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
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
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
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)
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
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
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)
