Slides HeartFailureAndAngina CardiovascularPharma

Cardiology: Heart Failure and
Angina
With Dr. Pravin J. Shukle
Neuer Nutzer, sanar@click2mail.net

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Angina
Drugs used in angina pectoris
Vasodilators Cardiac depressants Other drugs
Nitrates Calcium blockers β-blockers Metabolism

(verapamil) (propranolol) modifiers;
rate inhibitors
Intermediate (oral Long duration
nitroglycerin) (transdermal
nitroglycerin)
Short duration
(sublingual
nitroglycerin)

Nitrates
• Inhaled nitrates (amyl nitrate)
• Sublingual nitroglycerin (NitroTab)
• Oral nitroglycerin (isosorbide dinitrate, ISDN)
• Transdermal nitroglycerin (Nitro patch)

Nitrates
• Nitroglycerin is the same ingredient as in dynamite.
• Venodilator reduced cardiac output and oxygen

demand (preload)
• Arteriodilator opens up myocardial vascular bed,

reduces afterload
1899-1900, unknown. https://commons.wikimedia.org/wiki/File:PSM_V56_D0465_Hollow_dynamite_cartridge_elevation_view.png

Nitrates
Rapidly de-nitrated in liver

• 2-dinitrates like glyceryl dinitrate (vasodilator)
• Mononitrates (less active) glyceryl mononitrate,

isosorbide mononitrate
Release NO (nitric oxide)

• Stimulates cGMP and dephosphorylation of light chain
myosin phosphate

Nitrates
Rapidly de-nitrated in liver

• 2-dinitrates like glyceryl dinitrate (vasodilator)
• Mononitrates (less active) glyceryl mononitrate,

isosorbide mononitrate
Release NO (nitric oxide)

• Stimulates cGMP and dephosphorylation of light chain
myosin phosphate

Nitrates
Side effects
GTP
• Headache
Guanylyl cyclase + Nitrates

Drug interactions
• PDE5 inhibitors Erectile tissue
(sildenafil and others) Smooth muscle
cGMP
relaxation Blood vessels
• Methemoglobinemia at high
blood concentrations Sildenafil,
Phosphodiesterase 5 vardenafil,
tadalafil
Occupational disease
• GMP

Nitrates in the Treatment of Cyanide Poisoning
Kit components Administration
Amyl nitrite • Methemoglobin inducers
• Methemoglobin reversibly binds with cyanide

Sodium nitrite to form cyanmethemoglobin
Sodium thiosulfate • Helps convert cyanide to thiocyanate,

which is excreted renally

Cardiac Depressants and Vasodilators Calcium Channel Blockers
Dihydropyridine (DHP CCB)
• Amlodipine (Norvasc®), Felodipine Dihydropyridine

Phenethylamine
(Plendil®), Nifedipine (Procardia®,
Benzodiazepine
Adalat®), 23 others
• Mostly a blood pressure drug
Lipid membrane
• Used in angina
• May cause reflex tachycardia

(caution in ischemia)
• May worsen proteinuria in patients with

nephropathy1
Aktories et al., Allgemeine und spezielle Pharmakologie und Toxikologie, 10. Auflage, Abb. 18.14, PD; 1. Remuzzi G, Scheppati A,
Ruggenenti P (2002). "Clinical Practice. Nephropathy in Patients with Type 2 Diabetes". New England Journal of Medicine. 346 (15): 1145 51
Nondihydropyridine (NDHP CCB)
Phenylalkylamine NDHP CCBs Dihydropyridine

Phenethylamine
• Verapamil (Isoptin®, Calan®), Benzodiazepine
Fendiline, Gallopamil
• Reduces inotropy and chronotropy,
Lipid membrane
• Reduces coronary vasospasm,
ischemia
• Great for treatment of angina
Nondihydropyridine
Benzothiazepine NDHP CCBs
• Diltiazem (Cardizem)
Non-cardiac Calcium Channel Blockers
Gabapentinoids
• Gabapentin, pregabalin (Lyrica®)
• Block α2δ subunit containing

voltage-gated calcium channels
• Neuropathic pain
• Epilepsy
Ethanol
• Blocks L-type calcium channels
• Relaxes urinary bladder

Michelangelo, Drunken Noah, PD
All CCBs side effects:
• Constipation, pretibial edema, Dihydropyridine

Phenethylamine
nausea, flushing, dizziness
Benzodiazepine
(from low bp)
DHPS (nifedipine, amlodipine)

side effects:
Lipid membrane
• Increased proteinuria
• Reflex tachycardia
• Increased ischemia
• Marked lowering of blood pressure

NDHPs (diltiazem, verapamil)

side effect:
Dihydropyridine
Phenethylamine
• Decreased proteinuria
Benzodiazepine
• Decreased ischemia
• Bradycardia/AV block/sinus node

Lipid membrane
depression
Cardiac Depressants and Vasodilators Beta-Blockers
• Propranolol and others
• Reduce heart rate, cardiac force, blood

pressure
• Used in prevention only; not for treating

acute attack
• Not useful against vasospastic form

Metabolic Rate Modifiers: pFOX Inhibitors
Ranolazine (Ranexa®), trimetazidine (Vastarel®)
• Partial fatty acid oxidation inhibitors

(pFOX inhibitor)
• Increases efficiency of oxygen utilization
• Shifts energy production from fatty acids to

glucose
• May also have an effect on slow sodium

channels in the heart
• Reduced heart rate, reduced contractile
force (less Ca intracellularly)

Ivabradine
Corlanor® (US), Procoralan®, Coralan® (HK, Au, Si),
Corlentor® (Sp, It, Rom), Lancora® (Can), Coraxan®
Mechanism of action
(Rus), Ivabid® (Ind)
• Inhibits the slow sodium/potassium
channel of the sinoatrial node (If )
channel
• Reduction of heart rate (pacemaker

current)
• No change in inotropy
MarinaVladivostok, CC0 1.0

Ivabradine
Uses
• Angina
• Inappropriate sinus tachycardia
• Heart failure
Adverse effects
• Luminous phenomena
• Bradycardia, AV block, dizziness, blurred

vision
Ivabradine
Contraindications
• Sick sinus syndrome
• On CYP 3A4 inhibitors

(ketoconazole, macrolides)
• With verapamil or diltiazem
Caution: HF with
tachycardia

Heart Failure
Vasodilators/preload Cardiac remodeling/neuro-

Inotropes
reducers hormonal activity
Cardiac glycosides Nitroprusside ACE inhibitors

PDE inhibitors Loop
(digoxin) nitrates
(milrinone) diuretics
hydralazine
ARBs
β-agonists
(dobutamine) Spironolactone
Beta blockers
Nesiritide
blockers Neprolysin
inhibitors

Cardiac Glycosides
Digoxin (digitalis)
Na+/Ca2+ Na+/K+-
Na+
Ca2+ exchanger ATPase K+
Digitalis
• Derived from the digitalis (foxglove) plant
• Inhibits Na+/K+ ATPase

Ca2+ Na+ K+
• Increases intracellular sodium
• Results in less excretion of calcium
through the Ca2+/Na+ cotransporter TN-C Inotropy
Ca++binding

Cardiac Glycosides
Digoxin (digitalis)
• Reduces symptoms of heart failure
• Reduces hospitalization
• Does not prolong life
Dosing:
• Narrow therapeutic window
• Drug accumulates in body; serum monitoring

required
Tbc, PD
Cardiac Glycosides
Digoxin (digitalis)
Interactions/side effects:
• Interacts with quinidine
• Toxicity increased with hypoK+, hypoMg2+

and hyperCa2+
Toxicity:
• Arrhythmia, nausea, vomiting, diarrhea
• Arrhythmia due to calcium overload
Tbc, PD
β1 Agonists
Dobutamine, dopamine
• ICU/CCU drug (intravenous)
• Not appropriate for chronic heart failure
• Tolerance
• Arrhythmogenic
• No oral medication

Phosphodiesterase Inhibitors
Milrinone (Primacor®)
Norepinephrine
Sympathetic
• ICU/CCU drug (intravenous) nerve
NE
• Inotropic action Epinephrine
NE EPI
• Increase cAMP by
inhibiting PDE3 b1 b2
Gs Gs-protein
• This increases intracellular
levels of calcium AC Adenylyl cyclase
Contraction
• Increased strength of ATP
contraction (inotropy) cAMP Cardiac muscle
PDE3 AMP
cAMP-dependent
phosphodies-
terase (type 3)
Phosphodiesterase Inhibitors
Milrinone (Primacor®)
Norepinephrine
• ICU/CCU drug (intravenous) Sympathetic

nerve
NE
• Inotropic action
Epinephrine
• Vasodilatory action NE EPI
• Direct action at the level b1 b2

Gs Gs-protein
of vascular smooth muscle
Contraction AC Adenylyl cyclase
• Arrhythmogenic, avoid in
chronic heart failure cAMP ATP Cardiac muscle
• Increases mortality in PDE3 AMP
cAMP-dependent
chronic heart failure phosphodies-
terase (type 3)
Direct Vasodilators
Nitrates (nitroprusside, nitroglycerin)
Nesiritide
• Natriuretic peptide causes vasodilation and volume
reduction simultaneously
• Given IV infusion in acute heart failure only

Direct Vasodilators
Hydralazine, Isosorbide Dinitrate

• One or both in combination
• Reduces mortality in African Americans
Calcium channel blockers

• No value in heart failure

Diuretics Loop Diuretics
Proximal Distal convoluted tubule

convoluted tubule
Cortex
Medulla
Proximal Thick Collecting

straight tubule ascending limb duct
of loop

Diuretics Loop Diuretics
Furosemide R
(Lasix )
Cortex
Ethacrynic acid
Medulla Bumetanide,
(Edecrin) ethacrynic acid,
furosemide
Bumetanide

Diuretics Thiazide Diuretics
Thiazide, metolazone
Hydrochlorothiazide,
Indapamide
Cortex
Indapamide may be
Medulla
better tolerated.
Metolazone is given in
acute situations.

Potassium Sparing Diuretics
Amiloride
Amiloride, spironolactone, triamterene
Spironolactone
Triamterene
Cortex
Medulla

Renin-angiotensin Agents
ACE inhibitors
Reduces: Captopril (CapotenR)

Enalapril (VasotecR)
• Morbidity and mortality in heart failure
Lisinopril (ZestrilR, PrinivilR)
• Aldosterone secretion Benazepril (LotensinR)
• Water retention Fosinopril (MonoprilR)
Quinapril (AccuprilR)
• Vascular resistance
Perindopril (AceonR, CoversylR)
Trandolapril (MavikR)

Angiotensin Receptor Blockers (ARB) ARBs

• -inferior Azilsartan (EdarbiR)
Candesarten(AtacandR)
• Cardiologists favor ACE inhibitors,
ARBs are favored by everyone else. Eposartan (TevetenR)
Losartan (CozaarR)
Direct renin inhibitors (DRI) Irbesartan (AvaproR)
• Not a lot of information Olmesartan (OlmetecR)
Telmisartan (MicardisR)
• May be effective, not routinely used
Valsartan (DiovanR)

Angiotensin Receptor Blockers (ARB)

• -inferior
• Cardiologists favor ACE inhibitors,

ARBs are favored by everyone else.
DRIs
Direct renin inhibitors (DRI)

Aliskiren (RazilezR)
• Not a lot of information
• May be effective, not routinely used

β1-Blockers
• Only used after patient has been stabilized; may be harmful in acute heart failure
• Reduces heart rate and increases stroke volume
• Reduces overall mortality and progression of chronic heart failure
• Carvedilol is the favorite β-blocker in heart failure

• Has α1, β1 and β2 effects
• Nebivolol is a new β-blocker with actions on NO

• Investigational, but experience in Europe is positive

Heart Failure

Inotropes

PDE inhibitors Loop
(digoxin) nitrates
hydralazine
ARBs
β-agonists
Beta blockers
Nesiritide
blockers Neprilysin
inhibitors

Ivabradine
Corlanor® (US), Procoralan®, Coralan® (HK, Au,
Si), Corlentor® (Sp, It, Rom), Lancora® (Can),
Coraxan® (Rus), Ivabid® (Ind)
Adverse effects:
• Luminous phenomena
• Bradycardia, AV block, dizziness, blurred
vision

Ivabradine
Corlanor® (US), Procoralan®, Coralan® (HK, Au,
Contraindications: Si), Corlentor® (Sp, It, Rom), Lancora® (Can),
Coraxan® (Rus), Ivabid® (Ind)
• Sick sinus syndrome
• On CYP 3A4 inhibitors (ketoconazole,

macrolides)
• With verapamil or diltiazem
•
tachycardia

Heart Failure

Inotropes

PDE inhibitors Loop
(digoxin) nitrates
hydralazine
ARBs
β-agonists
Beta blockers
Nesiritide
blockers Neprilysin
inhibitors

Heart Failure Neprilysin
Other names:
• Membrane metalloendopeptidase
(MME)
• Neutral endopeptidase (NEP)
• Cluster of differentiation 10 (CD10)
• Common acute lymphoblastic
leukemia antigen (CALLA)
Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, PD

Heart Failure Neprilysin
Zinc-dependent metalloproteinase that breaks

down:
• Natriuretics
• Atrial natriuretic peptide (ANP)
• Brain natriuretic peptide (BNP)
• Vasodilators
• Bradykinin
• Adrenomedullin
• Glucagon, enkephalins, substance P,
neurotensin, oxytocin, amyloid β protein

Heart Failure Neprilysin Inhibitors
• Omipatrilat (withdrawn due to angioedema)
• Sacubitril
• Entresto®: combination of
valsartan/sacubitril

Heart Failure Entresto®
• Entresto®: combination of valsartan/sacubitril
• ARNi: angiotensin receptor-neproysin

inhibitor
© by Dr. Pravin J. Shukle

Current use:
• Heart failure with reduced ejection fraction

(HFrEF)

Benefits:
• Switching 100 people from an ACE or ARB to

Entresto® for 2 3 years would prevent:
• 3 deaths
• 5 hospitalizations for heart failure
• 11 hospitalizations overall

Side effects:
• Cough
• Angioedema
• Renal failure
• Low blood pressure
• Increased potassium

Caution:
• Washout ACE inhibitors for 36 hours
• Neprilysin also clears out amyloid β from CSF

• Amyloid β

Question 1: A Good Reason to Get Chest Pain
A 60-year-old man has hypertension. He presents to the ER with chest pains

radiating to the left arm while having intercourse. He has had ViagraR earlier
that evening. The nurse practitioner gave nitroglycerin to the patient. The
patient now has a blood pressure of 66/30.
Why did this happen?
A. Interaction at the monoamine oxidase pathway causing excess tyramine
B. Interaction at the nitric oxide pathway, causing direct vasodilation
C. Excess cGMP, causing direct vasodilation
D. The patient appears to have been poisoned with cyanide.
E. This appears to be a drug allergy.

Question 1: A Good Reason to Get Chest Pain
A 60-year-old man has hypertension. He presents to the ER with chest pains

radiating to the left arm while having intercourse. He has had ViagraR earlier
that evening. The nurse practitioner gave nitroglycerin to the patient. The
patient now has a blood pressure of 66/30.
Why did this happen?
A. Interaction at the monoamine oxidase pathway causing excess tyramine
B. Interaction at the nitric oxide pathway, causing direct vasodilation
C. Excess cGMP, causing direct vasodilation
D. The patient appears to have been poisoned with cyanide.
E. This appears to be a drug allergy.

Question 2: Rx Fx
The following are effects or reflex/side effects of nitroglycerin:
A. Headache
B. Increased inotropy
C. Increased chronotropy
D. Increased transmyocardial tension
E. Blockage of L-type calcium channels

Question 2: Rx Fx
A. Headache
B. Increased inotropy
D. Increased transmyocardial tension
E. Blockage of L-type calcium channels

Question 2: Rx Fx
This is a good question to test your understanding of how nitrates work.

A. Headache
They are direct vasodilators, which will cause a reduction of vascular tone
and preload, which will
B. Increased inotropy cause lowered diastolic pressures. Therefore, the
tension across the myocardium is reduced.
Nitrates do not affect strength of contraction (inotropy), conduction velocity
(chronotropy), nor do they block
D. Increased transmyocardial L-type channels (
tension
Side effects include

E. Blockage headache,
of L-type flushing, and lightheadedness due to low bp,
calcium channels.
and reflex tachycardia.

Question 3: The Next Step
An 88-year-old man presents to your clinic with palpitations. He has a history
of MI in 1995, and was placed on nitropatch, benazepril, aspirin, and
verapamil. In 2000, he was placed on digoxin after a diagnosis of heart
failure was made. Three months ago, he was placed on Lasix 40 mg/day.
He presents with evidence of tachydysrhythmia, depressed ST segments on

ECG, and small or inverted T waves. There is no chest pain. Bloodwork was
ordered. In the meantime, what should you do?
A. Stop the ACE inhibitor and the digoxin.

B. Stop the lasix and the digoxin.
C. Stop the verapamil and the digoxin.
D. Stop the verapamil and the nitropatch.
E. Stop the verapamil and the aspirin.

He presents with evidence of tachydysrhythmia, depressed ST segments on

ECG, and small or inverted T waves. There is no chest pain. Bloodwork was
ordered. In the meantime, what should you do?

B. Stop the lasix and the digoxin.

One has to be careful with digoxin. A low potassium, a low magnesium,

and a low calcium can increase the arrhythmogenic effects of digoxin. This
question deals with drugs that can cause these electrolyte abnormalities.
Lasix canthe
B. Stop cause
lasixlow
andpotassium and low magnesium. We will wait for the
the digoxin.
labs, which probably will show a low potassium. An MI cannot be ruled out
yet, but it is not one of the choices in the question.

Verapamil usually does not affect electrolytes. It reduces heart rate, and a
combination of digoxin and a CCB may cause excessive bradycardia.
In this case, the patient is tachycardic.
Aspirin
B. Stopisthe
notlasix
relevant to this
and the case, other than it reduces the risk of
digoxin.
stroke in arrhythmia.
The answer
D. Stop the is B. We want
verapamil andto stop
the the lasix and digoxin until we get his lab
nitropatch.
results back.

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Cardiology: Heart Failure and

With Dr. Pravin J. Shukle

Neuer Nutzer, sanar@click2mail.net

Vasodilators Cardiac depressants Other drugs

Nitrates Calcium blockers β-blockers Metabolism

Neuer Nutzer, sanar@click2mail.net

• Inhaled nitrates (amyl nitrate)

• Sublingual nitroglycerin (NitroTab)

• Oral nitroglycerin (isosorbide dinitrate, ISDN)

• Transdermal nitroglycerin (Nitro patch)

Neuer Nutzer, sanar@click2mail.net

• Nitroglycerin is the same ingredient as in dynamite.

• Venodilator reduced cardiac output and oxygen

• Arteriodilator opens up myocardial vascular bed,

1899-1900, unknown. https://commons.wikimedia.org/wiki/File:PSM_V56_D0465_Hollow_dynamite_cartridge_elevation_view.png

Rapidly de-nitrated in liver

• Mononitrates (less active) glyceryl mononitrate,

Release NO (nitric oxide)

1899-1900, unknown. https://commons.wikimedia.org/wiki/File:PSM_V56_D0465_Hollow_dynamite_cartridge_elevation_view.png

Rapidly de-nitrated in liver

• Mononitrates (less active) glyceryl mononitrate,

Release NO (nitric oxide)

1899-1900, unknown. https://commons.wikimedia.org/wiki/File:PSM_V56_D0465_Hollow_dynamite_cartridge_elevation_view.png

Guanylyl cyclase + Nitrates

Neuer Nutzer, sanar@click2mail.net

Kit components Administration

Amyl nitrite • Methemoglobin inducers

• Methemoglobin reversibly binds with cyanide

Sodium thiosulfate • Helps convert cyanide to thiocyanate,

Neuer Nutzer, sanar@click2mail.net

Dihydropyridine (DHP CCB)

• Amlodipine (Norvasc®), Felodipine Dihydropyridine

• Mostly a blood pressure drug

• May cause reflex tachycardia

• May worsen proteinuria in patients with

Nondihydropyridine (NDHP CCB)

Phenylalkylamine NDHP CCBs Dihydropyridine

• Gabapentin, pregabalin (Lyrica®)

• Block α2δ subunit containing

• Blocks L-type calcium channels

• Relaxes urinary bladder

All CCBs side effects:

• Constipation, pretibial edema, Dihydropyridine

DHPS (nifedipine, amlodipine)

• Marked lowering of blood pressure

NDHPs (diltiazem, verapamil)

• Bradycardia/AV block/sinus node

• Propranolol and others

• Reduce heart rate, cardiac force, blood

• Used in prevention only; not for treating

• Not useful against vasospastic form

Neuer Nutzer, sanar@click2mail.net

Ranolazine (Ranexa®), trimetazidine (Vastarel®)

• Partial fatty acid oxidation inhibitors

• Increases efficiency of oxygen utilization

• Shifts energy production from fatty acids to

• May also have an effect on slow sodium

Neuer Nutzer, sanar@click2mail.net

• Reduction of heart rate (pacemaker

MarinaVladivostok, CC0 1.0

• Inappropriate sinus tachycardia

• Bradycardia, AV block, dizziness, blurred

• On CYP 3A4 inhibitors

• With verapamil or diltiazem