vasodilators and the treatment of angina pectoris
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Vasodilators and the Treatment of Angina PectorisERWIN P. CARABEO, MD, FPCPDepartment of PharmacologySan Beda College of Medicine
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Ischemic Heart Diseasemost common cardiovascular disease in developed countries
CAD; CASHD
cause: imbalance between oxygen requirement of the heart and the oxygen supply
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Angina Pectorischest pain caused by the accumulation of metabolites resulting from myocardial ischemia
atheromatous obstruction of the large coronary vessels
types: classic, unstable, variant
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Classic Angina
character: squeezing or pressing; substernalprecipitated by effort; relieved by restduration:
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Unstable Angina
change in character, frequency and duration of chest pain
crescendo angina
high risk for myocardial infarction
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Variant Angina
Vasospastic or Prinzmetal angina
transient spasm of portions of the coronary arteries
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Treatment Goals
decrease myocardial oxygen demand
increase myocardial oxygen supply
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Drug Groups Used in Angina
organic nitrates
calcium channel blockers
beta blockers
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Nitrates and Nitrites
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nitroglycerine: prototype
lose potency when stored; should be kept in tightly closed glass containers
not sensitive to light
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Pharmacokineticsorganic nitrate reductase in liver inactivation of the drug very low oral bioavailability
sublingual route is preferred; total duration of effect is brief (15-30 min)
other routes: transdermal and buccal
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Pharmacokineticsonce absorbed, nitrate compounds have half lives of only 2-8 minutes
dinitro derivatives (metabolites) provide most of the therapeutic activity of oral nitrates
isosorbide mononitrate active metabolite of ISDN; bioavailability of 100%
excretion: kidneys
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PharmacodynamicsMOA in smooth muscle
Nitroglycerin denitration (glutathione S transferase release of free nitrite ion nitric oxide activation of guanyl cyclase increase in cGMP smooth muscle relaxation
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PharmacodynamicsEffects on Vascular Smooth Muscle
nitroglycerine relaxes all types of smooth muscles;no direct effect on cardiac or skeletal muscles
direct result: marked relaxation of veins increased venous capacitance and decreased ventricular preload
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Pharmacodynamics
Increased venous capacitance decreased cardiac output orthostatic hypotension and syncope
meningeal artery pulsations throbbing headache
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Pharmacodynamics
indirect effects of nitroglycerin due to compensatory response evoked by baroreceptors and hormonal mechanisms: tachycardia and increased contractility
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Pharmacodynamics
in normal subjects (without coronary disease): significant but transient increase in coronary blood flow
no evidence of total increased coronary blood flow in patients with obstructive coronary disease but redistribution of blood flow from normal to ischemic areas
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Pharmacodynamics
Effects on other smooth muscle organs
relaxation of bronchi, GIT and GUT
nitric oxide increase in cGMP enhanced erection
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Sildenafil prototype drug for erectile dysfunctionincreases cGMP by inhibiting its breakdowntaken orallyshould not be used with nitratestadalafil, vardenafil
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PharmacodynamicsAction on platelets
nitroglycerin nitric oxide stimulation of guanyl cyclase increase in cGMP decreased platelet aggregation
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ToxicityAcute adverse effects:
orthostatic hypotension
tachycardia
throbbing headache
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Tolerance
with continuous exposure to nitrates
more pronounced when long acting preparations are used (oral, transdermal)
mechanism is not clear
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Beneficial Effects in Angina Patients
decreased ventricular volume, decreased arterial pressure, decreased ejection time decreased myocardial oxygen demand
vasodilation of epicardial coronary arteries relief of coronary spasm
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Beneficial Effects in Angina Patients
increased collateral flow improved perfusion to ischemic myocardium
decreased LV diastolic pressure improved subendocardial perfusion
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Potential Deleterious Effects
reflex tachycardia, reflex increase in contractility increased myocardial oxygen requirement
decreased diastolic perfusion time due to tachycardia decreased coronary perfusion
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Calcium Channel Blockers
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calcium influx is necessary for the contraction of smooth and cardiac muscle
L type calcium channel dominant type in cardiac and smooth muscles
verapamil prototype
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Mechanism of Action
binding with receptors in the calcium channel reduced frequency of opening in response to depolarization decrease in transmembrane calcium current smooth muscle relaxation, reduction in contractility, decreased SA and AV node conduction velocity
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Organs System Effects
Smooth muscle: relaxation vasodilation decreased BP
Cardiac muscle: reduced impulse generation in the SA node and conduction in the AV node slowing down of heart rate
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Organ System Effects
Cardiac muscle: reduced contractility
Skeletal muscle: not depressed by calcium blockers
Cerebral blood vessel: reduces vasospasm following subarachnoid hemorrhage (nimodipine & nicardipine)
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Toxicitydirect extension of therapeutic action:
cardiac depression cardiac arrest
bradycardia
AV block
heart failure
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Clinical Usesangina
hypertension
dysrhythmia (SVT)
migraine
Reynauds phenomenon
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Beta Blockers
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beneficial effects are due to their hemodynamic effects
decreased heart rate, decreased BP, decreased contractility decreased myocardial O2 demand
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Cointraindications
asthma
severe bradycardia
AV block
severe LV failure
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Newer Antianginals
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pFOX Inhibitors
metabolic inhibitors
moa: inhibition of fatty acid oxidation in the myocardium reduced oxygen requirement
trimetazidine, ranolazine
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If Sodium Channel Blockers
moa: reduced cardiac rate thru inhibition of hyperpolarization-activated sodium channel in the SA node decreased myocardial O2 demand
ibavradine
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Thank you!!!
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