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Vasodilators and the Treatment of Angina PectorisERWIN P. CARABEO, MD, FPCPDepartment of PharmacologySan Beda College of Medicine
Ischemic Heart Diseasemost common cardiovascular disease in developed countries
CAD; CASHD
cause: imbalance between oxygen requirement of the heart and the oxygen supply
Angina Pectorischest pain caused by the accumulation of metabolites resulting from myocardial ischemia
atheromatous obstruction of the large coronary vessels
types: classic, unstable, variant
Classic Angina
character: squeezing or pressing; substernalprecipitated by effort; relieved by restduration:
Unstable Angina
change in character, frequency and duration of chest pain
crescendo angina
high risk for myocardial infarction
Variant Angina
Vasospastic or Prinzmetal angina
transient spasm of portions of the coronary arteries
Treatment Goals
decrease myocardial oxygen demand
increase myocardial oxygen supply
Drug Groups Used in Angina
organic nitrates
calcium channel blockers
beta blockers
Nitrates and Nitrites
nitroglycerine: prototype
lose potency when stored; should be kept in tightly closed glass containers
not sensitive to light
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
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
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
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
Pharmacodynamics
Increased venous capacitance decreased cardiac output orthostatic hypotension and syncope
meningeal artery pulsations throbbing headache
Pharmacodynamics
indirect effects of nitroglycerin due to compensatory response evoked by baroreceptors and hormonal mechanisms: tachycardia and increased contractility
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
Pharmacodynamics
Effects on other smooth muscle organs
relaxation of bronchi, GIT and GUT
nitric oxide increase in cGMP enhanced erection
Sildenafil prototype drug for erectile dysfunctionincreases cGMP by inhibiting its breakdowntaken orallyshould not be used with nitratestadalafil, vardenafil
PharmacodynamicsAction on platelets
nitroglycerin nitric oxide stimulation of guanyl cyclase increase in cGMP decreased platelet aggregation
ToxicityAcute adverse effects:
orthostatic hypotension
tachycardia
throbbing headache
Tolerance
with continuous exposure to nitrates
more pronounced when long acting preparations are used (oral, transdermal)
mechanism is not clear
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
Beneficial Effects in Angina Patients
increased collateral flow improved perfusion to ischemic myocardium
decreased LV diastolic pressure improved subendocardial perfusion
Potential Deleterious Effects
reflex tachycardia, reflex increase in contractility increased myocardial oxygen requirement
decreased diastolic perfusion time due to tachycardia decreased coronary perfusion
Calcium Channel Blockers
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
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
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
Organ System Effects
Cardiac muscle: reduced contractility
Skeletal muscle: not depressed by calcium blockers
Cerebral blood vessel: reduces vasospasm following subarachnoid hemorrhage (nimodipine & nicardipine)
Toxicitydirect extension of therapeutic action:
cardiac depression cardiac arrest
bradycardia
AV block
heart failure
Clinical Usesangina
hypertension
dysrhythmia (SVT)
migraine
Reynauds phenomenon
Beta Blockers
beneficial effects are due to their hemodynamic effects
decreased heart rate, decreased BP, decreased contractility decreased myocardial O2 demand
Cointraindications
asthma
severe bradycardia
AV block
severe LV failure
Newer Antianginals
pFOX Inhibitors
metabolic inhibitors
moa: inhibition of fatty acid oxidation in the myocardium reduced oxygen requirement
trimetazidine, ranolazine
If Sodium Channel Blockers
moa: reduced cardiac rate thru inhibition of hyperpolarization-activated sodium channel in the SA node decreased myocardial O2 demand
ibavradine
Thank you!!!