ischemic heart disease (physiology/pharmacology)

Question 1

Intrinsic regulation

Answer 1

local metabolites from working cardiac muscle (adenosine, lactate, Ph, K, the major mechanism for increased flow during periods of increased metabolic demand– auto regulationor metabolic regulation)

Vasodilators produced by endothemim (NO, prostacyclin)

Tone of sympathetic nerves: a1 receptors (constriction), B2 receptors (dilation minor)

When demand for oxygen increases– arterioles dilate allowing for increased flow, coronary flow reserve is the maximal increase in blood flow achievable above normal resting flow (obstruction decreases this ability)

Question 2

impact of vessel obstruction on myocardial distribution of blood flow

Answer 2

sub endocardium is more susceptible to ischemia esp during exertion

Reduced perfusion pressure distal to obstruction

Elevated LV end diastolic pressure that occurs during exertion impedes subendocardial flow, increase ht rt decreases time during diastole (when the subendocardium receives blood flow)

Question 3

ECG change with subendocardial or transmural ischemia

Answer 3

Subendocardial- ST depression, or T wave inversion

Transmural ischemia- st elevation

Question 4

impact of endothelial dysfunction

Answer 4

can also contribute to reduced myocardial oxygen supply

Contributes to ischemia by innappropriate vasoconstriction (impaired endothelial vasodilators), loss of normal anti thrombotic properties

Question 5

consequences of ischemia

Answer 5

inadequate oxygenation: reduced ATP generation– systolic contraction and diastolic relaxation, consequent elevation in diastolic pressure– precipitates pulmonary congestion and the symptom of dyspnea

Local accumulation of metabolic waste products (lactate, adenosine) can activate pain receptors (angina, and can precipitate arrhythmias)

Fate of myocardium depends on severity and duration of ischemia, Can result in temporary contractile dysfunction, myocardial infarction

stable- predictable chest pain w/ exertion, inappropriate vasoconstriction
unstable- due to rupture platelet aggregation and thrombosis

Question 6

variant angina

Answer 6

episodes of focal coronary artery spasm in the absence of atherosclerotic lesions

Prinzemetal angina, can be at rest

due to increased sympathetic activity in combo with endothelial dysfunction

Question 7

Silend ischemia and syndrome X

Answer 7

Silent ischemia- episodes of cardiac ischemia that sometime occur in the absence of perceptible discomfort or pain

Syndrome X:pts w/ typical signs of angina, no atherosclerosis, inadequate vasodilator reserve

Question 8

Chronic stable angina clinical presentation

Answer 8

chest pain, diffuse, sometimes tachy cardia, diaphoresis, nausea

Dyspnea (rales) and abnormal heart sounds (S4)- fatigue and weakness
ECG during ischemia- ST depression and t inversion

Stress test: provactive exercise or dobutamine (myocardial oxygen demand increases) or produce coronary vasodilation (adenosine)

Question 9

Treatment of chronic/stable angina

Answer 9

decrease O2 demand (lower hrt, contractility, wall tension)

Increase O2 supply (improve blood flow, increase collateral blood flow, stop coronary spasm, dilate eccentric stenosis)

Question 10

Nitrates

Answer 10

General vasodilators, but much greater effect on venous blood vessels

Converted to NO in smooth muscle (activates Gcyclase–> increase cGMP– activates PKG kinase– phosphorylates–> decreased calcium and dephosphorylation of myosin)

Nitroglycerine and Isosorbide nitates-

Question 11

Nitrates effects on the ischemic heart

Answer 11

venodilation increases venous capacitance which decreases preload (results in reduced diastolic wall tension/O2 demand) slight increas in blood flow to subendocardial wall

At higher doses can cause arterial vasodilation (decreases afterload)- systolic wall tension is lowered, but at the risk of reflextachycardia

Question 12

Nitrates uses

Answer 12

Acute therapy: Nitroglycerin for immediate relief of an angina episode. administered sublingually to produce rapid onset and avoids 1st pass metabolism

Duration of action typically 10-30 min, limited shelf life

PROHYLACTIC: isosorbide di or mono- nitrate, and dermal patches, slow releasing formulation of nitroglycerin used for prophylaxis to reduce the incidence of angina

Question 13

nitrates pharmacokinetics

Answer 13

Nitroglycerin inactivated by a high capacity organic nitrate reductase in the liver, low F due to extensive 1st pass metabolism( short t.5)

Isosorbide dinitrate metabolized by liver to mononitrite active form, mononitrate is not metabolized

Question 14

SE of nitrites

Answer 14

due to cardiovascular actions: headache, dizziness, hypotension, reflex tachycardia w/higher doses, flushing

Drug interactions: Phosphodiesterase 5 inhibitors (sildenafil)- can produce unsafe hypotension

Question 15

Tolerance of nitrates

Answer 15

Complete tolerance in a few hours if used continuously (reverses rapidly)

Limits the effectiveness of slow release forms of nitrates for maintenance therapy (smallest effective dose)- schedule a nitrate free period for 8 hours

Question 16

Beta adrenergic receptor blockkers

Answer 16

Exert anti angina effect primarily by reducing O2 demand (decreases the force of ventricular contraction and heart rate due to blockade of effects of endogenous catecholamines on B1 receptors)

Both non selectives (propranolol, timolol, carvedilol) and B-1 selective antagonists (metoprolol, atenolol) are effective

Question 17

B blocker effect on ischemic heart

Answer 17

Decrease O2 demand (decrease heart rate, contractility, BP afterload) Small increase in O2 supply to ischemic areas, by slowing heart rate–> more time in diastole/ blood flow to subendocardium

Decrease in CO–> compensatory increase in preload–> increased Wall tension

Question 18

B blocker uses

Answer 18

Only used for prophylaxis of stable angina- decreases the frequency of episodes of angina and need for nitroglycerin

Considered ineffective/contraindicated for variant (vasospastic angina)- worsens by blocking B2s –> coronary vasodilation, a receptors unopposed–> vasoconstriction (any catecholamine left will activate a receptors)

Question 19

B blocker contraindications, SEs

Answer 19

PTs with COPD
w/ acutely decompensated heart failure
w/ bradycardia/certain types of Heart block
insulin treated diabetes
Reynauds disease or variant angina (vasospasms)

SE: fatigue, insomnia, sexual dysfunction

Sudden discontinuations–intensifies ischemia (increased expression of B receptors, rebound tachycardia)

Question 20

Calcium channel blockers

Answer 20

block voltage L-type Ca channels in myocardium and blood vessels, USED FOR prophylaxis of chronic stable angina (decrease anginal episodes)

dihydropyridines: potent arterial vasodilators, relieves ischemia by decreasing O2 demand (decreases wall stress by reducing afterload), also increases O2 supply by coronary vasodilation, AMLODIPINE NIFEDIPINE

Non-DHPS: arterial vasodilators, less potent than DHPs, decreasing O2 demand (reduce force of contraction and heart rate) VERAPAMIL and DILTIAZEM

Question 21

CCBs Adverse effects

Answer 21

Constipation, headache, flushing dizziness, bradycardia (verapamil, diliazem)

Edema
DHP may produce reflex stimulation of heart rate due to vascular effects

Question 22

Current recommendations for meds of chronic stable Angina

Answer 22

B blocker as 1st line therapy

long acting nitrite/ longacting CCB in combo with B blocker when initial treatment with B blocker is unseccessful or as a substitute for B blocker is contraindicated

Fast acting nitrates for acute anginal episodes

Some drug combos have added benefits (B blocker prevents reflex tachycardia by nitrates

Should avoid B blocker w/ nondihdropyridine CCB (can cause additive negative inotropic effect can cause cardiodepression

Question 23

Ranolazine

Answer 23

does not work by affecting heart rate or vasodilation

inhibits late sodium current in cardiac myocytes, which indirectly decreases CA influx

Question 24

Ivabradine

Answer 24

Inhibits funny channel in SA and AV node, slows hrt rate–myocaridal O2 demand

Question 25

Medical therapy to prevent disease progression and acute coronary syndrome

Answer 25

life style modification, lipid regulated thrapy (statins)

Anitplatelet therapy (platelet aggregation and thrombosis are key elements in pathophysiology of unstable angina and acute MI)- aspirin, ADP-p2y12 receptor blockers (clopidigrel) if aspirin is contraindicated

Question 26

Revascularization

Answer 26

inadequate response to med therapy, Percutaneous coronary intervention (PCI) CABG

Question 27

Variant angina

Answer 27

focal coronary artery spasm

Pharmacologic management: CCB 1st line therapy with addition of long acting nitrate if improvement in symptoms is not CCB

short acting nitrates for acute event

avoid use of B Blockers (ineffectinv and can precipitate vasospasm)

Question 28

Acute coronary syndromes (ACS)

Answer 28

disruption of a plaque with subsequent platelt aggregation and formation of an intra coronary thrombus

Form of ACS that results depends on the degree of Coronary obstruction and associated ischemia

Unstable angina (partially occlusive thrombus, but no myocyte necrosis

NON ST Elevation MI: (partially occlusive thrombus w/ myocyte necrosis), can have ST depression, or T wave inversion

ST elevation MI ( complete thrombus occlusion, myocyte necrosis0

Question 29

Clinical features of unstable Angina

Answer 29

acceleration of ischemic symptoms, sudden increase in frequency duration and or intensity of ischemic episodes (crescendo pattern), episodes of angina at rest

new onset of angina episodes

Person may progress–ACs and develop necrosis

Question 30

Clinical features of acute MI (STEMI NSTEMI

Answer 30

severe persistent chest pain, sympathetic effect (diaphoresis, cool and clammy skin)

Parasym (vagal effect, nausea, vomiting weakness)

Inflammatory response (mild fever)

Cardiac findings (S4 and S3, dyskinetic buldge, systolic murmur

Question 31

Serum markers of Infarction

Answer 31

Cardiac troponins (cTn)- begin to rise 2-4 hrs peaks at 18-36 h

Creatine Kinase: CK MB

Question 32

treatment of acs

Answer 32

rapid, anti ischemic med to restore O2 demand (B blocker, Nitrates, CCB)

antithrombotic therapy (antiplatelet and anticoaguats)

Adjuct therapy: ACE inhibitor, HMGCoA reductase

Most important predictors for post MI morbidity (LV dysfunction)

Standard : aspirin, P2y12 inhibitor, B blocker, HMG CoA inhibitor, ACE inhibitor, aldosterone antagonist

if ejection fraction is <30% =:( death