Subject: Topic: Lecturer:
PHARMACOLOGY
2.2 VASODILATORS & TREATMENT OF ANGINA Dr. Paguirigan
First Semester A.Y. 2015-‐2016
PATHOPHYSIOLOGY OF ANGINA
A. DETERMINANTS OF CARDIAC OXYGEN REQUIREMENT • The treatment of coronary insufficiency is based on physiologic
factors that control myocardial oxygen requirement
MYOCARDIAL FIBER TENSION • Major determinant of cardiac oxygen requirement
o The higher the tension, the greater the oxygen requirement • Several variables contribute to fiber tension:
o Preload o Afterload o Heart rate o Cardiac contractility PRELOAD • Diastolic filling pressure
• Function of blood volume and venous tone
• Because venous tone is mainly controlled by sympathetic outflow, activities that increase sympathetic activity usually increase preload
AFTERLOAD • Arterial blood pressure
• One of the systolic determinants of oxygen requirement • Arterial blood pressure depends on peripheral vascular
resistance, which is determined by sympathetic outflow to the arteriolar vessels and other factors
HEART RATE • Contributes to time-‐integrated fiber tension
o At fast heart rates, fibers spend more time at systolic tension levels
o At faster rates, diastole is abbreviated and constitutes the time available for coronary flow
§ Coronary blood flow is low or nil during systole
• Systolic blood pressure and heart rate may be mutiplied to yield the double product
• DOUBLE PRODUCT
o Measure of cardiac work and oxygen requirement
o In patients with atherosclerotic angina, effective drugs reduce
the double product
CARDIAC CONTRACTILITY • Force of cardiac contraction
• Another systolic factor controlled mainly by sympathetic outflow to the heart
• EJECTION TIME for ventricular contraction o Inversely related to force of contraction o Influenced by impedance to outflow
• Increased ejection time increases oxygen requirement
B. TYPES OF ANGINA • There are three forms of angina pectoris:
o Atherosclerotic angina o Vasospastic angina o Unstable angina
ATHEROSCLEROTIC ANGINA
• Also known as ANGINA OF EFFORT or CLASSIC ANGINA • Associated with atheromatous plaques that partially occlude
one or more coronaries
• When cardiac work increases, for example, in exercise, o Obstruction of flow results in accumulation of acidic
metabolites
o Ischemic changes stimulate myocardial pain-‐mediating nerve endings
• Constitutes 90% of angina cases
• Depending on the rate of progression of atheromas, it may last for years with little change
VASOSPASTIC ANGINA
• Also known as VARIANT ANGINA or PRINZMETAL’S ANGINA • Involves reversible spasm of coronaries usually at the site of an
atherosclerotic plaque
o Spasm may occur at any time, even during sleep • May deteriorate into unstable angina
UNSTABLE ANGINA • Also known as CRESCENDO ANGINA
• Caused by diminished coronary flow that results from a combination of
o Athersclerotic plaques
o Platelet aggregation at fractured plaques o Vasospasm
• Immediate precursor of a myocardial infarction • Treated as medical emergency
C. THERAPEUTIC STRATEGIES • CORONARY OXYGEN DELIVERY INADEQUATE FOR
MYOCARDIAL OXYGEN REQUIREMENT o The defect that causes anginal pain • This defect can be corrected in two ways by:
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o Increasing oxygen delivery o Reducing oxygen requirement
• Pharmacologic therapies include nitrates, calcium-‐channel blockers, beta-‐blockers
o These three groups reduce oxygen requirement in atherosclerotic angina
o Nitrates and calcium-‐channel blockers can also increase oxygen delivery by reducing vasospasm
§ But only in the vasospastic form • MYOCARDIAL REVASCULARIZATION
o Corrects coronary obstruction either by § Bypass grafting
§ Angioplasty
• Enlargement of the lumen by means of a special catheter
NITRATES
CATEGORY EXAMPLE DURATION OF
ACTION Very short Inhaled amyl nitrite 3 – 5 minutes
Short Sublingual nitroglycerin or
isosorbide dinitrate (for nitroglycerin) 10 – 20 minutes 10 – 30 minutes
(for isosorbide dinitrate)
Intermediate Oral regular or sustained-‐ release nitroglycerin or isosorbide dinitrate
4 – 6 hours (for oral regular)
4 – 8 hours (for oral sustained-‐
release)
Long Transdermal nitroglycerin
patch 8 – 10 hours
NITROGLYCERIN • CLASSIFICATION AND PHARMACOKINETICS:
o Active ingredient in dynamite o Most important of the nitrates
o Available in forms that provide a range of durations of action from 10 – 20 minutes (sublingual) to 8 – 10 hours
(transdermal)
o Also known as GLYCERYL TRINITRATE o Rapidly denitrated in the liver
§ First to the dinitrate (glyceryl dinitrate), which retains a significant vasodilating effect
• Active
§ Then, more slowly to the mononitrate, which is less active o Because of the high enzyme activity in the liver, first-‐pass
effect is large – 90%
o Efficacy of oral nitroglycerin results from high levels of glyceryl dinitrate in the blood
o Effects of sublingual nitroglycerin are mainly the result of the
unchanged drug • CLINICAL USES:
o SUBLINGUAL TABLET: duration of action of 10 – 20 minutes o ORAL NORMAL-‐RELEASE: duration of 4 -‐6 hours
o ORAL SUSTAINED-‐RELEASE: duration of 4 – 8 hours o TRANSDERMAL:
§ Placed on anterior chest wall for steady release of nitroglycerin for 24 hours
§ Tolerance develop after about 8 hours with markedly decreasing effectiveness
§ Patches should be removed after 8 – 10 hours to allow recovery of sensitivity to the drug
ISOSORBIDE DINITRATE • CLASSIFICATION AND PHARMACOKINETICS:
o Available in sublingual and oral forms
o Rapidly denitrated in the liver to isosorbide mononitrate o ISOSORBIDE MONONITRATE
§ Active
§ Available as a separate drug for oral use • CLINICAL USES:
o SUBLINGUAL ISOSORBIDE DINITRATE
o ORAL NORMAL RELEASE ISOSORBIDE DINITRATE o ORAL SUSTAINED-‐RELEASE ISOSORBIDE DINITRATE
AMYL NITRITE • CLASSIFICATION AND PHARMACOKINETICS:
o Volatile
o Rapidly-‐acting vasodilator that was used for angina by inhalation
o No longer prescribed • CLINICAL USES:
o INHALED AMYL NITRITE: duration of action of 3 – 5 minutes
MECHANISM OF ACTION
• Denitration of the nitrates within the smooth muscle cells o Releases nitric oxide (NO), which stimulates guanylyl cyclase
that causes an increase of the second messenger cGMP and leads to smooth muscle relaxation by dephosphorylation of myosin light chain phosphate
CARDIOVASCULAR SYSTEM EFFECTS
• Smooth muscle relaxation leads to peripheral venodilation, which results in reduced cardiac size and cardiac output through reduced preload
• Reduced afterload o From arteriolar dilation
o May contribute to an increase in ejection and a further decrease in cardiac size
• Venodilation
o Leads to decreased diastolic heart size and fiber tension • Arteriolar Dilation
• Overall reduction in myocardial fiber tension, oxygen consumption and double product
PRIMARY MECHANISM OF THERAPEUTIC BENEFIT • ATHEROSCLEROTIC ANGINA
o Reduction of the oxygen requirement
o Increase in coronary flow in ischemic areas is less likely • VASOSPASTIC ANGINA
o Reversal of coronary spasm and increased blood flow • Reflex tachycardia often occurs when nitroglycerin reduces the
blood pressure
ORGAN SYSTEM EFFECTS
• Nitrates relax the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract
• Intravenous nitroglycerin, sometimes used in unstable angina, reduces platelet aggregation
TOXICITY • NITRATE TOXICITY
o Most common toxic effects of nitrates are responses evoked by vasodilation
§ Tachycardia
• From baroreceptor reflex § Orthostatic hypotension
• Direct extension of the venodilator effect
§ Throbbing headache
• From meningeal artery vasodilation o Do not cause methemoglobinemia
o In the past, nitrates were responsible for several occupational diseases in munitions plants in which workplace
contamination by these volatile chemicals was severe o “MONDAY DISEASE”
§ most common form of these diseases
§ alternating development of tolerance (during the work week) and loss of tolerance (over the weekend) for the vasodilating action, resulting in headache, tachycardia and dizziness every Monday
• NITRITE TOXICITY
o Cause methemoglobinemia at high concentrations o Has potential antidotal action in cyanide poisoning
NITRITES IN THE TREATMENT OF CYANIDE POISONING • Cyanide ion rapidly complexes with the iron in the cytochrome
oxidase resulting in a block of oxidative metabolism and cell death
• Iron in methemoglobin has a higher affinity for cyanide than the iron in cytochrome oxidase
• Nitrites convert the ferrous iron in hemoglobin to the ferric form, yielding methemoglobin
• Cyanide poisoning can be treated by:
o Immediate exposure to amyl nitrite, followed by
o Intravenous administration of sodium nitrate, which rapidly
increases the methemoglobin level to the degree necessary to remove a significant amount of cyanide from cytochrome oxidase, followed by
o Intravenous sodium thiosulfate, which converts
cyanmethemoglobin to thiocyanate and methemoglobin • THIOCYANATE
o Less toxic than cyanide o Excreted by the kidney
CALCIUM CHANNEL – BLOCKING DRUGS CLASSIFICATION & PHARMACOKINETICS • Typified by:
o NIFEDIPINE o DILTIAZEM o VERAPAMIL • All are orally active
• Most have half-‐lives of 3 – 6 hours
NIMODIPINE
• Another member of dihydropyridine family with similar properties
• Approved only for management of stroke associated with subarachnoid hemorrhage
BEPRIDIL
• Drug somewhat similar in structure to verapamil
• Has a longer duration of action but greater cardiovascular toxicity than the other calcium channel blockers
• May induce torsade de pointes and other arrhythmias
MIBEFRADIL • Newest calcium blocker
• Not a dihydropyridine
• Blocks cardiac “T-‐type” calcium channels as well as “L-‐type” calcium channels
MECHANISM OF ACTION
• Almost all of these drugs block voltage-‐dependent “L-‐type” calcium channels, the most important calcium channels in cardiac and smooth muscle
• Decreasing calcium influx during action potentials in a frequency-‐ and voltage-‐dependent manner will reduce intracellular calcium concentration and muscle contractility • None of the calcium channel-‐blockers interfere with calcium-‐
dependent neurotransmitter or hormone release because these processes does not utilize “L-‐type” or “T-‐type” channels
EFFECTS & CLINICAL USE • Relax blood vessels, uterus, bronchi and gut
• All calcium channel-‐blockers reduce blood pressure and double product in patients with angina
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• In atherosclerotic angina, these drugs are effective if combined with nitrates
• These drugs are used in: o Angina o Hypertension o Supraventricular tachycardia o Migraine o Preterm labor o Stroke o Raynaud’s phenomenom • DILTIAZEM and VERAPAMIL
o Reduce rate of heart contractility and block levels of calcium conduction in the heart
o Can treat AV nodal arrhythmias • NIFEDIPINE
o Evoke greater vasodilation
§ The resulting sympathetic reflex prevents bradycardia and may actually increase the heart rate
o Can be used to abort an acute anginal attack TOXICITY • Can cause: o Constipation o Edema o Nausea o Flushing o Dizziness
• More serious adverse effects: (more common with verapamil) o Congestive heart failure
o Atrioventricular blockade o Sinus node depression
• Bepridil may induce torsade de pointes and other arrhythmias
BETA-‐BLOCKING DRUGS MECHANISM OF ACTION • Include: o Propranolol o Timolol o Nadolol o Carvedilol o Labetalol o Metoprolol o Atenolol o Osmolol o Butoxamine
• Effective in the prophylaxis of atherosclerotic angina attacks • Actions include both:
o Beneficial effects: § Decreased heart rate § Decreased cardiac force § Decreased blood pressure o Detrimental effects:
§ Increased heart size
§ Longer ejection period o Reduced double product
CLINICAL USE • Used only for prophylactic therapy of angina • Are of no value in an acute attack
• Effective in preventing exercise-‐induced angina • Ineffective against vasospastic form of angina • Combination of beta-‐blockers with nitrates is useful
o Because the undesirable compensatory effects evoked by the nitrates (tachycardiac and increased cardiac force) are prevented or reduced by beta-‐blockade
NONPHARMACOLOGIC THERAPY FOR ANGINA • MYOCARDIAL REVASCULARIZATION BY
o CORONARY ARTERY BYPASS GRAFT (CABG)
o PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY (PTCA)
§ Important therapies in severe angina
§ Only methods capable of consistently increasing coronary flow in atherosclerotic angina and increasing double product
PRAYER BEFORE STUDYING
Holy Spirit, Giver of all good gifts, enter into my mind and heart. Give me the gift of knowledge and the grace to use it wisely.
Help me in all my endeavors. Give me perseverance and fortitude. Help my memory, that I may remember what I learn
and recall it when necessary. Guide me in the classroom.
You who are the Way, the Truth, and the Life, Let me not be deceived by false teaching.
Our Lady of Good Studies, pray for me. Amen.
Subject: Topic: Lecturer:
PHARMACOLOGY
2.2 VASODILATORS & TREATMENT OF ANGINA Dr. Paguirigan
First Semester A.Y. 2015-‐2016
APPENDIX
Nitrates Alone Beta-‐blockers or Calcium
channel-‐blockers Alone blockers or Calcium channel-‐Combined Nitrate and Beta-‐ blockers
Heart Rate Reflex increase Decrease Decrease
Arterial Pressure Decrease Decrease Decrease
End-‐diastolic Pressure Decrease Increase Decrease
Contractility Reflex increase Decrease No effect or Decrease
Ejection time Reflex decrease Increase No effect
Table 1 – Effects of nitrates alone and with beta-‐blockers or calcium channel-‐blockers in angina pectoris DRUG SELECTIVITY PARTIAL AGONIST
ACTIVITY LOCAL ANESTHETIC ACTION LIPID SOLUBILITY ELIMINATION HALF-‐LIFE BIOAVAILABILITY APPROXIMATE
Acebutolol Beta-‐1 Yes Yes Low 3 – 4 hours 50%
Atenolol Beta-‐1 No No Low 6 – 9 hours 40%
Esmolol Beta-‐1 No No Low 10 minutes
Carvedilol None No No No data 7 – 10 hours 25 – 35%
Labetalol None Yes Yes Moderate 5 hours 30%
Metoprolol Beta-‐1 No Yes Moderate 3 – 4 hours 50%
Nadolol None No No Low 14 – 24 hours 33%
Pindolol None Yes Yes Moderate 3 – 4 hours 90%
Propranolol None No Yes High 3.5 – 6 hours 30%
Timolol None No No Moderate 4 – 5 hours 50%
