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!!!