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Cardiac Pharmacology. Ted Williams Pharm D Candidate OSU/OHSU College of Pharmacy. The big, scary picture. CNS. Baroreflex. I-1. α 2. Vagus Nerve. Preload. Afterload. α 1. GI Vasculature. B1. ANP. Aldosterone. B2. Renin. NO. M2 -. B1 +. Conductivity. Na↑ HCO3↓.

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cardiac pharmacology

Cardiac Pharmacology

Ted Williams

Pharm D Candidate

OSU/OHSU College of Pharmacy

the big scary picture
The big, scary picture

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

breaking it down
Breaking it Down
  • Direct Cardiac Agents
  • Peripheral Vascular Agents
  • Renal Agents
reality check
Reality Check
  • The pharmacology really isn’t that simple, but it is a helpful framework
direct cardiac agents
Direct Cardiac Agents
  • Beta Blockers (BB)
  • Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB)
  • Digitalis Glycoside (De-GOX-in)
  • Aldosterone antagonists
    • Well explain why this is here later
peripheral vascular agents
Peripheral Vascular Agents
  • Dihydropyridine CCB
  • Nitrates
  • Hydralazine
  • Phosphodiesterase Inhibitors
  • Alpha 1 Antagonists
  • Phentolamine
renal agents
Renal Agents
  • ACE Inhibitors
  • Angiotensin 2 Inhibitors
  • Diuretics
    • Carbonic Anhydrase Inhibitors
    • Loop
    • Thiazide Diuretics
    • Aldosterone Antagonists
    • Potassium Sparing Diuretics
mixed bag
Mixed Bag
  • Selective I-1 Imidazoline Receptor Agonists
hypertension in 30 seconds
Hypertension in 30 seconds
  • Excessive vascular volume
  • Low Compliance of vasculature
  • Increased activity of the ReninAnginotensin System
ischemic heart disease in 30 seconds
Ischemic Heart Disease in 30 Seconds
  • Cardiac Muscle has insufficient oxygen
  • Two Solutions
    • Reduce cardiac Oxygen demand
      • Increase Preload
      • Reduce Contractility
      • Reduce Afterload
    • Increase cardiac oxygen supply
      • Increase Coronary Flow
      • Increase Oxygen extraction
heart failure in 30 seconds
Heart Failure in 30 Seconds
  • Chronic overwork of the heart muscle causes hypertrophic remodeling
  • Reduced cardiac output
  • Fluid retention
cardiac fluid dynamics in 30 seconds
Cardiac Fluid Dynamics in 30 Seconds

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

direct cardiac agents bb
Direct Cardiac Agents – BB
  • Selectivity
    • Beta 1 Selective
    • Beta 1/2 Non-Selective
    • Alpha 1, Beta 1/2 Non-Selective
    • Alpha 2, Beta 1/2 Non-Selective
  • Intrinsic Sympathomimetic Activity (ISA)
    • ISA
      • No long term mortality benefit Post MI
      • Non-ISA do have benefit post MI
    • Non-ISA
beta blocker targets
Beta Blocker Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

beta blocker targets1
Beta Blocker Targets
  • Beta 1 blockade
    • “Cardioselective”
    • Inhibits sympathetic contractility, inotropy, and conductivity of the heart
    • Inhibits sympathetic renin secretion in the kidneys
  • Best Tolerated Beta 1 Blockers
    • Atenolol
    • Acebutolol
    • Bisoprolol
    • Metoprolol
beta blocker targets2
Beta Blocker Targets
  • Beta 2 blockade
    • Beta 2 receptors inhibit smooth muscle contractions in the lungs and GI tract
    • Beta 2 blockade is useful for restricting hepatic blood flow for patient with Liver Cirrhosis, but generally not a therapeutic effect for CVD
  • Commonly Used Beta 2 Blockers
    • Propranolol
    • Nadolol
beta blockers and hypertension
Beta Blockers and Hypertension
  • Primarily a function of Beta 1 Blockade
    • Inhibition of sympathetic cardiac stimulation of the SA node
    • Inhibition of Renin secretion
  • Secondary effects of Beta 2 Blockade
    • Vasodilation of GI Vasculature
  • Place in Therapy
    • Second line monotherapy for uncomplicated hypertension
    • Important agent for Hypertension with other cardiovascular co-morbidities
      • Stroke
      • MI
      • CHF
beta blockers and ischemic heart disease
Beta Blockers and Ischemic Heart Disease
  • Reduces Cardiac Oxygen Demand by limiting maximum stimulation (Heart Rate)
  • Place in Therapy
    • First Line for Stable Angina
    • Decreases Morbidity (Reduced Symptoms)
    • Decreases Mortality (Prolongs life)
    • Only Non-ISA
beta blockers and heart failure
Beta Blockers and Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

beta blockers and heart failure1
Beta Blockers and Heart Failure
  • Particular Effects
    • Decreased Heart Rate
    • Decreased Contractility
    • Decreased Afterload
    • Increased Preload
    • Increased Stroke Volume via Preload
  • Net Effect
    • Increased Cardiac Output
  • Place in Therapy
    • Stage B, C (myocardial damage present)
    • Improves Morbidity
targets for mixed alpha beta blockers
Targets for Mixed Alpha/Beta Blockers

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

targets for mixed alpha beta blockers1
Targets for Mixed Alpha/Beta Blockers
  • Alpha 1 Blockade
    • Peripheral Vasodilation by inhibition of Gq Signaling pathway
      • Additional Reduced Afterload
    • Place In therapy
      • Heart Failure in particular
    • Examples
      • Carvedilol (alpha-1, beta 1/2)
      • Labetalol (alpha-1, beta 1/2)
  • Alpha 2 Blockade
    • CNS Inhibition the inhibition of the baroreflex
      • Inhibits sympathetic increases in blood pressure
    • PNS inhibition of the negative feedback on vagal cardiac stimulation
  • Alpha 2 Agonists
    • Stimulates Negative feedback on Beta 1 neurons controlling Heart Rate
      • Enhances Beta Blockade
    • Celiprolol (alpha-2 agonist, beta-1 blockade)
non dhp ccb targets
Non-DHP CCB Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

non dhp ccb targets1
Non-DHP CCB Targets
  • Use dependent tissue selectivity
    • Binds to the open state of the channel
    • The more often the channel opens, the more drug exposure and therefore the more tissue “selective”
    • Peripheral vasodilation present, but not as strong as with DHP CCB
  • Cardioselective
  • Verapamil
  • Diltiazem
non dhp ccb and hypertension
Non-DHP CCB and Hypertension
  • First line monotherapy, with a few restrictions
  • BPReductions primarily due to decreased heart rate and contractility reducing cardiac output
non dhp ccb and ischemic heart disease
Non-DHP CCB and Ischemic Heart Disease
  • Reduces Contractility
  • Reduces Heart Rate
  • Second line behind Beta Blockers for symptom relief
  • Not strongly supported to improve prognosis
  • First line for vasospastic Angina
  • Use with extreme caution in combination with beta blockers due to risk of AV Block
non dhp ccb and heart failure
Non-DHP CCB and Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

non dhp ccb and heart failure1
Non-DHP CCB and Heart Failure
  • Specific Effects
    • Decreased Contractility
    • Decreased Conductivity
    • Decreased Automaticity
  • Net Effects
    • Decreased cardiac output
  • Increases Edema via peripheral vasodilation, a major no-no for HF patients
  • Place in Therapy
  • Contraindicated in Systolic Heart Failure (most common kind of Heart Failure)
  • Should be discontinued by Stage C Heart failure, even with compelling indications
digitalis targets
Digitalis Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

digitalis targets1
Digitalis Targets
  • Increases cardiac contractility by increasing calcium levels
    • Cellular target is Sodium Potassium ATPase which is loosely coupled with Sodium Calcium Exchanger
  • Sympatholytic suppression of ReninAngiotensin System
  • Increases ParasympatheticVagal Tone
    • Reduces Preload
    • Reduces Heart Rate
digitalis and hypertension
Digitalis And Hypertension
  • Neutral Effects on Blood Pressure
  • …Move along, nothing to see here
digitalis and ischemic heart disease
Digitalis And Ischemic Heart Disease
  • The improved cardiac function of Digitalis glycoside is only present in the hypertrophied heart.
  • Mason, D. Digitalis and Angina Pectoris. Chest 1973;64;415-416
digitalis and heart failure
Digitalis And Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

digitalis and heart failure1
DigitalisAnd Heart Failure
  • Heart Failure is the only real use…
  • Specific Effects
    • Increased Contractility dominates
    • Decreased Preload
    • Decreased Heart Rate
  • Net Effect
    • Increased Cardiac Output
  • Symptom management only
    • No improvement in mortality
    • Although RADIANCE and PROVED demonstrated worsening outcomes when Digitalis was discontinued
aldosterone antagonists targets
Aldosterone Antagonists Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

aldosterone antagonists targets1
Aldosterone Antagonists Targets
  • Blocks Collagen deposition (fibrosis) in the myocardium
  • Minor Potassium sparing diuresis by blocking sodium reabsorption in the distal convoluted tubules and collecting ducts (potassium sparing)
  • Examples
    • Spironolactone
    • Eplerenone
aldosterone antagonists and hypertension
AldosteroneAntagonistsAnd Hypertension
  • Minor blood pressure effects due to diuresis
  • Side effects limit efficacy
    • Gynecomastia in men due to testosterone production antagonism
aldosterone antagonists and heart failure
Aldosterone AntagonistsAnd Heart Failure
  • Decrease in Preload due to decreased blood pressure
  • Real benefit is the inhibition of myocardial fibrosis
  • 25mg QD with no titration
peripheral vascular agents1
Peripheral Vascular Agents
  • Dihydropyridine CCB (DHP-CCB)
  • Nitrates
  • Hydralazine
  • Phosphodiesterase Inhibitors (PDE)
  • Alpha 1 Antagonists
  • Phentolamine
dhp ccb targets
DHP-CCB Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

dhp ccb targets1
DHP-CCB Targets
  • State Dependent Binding
    • Bind to the inactive state of the channel
    • The less active the tissue, the greater selectivity for the tissue
  • Arterial vascular smooth muscle relaxation
    • Reducing Afterload
    • Some Baroreflex triggering
dhp ccb and hypertension
DHP-CCB and Hypertension
  • First line monotherapy
  • Preferred over Non-DHP for patients with HF
  • Preferred over Non-DHP for patients taking BB
dhp ccb and ischemic heart disease
DHP-CCB and Ischemic Heart Disease
  • Reduces Afterload
  • Second line after Beta Blockers
  • Improves morbidity only
    • Mortality benefit not adequately demonstrated
  • Preferred in patients with HF over Non-DHP
dhp ccb and heart failure
DHP-CCB and Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

dhp ccb and heart failure1
DHP-CCB and Heart Failure
  • Reduces Afterload
  • Minor effects on Contractility, Heart Rate, and Conductivity
  • Net effect is a reduction of cardiac output
  • Increases Edema via peripheral vasodilation, a major no-no for HF patients
nitrate targets
Nitrate Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

nitrate targets1
Nitrate Targets
  • PeripheralVasodiation by promoting Nitric Oxide Release
    • Veins
    • Arteries
    • Arterioles
  • Decrease Preload
nitrate and hypertension
Nitrate And Hypertension
  • Not particularly helpful
nitrate and ischemic heart disease
Nitrate And Ischemic Heart Disease
  • Short acting first line for Angina Attacks
  • Long acing second line after Beta Blockers for Symptom Relief
nitrate and heart failure
Nitrate And Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

nitrates and heart failure
Nitrates And Heart Failure
  • Decreases Preload
  • Not for monotherapy
  • Combine with Hydralazine (as BiDil), indicated in State C Heart Failure
    • More on that next…
hydralazine targets
Hydralazine Targets

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

hydralazine targets1
Hydralazine Targets
  • MOA not well understood
  • May affect calcium mobilization
  • May increase Nitric oxide production
  • Arterial vasodilation
    • Generally triggers baroreflex
    • Reduces Afterload
hydralazine and hypertension
HydralazineAnd Hypertension
  • May be used for refractory hypertension
  • Baroreflex limits use
hydralazine and heart failure
HydralazineAnd Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

hydralazine and heart failure1
Hydralazine And Heart Failure
  • Combination of Hydralazine and IsosorbideDinitrate (BiDil)
    • Hydralazine decreases Afterload
    • Nitrate decreases Preload
    • Combination Decreases mortality and hospitalizations
    • Mechanism not well understood
pde inhibitor targets
PDE Inhibitor Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

pde inhibitor targets1
PDE Inhibitor Targets
  • Increases cGMP levels
  • Increases Contractility (Inotropy)
    • Increases Calcium Influx
    • Increases Calcium release from the SR via RyR channels
  • Peripheral vasodiation by inhibition of smooth muscle contractions
    • That means decreased Afterload
    • Some decrease in Preload secondary to afterload reductions, but that’s standard stuff
  • Rapid Resistance develops with continuous use
pde inhibitors and ischemic heart disease
PDE InhibitorsAnd Ischemic Heart Disease
  • Mechanistic support not there
pde inhibitors and heart failure
PDE InhibitorsAnd Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

pde inhibitors and heart failure1
PDE Inhibitors And Heart Failure
  • Specific Effects
    • Increased Contractility
    • Decreased Afterload
  • Net effect
    • Increased Cardiac Output
  • Clinical data
    • No demonstrated benefits over Digitalis
    • Increased mortality
    • Increased Arrhythmia
    • Rapid Tolerance
  • Place in therapy
    • Some suggest there use for acute decompensated heart failure, but no clear support
alpha 1 antagonist targets
Alpha 1 Antagonist Targets

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

alpha 1 antagonist targets place in therapy
Alpha 1 Antagonist Targets & Place in Therapy
  • Inhibition of sympathetic simulation of vascular smooth muscle
    • That means reduced Afterload!
  • Really use for BPH, not CVD
    • But has some synergistic effects for people with BPH and CVD
    • Reduced BP
    • Reduced Afterload & increased Cardiac Output
  • Examples
    • Prazosin
    • Doxazosin
    • Terazosin
    • Tamsulosin
renal agents1
Renal Agents
  • ACE Inhibitors
  • Angiotensin 2 Inhibitors (ARBs)
  • Diuretics
    • Carbonic Anhydrase Inhibitors
    • Loop
    • Thiazide Diuretics
    • Aldosterone Antagonists
    • Potassium Sparing Diuretics
ace inhibitor targets
ACE Inhibitor Targets

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

ace inhibitor targets1
ACE Inhibitor Targets
  • Inhibition of Angiotensin Converting Enzyme
    • Inhibition of the conversion of Angiotensin I to Angiotensin II
    • Inhibition of the Degredation of Bradykinins
    • Cough
  • Peripheral Vasodilation
    • ATII causes peripheral vasoconstriction
  • Reduced GFR
    • ATII preferential activity on Efferent arterioles
  • Reduced Antidiuretic Hormone (ADH) Production
    • Reduced fluid volume
  • Reduced Aldosterone Production
    • Reduced fluid volume
ace inhibitor and hypertension
ACE Inhibitor And Hypertension
  • First lineMonotherapy
  • May synergistic effects with nephropathy, diabetes, kidney diease, MI, and HF
ace inhibitor and ischemic heart disease
ACE Inhibitor And Ischemic Heart Disease
  • Short Answer
    • Get them on and ACEI
  • Long Answer
    • Strong evidence for improvedprognosis in patient with Diabetes or any CVD (HTN, MI, HF)
    • Moderate evidence for all patients for improvedprognosis
ace inhibitor and heart failure
ACE Inhibitor And Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

ace inhibitor and heart failure1
ACE Inhibitor And Heart Failure
  • Reduced Afterload
  • Possible benefit of reduced aldosterone production & fibrosis
  • Clinical data supporting reduction in Morbidity/Mortality
  • Indicated for Stage A with any compelling indication (HTN, MI, Diabetes, etc)
  • Indicated in all other stages
arb targets
ARB Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

arb targets1
ARB Targets
  • All ATII receptors
    • Theoretical benefit over ACEI, but not demonstrated
    • No effect on bradykinins
  • Physiological effects
    • Peripheral vasodilation
    • Reduced GFR and arteriole vasodilation
    • Reduced ADH production
    • Reduced Aldosterone Production
    • Reduced fluid volume
arb place in therapy
ARB Place in therapy
  • Second line
    • ACEI have more data and are cheaper, so start with them
carbonic anhydrase inhibitor targets
Carbonic AnhydraseInhibitor Targets

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

carbonic anhydrase inhibitors
Carbonic Anhydrase Inhibitors
  • Work in the proximal convoluted tubule
  • Too much opportunity for later water reabsorption, not really used in CVD
  • Not used much for diuresis, but used in Acid/Base Imbalances and Renal Failure
loop diuretic targets
Loop Diuretic Targets

CNS

Baroreflex

I-1

α 2

Vagus Nerve

Preload

Afterload

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

loop diuretic targets1
Loop Diuretic Targets
  • Inhibit Na, K, Ca, Mg Reabsorption in the Loop of Henle
  • Powerful diuresis and volume reduction
  • Decreased Afterload
loop diuretic and hypertension
Loop Diuretic And Hypertension
  • Not used much for BP reduction
  • May be useful in patients with Edema
loop diuretic and ischemic heart disease
Loop Diuretic And Ischemic Heart Disease
  • No mechanism, no indication
loop diuretic and heart failure
Loop Diuretic And Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

loop diuretic and heart failure1
Loop Diuretic And Heart Failure
  • Stage C,D Heart failure for management of fluid volume and Edema
  • Symptom relief only
thiazide diuretic targets
Thiazide DiureticTargets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

thiazide diuretic targets1
Thiazide DiureticTargets
  • Inhibition of Sodium/Cl reuptake
    • loosely coupled with Potassium excretion
    • Potassium Sparing
    • Moderate diuresis & afterload reduction
  • Therapeutic value appears to be beyonddiuresis
thiazide diuretic and hypertension
Thiazide DiureticAnd Hypertension
  • Gold standard monotherapy
thiazide diuretic and heart failure
Thiazide DiureticAnd Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

thiazide diuretic and heart failure1
Thiazide DiureticAnd Heart Failure
  • Provides some benefits due to decreased afterload
  • Stage C generally requires loops for edema control
potassium sparing diuretics targets
Potassium Sparing DiureticsTargets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

potassium sparing diuretics targets place in therapy
Potassium Sparing DiureticsTargets & place in therapy
  • Inhibition of Sodium channels in the distal convoluted tubule and collecting duct
    • Modest Diuresis
    • Potassium Sparing
  • Really just used as Add On therapy for Hypokalemia
i 1 agonist targets
I-1 Agonist Targets

CNS

Baroreflex

Preload

Afterload

I-1

α 2

Vagus Nerve

α 1

GI Vasculature

B1

ANP

Aldosterone

B2

Renin

NO

M2 -

B1

+

Conductivity

Na↑

HCO3↓

Na↑ K↓

Na Cl↑

+ K↓

ATII

Na↑

PG

Na↑ Ca↑

Mg↑ K↑

H2O

ADH/Vasopressin

i 1 agonist targets1
I-1 Agonist Targets
  • Imidazoline-1 Receptor Agonists
    • InhibitsRenin Production
      • Reduced ADH
      • Reduced Aldosterone
      • Peripheral Vasodilation
    • Inhibits Sympathetic Vagal cardiac stimulation (sympathlytic)
      • Reduced heart Rate
i 1 agonist s and hypertension
I-1 Agonists and Hypertension
  • Reduction in blood pressure
  • No strong evidence, not part of guidelines yet
i 1 agonists and ischemic heart disease
I-1 Agonists and Ischemic Heart Disease
  • Sympatholytic mechanism may have an indication
  • No strong evidence yet
  • Moxonidine
i 1 agonists and heart failure
I-1 Agonists and Heart Failure

Contractility

Preload

Afterload

+

+

-

Heart

Rate

Stroke

Volume

+

+

Cardiac

Output

i 1 agonists and heart failure1
I-1 Agonists and Heart Failure
  • Specific Effects
    • Reduced Heart Rate (decreasing Cardiac output)
    • Decreased Afterload (Increasing cardiac output)
  • Net Effect…
    • Increased Mortality
    • MOXCON Trial stopped due to increased mortality of 54 deaths with Moxonidinevs 32 with placebo in over 950 patients in each arm.
conclusions
Conclusions
  • Mechanisms suggest potential indications
    • Cardiac output
    • Renin-Angiotensin System
    • Target Tissues
  • Clinical data usually required to determine actual efficacy and safety
    • Balance of Cardiac Output parameters
    • MOXCON
    • BiDil