Part 6Part 6 Antianginal DrugsAntianginal Drugs

• Organic nitratesOrganic nitrates• receptor blockersreceptor blockers• Calcium channel blockersCalcium channel blockers

Coronary vessels:Coronary vessels: blood supply for the blood supply for the heartheart

1. OVERVIEW1. OVERVIEW

Coronary atherosclerosis:Coronary atherosclerosis:

cause of cardiac ischemiacause of cardiac ischemia

Distribution of coronary arteries in the heartDistribution of coronary arteries in the heart

Ischemia (Ischemia (angina pectorisangina pectoris ): ):

imbalance between oxygen demand and supplyimbalance between oxygen demand and supply

Classification of angina pectoris:Classification of angina pectoris:

Exertional angina (Exertional angina ( 劳累性心绞痛劳累性心绞痛 )) Stable anginaStable angina ( ( 稳定性心绞痛稳定性心绞痛 )) Initial onset angina (Initial onset angina ( 初发型心绞痛初发型心绞痛 )) Accelerated angina (Accelerated angina ( 恶化性心绞痛恶化性心绞痛 ))

Spontaneous angina (Spontaneous angina ( 自发性心绞痛自发性心绞痛 )) Angina decubitus (Angina decubitus ( 卧位型心绞痛卧位型心绞痛 )) Variant or vasospastic anginaVariant or vasospastic angina ( ( 变异性变异性 [[痉挛性痉挛性 ]]心绞心绞

痛痛 )) Acute coronary insufficiency (Acute coronary insufficiency ( 急性冠脉功能不全急性冠脉功能不全 )) Postinfarction angina (Postinfarction angina ( 梗死后心绞痛梗死后心绞痛 ))

Mixed angina (Mixed angina ( 混合性心绞痛混合性心绞痛 ))

Unstable anginaUnstable angina (( 不稳定性心绞痛不稳定性心绞痛 ))

1. OVERVIEW1. OVERVIEW

Myocardial Myocardial oxygen demandoxygen demand is chiefly deter is chiefly determined by:mined by:

• ContractilityContractility

• Heart rate Heart rate

• Wall tensionWall tension• Preload (venous return )Preload (venous return )

• Afterload (arteriolar resistance)Afterload (arteriolar resistance)

1. OVERVIEW1. OVERVIEW

preloadpreloadafterloadafterload

Myocardial Myocardial oxygen demandoxygen demand is di is diminishedminished by:by:

• Reducing contractilityReducing contractility• Reducing heart rate Reducing heart rate • Reducing the preloadReducing the preload• Reducing the afterloadReducing the afterload

1. OVERVIEW1. OVERVIEW

Wall tension Wall tension

1. OVERVIEW1. OVERVIEW

•Myocardial Myocardial oxygen oxygen supplysupply is chiefly is chiefly determined by:determined by:

• AV oxygen differenceAV oxygen difference• Regional myocardial Regional myocardial distribution distribution • coronary blood flow: coronary blood flow:

• vascular resistance, artery pressure

Effects of antianginal drugs:Effects of antianginal drugs:

Reducing oxygen demandsReducing oxygen demands Reducing heart rate and contractilityReducing heart rate and contractility

Dilating systemic arteries and veins ( Dilating systemic arteries and veins ( wall tension by lowe wall tension by lowering heart loads)ring heart loads)

Increasing oxygen supplyIncreasing oxygen supply Dilating conduct coronary arteries ( Dilating conduct coronary arteries ( coronary blood flow) coronary blood flow)

Promoting regional distribution ( Promoting regional distribution ( in ischemic regions) in ischemic regions)

Others:Others:

Anti- platelet coagulation and thrombus formationAnti- platelet coagulation and thrombus formation

1. OVERVIEW1. OVERVIEW

2.1 Nitrates2.1 Nitrates

NitroglycerinNitroglycerin ((硝酸甘油硝酸甘油 ))

A. Pharmacological actionsA. Pharmacological actions

Dilating vessels and reducing heart loadsDilating vessels and reducing heart loads wall tension wall tension ; ; reflex tachycardiareflex tachycardia

Redistribution of coronary circulationRedistribution of coronary circulation

dilating conduct artery:dilating conduct artery: collateral circulation collateral circulation reducing wall tension:reducing wall tension: blood flow in ischemic subendocardial area blood flow in ischemic subendocardial area

2. Antianginal drugs2. Antianginal drugs

Influence of organic nitrates and dipyridamole Influence of organic nitrates and dipyridamole on the blood supply of ischemic areaon the blood supply of ischemic area

2. Antianginal drugs2. Antianginal drugs

Mechanism of the effect of nitroglycerin and other nitratesMechanism of the effect of nitroglycerin and other nitrates

2. Antianginal drugs

Mechanism of the effect of nitroglycerin and other nitratesMechanism of the effect of nitroglycerin and other nitrates

B. Clinical usesB. Clinical uses• Angina pectoris: Angina pectoris: all kinds, especially stable typeall kinds, especially stable type

• Heart failureHeart failure ：： reducing heart loads due to vasodilationreducing heart loads due to vasodilation

C. Adverse reactionsC. Adverse reactions• Increase in heart rate and contractilityIncrease in heart rate and contractility• Symptoms due to vasodilation:Symptoms due to vasodilation: headache, flash, postural headache, flash, postural hypotension, collapse, hypotension, collapse, ectect..• Others:Others: methaemoglobinaemia methaemoglobinaemia （高铁血红蛋白）（高铁血红蛋白）

• Tolerance : avoiding steady-state plasma concentration; avoiding steady-state plasma concentration; • supplement of agents containing –SH supplement of agents containing –SH (captopril)(captopril)

2. Antianginal drugs2. Antianginal drugs

2.1 Other nitrates Isosorbide dinitrate (( 硝酸异山梨酯硝酸异山梨酯 ))

Isosorbide-5-mononirate (5-(5- 硝酸异山梨酯硝酸异山梨酯 )) Compared with nitroglycerin:Compared with nitroglycerin:• Similar but weaker effect

• Acting slowly but lasting longer

• Larger individual variation and more adverse effects

2. Antianginal drugs2. Antianginal drugs

2.2 2.2 receptor blockers receptor blockers

A. Pharmacological actionA. Pharmacological action• Reducing oxygen demand:Reducing oxygen demand:• heart rate and contractility heart rate and contractility • Increasing oxygen supply:Increasing oxygen supply:• diastolic period diastolic period : : perfusion time perfusion time • vascular tone in normal regions vascular tone in normal regions : : • blood flow in ischemic regions blood flow in ischemic regions

• Others:Others:• Improving myocardial metabolismImproving myocardial metabolism• Inhibiting coagulation of plateletsInhibiting coagulation of platelets

2. Antianginal drugs2. Antianginal drugs

B. Clinical usesB. Clinical uses stablestable and and unstableunstable pectorispectoris, , especially associated with especially associated with

hypertension or arrhythmias, even with myocardial infarctionhypertension or arrhythmias, even with myocardial infarction; ; but not but not used forused for variant angina pectorisvariant angina pectoris

C. NotesC. Notes• Dose individualization: Dose individualization: starting from small dosestarting from small dose • Withdraw gradually and slowly: Withdraw gradually and slowly: symptomsymptom reboundrebound

• Combination with nitroglycerinCombination with nitroglycerin

2. Antianginal drugs2. Antianginal drugs

2.3 Calcium channel blockers2.3 Calcium channel blockers

2. Antianginal drugs2. Antianginal drugs

2.3 Calcium channel blockers2.3 Calcium channel blockers

A. Pharmacological actionsA. Pharmacological actions

• Reducing myocardial oxygen remand:Reducing myocardial oxygen remand:• heart loads heart loads : : nifedipinenifedipine

• heart rate and contractilityheart rate and contractility :: verapamil and diltiazemverapamil and diltiazem

• Increasing myocardial blood supplyIncreasing myocardial blood supply• Protecting ischemic myocardial cellsProtecting ischemic myocardial cells• Inhibiting coagulation of plateletsInhibiting coagulation of platelets

2. Antianginal drugs2. Antianginal drugs

Actions of calcium channel blockersActions of calcium channel blockers

B. Clinical usesB. Clinical uses

stable and variant type:stable and variant type:

nifedipine, verapamil, diltiazemnifedipine, verapamil, diltiazem

unstable type:unstable type:

verapamil, diltiazemverapamil, diltiazem

2. Antianginal drugs2. Antianginal drugs

Actions of DHP (like nifedipine) are similar to those of nitroglycerinActions of DHP (like nifedipine) are similar to those of nitroglycerin

Actions of verapamil and diltiazem are similar to those of Actions of verapamil and diltiazem are similar to those of blockers blockers

2.4 Other drugs2.4 Other drugs

ACEIs ACEIs （血管紧张素转化酶抑制药）（血管紧张素转化酶抑制药）•Treating hypertension and preventing ischemic heart Treating hypertension and preventing ischemic heart disease disease •Reducing heart loadsReducing heart loads•Inhibiting cardial remodeling Inhibiting cardial remodeling

Nicorandil Nicorandil （尼可地尔）（尼可地尔）

• Opening ATP-sensitive KOpening ATP-sensitive K++ channel (K channel (KATPATP) ) • Lowering intracellular CaLowering intracellular Ca2+2+

• Providing NO (like nitroglycerin)Providing NO (like nitroglycerin)•Inducing ischemic preconditioning Inducing ischemic preconditioning

2. Antianginal drugs2. Antianginal drugs

Molsidomine Molsidomine （吗多明）（吗多明）•Inhibiting adenosine uptake and cAMP degradation Inhibiting adenosine uptake and cAMP degradation •Inhibiting pletelet aggregationInhibiting pletelet aggregation•Promoting collateral circulation after long-term usePromoting collateral circulation after long-term use

Dipyridamole Dipyridamole （双嘧达莫，潘生丁）（双嘧达莫，潘生丁）

• Inhibiting adenosine uptake and cAMP degradation Inhibiting adenosine uptake and cAMP degradation •Inhibiting pletelet aggregationInhibiting pletelet aggregation•Promoting collateral circulation after long-term usePromoting collateral circulation after long-term use

2. Antianginal drugs2. Antianginal drugs

nitroglycerinnitroglycerin blockers blockers CaCa2+2+ antagonists antagonists combination*combination*

Heart rateHeart rate Contractility Contractility //Wall tensionWall tension // //

Oxygen demandOxygen demand Blood pressureBlood pressure

: increase, : increase, : markedly increase; : markedly increase; : decrease, : decrease, : markedly decrea: markedly decrease; se; : variable according to the dose and effect of each drug ; : variable according to the dose and effect of each drug ; * * bl bl

ockersockers combined with nitroglycerin or Cacombined with nitroglycerin or Ca2+2+ antagonists ( antagonists (nifedipine; combinifedipine; combination with verapamil/diltiazem not be recommendatednation with verapamil/diltiazem not be recommendated))

Caution:Caution: Combination may potentiate the antianginal effects,Combination may potentiate the antianginal effects, but may induce severe hypotension but may induce severe hypotension

3. Summary of antianginal drugs3. Summary of antianginal drugs

SammarySammary

Cardiovascular Cardiovascular pharmacologypharmacology

Overview of Cardiovascular DiseasesOverview of Cardiovascular Diseases

• Common Cardiac DiseasesCommon Cardiac Diseases• Abnormal contractilityAbnormal contractility ：： Heart failuresHeart failures• Abnormal rhythmsAbnormal rhythms ：： ArrhythmiasArrhythmias• Abnormal blood supplyAbnormal blood supply ：： Ischemic heart diseases Ischemic heart diseases • Myocardial disordersMyocardial disorders

• Common vascular diseasesCommon vascular diseases• Abnormal systematic resistanceAbnormal systematic resistance ：： HypertensionHypertension• Dysfunction of coronary vesselsDysfunction of coronary vessels ：： Coronary vascular diseasesCoronary vascular diseases• Dysfunction of cerebral vesselsDysfunction of cerebral vessels ：： Cerebral ischemia, hemorrhageCerebral ischemia, hemorrhage• Dysfunction of pulmonary vesselsDysfunction of pulmonary vessels ：： Pulmonary hypertensionPulmonary hypertension• Dysfunction of peripheral vessels: Dysfunction of peripheral vessels: Peripheral vascular disorderPeripheral vascular disorder• Arteriosclerosis: Arteriosclerosis: basis of most CVS diseasesbasis of most CVS diseases

Overview of Cardiovascular Drugs Overview of Cardiovascular Drugs

• Classification based on target organs/tissuesClassification based on target organs/tissues• HeartHeart：： Heart failures, arrhythmias, cardiac ischemiaHeart failures, arrhythmias, cardiac ischemia• VesselsVessels：： Vasodilatation, vasoconstriction, arterioscVasodilatation, vasoconstriction, arteriosc

lerosislerosis

• Classification based on the mechanismsClassification based on the mechanisms• Ion channelsIon channels ：： CaCa2+2+, Na, Na++, K, K+ + channelschannels

• ReceptorsReceptors：： Adrenoceptors, ATAdrenoceptors, AT11 receptors, receptors, etc.etc.

• EnzymesEnzymes：： ACEI, NaACEI, Na++-K-K++-ATPase, HMG-CoA reductas-ATPase, HMG-CoA reductasee

• OthersOthers：： DiureticsDiuretics

Cardiovascular Drugs Cardiovascular Drugs

• Antiarrhthemic drugsAntiarrhthemic drugs• Classification; Typical drugs and their propertiesClassification; Typical drugs and their properties

• Antihypertensive drugsAntihypertensive drugs• Classification; Properties of 6 main drug classesClassification; Properties of 6 main drug classes

• Drugs for treating heart failureDrugs for treating heart failure• Classification; ACEIs, Classification; ACEIs, blockers, cardiac glycoide blockers, cardiac glycoide

• Antiatheroscleotic drugsAntiatheroscleotic drugs• HMG CoA reductase inhibitors (statins)HMG CoA reductase inhibitors (statins)

• Antianginal drugsAntianginal drugs• Nitroglycerin; Nitroglycerin; blockers; Ca blockers; Ca22+ antagonists+ antagonists