ischemic heart disease (physiology/pharmacology) Flashcards
(32 cards)
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
