cardiac pharmacology
DESCRIPTION
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↓. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/1.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Cardiac Pharmacology
Ted WilliamsPharm D Candidate
OSU/OHSU College of Pharmacy
![Page 2: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/2.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
The big, scary picture
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 3: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/3.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Breaking it Down
• Direct Cardiac Agents• Peripheral Vascular Agents• Renal Agents
![Page 4: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/4.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Reality Check
• The pharmacology really isn’t that simple, but it is a helpful framework
![Page 5: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/5.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Direct Cardiac Agents
1. Beta Blockers (BB)2. Non-Dihydropyridine Calcium Channel
Blockers (Non-DHP CCB)3. Digitalis Glycoside (De-GOX-in)4. Aldosterone antagonists– Well explain why this is here later
![Page 6: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/6.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Peripheral Vascular Agents
1. Dihydropyridine CCB2. Nitrates3. Hydralazine4. Phosphodiesterase Inhibitors5. Alpha 1 Antagonists
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Renal Agents
1. ACE Inhibitors2. Angiotensin 2 Inhibitors3. Diuretics
i. Carbonic Anhydrase Inhibitorsii. Loopiii. Thiazide Diureticsiv. Aldosterone Antagonistsv. Potassium Sparing Diuretics
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Mixed Bag
• Selective I-1 Imidazoline Receptor Agonists
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hypertension in 30 seconds
• Excessive vascular volume• Low Compliance of vasculature• Increased activity of the Renin Anginotensin
System
![Page 10: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/10.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Heart Failure in 30 Seconds
• Chronic overwork of the heart muscle causes hypertrophic remodeling
• Reduced cardiac output• Fluid retention
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Cardiac Fluid Dynamics in 30 Seconds
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Renin Angiotensin Pathway
![Page 14: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/14.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Beta Blocker Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 16: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/16.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 17: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/17.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Beta Blockers and Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Targets for Mixed Alpha/Beta Blockers
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 23: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/23.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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)
![Page 24: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/24.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Non-DHP CCB Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 25: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/25.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Non-DHP CCB and Hypertension
• First line monotherapy, with a few restrictions• BP Reductions primarily due to decreased
heart rate and contractility reducing cardiac output
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Non-DHP CCB and Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Digitalis Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 31: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/31.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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 Renin
Angiotensin System• Increases Parasympathetic Vagal Tone– Reduces Preload– Reduces Heart Rate
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Digitalis And Hypertension
• Neutral Effects on Blood Pressure• …Move along, nothing to see here
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Digitalis And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Digitalis And 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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Aldosterone Antagonists Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 37: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/37.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Aldosterone Antagonists And Hypertension
• Minor blood pressure effects due to diuresis• Side effects limit efficacy– Gynecomastia in men due to testosterone
production antagonism
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Aldosterone Antagonists And Ischemic Heart Disease
• Where’s the MOA?
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Aldosterone Antagonists And Heart Failure
• Decrease in Preload due to decreased blood pressure
• Real benefit is the inhibition of myocardial fibrosis
• 25mg QD with no titration
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Peripheral Vascular Agents
1. Dihydropyridine CCB (DHP-CCB)2. Nitrates3. Hydralazine4. Phosphodiesterase Inhibitors (PDE)5. Alpha 1 Antagonists
![Page 42: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/42.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
DHP-CCB Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 43: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/43.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 44: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/44.jpg)
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
DHP-CCB and Hypertension
• First line monotherapy• Preferred over Non-DHP for patients with HF• Preferred over Non-DHP for patients taking BB
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Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
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Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
DHP-CCB and Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 47: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/47.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 48: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/48.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrate Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 49: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/49.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrate Targets
• Peripheral Vasodiation by promoting Nitric Oxide Release1. Veins2. Arteries3. Arterioles
• Decrease Preload
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Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrate And Hypertension
• Not particularly helpful
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Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrate And Ischemic Heart Disease
• Short acting first line for Angina Attacks• Long acing second line after Beta Blockers for
Symptom Relief
![Page 52: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/52.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrate And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 53: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/53.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Nitrates And Heart Failure
• Decreases Preload• Not for monotherapy• Combine with Hydralazine (as BiDil), indicated
in State C Heart Failure–More on that next…
![Page 54: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/54.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 55: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/55.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine Targets
• MOA not well understood• May affect calcium mobilization• May increase Nitric oxide production• Arterial vasodilation– Generally triggers baroreflex– Reduces Afterload
![Page 56: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/56.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine And Hypertension
• May be used for refractory hypertension• Baroreflex limits use
![Page 57: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/57.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine And Ischemic Heart Disease
• No data for use…
![Page 58: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/58.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 59: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/59.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Hydralazine And Heart Failure
• Combination of Hydralazine and Isosorbide Dinitrate (BiDil)– Hydralazine decreases Afterload– Nitrate decreases Preload– Combination Decreases mortality and
hospitalizations–Mechanism not well understood
![Page 60: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/60.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
PDE Inhibitor Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 61: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/61.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 62: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/62.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
PDE Inhibitors And Hypertension
• No data for use…
![Page 63: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/63.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
PDE Inhibitors And Ischemic Heart Disease
• Mechanistic support not there
![Page 64: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/64.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
PDE Inhibitors And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 65: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/65.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 66: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/66.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Alpha 1 Antagonist Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 67: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/67.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 68: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/68.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Renal Agents
1. ACE Inhibitors2. Angiotensin 2 Inhibitors (ARBs)3. Diuretics
i. Carbonic Anhydrase Inhibitorsii. Loopiii. Thiazide Diureticsiv. Aldosterone Antagonistsv. Potassium Sparing Diuretics
![Page 69: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/69.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ACE Inhibitor Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 70: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/70.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 71: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/71.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ACE Inhibitor And Hypertension
• First line Monotherapy• May synergistic effects with nephropathy,
diabetes, kidney diease, MI, and HF
![Page 72: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/72.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ACE Inhibitor And Ischemic Heart Disease
• Short Answer– Get them on and ACEI
• Long Answer– Strong evidence for improved prognosis in patient
with Diabetes or any CVD (HTN, MI, HF)–Moderate evidence for all patients for improved
prognosis
![Page 73: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/73.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ACE Inhibitor And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 74: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/74.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 75: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/75.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ARB Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 76: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/76.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 77: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/77.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
ARB Place in therapy
• Second line – ACEI have more data and are cheaper, so start
with them
![Page 78: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/78.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Carbonic Anhydrase Inhibitor Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 79: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/79.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 80: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/80.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 81: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/81.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic Targets
• Inhibit Na, K, Ca, Mg Reabsorption in the Loop of Henle
• Powerful diuresis and volume reduction• Decreased Afterload
![Page 82: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/82.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic And Hypertension
• Not used much for BP reduction• May be useful in patients with Edema
![Page 83: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/83.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic And Ischemic Heart Disease
• No mechanism, no indication
![Page 84: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/84.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 85: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/85.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Loop Diuretic And Heart Failure
• Stage C,D Heart failure for management of fluid volume and Edema
• Symptom relief only
![Page 86: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/86.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 87: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/87.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic Targets
• Inhibition of Sodium/Cl reuptake– loosely coupled with Potassium excretion– Potassium Sparing–Moderate diuresis & afterload reduction
• Therapeutic value appears to be beyond diuresis
![Page 88: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/88.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic And Hypertension
• Gold standard monotherapy
![Page 89: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/89.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic And Ischemic Heart Disease
• Not particularly useful
![Page 90: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/90.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic And Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 91: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/91.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Thiazide Diuretic And Heart Failure
• Provides some benefits due to decreased afterload
• Stage C generally requires loops for edema control
![Page 92: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/92.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
Potassium Sparing DiureticsTargets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
I-1
Baroreflex
Renin
H2O
![Page 93: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/93.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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
![Page 94: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/94.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
I-1 Agonist Targets
B1
ATII
ADH/Vasopressin
Aldosterone
α 1
Na↑ K↓
Na↑ Ca↑Mg↑ K↑
Na↑HCO3↓
NO
PG
B2
Na↑
Na Cl↑+ K↓
ANPGI Vasculature
AfterloadPreload
Conductivity
M2 - B1+
CNS α 2
Vagus Nerve
Baroreflex
Renin
H2O
I-1
![Page 95: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/95.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
I-1 Agonist Targets
• Imidazoline-1 Receptor Agonists– Inhibits Renin Production• Reduced ADH• Reduced Aldosterone• Peripheral Vasodilation
– Inhibits Sympathetic Vagal cardiac stimulation (sympathlytic)• Reduced heart Rate
![Page 96: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/96.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
I-1 Agonists and Hypertension
• Reduction in blood pressure• No strong evidence, not part of guidelines yet
![Page 97: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/97.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
I-1 Agonists and Ischemic Heart Disease
• Sympatholytic mechanism may have an indication
• No strong evidence yet• Moxonidine
![Page 98: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/98.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
I-1 Agonists and Heart Failure
Contractility Preload Afterload
StrokeVolume
HeartRate
CardiacOutput
-+ +
+ +
![Page 99: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/99.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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 Moxonidine vs 32 with placebo in over 950 patients in each arm.
![Page 100: Cardiac Pharmacology](https://reader035.vdocuments.site/reader035/viewer/2022062521/56816835550346895dddeaca/html5/thumbnails/100.jpg)
Copyright
Ted D. Willia
ms
PharmD Candidate
OSU/OHSU College of
Pharmacy
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