → Contraction

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2⃣ Voltage-gated calcium channels

• Depolarization opens Ca²⁺ channels

• Ca²⁺ flows in

• ↑ Ca²⁺ → contraction

👉 That’s why calcium channel blockers cause relaxation.

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3⃣ Ligand-gated cation channels

• Na⁺ enters

• Causes depolarization

• Opens Ca²⁺ channels

• → contraction

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4⃣ Depolarization

Depolarization = membrane becomes more positive
→ opens voltage Ca²⁺ channels
→ more Ca²⁺
→ contraction

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RIGHT SIDE: RELAXATION

Now the opposite mechanisms.

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5⃣ Inhibitory GPCRs (Gs-coupled)

• In vascular smooth muscle - receptors are typically β₂

Examples:

• β₂ agonists

• Adenosine

• Prostaglandins

They activate:

AC → ↑ cAMP → PKA activation

PKA:

• Inhibits Ca²⁺ entry

• Promotes Ca²⁺ sequestration

• Reduces myosin light chain kinase activity

→ Relaxation

So:
Gs → cAMP ↑ → PKA → Relaxation

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6⃣ ANP receptor (membrane guanylate cyclase)

ANP → activates guanylate cyclase
→ ↑ cGMP
→ PKG activation
→ ↓ intracellular Ca²⁺
→ Relaxation

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7⃣ Nitric Oxide (NO) - mediator produced by vascular endothelial cells - diffuses to smooth muscle layer below

NO diffuses into cell
→ activates soluble guanylate cyclase
→ produces ↑ cGMP
→ PKG
→ Relaxation - decreases contraction

This is how:

• Nitrates work

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8⃣ Potassium channels

Opening K⁺ channels:

• K⁺ leaves cell

• Hyperpolarization

• Ca²⁺ channels close

• ↓ Ca²⁺

• Relaxation

So:
Hyperpolarization → Relaxation

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9⃣ PDE (Phosphodiesterase) - family enzymes which break down cyclic nucleotides (cAMP and cGMP), inhibiting it, prevents breakdown, getting build up of the cyclic nucleotides, has a relaxant action since these promote PKA and PKG which decrease contraction

Breaks down:

• cAMP

• cGMP

So PDE:

• ↓ relaxation signals

• Promotes contraction

That’s why PDE inhibitors cause relaxation.

Describe how Noradrenaline affects vascular smooth muscle and how it effects cardiac muscle cells.

Vascular Smooth Muscle

Main receptor: α1

1⃣ Noradrenaline binds α1 receptor → α1 is coupled to Gq

2⃣ Gq activates phospholipase C (PLC)

3⃣ PLC cleaves PIP₂ into:

• IP₃

• DAG

4⃣ IP₃ increases intracellular Ca²⁺

• IP₃ binds receptors on sarcoplasmic reticulum

• Ca²⁺ is released into cytoplasm ↑ intracellular Ca²⁺

5⃣ Ca²⁺ binds calmodulin → Forms Ca²⁺–calmodulin complex

6⃣ Ca²⁺–calmodulin activates MLCK

(MLCK = Myosin Light Chain Kinase)

7⃣ MLCK phosphorylates myosin light chains

→ Allows actin–myosin interaction
→ Cross-bridge cycling

8⃣ Result: Smooth muscle contraction → Vasoconstriction

β2 Receptors:

• 1⃣ β2 receptor activation
  → Coupled to Gs

  2⃣ Gs activates adenylyl cyclase (AC)
  → Converts ATP → cAMP

  3⃣ ↑ cAMP - inhibitory effect by activating PKA

  4⃣ PKA inhibits myosin light chain kinase (MLCK)

  MLCK is the enzyme that phosphorylates myosin → allows contraction.

  So when PKA inhibits MLCK:

  • ↓ Myosin phosphorylation

  • ↓ Actin–myosin interaction

  • → Smooth muscle relaxation (vasodilation)

Cardiac Muscle Cell

Main receptor: β1

• NA → β1 receptor

• Coupled to Gs

• Gs → Adenylyl cyclase

• ↑ cAMP

• Activates PKA

• PKA increases Ca²⁺ entry

• ↑ Ca²⁺ availability inside cardiac cells

Effects:

• ↑ Heart rate (positive chronotropy)

• ↑ Contractility (positive inotropy)

How does PKA affect VSM and Cardiac muscle differently?

❤ In cardiac muscle → PKA increases contraction

PKA (activated by β₁ receptors → ↑ cAMP) phosphorylates:

• L-type Ca²⁺ channels → ↑ Ca²⁺ influx

• Ryanodine receptors (RyR2) → ↑ Ca²⁺ release from SR

• Phospholamban → ↑ Ca²⁺ reuptake (faster relaxation but more Ca²⁺ available next beat)

🔹 Net effect: ↑ intracellular Ca²⁺ during systole → stronger contraction (positive inotropy)

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🫀 In smooth muscle → PKA causes relaxation

PKA:

• Inhibits myosin light chain kinase (MLCK)

• ↓ Myosin light chain phosphorylation

• ↓ Actin–myosin interaction

🔹 Net effect: Reduced contraction → relaxation

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🔑 Why the difference?

• Cardiac muscle contraction depends mainly on Ca²⁺ availability

• Smooth muscle contraction depends mainly on MLCK activity

So PKA increases Ca²⁺ handling in cardiac muscle (→ contraction) but inhibits MLCK in smooth muscle (→ relaxation).

Define the following:

• Inotropy

• Chronotropy

• Lusitropy

• Inotropy - force of contraction

• Positive = increase

• Negative = decrease

• Chronotropy - speed of contraction

• Lusitropy - diastolic relaxation of the ventricles

What are the three main approaches to treat heart failure?

• Goals → subsequent drugs to treat these objectives.

Principle issue in HF is a decrease in cardiac output, resulting in a decrease in tissue perfusion, inability to meet body’s metabolic needs.

• Stimulate the heart

• Sympathomimetics - mimic A / NA

• Offload the heart

• Diuretics - offload pressure

• Vasodilators - reduce pre-load and CVP, improving tissue perfusion (due decrease RAAS activation)

• Inodilators

• An inodilator is a type of medication that combines two distinct actions: it acts as a positive inotrope (increasing the strength of heart muscle contraction) and a peripheral vasodilator

How do B1-agonists affect cardiac muscle cells?

B₁-agonists stimulate adenylate cyclase via a G- protein

→ increase cAMP - which activates PKA → triggering

→ increased Ca2+

→ increased contraction

Describe the key features of the sympathomimetics.

• What effects do catecholamines have at their drug target and what are they used for in context of the heart?

A sympathomimetic is a substance (like a drug or chemical) that mimics the effects of the sympathetic nervous system, essentially activating the body's "fight-or-flight" response by increasing heart rate, blood pressure, and alertness, often by acting on adrenaline-like receptors.

All catecholamines (Like A and NA) stimulate ß-receptors

• Also stimulate a-receptors

→ causing: vasoconstriction, increased HR, pro-arrhythmic, not necessarily beneficial

• Used in resuscitation, not for heart failure

Describe key features of Dobutamine.

Dobutamine - synthetic B₁-agonist - type of sympathomimetic

• Potent positive inotrope

• Little effect on heart rate, little effect on blood pressure, mainly targets inotropic action

• Indicated in life threatening heart failure with severely impaired systolic function, not useful as long-term treatment

• Short term treatment - intensive care

• up to 3 days

• Residual benefit

• Down-regulates ß-receptors, can no longer be activated

• Monitor BP, HR, rhythm

What is a diuretic?

• A substance that promotes production of urine ie increases excretion of water (and electrolytes)

• Can be used to help relieve the load on the heart

What do diuretics cause?

• INCREASED URINE FLOW (DIURESIS)

• INCREASED Na+ EXCRETION (NATRIURESIS)

What are the main indications for use of diruetics?

• Treatment & control of systemic oedema e.g. from cardiac, hepatic & renal (glomerular) disease AND

ALL patients with signs of congestive heart failure should receive a diuretic* - this is the most frequent indication for diuretics

• (* the only exception to the use of diuretics in CHF is cardiac tamponade)

• Blood volume may increase by 30% in severe CHF

What are the functions of diuretics in HF?

• List the main categories.

• Treatment & control of systemic oedema e.g. from cardiac, hepatic & renal (glomerular) disease

• Loop Diuretics

  • Furosemide

  • Torasemide

• Thiazides

• K+ Sparing Diuretics

  • Amiloride

  • Spironolactone

• Osmotic Diuretics

  • Mannitol

• Carbonic Anhydrase Inhibitors

Describe the main features of the Loop Diuretics.

E.g. furosemide

• secreted into PCT, but act in thick ascending limb of Loop of Henle

• inhibits Na+/K+/2Cl carrier (Which is the drug target) in the luminal membrane by combining with the Cl binding site

• causing loss of these ions, (So they are not reabsorbed, along) with water, in the urine

• also induce renal PG synthesis - increase renal blood flow - further enhances the effect

Also affects the TAL:

• Na+, K+ and Cl are not absorbed as normal in TAL

• Osmolarity of interstitial fluid is reduced since the electrolyte carrier is inhibited

• Thus drive for water reabsorption in descending loop is reduced

• Leads to diuresis

Why are loop diuretics considered “high-ceiling” drugs?

• Potent, "high ceiling" drugs = Loop diuretics are called "high ceiling" because they can induce a profound diuresis—up to of filtered sodium—by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. (Since this carrier is responsible for high proportion of sodium reabsorption)

• This high-capacity site allows for a greater maximum effect (ceiling) than other diuretics, allowing for continued increases in drug dosage to produce higher urine output.

• “Low-ceiling” means, even at high doses, the drug only achieves moderate diuresis (Such as thiazides).

• can increase Na+ excretion from ~ 1% (Normal) up to >15-25%

• dose control essential

• rapid in onset of action

• 10-20min i/v, 1-1.5hrs PO (well absorbed); last 4-6hrs

• Furosemide is the diuretic of choice for most veterinary applications, must be given more frequently

• Torasemide (available since 2015), longer halflife so once a day dosing

• side-effects:

• Dehydration, pre-renal azotaemia, electrolyte disturbances (esp. K+, Na+ Mg++)

• Ototoxicity (Toxic to the ear) (at very high doses or when used in combination with aminoglycosides)

Describe key features of the Thiazides.

Hydrochlorothiazide - main example

Thiazide refers to a class of drugs, primarily thiazide diuretics, often called "water pills," that treat high blood pressure (hypertension) and fluid retention (edema) by making the kidneys excrete more salt and water, reducing blood volume and lowering blood pressure. They work by blocking sodium reabsorption in the kidneys, leading to increased urination.

• secreted into PCT, but act in the DCT

• block Na+/Cl reabsorption via transporter

• causing loss of Na+, H+, K+, Mg++,Cl, with water, in the urine (Due to different transport pathways)

• mechanism dependent on renal PG production

• Need sufficient renal blood flow which is regulated by PG, lack of blood flow = drugs not active

What are the main pharmacokinetic properties of the Thiazides.

• potency - mild-moderate (between low and high ceiling, 1% to 5-8%)

• ineffective if renal blood flow is low

• slower onset, longer acting than furosemide

• good oral absorption

• side-effects:

• as for furosemide

• alkalosis (Electrolyte disturbances)

• insulin resistance (Disrupts potassium levels)

What is the function of Aldosterone in the RAAS?

• What drugs inhibit it’s effects?

Aldosterone - part of RAAS

• Normal action: acts on distal tubules/collecting ducts to increase reabsorption of ions and water

• conserves Na+/secretes K+

• Water retention, increased blood pressure and increased blood volume

• Aldosterone antagonists (such as spironolactone) are a class of potassium-sparing diuretics that work by blocking the action of aldosterone, thereby increasing sodium/water excretion while retaining potassium in the body.

Describe the following features of these two K+ sparing diuretics:

• Amiloride

• Spironolactone

• Amiloride - K+ sparing diuretic

• Acts at the collecting tubule

• Block luminal sodium channel

• Indirectly decreases K+ loss

• Weak diuretic

• Can be esed in combination with others to reduce hypokaleamia

• Spironolactone - K+ sparing diuretic

• Aldosterone antagonist (competitive) - blocks elevated aldosterone associated with heart failure

• Weak diuretic

• Used:

• In combination with others to reduce hypokaleamia

• to counter "aldosterone escape (see ACE inhibitors)

Safety:

• No apparent adverse effects in dogs (except reversible prostatic atrophy), but skin reactions seen in cats

Describe the features of these diuretics:

• Osmotic Diuretics

• Carbonic Anhydrase Inhibitors

Osmotic Diuretics

• filtered & effective mainly in PCT + loop

• Enter filtrate and modify the osmolarity, increase tonicity to help retain water in the urine

• eg: mannitol used as 10-20% solⁿ. i/v (poor Gl absorption)

Carbonic anhydrase inhibitors

• secreted into PCT

• inhibit tubular production of H+ for Na+/H+ exchange

• As carbonic anhydrase normally breaks down carbonic acid into bicarbonate and H+ ions, inhibitors disrupt this process, which are needed for transporter

• leads to increased NaHCO₃ & water (& K+) excretion

• cause acidosis

• can be used topically for glaucoma