ischemic heart disease (physiology/pharmacology) Flashcards
Intrinsic regulation
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)
impact of vessel obstruction on myocardial distribution of blood flow
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)
ECG change with subendocardial or transmural ischemia
Subendocardial- ST depression, or T wave inversion
Transmural ischemia- st elevation
impact of endothelial dysfunction
can also contribute to reduced myocardial oxygen supply
Contributes to ischemia by innappropriate vasoconstriction (impaired endothelial vasodilators), loss of normal anti thrombotic properties
consequences of ischemia
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
variant angina
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
Silend ischemia and syndrome X
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
Chronic stable angina clinical presentation
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)
Treatment of chronic/stable angina
decrease O2 demand (lower hrt, contractility, wall tension)
Increase O2 supply (improve blood flow, increase collateral blood flow, stop coronary spasm, dilate eccentric stenosis)
Nitrates
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-
Nitrates effects on the ischemic heart
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
Nitrates uses
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
nitrates pharmacokinetics
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
SE of nitrites
due to cardiovascular actions: headache, dizziness, hypotension, reflex tachycardia w/higher doses, flushing
Drug interactions: Phosphodiesterase 5 inhibitors (sildenafil)- can produce unsafe hypotension
Tolerance of nitrates
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
Beta adrenergic receptor blockkers
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
B blocker effect on ischemic heart
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
B blocker uses
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)
B blocker contraindications, SEs
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)
Calcium channel blockers
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
CCBs Adverse effects
Constipation, headache, flushing dizziness, bradycardia (verapamil, diliazem)
Edema
DHP may produce reflex stimulation of heart rate due to vascular effects
Current recommendations for meds of chronic stable Angina
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
Ranolazine
does not work by affecting heart rate or vasodilation
inhibits late sodium current in cardiac myocytes, which indirectly decreases CA influx
Ivabradine
Inhibits funny channel in SA and AV node, slows hrt rate–myocaridal O2 demand
Medical therapy to prevent disease progression and acute coronary syndrome
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
Revascularization
inadequate response to med therapy, Percutaneous coronary intervention (PCI) CABG
Variant angina
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)
Acute coronary syndromes (ACS)
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
Clinical features of unstable Angina
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
Clinical features of acute MI (STEMI NSTEMI
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
Serum markers of Infarction
Cardiac troponins (cTn)- begin to rise 2-4 hrs peaks at 18-36 h
Creatine Kinase: CK MB
treatment of acs
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
