CAD/HF Flashcards
1
Q
Significance of CAD?
A
- Heart Disease is the leading cause of death in the US ~ 600,000 lives each year
- ~7 million Americans experience angina
- *Atherosclerosis is a leading cause of angina
- Angina is an indication of myocardial ischemia which potentially can lead to
- Ischemia/Infarction
- Congestive heart failure
- Life-threatening arrhythmias
2
Q
What is coronary blood flow in young, healthy heart at rest?
A
- Coronary blood flow is 70ml/min/100g at rest
- ~5% the cardiac output
- % Oxygen extracted from myocardial tissue beds is VERY HIGH = 70%
3
Q
What is coronary blood flow in the young, healthy heart during intense exercise?
A
- Intense Exercise
- Coronary blood flow increases 2-4 fold
- (Supply)
- Coronary blood flow increases 2-4 fold
- However cardiac demands increase proportionally higher
- CO to the body increases 4-7 fold
- Preload
- Heart rate
- Contractility
- (Demand)
- CO to the body increases 4-7 fold
4
Q
What determines coronary blood flow throught the cardiac cycle?
A
Physical factors:
- During systole, the pressure exerted by the myocardium on vessels that pass through it equals or exceeds the perfusion pressure, so coronary flow occurs only during diastole.
- Systolic contraction impedes coronary artery filling because the increase in intramural pressure
- Redistributes blood flow from the subendocardial to the subepicardial layers
- Compresses the arterioles and capillaries
-
Perfusion pressure to the left ventricle = DBP – LVEDP
- most interested in DBP in pt with CAD
- Systolic contraction impedes coronary artery filling because the increase in intramural pressure
Vascular control by metabolites
- A change in the metabolites produced by myocardial cells in response to decreased PO2 causes coronary vasodilation (adenosine)
- even slight dilation of coronary will hve profound impact on blood flow (remember pousilles law)
Neural and humoral control
- Sympathetic innervation
- Large vessels- Alpha (vasoconstriction effects);
- smaller vessels (subendocardium)- Beta-2 (dilator effects)
5
Q
When are coronaries perfused?
A
Diastole
- diastolic time is very important
- treat by getting heart rate down is very improtant in order to allow filling time during diastole, and therefore better coronary perfusion
6
Q
Pathophysiology of angina? Normal healthy physio vs stable, usntable, variant angina?
A
-
Normal-
- Patent lumen
- Normal endothelial function
- PLT aggregation inhibited
- can release NO when stimulated by bradykinin which can cause dilation. smooth layer, discrouages plt from aggregating. allows coronaries to adapt to diff metabolic demand
-
Stable angina
- lumen narrowed by plaque
- inappropriate vasoconstriction
- pt has atherosclerotic plaque (pouseille’s law)
- internal diamater reduced, dramatic drop in flow
- endothelial layer not as healthy and not as effective at releasing NO to influence smooth muscle/tone during exercise
- usually have CP after exertion
-
Unstable angina
- plaque ruptured
- PLT aggregation
- PLT can eventually occlude vessel and prevent downstream oxygenation causing infarction
- thrombus formation
- unopposed vasoconstriction
-
Varient angina (prinzmetal angina)
- no overt plaque
- intense vasospasm
-
very rare form, a/w reynaud’s dx
- 2% case, don’t know what casuses it.
-
intense vasospasm, my be related to inappropriate thomboxane or excessive alpha adrenergic activitiy
- avoid bb in variant angina because it’ll block beta 2. anytime you have excessive vasospasm, avoid blocking good guys (beta 2)
7
Q
What increases myocardial O2 demans?
A
- Tachycardia
- High afterload
- High preload
- Increased contractility
8
Q
What cna increase O2 supply?
A
- Hemoglobin Concentration- also don’t want polycythemia, need normal
- Oxygen Saturation
- Bradycardia (within reason)- HR 30 not ok, but high 50/60s is optimizing diastolic filling time
- Increased diastolic blood pressure- robust
- Low Normal Preload
- Decreased Contractility- increase supply, decrease demand
9
Q
What can be done to HR to achieve hemodynamic goal in CAD? Indicated drugs, Contraindicated/use with caution?
A
Goal: slow HR
Indicated drugs:
- Beta blockers
- Ca channel Blockers
Contraindicated
- isoproterenol
- dobutamine
- ketamine
- pancuronium
10
Q
Goal of preload in order to meet hemodynamic goals in CAD?
A
Goal- low normal
Indicated
- NTG
- Diuretics
Contraindicated/caution
- Volume overload
11
Q
Goal for afterload to meet hemodynamic goal in CAD? Indicated meds? Contraindicated?
A
Afterload- high normal (referring to DBP)
Indicated
- phenylephrine
Contraindicated/use with caution
- Nitroprusside
- High-dose volatile agent
12
Q
Contracitlity hemodynamic goals in CAD? Indicated drugs? ContrindicateD?
A
Goals- contracility normal- decreased
Indicated
- Beta blocker
- CCB
- High dose VA
Contraindicated/use with caution
- Epinephrine
- Dopamine
13
Q
Stable angina treatment?
A
- A: ASA, antianginals (nitrates, CCB, b-blockers)
- B: Blood pressure (controlled)
- C: cholesterol (statin), cigarettes (stop)
- D: diet, diabetes
- E: education, exercise
14
Q
What is microvascular angina?
A
aka coronary syndrome X
- Women would have complaints of angina and evidence of ischemia on stress test, but angiography wouldn’t show any occlusions
- Do have vasoreactive issues but in very small, microvascular arterioles
- unsure what causes this, more common in women
- recently dx condiiton and a lot of these drugs aren’t specifically tested for this
- in next 10 years may have more discusison on what to use for these pt
- right now we use smae meds…
- recently dx condiiton and a lot of these drugs aren’t specifically tested for this
15
Q
What are organic nitrates?
A
- ↑ [] of nitric oxide in smooth muscle cells
- for some reason, cells don’t produce enough NO on their own. this provides exogenous source
- Used stable angina, MI, variant angina, microvascular angina
- Chemical structure and metabolism
-
nitro most common rescue (SL)- short half life
- avoids first pass effect with SL
-
Isosorbide dinitrate
- developed for longer 1/2 life- taken once a day
-
has active metabolites and used for longer control
- isosorbide 5-mononitrate
16
Q
NO Signal pathway?
A
- Bradykinin stimulates G coupled receptors
- goes on to increase Ca which increases Ca-calmodulin
- Stimulates eNOS (endotheline nitric oxide synthase–> NO
- NO diffuses across down to vascular smooth muscle cell and increase activity of soluble guanylyl cyclase
- increase cGMP from GRP
- Increase PKG activity
- promotes intracellelar ca sequestration into SR
- Decrease intracellular ca levels from VG Ca channels on plasma membrane
- causes relaxation of smooth muscle
Figure 19-2. Regulation of vasorelaxation by endothelial-derived nitric oxide (NO). Endogenous vasodilators, eg, acetylcholine and bradykinin, activate NO synthesis in the luminal endothelial cells, leading to calcium (Ca2+) efflux from the endoplasmic reticulum into the cytoplasm. Calcium binds to calmodulin (CaM), which activates endothelial NO synthase (eNOS), resulting in NO synthesis from L-arginine. NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cGMP synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. PKG can also block other pathways that lead to muscle contraction. cGMP signaling is terminated by phosphodiesterases, which convert cGMP to guanosine monophosphate (GMP).
17
Q
How do nitrates produce NO?
A
Mitochondrial aldehyde dehydrogenase
(takes out endothelial cell requirement for NO)
18
Q
What is a potential interaction with phosphodiesterase inhibitors and nitrates?
A
- Phosphodiesterase will inactivate cGMP normally
- inhibitors will stop phosphodiesterase activity and increase signaling thorugh PKG pathway and prolong activity of cGMP
- Nitrate with sidenafil (phosphodiesterase inhibitor) can get too much Ca inhibition and become profoundly hypotensive
19
Q
Nitrates MOA?
A
- Nitrates release nitric oxide after they are metabolized
- Probable enzymatic reaction with tissue –SH groups
- NO activates soluble guanylate cyclase increasing cGMP, which increases protein kinase G
- activating a cascade that ends with the dephosphorylation of myosin light chains and sequestration of intracellular calcium = relaxation of the vessel.
20
Q
What are the anti-anginal actions of nitrates?
A
- Venodilation= ↓ Ventricular preload
- ↓ ventricular volume/ ↓ myocardial wall tension
- ↓ O2 requirements
- ↓ Afterload (from arterial vessels)
- Dilation of epicardial stenosis
- Enhanced flow to ischemic regions (esp. subendocardium)
- Platelet inhibition
- Reduced oxygen consumption
- ↓ cardiac preload (venodilation)
- ↓afterload (dilation of large muscular arteries)
-
Preferential dilation of collateral vessels serving ischemic areas
- dilates areas that are ischemic!
- Attenuation of coronary spasm
- Also presumed to work like nitric oxide on cardiac muscle and increase the rate of relaxation (lusiotropic action= decrease in diastolic pressure. ability of the ventricle to relax)
21
Q
Routes for NTG?
A
- Sublingual- ONSET 3 MIN
- Tablets- shouldn’t swallow, keep under tongues
- first pass is high, would need higher PO dose
- Spray
- Tablets- shouldn’t swallow, keep under tongues
- Oral
- Topical- long term control
- Ointment
- Patches
- Intravenous
22
Q
NTG Metabolism and S/E?
A
- 90% degraded by the liver to inactive metabolites
- E1/2t IV = 1.5 minutes
- Sublingual and transdermal bypasses liver and first pass metabolism
- Adverse Effects:
- headaches (cerebral vasodilation)
- postural hypotension (fainting)
- methemoglobinemia (usually only with high doses IV/liver disease)
23
Q
What is nitrate tolerance?
A
- Pharmacologic tolerance
- Limits efficacy irrespective of route of administration-
- Tolerance to adverse effects
- Nitrate-free intervals necessary (unsure why this happens maybe depeltes enzymes for ENOS-NO, or increases superoxide anion production which antagnoizes effect of NO)
- Removal of patch at night
- Oral isosorbide mononitrate
- High bioavailability and long T1/2 provide adequately high levels followed by low levels
24
Q
Nitrat drug interactions?
A
- Sildenafil(Viagra), tadalafil (Cialis), vardenafil (Levitra)
- Inhibits phosphodiesterase which breaks down cGMP
- Additive effect
- Severe hypotension
- Treat with phenylephrine
- need 24 hours between drugs!!
25
Use of beta adrenergic antagonists in CAD?
* Essentially provide a more favorable O2 supply and demand balance
* Used in the prevention of stable angina and in unstable angina
* ↓O2 demand by decreasing CO
* ↓catecholamine-mediated increases in automaticity (SA node- decrease stage 4 depolarization) and conduction (AV node) = (↓ heart rate)
* Have some negative inotropic effect (↓contractility)
* Improve diastolic filling time (increase supply)
* ↓ CO is more dramatic during activity than at rest
* Use primarily Beta-1 selective agents
* Metoprolol
* Atenolol
* Improve survival in CAD
* DO NOT discontinue suddenly!
* Avoid in variant angina (theoretical) because we want B2 dilation of coronaries
26
S/E Beta adrenergic antagonists?
* depression
* insomnia
* mask hypoglycemic warning signs in DM
* exercise intolerance
* bronchospasm in asthmatics
27
What is MOA of CCB?
* Block entry of Ca2+(All classes)
* Cardiac muscle: ↓ inotropic effect, ↓ contractility
* Coronary vascular dilation (good choice in variant angina)
* Systemic arterial dilation→decrease afterload→decrease wall tension
* Slow Ca2+ channel recovery (Phenylalkylamines)
* SA node: chronotropic effect, HR↓
* AV node: dromotropic effect, decrease conductivity, HR↓
* Non- -competitive antagonists
* block voltage sensitive -L-type Ca channel
28
What are the 3 classes of CCB?
* Dihydropyridines- *more selective vascular*
* Nifedipine (Procardia, Adalat)
* Amlodipine (Norvasc)
* Nicardipine (Cardene)
* Felodipine
* Phenylalkylamines- *more selective cardiac*
* Verapamil
* Modified Benzothiazepines- *mix vascular/cardiac, intermediate*
* Diltiazem
## Footnote
*sometimes phenylalkylamines and modified benzothiazepines are known as the non-dihydropyridines*
29
Nifedipine selectivity, a/e, contraindications, drug interactions
Selectivity- Vascular- *can be good choice for pt with HTN and angina*
Adverse effects
* Reflexive tachycardia
* Headache
* Dizziness, Palpitations
* Flushing, Hypotension
* Leg edema
Contraindications/caution
* Hypotension
* Severe aortic valve stenosis
Drug interaction
* Beta-blockers OK- *because not getting cardiac effects of CCB and can have reflexive tachycardia*
30
Verapamil selectivity, a/e, contraindication/cuation, drug interactions?
Selective- Cardiac
A/E
* Hypotension
* Facial flushing
* Constipation
* Nausea
* Headache
* Dizziness
* Gingival hyperplasia
Contraindications
* Sick sinus syndrome
* AV block
* LV dysfunction
* Digitalis/Quinidine toxicity
Drug interactions
* Beta-blockers- **NEVER OK TO COMBINE!!! Huge decrease at AV/SA node with cardiac-selective CCB and BB**
* Cimetidine
* Carbamazepine
* Cyclosporine
* Digoxin
31
Diltiazem selectivity, a/e, contraindication/caution, drug interactions?
Selectiviey --Vascular: Cardiac
A/E
* “Relatively infrequent”
Contraindication/caution
* Sick sinus syndrome
* AV block
* LV dysfunction
Drug interactions
* **Beta-blockers**
* Ecainide
* Cimetidine
* Cyclosporine
* Carbamazepine
* Lithium carbonate
* Disopryramide
* Digoxin
32
What is ranolazine?
* Inhibits the late sodium current (INA), reducing calcium overload in ischemic myocardial cells
* Improves ischemic myocyte ATP levels
* Enhances cardiac contractility
* *This med works on reducing metabolic demand (unlike previous CCB which affect supply/demand by some hemodynamic affect)*
* *Late sodium current during plateau phase of myocardial cells can be significant in ischemia*
* *this can place huge Na load on cell*
* *can then end up with Ca overload*
* *reversal of Na/Ca sarcolemma exchanger*
* *end up with lots of Ca in cell*
* *won't get diastolic relaxation and can't fill*
* *Ranolazine improces microscopic o2 supply/demand balance*
* *Good in microvascular angina*
33
Ranolazine metabolism? A/E? Drug interactions?
* Cytochrome P-450 (CYP3A4) metabolism
* Dose dependent adverse effects
* Dizziness
* Nausea
* Constipation
* Prolonged QT interval (average increase 2-5 ms.) *(of note, not significant increase by med itself but when taken with other meds that increase qt interval)*
* Contraindicated in patients with hepatic disease
* Drug Interactions
* Digoxin, simvastatin, cyclosporine, macrolide antibiotics, ketoconazole (CYP3A4 inhibition)
* Drugs that prolong the QT interval
34
Unstable angina treatment summary?
* Unstable angina, Non ST elevation MI (partial occlusion)
* Antianginal drugs
* Heparin, ASA
* GPIIb/IIIa antagonists (eptifibatide (Integrilin)
* Clopidogrel (Plavix)
* ST elevation MI (total occlusion)
* Surgery
* Thrombolytics (Streptokinase, alteplase (tPA))
35
Stable angina management when they have acute angina?
* Nitrates
* β-blockers
* Ca2+ channel blockers
* Ranolazine as well
36
Unstable angina treatment during acute angina?
* Nitrates
* β-blockers
* Ca2+ channel blockers (?)
* Aspirin/clopidogrel
* Heparin/thrombolytics
* Glycoprotein IIb/IIIa receptor inhibitor
37
Variant angina treatment during acute angina?
* Nitrates
* Ca2+ channel blockers
38
What is impact of chronic SNS nad RAAS activation in SHORT TERM?
* In failing heart, not getting adequate tissue perfusion
* causes major activation of SNS nad RAAS
* in short term- beneficial effect maintaining CO
* allows pt to tolerate short term and meet O2 demands of tissue
* ANG II stimualed by renin (rate limiting step)
* release renin when decrease na/cl to juxtaglomerular apparatus
* less flow through glomerulus, GFR reduced and increase renin release
* Baroreceptos in kidney respond by releasing renin
* beta 1 stimualted renin release as well
* ang II causes additional downsteram effects
* augments sns
* enhance Na/Cl reabsorption and K excretion
* enhance aldosterone secretion
* arteriolar vasoconstriction
* ADH secretion (increase H2O reabsorption in collecting ducts)
39
What occurs with chronic SNS and RAAS activation?
* Results in enhaned myocardial dysfunciton and ventricular and vascular remodeling (aldosteron major contributor)
* pharmacologically we want to
* 1) help pt feel better by reducing symptoms angina
* 2) reduce pathological remodeling and overactivation of RAAS/SNS in order to slow progression HF
40
What is the vicious cycle with RAAS system in HF?
* Too much afterload (from vasoconstriction)
* systemic vasuclar resistance/lv systolic wall stress
* Too much preload (from na/h2o retention)
* the stretch of LV myocytes at end diastole
41
How is the frank starling curve different in physiologic states?
* Preload
* if normal person given lasix, will see dramatic drop in SV (CO)
* if HF patient gets lasix, only partial decrease in CO but can get them out of pulmonary congestion
* fairly preload independent
* Afterload
* if normal person has increase in afterload, can be pretty sig increase before we see drop off in CO
* Someone with mod/severe HF can only tolerate a minimal increase in afterload before their CO drops significantly (afterload sensitive)
42
Ventricular dysfunction in HF?
Systolic dysfunction (EF \< 40%)
* Coronary Artery Disease
* Nonischemic Cardiomyopathy
* Hypertension
* Valvular disease
* Alcohol
* Thyroid disease
* Cardiotoxic drugs
Diastolic dysfunction (impaired filling)
* Cardiomyopathies
* Incomplete relaxation of the LV during ischemia (myocytes need ATP for both contraction and relaxation).
* *Can also be due to late Na current causing increase Ca nd impairment in relaxation*
43
Physiologic goals of drug therapy for heart failure?
* Reduce preload
* Diuretics
* Aldosterone antagonists
* Venodilators
* ACEIs
* Reduce afterload
* ACEIs
* b-blockers
* Vasodilators
* Increase inotropy
* Cardiac glycosides
* Sympathomimetic amines
* Phosphodiesterase inhibitors
44
Hemodynamic goal of HR in CHF? Indicated drugs? C/I/caution?
**Goal**: Normal to Elevated
**iNDICATED DRUGS:**
* Dopamine
* Dobutamine
**Contraindicated/caution:**
* Beta-Blockers (high doses)
45
Preload hemodynamic goals in CHF? INdicated meds? contraindicated/caution?
Goal- Normal
Indicated drugs:
* IV Fluids if decreased
Contraindicated/caution:
* Nitroglycerin\* – (use with caution if low preload)
* Thiopental
46
Afterload hemodynamic goals in CHF? Indicated drugs, c/i/caution?
Goal- Low
Indicated drugs
* ACE inhibitors
* Nitroprusside
* Amrinone
Contraindicated/caution
* Phenylephrine- *too much afterload will cause CO to drop precipitously. avoid any drug with large amount of vasoconstriction like NE as well*
47
Contractility hemodynamic goal in CHF. Indicated drugs, contraindicated
Goal- Increased contractility
Indicated med:
* Dopamine
* Dobutamine
* Epinephrine
* Amrinone
Contrindicated/caution meds
* High dose inhaled agents
* High dose beta blockers
48
Diuretic use in CHF?
* Alleviate congestive symptoms – use with caution though **_consider preload status before giving_**
* No evidence of **mortality** benefit with thiazide or loop diuretics
* Loop diuretics most commonly used
* Furosemide, bumetanide, torsemide
* Inhibit Na+-K+-2Cl- cotransporter in loop of Henle
* Increase excretion of Na+, K+, H2O
49
How do distal tubule and loop diuretics use?
* Distal tubule: 5-10% increase Na excretion (weak diuretic)
* Thiazides
* Metolazone (Zaroxolyn)
* K+-sparing (spironolactone, eplerenone)
* Lose effectiveness when Creat Cl \< 30 ml/min
* Loop diuretics: 20-25% increase Na excretion
50
What are aldosterone antagonist
* ex- Spironolactone
* Potassium-sparing diuretic that acts as a competitive antagonist at **aldosterone receptor**
* Decreases K+/Na+ exchange in distal tubule and collecting duct of nephron
* *mild diuretic effect as well*
* RALES showed 30% reduced mortality
* *antagnoizing aldosterone is best to prevent long term remodeling*
* *good at prolongign life and decreasing progression CHF*
* If given with an ACE really have to monitor K levels as both decrease excretion
51
What are sprionolactone and eplerenone?
* Spironolactone (Aldactone)
* Inhibits both androgen and mineralocorticoid receptors
* AE: gynecomastia, impotence
* Eplerenone (Inspra)
* More selective
* Less AE
52
NTG as venodialtor in HF?
* Increases venous capacitance which reduces venous return to heart
* Decrease myocardial oxygen demand
* Alleviate ischemia which improves diastolic relaxation
* Improved LV compliance in addition to preload reduction
* **Use with caution though…**…don’t decrease preload too much **these patients need adequate preload.**
53
MOA of ACE inhibitors?
* MOA: Inhibits the enzyme (ACE) that coverts angiotensin I to angiotensin II. Angio II plasma concentration is reduced.
* Cardiovascular Effects
* **Lowers afterload and preload**:
* arterial\>venous dilation- *great because preload is not as much of an issue, afterload more of an issue. getting afterload normalized is helpful*
* **increase** Na+ and H2O excretion and **decrease** K+ excretion (**decrease** aldosterone released)
* Down-regulates sympathetic adrenergic activity reducing the effects of angiotensin II on release and reuptake of norepinephrine.
* Improve oxygenation to heart muscle
* \***Reduces maladaptive compensatory responses and remodeling** + prolongs life after heart failure diagnosis
54
How have ACE inhibitors help in CHF?
Randomized clinical trials have demonstrated in heart failure ACE inhibitors IMPROVE:
1. Reported quality of life
2. Left ventricular function
3. Myocardial and vascular remodeling
4. Exercise tolerance
5. # of hospitalizations
6. Life expectancy
55
A/E of ace inhibitors?
* Orthostatic hypotension(especially with 1st dose)
* Dry Cough- *increase bradykinin because ACE inhibitors also block kinase II*
* Angioedema (rare but very serious)
* *also from increase bradykinin*
* Hyperkalemia (reduced aldosterone)
* Dysgeusia and rash
* Renal failure
* Caution in patients with acute renal impairment or bilateral renal stenosis
* *renal artery stenosis depends on compensation from efferent vasoconstriction in order to keep GFR up. if you remove that vasoconstriciton, gfr drops and get renal failure*
* Neutropenia (rare but very serious)
* Pregnancy (fetal injury)
* Lung cancer??
56
MOA of Angiotensin II Receptor BLockers (ARBS)?
* MOA : Directly block angiotensin II receptors (AT1). Therefore, angiotensin II activity is antagonized.
* NO impact on bradykinin levels.
* Cardiovascular Effects (Similar to ACE-Inhibitors)
* Lowers afterload and preload:
* arterial\>venous dilation
* increase Na+ and H2O excretion and decrease K+ excretion (decrease aldosterone released)
* Down-regulates SNS activity reducing the effects of angiotensin II on release and reuptake of NE.
* Improve oxygenation to heart muscle
* Reduce inappropriate remodeling of the myocardium & vasculature (not as well as ACE inhibitors though – no enhancement of bradykinin [] )
Randomized clinical trials have demonstrated decreased # of hospitalizations and mortality similar to ACEI
57
A/E ARBS?
* Adverse Effects- low incidence of side effects compared to other anti-hypertensive agents
* Angioedema
* Renal failure
* Use caution in patient’s with acute renal impairment
* “Might” promote cancer
* Pregnancy (fetal injury)
58
What are Angiotensin Neprilysin INhibitors (ARNIs)?
* Neprilysin is enzyme that degrade natriuretic peptides
* want to block nepilysin (SACUBITRIL) , so natriuretic peptides will remain in blood causing:
* vasodilation
* natriuresis
* diuresis
* inhibition of pathologic growth/fibrosis
* neprilysin also degrade angiotensin II
* If you give ARNIs, then more ANG II in blood causing effects
* therefore, need to give ARB with ANRI to block AT1 receptor and negate effects of ang II
59
Side effects ARNIs?
* Hypotension
* Hyperkalemia (from drop in aldosterone)
* Increased bradykinin (sacubitril also increase bradykinin)
* cough (5%)/angioedema (less than ACEI)
* Contraindicated with ACEI (additive influence on bradykinin [] = additive angioedema risk)
* Theoretical increased risk of Alzheimer’s Disease
* Neprilysin also breaks down beta-amyloid peptide in the brain
60
Beta blocker use in heart failure?
* Improve LV ejection fraction, increase exercise tolerance, slow progression HF, increase survival (especially when given with an ACE inhibitor)
* Why?
* Many of the deleterious effects in the heart are β1-mediated
* decrease SNS stimulation?
* Protection from dysrhythmia?
* *decrease risk from beta blockade heart*
* Decreased angiotensin II and aldosterone concentrations
* *from blockade at Beta 1 receptors in kidney*
* Do not use in acute decompensated heart failure
## Footnote
*slowly titrate BB on and overtime will see improvement in LV EF etc...*
61
What is Iso sorbide dinitrate/hydralazine combo?
* AKA Bidil
* Studies are with BiDil (fixed-dose combination of hydralazine and isosorbide dinitrate)
* Gain the benefit of the **arterial** dilating effect of hydralazine and the **venodilating** effect of the nitrate
* The combination of hydralazine and isosorbide dinitrate is recommended for black patients who remain symptomatic despite concomitant use of ACEIs, beta blockers, and aldosterone antagonist
* Combination exerts a favorable effect on exercise capacity and has a significant life-prolonging effect
* An alternative therapy to an ACE inhibitor/ARB when renal insufficiency, hyperkalemia, cough/angioedema preclude their use
* A lupus-like syndrome in response to hydralazine has only rarely been reported
62
What is digoxin?
Cardiac Glycoside- increases inotropy
* MOA: Selective inhibitor of the sodium-potassium-adenosine triphosphate (ATPase) system: “sodium pump” in cardiac myocytes
* **block Na/K ATPase system**--\> influences Na/Ca exchanger to increase Ca--\> improve contractility
* **Sensitizes the cardiac baroreceptors**
* decrease SNS tone and renin release (because we're improving CO)
* **Increase parasympathetic (vagal) activity** (*according to rang and dale, the mechanism of this action is unknown)*
* decrease SA node activity
* decrease conduction velocity; **increase** AV refractory period
* **increase** intracellular calcium and sodium
* Overall effects:
* * **increase** contractility ( inotrope used in heart failure)
* TX of supraventricular dysrhythmias (atrial fib)
* **decrease** HR, preload and afterload
* **_Overall increased stroke volume and cardiac output_**
63
Why is digoxin considered a 2nd/3rd line drug?
* It has a narrow therapeutic index
* 0.5 – 1.2 ng/ml
* Multiple drug interactions, sensitive to serum potassium, calcium and magnesium levels, renal disease
* It can increase automaticity and slow AV nodal conduction causing life threatening dysrhythmias
* Onset of action 30 – 60 min
* Half-life 36 hours
* 7 days to reach steady state serum concentrations
* **90% renally excreted**
* Antidote: digoxin immune Fab (Digibind, DigiFab)
* **\* Improves symptoms NOT survival**
* *women may hve higher mortality on digoxin*
64
Digoxin interactions?
* Pharmacodynamic interactions
* Increased risk of AV block with b-blockers
* b-blockers and CCBs decrease contractility
* Pharmacokinetic interactions
* Antibiotics increase absorption
* Verapamil, quinidine, amiodarone increase digoxin levels by affecting Vd and/or renal clearance
65
Dobutamine?
* Stimulation of b1 increases cardiac contractility
* Stimulation of vascular b2 causes arterial vasodilation and reduced afterload
* *not useful for long term outcomes*
* *can be used short term, icu OR*
* *more potent B1 at myocytes, pronounced increase in contractility*
* *not huge increase in HR*
* *Stimulate B2 in arterial/venous beds reduced afterload as well*
* *Normalization afterload and enhanced contractility*
* *good if pt BP low d/t poor contractility*
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Phophodiesterase inhbiitors MOA?
* Selective PDE III
* Inhibit **degradation** of **cAMP** in cardiac myocytes and vascular smooth muscle
* “inodilators”
* Combination effect
* Increased contractility (increased intracellular Ca)
* Minimal increase in myocardial oxygen demand
* Good choice for B-blocker overdose
* Arterial and venous dilation decreases afterload and preload
* Mild bronchodilation
* Improved diastolic relaxation by increasing Ca removal from mycoplasm after action potential
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What is Amrinone?
Phosphodiesterase inhibitor
* Increased CO & Left ventricle EF
* Decreased LVEDP, pulmonary wedge pressures
* HR increase slightly and BP decreases slightly
* E1/2t = 6hrs
* 0.5-1.5 mg/kg IV; onset 5 minutes; DOA 2 hours
* infusion 2-10mcg/kg/min; total max dose 24 hrs= 10 mg/kg.
* Renal excretion (unchanged) predominate method of clearance
* Hypotension and thrombocytopenia main adverse effects
* May promote arrhythmias via increased intracellular calcium
* Wide TI – toxicity unlikely
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What is Milrinone?
Phosphodiesterase inhibitor
* Similar hemodynamic effects as Amrinone with less **tachycardia & thrombocytopenia**
* popular post CPB & to manage acute heart failure
* 50mcg/kg IV with gtt at 0.5mcg/kg/min.
* E1/2 2.7 hours
* 80% excreted unchanged kidneys
* Wide TI – toxicity unlikely
* Long term use has not been shown to improve M and M (may actually increase it – so more an acute mgt application)
* Is helpful in treating pulmonary HTN
