Flashcards in CAD/HF Deck (68)
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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
Q
Use of beta adrenergic antagonists in CAD?
A
- 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
- ↓O2 demand by decreasing CO
- 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
Q
S/E Beta adrenergic antagonists?
A
- depression
- insomnia
- mask hypoglycemic warning signs in DM
- exercise intolerance
- bronchospasm in asthmatics
27
Q
What is MOA of CCB?
A
- 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
Q
What are the 3 classes of CCB?
A
- Dihydropyridines- more selective vascular
- Nifedipine (Procardia, Adalat)
- Amlodipine (Norvasc)
- Nicardipine (Cardene)
- Felodipine
- Phenylalkylamines- more selective cardiac
- Verapamil
- Modified Benzothiazepines- mix vascular/cardiac, intermediate
- Diltiazem
sometimes phenylalkylamines and modified benzothiazepines are known as the non-dihydropyridines
29
Q
Nifedipine selectivity, a/e, contraindications, drug interactions
A
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
Q
Verapamil selectivity, a/e, contraindication/cuation, drug interactions?
A
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
Q
Diltiazem selectivity, a/e, contraindication/caution, drug interactions?
A
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
Q
What is ranolazine?
A
- 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
Q
Ranolazine metabolism? A/E? Drug interactions?
A
- 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
Q
Unstable angina treatment summary?
A
- 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
Q
Stable angina management when they have acute angina?
A
- Nitrates
- β-blockers
- Ca2+ channel blockers
- Ranolazine as well
36
Q
Unstable angina treatment during acute angina?
A
- Nitrates
- β-blockers
- Ca2+ channel blockers (?)
- Aspirin/clopidogrel
- Heparin/thrombolytics
- Glycoprotein IIb/IIIa receptor inhibitor
37
Q
Variant angina treatment during acute angina?
A
- Nitrates
- Ca2+ channel blockers
38
Q
What is impact of chronic SNS nad RAAS activation in SHORT TERM?
A
- 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
Q
What occurs with chronic SNS and RAAS activation?
A
- 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
Q
What is the vicious cycle with RAAS system in HF?
A
- 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
Q
How is the frank starling curve different in physiologic states?
A
- 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
Q
Ventricular dysfunction in HF?
A
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
Q
Physiologic goals of drug therapy for heart failure?
A
- Reduce preload
- Diuretics
- Aldosterone antagonists
- Venodilators
- ACEIs
- Reduce afterload
- ACEIs
- b-blockers
- Vasodilators
- Increase inotropy
- Cardiac glycosides
- Sympathomimetic amines
- Phosphodiesterase inhibitors
44
Q
Hemodynamic goal of HR in CHF? Indicated drugs? C/I/caution?
A
Goal: Normal to Elevated
iNDICATED DRUGS:
- Dopamine
- Dobutamine
Contraindicated/caution:
- Beta-Blockers (high doses)
45
Q
Preload hemodynamic goals in CHF? INdicated meds? contraindicated/caution?
A
Goal- Normal
Indicated drugs:
- IV Fluids if decreased
Contraindicated/caution:
- Nitroglycerin* – (use with caution if low preload)
- Thiopental
46
Q
Afterload hemodynamic goals in CHF? Indicated drugs, c/i/caution?
A
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
Q
Contractility hemodynamic goal in CHF. Indicated drugs, contraindicated
A
Goal- Increased contractility
Indicated med:
- Dopamine
- Dobutamine
- Epinephrine
- Amrinone
Contrindicated/caution meds
- High dose inhaled agents
- High dose beta blockers
48
Q
Diuretic use in CHF?
A
- 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
Q
How do distal tubule and loop diuretics use?
A
- 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
Q
What are aldosterone antagonist
A
- 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
Q
What are sprionolactone and eplerenone?
A
- Spironolactone (Aldactone)
- Inhibits both androgen and mineralocorticoid receptors
- AE: gynecomastia, impotence
- Eplerenone (Inspra)
- More selective
- Less AE
52
Q
NTG as venodialtor in HF?
A
- 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
Q
MOA of ACE inhibitors?
A
- 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
- Lowers afterload and preload:
- *Reduces maladaptive compensatory responses and remodeling + prolongs life after heart failure diagnosis
54
Q
How have ACE inhibitors help in CHF?
A
Randomized clinical trials have demonstrated in heart failure ACE inhibitors IMPROVE:
- Reported quality of life
- Left ventricular function
- Myocardial and vascular remodeling
- Exercise tolerance
- # of hospitalizations
- Life expectancy
55
Q
A/E of ace inhibitors?
A
- 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
Q
MOA of Angiotensin II Receptor BLockers (ARBS)?
A
- 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)
- Lowers afterload and preload:
- 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
Q
A/E ARBS?
A
- 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
Q
What are Angiotensin Neprilysin INhibitors (ARNIs)?
A
- 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
- want to block nepilysin (SACUBITRIL) , so natriuretic peptides will remain in blood causing:
- 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
Q
Side effects ARNIs?
A
- 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
Q
Beta blocker use in heart failure?
A
- 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
slowly titrate BB on and overtime will see improvement in LV EF etc…
61
Q
What is Iso sorbide dinitrate/hydralazine combo?
A
- 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
Q
What is digoxin?
A
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
- increase contractility ( inotrope used in heart failure)
63
Q
Why is digoxin considered a 2nd/3rd line drug?
A
- 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
Q
Digoxin interactions?
A
- 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
Q
Dobutamine?
A
- 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
66
Q
Phophodiesterase inhbiitors MOA?
A
- 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
- Increased contractility (increased intracellular Ca)
67
Q
What is Amrinone?
A
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
68
Q
What is Milrinone?
A
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
