drugs for IHD Flashcards
midterm
1
Q
- Circulation within the myocardium
- Blood vessels
A
coronary circulation
2
Q
branch from the ascending aorta
A
coronary arteries
3
Q
drain into the coronary sinus
A
cardiac veins
4
Q
a condition in which there is an adequate supply of blood and oxygen to a portion of the myocardium
A
IHD
ischemic heart disease
5
Q
typically occurs when there is an imbalance between myocardial oxygen supply and demand
A
IHD
ischemic heart disease
6
Q
-most common cause of myocardial ischemia
-sufficient to cause a regional reduction in myocardial blood flow and inadequate perfusion of the myocardium supplied by the involved coronary artery
A
atherosclerotic disease of an epicardial coronary artery/ies
7
Q
*heart rate
*myocardial contractility
*myocardial wall tension
(stress)
A
determinants of oxygen demand
8
Q
*inspired level of oxygen
*pulmonary function
*hemoglobin concentration
and function
*level of coronary blood flow
A
determinants of oxygen supply
9
Q
- Reduced blood flow to the myocardium due to partial obstruction of coronary arteries
- Causes hypoxia (reduced oxygen supply)
- Weakens cells
- Angina pectoris
A
MYOCARDIAL ISCHEMIA
10
Q
chest pain (tightening/squeezing) that usually accompanies myocardial ischemia, radiates to the neck, chin, or left arm
A
Angina pectoris
11
Q
- a.k.a. heart attack
- Death of myocardial tissue due to complete obstruction of blood
flow of coronary arteries - Kills cells, which are replaced by noncontractile scar (fibrotic)
tissue - Treatment: fibrinolytic
A
myocardial infarction
12
Q
- a man >50 years or a woman >60 years
- chest discomfort, usually described as heaviness, pressure, squeezing,
smothering, or choking - usually over the sternum
- crescendo-decrescendo
- typically lasts 2-5 min
- can radiate to either shoulder and to both arms, back, interscapular region, root of the neck, jaw, teeth, and epigastrium
A
typical patient with angina:
13
Q
Relieved by rest or NTG (nitroglycerin)
A
stable angina pectoris
14
Q
-patients have cardiac disease but without the resulting limitations of physical activities
-ordinary physical activities does not cause undue fatigue, palpitation, dyspnea or anginal pain
A
Class 1
15
Q
-patients have cardiac disease resulting in slight limitation of physical activity
-comfortable at rest
-ordinary physical activities results in fatigue, palpitation, dyspnea or anginal pain
A
class 2
16
Q
-patients have cardiac disease resulting in marked limitation of physical activity
-comfortable at rest
-less than ordinary physical activity causes fatigue, palpitation, dyspnea or anginal pain
A
class 3
17
Q
patients have cardiac disease resulting in inability to carry on physical activities without discomfort
-symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest
-if any physical activity is undertaken, discomfort is increased
A
class 4
18
Q
- chest discomfort is severe and has at least one of three features:
- (1) it occurs at rest (or with minimal exertion), lasting >10 minutes;
- (2) it is of relatively recent onset (i.e., within the prior 2 weeks); and/or
- (3) it occurs with a crescendo pattern (i.e., distinctly more severe,
prolonged, or frequent than previous episodes)
A
unstable angina
19
Q
Not relieved by rest or NTG
A
unstable angina
20
Q
- Variant angina
- Due to vasospasm
- Relieved by NTG and CCBs
A
prinzmetal’s angina
21
Q
-nitrates
-CCBs /calcium channel blockers
-beta blockers
-new anti-anginal drugs
A
anti anginal drugs
22
Q
- Nitroglycerin (SL, transdermal, buccal)
- Isosorbide dinitrate (SL)
- Isosorbide mononitrate (PO)
- Amyl nitrite (inhalational)
A
nitrates
23
Q
- MOA: intracellularly converted to nitrite ions and then to NO that
activates guanylate cyclase and increases cyclic guanosine
monophosphate (cGMP); elevated cGMP ultimately leads to
dephosphorylation of the myosin light chain, resulting in vascular
smooth muscle relaxation - Effects: vasodilation and decreased platelet aggregation
- Uses: stable angina, unstable angina, variant angina
- ADR: orthostatic hypotension, tachycardia, throbbing headache (due to vasodilation), tolerance (tachyphylaxis) – provide nitrate-free interval, methemoglobinemia (amyl nitrite)
- CI: PDE-5 inhibitors
A
nitrates
24
Q
- Nicotinamide nitrate ester
- MOA: preconditioning by activation of cardiac KATP channels
A
nicorandil
25
* Effects: relax blood vessel smooth muscle and cardiac muscle
* Uses: stable angina, variant angina
* ADR: cardiac depression, including bradycardia, atrioventricular
block, cardiac arrest, and heart failure
calcium channel blockers
26
* Effects: decreased HR, contractility
* Uses: stable angina, unstable angina
beta-blockers
27
* MOA: reduces a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchanger
* Use: stable angina (when unresponsive to other treatment)
ranolazine
28
* MOA: reduces cardiac rate by inhibiting the hyperpolarization-
activated sodium channel in the sinoatrial node
ivabradine
29
* pFOX inhibitor - partially inhibit the fatty acid oxidation pathway in
myocardium (oxidation of fatty acids in ischemic myocardium requires more oxygen per unit of ATP produced)
trimetazidine
30
* (1) tachycardia and increased contractility through sympathetic nervous system activation;
* (2) activation of RAAS;
* (3) the Frank–Starling mechanism, whereby increased preload increases
stroke volume;
* (4) vasoconstriction; and
* (5) ventricular hypertrophy and remodeling
*initially maintain cardiac function, they are responsible for the symptoms of HF and contribute to disease progression.
compensatory mechanisms that the relies on as cardiac function decreases
31
* Reduce symptoms and slow disease progression as much as
possible during relatively stable periods.
* Manage acute episodes of decompensated failure.
therapeutic goals for HF (heart Failure)
32
drugs for Chronic Systolic Heart Failure
Diuretics
Aldosterone receptor antagonist
Angiotensin converting enzyme
inhibitors
Angiotensin receptor blockers
Beta blockers
Cardiac glycosides
Vasodilators, Neprilysin inhibitor
Resynchronization & Cardioverter
therapy
33
block the enzyme neprilysin, which normally degrades natriuretic peptides (BNP, ANP), bradykinin, and angiotensin II. By inhibiting neprilysin, these peptides stay active longer, leading to vasodilation, natriuresis (sodium excretion), and reduced cardiac workload.
Neprilysin inhibitors
34
-no symptoms but risk factors present
-treat obesity, hypertension, diabetes,, hyperlipidemia
A / Prefailure
35
refers to elevated levels of lipids (cholesterol & triglycerides) in the blood, increasing the risk of atherosclerosis, cardiovascular disease (CVD), and stroke.
hyperlipidemia
36
-symptoms with severe exercise
-ACEi, ARB, B-bloker, diuretic
B / 1
37
-symptoms with marked (class 2) or mild (class 3) exercise
-add Aldosterone antagonist, digoxin, CRT, ARNI, Hydralazine/nitrate
C / 2/3
38
-severe symptoms at rest
-transplant, LVAD
D / 4
39
CRT
Cardiac Resynchronization Therapy
40
ARNI
Angiotensin Receptor-Neprilysin Inhibitors
41
left ventricular assist device
LVAD
42
-at high risk for HF but without structural heart disease or symptoms of HF
-patients with:
*hypertension
*atherosclerotic disease
*DM
*obesity
*metabolic syndrome
-or:
*using cardiotoxic drugs
*with family history of cardiomyopathy
stage A
43
-structural heart disease but without signs or symptoms of HF
-patients with:
*previous MI (myocardial infarction)
*LV remodeling
*LV hypertrophy & low ejection fraction
*asymptomatic valvular disease
stage B
44
-structural heart disease with prior or current symptoms of HF
-patients with:
*known structural heart disease
*HF signs and symptoms
stage C
45
-refractory HF
-patients with:
*marked HF symptoms at rest
*recurrent hospitalized despite guideline directed medical therapy
Stage D
46
goals for Stage A
*heart healthy lifestyle
*prevent vascular, coronary disease
*prevent LV structural abnormalities
47
drugs for stage A
-ACEI or ARB in appropriate patients for vascular disease or DM
-statins as appropriate
48
goals for stage B
-prevent HF symptoms
-prevent further cardiac remodeling
49
drugs for stage B
*ACEI or ARB in appropriate patients
*Beta-blockers in appropriate patents
in selected patients:
*implantable cardioverter- defibrillator (ICD)
*revascularization or valvular surgery as appropriate
50
goals for stage C
-control symptoms
-prevent hospitalization
-prevent mortality
51
drugs for stage C:
for patients with preserved EF (ejection fraction):
*diuretics
*treat comorbidities (HTN, AF, CAD, DM)
52
HTN
hypertension
53
AF
atrial fibrillation
54
CAD
coronary arterial disease
55
drugs for stage C
for routine use in patients with reduced EF
*Diuretics
*ACEI or ARB
*ARNI
*Beta -blockers
*Aldosterone antagonist
*Ivabradine
56
drugs for stage C
for use in selected patients with reduced EF
*Hydralazine
*ACEI or ARB
*Cardiac glycoside
57
drugs for stage C
for use in selected patients
*CRT
*ICD
*revascularization or valvular surgery
58
CRT
cardiac resynchronization therapy
59
ICD
Implantable cardioverter defibrillator
60
goals for Stage D
-control symptoms
-improve HRQOL
-reduce hospital readmissions
-establish end of life goals
61
HRQOL
health related quality of life
62
options for stage D
-advanced care measures
-heart transplant
-chronic inotropes/neseritide
-temporary or permanent mechanical support
-experimental surgery or drugs
-palliative care & hospice
-ICD deactivation
63
--the mainstay in management of symptomatic heart failure, especially if edema is present
-by dietary salt restriction and a diuretic
sodium removal
64
**cornerstone of HF therapy
* Angiotensin Converting Enzyme Inhibitors (ACEIs)
* Angiotensin (AT1) Receptor Blockers (ARBs)
* Beta Blockers
* Mineralocorticoid Receptor Antagonists (MRAs)/Aldosterone Antagonists
* Angiotensin Receptor/Neprilysin Inhibitor (ARNI)
Treatment Principle I: Neurohumoral Modulation
65
* Diuretics
Treatment Principle II: Preload Reduction
66
* Hydralazine-Isosorbide Dinitrate
Treatment Principle III: Afterload Reduction
67
* Cardiac Glycosides
Treatment Principle IV: Increasing Cardiac Contractility
68
* Ivabradine
Treatment Principle V: Heart Rate Reduction
69
Benazepril
Captopril
Enalapril
Fosinopril
Lisinopril
Moexipril
Perindopril
Quinapril
Ramipril
Trandolapril
ACE inhibitors (ACEI)
70
*inhibition of ACE: ↓ Angiotensin II &
↑ bradykinin
ace inhibitors MOA
71
-contributes to therapeutic efficacy of ACEIs and may explain why ARBs have not been consistently associated w/
improved survival in HFrEF
bradykinin
72
HFrEF
heart failure with reduced ejection fraction
73
ACE INHIBITORS: EFFECTS
↓ peripheral resistance → ↓ afterload
vasodilator
74
ACE INHIBITORS: EFFECTS
↓ water and salt retention by decreasing aldosterone secretion → ↓ preload
indirect diuretic
75
ACE INHIBITORS: EFFECTS
↓ sympathetic activity by decreasing angiotensin’s presynaptic effects on NE release
sympatholytic
76
ACE INHIBITORS: EFFECTS
↓ long-term remodeling of the heart and vessels
antiremodeling
77
* limits reflex tachycardia that accompanies vasodilation and BP lowering
* ↓ mortality and morbidity in HF
ACE INHIBITORS: EFFECTS
78
ACE INHIBITORS: CLINICAL USE
* first-line therapy for chronic HF
* first drug used in left ventricular dysfunction but no edema
* beneficial in all subsets of patients—from asymptomatic to severe chronic
HF
* cannot replace digoxin in patients already receiving the glycoside
79
ACE INHIBITORS: ADVERSE EFFECTS
* accumulation of bradykinin and substance P (w/c are metabolized by ACE)
* cough
* angioedema
* ↑ serum creatinine
* hyperkalemia
* allergic skin reactions
80
substance p (SP)
-11 amino acid long neuropeptide
-neurotransmitter
-transmits pain signals
81
ace inhibitor: adverse effect
COUGH
-the most frequent ADR
-necessitate change to ARBs
82
ace inhibitor: adverse effect
ANGIOEDEMA
-rare, but life-threatening (swelling of the skin & mucous membranes of the throat & asphyxia)
-requires cessation of ACEI & treatment w/ antihistamine, corticosteroid, or in severe cases, epinephrine
83
ace inhibitor: adverse effect
serum creatinine
* <20%: normal
* 20%–50%: careful observation and reduction of ACEI dosage
* >50%: stop ACEI and consult specialist for diagnosis of renal artery stenosis
84
Hyperkalemia
High Potassium
85
Candesartan
Eprosartan
Irbesartan
Losartan
Olmesartan
Telmisartan
Valsartan
Angiotensin (AT1) receptor blockers
86
* selective, competitive receptor antagonism at the AT1 receptor
ARBs MOA
87
* show the same pharmacological and toxicological profile as ACEIs
except induction of cough
* unopposed activity of AT2 receptor seems to confer no therapeutic
advantage to ARBs over ACEIs
ARBs effects
88
2nd choice in HF patients who do not tolerate ACEIs
ARBs
89
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
Beta blockers
90
beta blockers
cardioselective
Metoprolol
Bisoprolol
91
beta blockers
non-selective b-blocker & an a1 receptor antagonist
carvedilol
92
beta blocker
cardio selective
NO- mediated vasodilator
Nebivolol
93
* competitive inhibition of β receptor
BETA BLOCKERS: MOA
94
* ↓ HR and contractility
* slow cardiac relaxation
* slow AV conduction
* suppression of arrhythmias
* slight ↑ EF
* ↓ renin levels
* ↓ hospitalization,
BETA BLOCKERS: EFFECTS
95
WHY USE β BLOCKERS IN HEART FAILURE?
* Adaptation of the heart to decreasing stimulation by catecholamines and finding a new equilibrium at a lower adrenergic drive
* Protection of the heart from the adverse long-term consequences of
adrenergic overstimulation (e.g., increased energy consumption, fibrosis,
arrhythmias, and cell death) → ↓ HR and prolonged diastole → improved
perfusion (↓ effusion) and contractile function (due to negative force-
frequency relation)
* Reduction of cardiac remodeling through inhibition of the mitogenic
activity of catecholamines
96
BETA BLOCKERS: CLINICAL USE
* all patients with symptomatic HF (stage C, NYHA II–IV)
* all patients with left ventricular dysfunction (stage B, NYHA I) after
MI
* D&A:
* initiated only in clinically stable patients at very low doses, generally 1/8 of the final target dose
* titrated upward every 4 weeks
97
BETA BLOCKERS: ADVERSE EFFECTS
* if dose increased rapidly: low blood pressure, fluid retention, and
dizziness
* bradycardia
* reasonable target resting heart rate: 60–70/min
* AV block
* bronchoconstriction
* initial peripheral vasoconstriction (cold extremities) → vasodilation in
chronic treatment
* CI:
* new-onset or acutely decompensated heart failure – can precipitate acute decompensation of cardiac function
* asthma – w/ all β blockers
* COPD – w/ nonselective β blockers
98
Eplerenone
Spironolactone
Mineralocorticoid Receptor Antagonists
MRAs
Aldosterone Antagonists
99
* antagonism of nuclear receptors of aldosterone
* reduction of expression of ENaC (epithelial Na+-channel) in
collecting tubules → also act as K+-sparing diuretics
MRAs: MOA
100
Eplerenone
selective antagonist of the mineralocorticoid receptor
101
Spironolactone
nonspecific steroid receptor antagonist w/ similar affinity for progesterone and androgen receptors
102
MRAs: EFFECTS
* K+-sparing diuresis
* additional efficacy in suppressing the consequences of neurohumoral activation (unlike other diuretics)
* complete inhibition of aldosterone
* no aldosterone escape unlike w/ ACEI or ARB therapy
* reduction of fibrosis
* ↓ morbidity and mortality in severe HF who are also receiving ACEIs
and other standard therapy
103
MRAs CLINICAL USE
* all symptomatic HFrEF patients in stage C (NYHA class II–IV) at low
doses
* considered in all patients with moderate or severe HF
104
Sacubitril plus valsartan
Angiotensin Receptor Neprilysin Inhibitor (ARNI)
105
ARNI: MOA
* Sacubitril: inhibition of neprilysin → inhibition of metabolism of
ANP and BNP → ↑ ANP & BNP
106
neprilysin
– a peptidase mediating the enzymatic degradation and inactivation of natriuretic peptides [ANP, BNP, CNP], bradykinin, and substance P)
107
ANP
atrial natriuretic peptide
*vasodilation
*↑ Natriuresis & Diuresis
*inhibits RAAS
*lowers BP
108
BNP
B-Type Natriuretic Peptide
*Vasodilation
*↑ Natriuresis & Diuresis
*marker of HF severity
the most clinically relevant natriuretic peptide because it is used as a biomarker in HF diagnosis & prognosis.
109
CNP
C-Type Natriuretic Peptide
🔹 Local vascular effects
🔹 NO-mediated vasodilation
🔹 Minimal natriuretic action
110
Bradykinin
is a vasoactive peptide that plays a key role in:
✅ Vasodilation (via nitric oxide [NO] & prostacyclin)
✅ Increased vascular permeability
✅ Pain & inflammation
✅ Inhibition of RAAS
🔹 It is part of the kinin-kallikrein system (KKS) and is degraded by ACE (angiotensin-converting enzyme).
111
ARNI: EFFECTS
* inhibition of the RAAS + activation of beneficial axis of neurohumoral
activation (the natriuretic peptides)
* promotes the beneficial effects natriuresis, diuresis, and vasodilation of
arterial and venous blood vessels
* inhibits thrombosis, fibrosis, cardiac myocyte hypertrophy, and renin
release
* appears superior to the ACEI enalapril
* better pharmacological principle than giving the agonist BNP (nesiritide)
directly because it enhances endogenous regulation of plasma and
tissue levels
* ↓ rates of hospitalization and death from all cardiovascular causes in
HFrEF
112
ARNI: CLINICAL USE
* chronic HFrEF
* superior to enalapril in reducing high-sensitivity troponin-T levels
and rehospitalization of patients with acute decompensated HFrEF
* may become first choice in HF (see Four Pillars of Heart Failure)
113
High-Sensitivity Troponin-T (hs-TnT)
a biomarker of myocardial injury, detected at much lower levels than conventional troponin tests. It is used for:
✅ Early diagnosis of acute coronary syndrome (ACS) & myocardial infarction (MI)
✅ Risk stratification in heart failure (HF), chronic kidney disease (CKD), and sepsis
✅ Detection of subclinical cardiac injury (e.g., in hypertensive heart disease, myocarditis, or chemotherapy-induced cardiotoxicity)
114
Four Pillars of Heart Failure
ARNI
Beta-Blockers
MRAs
SGLT2 inhibitors
115
TREATMENT PRINCIPLE II: PRELOAD
REDUCTION
* in normal heart:
* Frank-Starling mechanism
* in HF:
* ↓ kidney perfusion → activation of the RAAS → fluid retention → ↑ filling
pressures (preload)
* congestion operates at the flat portion of positive force-length relationship → cannot generate sufficient force w/ ↑ preload → pulmonary and peripheral edema
116
edema
-abnormal accumulation of fluids in tissues leading to swelling
-can be localized or
-generalized (anasarca)
117
diuretics
* increase Na+ and water excretion
* improve symptoms of CHF by moving patients to lower cardiac filling pressures (preload)
* an integral part of the combination therapy of symptomatic forms
of HF
* should not be given to patients without congestion → activate
RAAS and may accelerate a vicious downward spiral
* reduces edema and congestion
* diuretic resistance may occur and cause clinical deterioration
118
LOOP DIURETICS
* Furosemide
* Torasemide
* Bumetanide
119
LOOP DIURETICS: MOA
* inhibition of NKCC2 (Na+-K+-2Cl symporter) in the ascending limb
of the LoH (loop of Henle)
120
Natriuresis
The process of increased sodium (Na⁺) excretion in urine.
121
Diuresis
An increase in urine volume due to reduced water reabsorption
122
LOOP DIURETICS: EFFECTS
* strong diuretic effect
* ↑ Na+ and fluid delivery to distal nephron segments
* inhibition of tubuloglomerular feedback (↓ in GFR due to increased Na+
and fluid sensed by macula densa) → stable action and unaffected GFR
(unlike carbonic anhydrase inhibitors and thiazide diuretics)
* → increased ENaC-mediated reabsorption of Na+ and more K+ excretion in the distal tubule → hypokalemia
123
ENaC
Epithelial Sodium Channel
-a sodium-selective ion channel found in the apical membrane of epithelial cells
124
LOOP DIURETICS: CLINICAL USE
* diuretics of choice in HF
125
THIAZIDE DIURETICS
* Hydrochlorothiazide (HCTZ)
* Chlorthalidone
126
THIAZIDE DIURETICS: MOA
* inhibition of NCC (Na+-Cl– cotransporter/symporter) in the distal
convoluted tubule
127
CLINICAL USE: THIAZIDE DIURETICS
* limited role in heart failure
* low maximal diuretic effect
* loss of efficacy at a GFR <30 mL/min
* may be tried in very mild HF (before loop diuretics)
* combination therapy w/ loop diuretics
* effective in those refractory to loop diuretics alone due to upregulation of
the Na+-Cl cotransporter in the distal convoluted tubule
128
ADVERSE EFFECTS: THIAZIDE DIURETICS
* hypokalemia (more severe than loop diuretics)
129
hypokalemia
a condition where blood potassium (K⁺) levels drop below 3.5 mEq/L
130
POTASSIUM-SPARING DIURETICS
* Amiloride
* Triamterene
131
POTASSIUM-SPARING DIURETICS: MOA
AND EFFECT
* inhibition of Na+ entry in ENaC (epithelial Na+-channel) in the
apical membrane of collecting tubule
* weak diuresis w/o K+ wasting
132
POTASSIUM-SPARING DIURETICS:
CLINICAL USE
* HTN: in combination with thiazides or loop diuretics to reduce K+ and Mg2+ wasting
* largely dispensable in the therapy of heart failure
133
TREATMENT PRINCIPLE III: AFTERLOAD
REDUCTION
* In HF, heart is exquisitely sensitive to increased arterial resistance
(afterload).
* Vasodilators reduce afterload and allow heart to expel blood
against lower resistance.
134
HYDRALAZINE-ISOSORBIDE DINITRATE
Hydralazine plus isosorbide dinitrate (BiDil)
135
ISDN: EFFECTS
* dilates large blood vessels e.g., venous capacitance and arterial conductance vessels
* a venous dilator → “venous pooling” and ↓ diastolic filling pressure
(preload)
* relieves pulmonary congestion and dyspnea
* only little effect on systemic vascular resistance (regulated by small-to-medium arterioles)
* tolerance (due to tachyphylaxis) – loss of effect and induction of a
pro-constrictory state with high levels of ROS
136
Tachyphylaxis
rapid decrease in response to a drug
137
HYDRALAZINE: EFFECTS
* unknown MOA
* Effects:
* an arteriolar dilator → ↓ afterload and ↑ CO
* relieves fatigue
* prevents nitrate tolerance by reducing ROS-mediated inactivation of NO
138
preload
filling pressure
-represents the volume of blood returning to the heart (venous return) and how much the ventricle fill
139
afterload
resistance to ejection
-pressure of the heart must overcome to eject blood during systole
140
HYDRALAZINE-ISDN: EFFECTS
* can reduce damaging remodeling of the heart
* ↓ mortality in African-Americans
141
HYDRALAZINE-ISDN: CLINICAL USE
* severe chronic HF w/ both ↑ filling pressures and ↓ CO and
responds poorly to other therapy
142
HYDRALAZINE-ISDN: ADVERSE EFFECTS
* hypotension – dose-limiting
* dizziness and headache
* hydralazine >200 mg: SLE (systemic lupus erythematous)
143
TREATMENT PRINCIPLE IV: INCREASING
CARDIAC CONTRACTILITY
* Failing heart is unable to generate force sufficient to meet the
needs of the body for perfusion of oxygenated blood.
* Chronic use does not improve life expectancy or cardiac
performance but is associated with excess mortality.
144
cardiac glycoside
digoxin
(lanoxin, Lanoxicaps)
* known for thousands of years
* were used erratically and with variable success until 1785
* Cardiac Glycosides and Sources:
* Digoxin from Digitalis lanata (white foxglove)
* Digitoxin from Digitalis purpurea (purple foxglove) and Digitalis lanata
145
CARDIAC GLYCOSIDES: MOA
* inhibition of Na+/K+-ATPase → ↓ Na+ efflux → ↑ intracellular Na+
→ ↓ Ca2+ efflux by Na+-Ca2+ exchanger (NCX) → ↑ Ca2+ sequestration by SERCA in SR → ↑ Ca2+ release from SR during
depolarization → ↑ interactions between actin and myosin →
sarcomere shortening → ↑ inotropy
* possible additional functions of Na+/K+-ATPase
* apoptosis
* cell growth and differentiation
* immunity
* carbohydrate metabolism
146
apoptosis
a regulated, energy-dependent process of programmed cell death that eliminates damaged, infected, or unnecessary cells without triggering inflammation
147
SERCA in SR
Sarco/Endoplasmic Reticulum Ca²⁺-ATPase in the Sarcoplasmic Reticulum
148
CARDIAC GLYCOSIDES: CARDIAC EFFECTS
* Mechanical Effect: ↑ cardiac contractility
* Electrical Effects:
* Direct Actions
* At therapeutic doses:
* early, brief prolongation of action potential
* followed by shortening (especially the plateau phase) – probably due to increased potassium conductance caused by increased intracellular calcium
* At toxic doses:
* less negative RMP
* delayed after-depolarizations (DADs)
* premature depolarizations (ectopic “beats”)
* bigeminy in ECG
* self-sustaining tachycardia
* Autonomic Actions
* At therapeutic doses: parasympathomimetic effects – useful in treatment of arrhythmias
* At toxic doses: sympathomimetic effects - sensitizes the myocardium; exaggerates all the toxic effects of the drug e.g., AV junctional rhythm, premature ventricular depolarizations,
bigeminal rhythm, ventricular tachycardia, and second-degree atrioventricular blockade
149
CARDIAC GLYCOSIDES: EFFECTS ON
OTHER ORGANS
* affect all excitable tissues, including smooth muscle and the CNS
* GIT
* most common site of toxicity outside the heart
* anorexia, nausea, vomiting, and diarrhea
* caused in part by direct effects and in part by CNS actions
* CNS
* vagal and chemoreceptor trigger zone stimulation
* disorientation and hallucinations (less often; more common in elderly)
* visual disturbances (e.g., impaired color perception)
* gynecomastia (rare)
150
CARDIAC GLYCOSIDES: INTERACTIONS WITH POTASSIUM
* inhibit each other’s binding to Na+/K+-ATPase
* hyperkalemia – reduces the enzyme-inhibiting actions of cardiac glycosides and decreases cardiac automaticity → reduces toxicity of digitalis
* hypokalemia – increases the enzyme-inhibiting actions of cardiac glycosides
151
CARDIAC GLYCOSIDES: INTERACTIONS WITH CALCIUM
* facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores
* hypercalcemia – increases the risk of a digitalis-induced arrhythmia
152
CARDIAC GLYCOSIDES: INTERACTIONS WITH MAGNESIUM
* opposite effects to Ca2+
153
CARDIAC GLYCOSIDES: CLINICAL USE
* heart failure
* D&A:
* slow loading (digitalization): 0.125–0.25 mg/d; safer and as effective as rapid
method
* rapid method: 0.5–0.75 mg q8h for 3 doses, followed by 0.125–0.25 mg/d
* given only when diuretics and ACE inhibitors have failed to control
symptoms
* provide relief of S/Sx in ≈50% of patients with normal sinus rhythm (usually
those w/ systolic dysfunction)
* reduces hospitalization and deaths from progressive heart failure at the
expense of an increase in sudden death
* the only inotropic agents used in chronic HF due to ↓ rate of HF–
associated hospitalizations w/o increasing mortality
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CARDIAC GLYCOSIDES: CLINICAL USE
* atrial fibrillation and atrial flutter
* requires higher Cp
* due to cardioselective parasympathomimetic effects
* depressed AV conduction helps control an excessively high ventricular rate
* paroxysmal atrial and AV nodal tachycardia
* but CCBs are preferred
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CARDIAC GLYCOSIDES: ADVERSE EFFECTS
* common
* narrow therapeutic index (≈2)
* visual changes (10%), GI disturbances (55%)
* xanthopsia, coronas (halos)
* anorexia, nausea, and vomiting
* requires dose reduction
* cardiac arrhythmias
* most frequent (90%) and most serious adverse effects
* include atrial fibrillation, AV block, and rarely, ventricular arrhythmias
* requires monitoring serum digitalis level, K+, and ECG
* requires monitoring and correcting electrolyte levels
* worsened by cardioversion (reserved for digitalis-induced ventricular fibrillation)
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CARDIAC GLYCOSIDES: ADVERSE EFFECTS
* severe intoxication
* elevated serum K+ (because of loss from the intracellular compartment of
skeletal muscle and other tissues)
* depressed automaticity (extreme bradycardia)
* cardiac arrest w/ antiarrhythmic agents
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CARDIAC GLYCOSIDES: ADVERSE EFFECTS
Treatment for extreme sinus bradycardia, sinoatrial block, or AV block grade II or III
* atropine IV
* temporary cardiac pacemaker – if atropine not successful
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CARDIAC GLYCOSIDES: ADVERSE EFFECTS
treatment for tachycardic ventricular arrhythmias, hypokalemia
* K+ infusion (40–60 mmol/d)
159
CARDIAC GLYCOSIDES: ADVERSE EFFECTS
treatment for digoxin toxicity
* administration of digitalis antibodies digoxin immune fab (ovine)
* Digibind®
* DigiFab®
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TREATMENT PRINCIPLE V: HEART RATE
REDUCTION
* HR is a strong determinant of cardiac energy consumption
* Higher HR in HF is associated with poor prognosis.
161
ivabradine
corlanor
162
IVABRADINE: MOA
* selective inhibition If sodium channel
* ↓ HR by inhibiting the hyperpolarization-activated sodium channel in the SA node
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IVABRADINE: CLINICAL USE
* HF and stable angina pectoris in patients not tolerating β blockers
or in whom β blockers did not sufficiently lower HR (<75/min)
164
IVABRADINE: ADVERSE EFFECT
* phosphenes (typical transient enhanced brightness in a restricted
area of the visual field)
* bradycardia
* atrial fibrillation
* QT prolongation
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DRUG TREATMENT OF CHRONIC DIASTOLIC HEART FAILURE
* less extensive evidence about superiority or inferiority of drugs in
HFpEF
* most clinical trials performed on systolic dysfunction
* Recommendations:
* Nebivolol – effective in both systolic and diastolic failure
* ACEIs, ARBs – useful
* control of HTN and hyperlipidemia
* Rhythm control – because atrial fibrillation is common in HFpEF
* Ivabradine – to increase ventricular filling time by decreasing HR
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