抗心绞痛药Antianginal DrugsAntianginal Drugs

• What’s Angina pectoris• Cause and the classification of angina pectoris :– Atheromatous obstruction of the large coronary vessels (atherosclerotic a

ngina, classic angina); 劳累性心绞痛：稳定型，初发型，恶化型– Transient spasm of localized portions of the large coronary vessels (angi

ospastic or variant angina); 自发性心绞痛：卧位型，变异型，急性冠脉功能不全，梗死后心绞痛– Both causes 混合性心绞痛

Unstable angina pectoris:Unstable angina pectoris: initial onset type; accelerated type; spontaneous typeinitial onset type; accelerated type; spontaneous type associated with atheroscleosis plaque and thrombus formationassociated with atheroscleosis plaque and thrombus formation may lead to myocardial infarctionmay lead to myocardial infarction

OverviewOverview

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

OverviewOverview

Coronary atherosclerosis:Coronary atherosclerosis:

cause of cardiac ischemiacause of cardiac ischemia

OverviewOverview

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

• Primary cause of angina pectoris:

– In classic angina, the imbalance occurs when the myocardial oxygen requirement increases; “angina of effort”

– In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm. “vasospastic or Prinzmetal's angina”

oxygen requirement

oxygen supply imbalance

OverviewOverview

preloadpreloadafterloadafterload

Myocardial Myocardial oxygen demandoxygen demand is is diminisheddiminished by:by:• Reducing contractilityReducing contractility• Reducing heart rate Reducing heart rate • Reducing the preloadReducing the preload• Reducing the afterloadReducing the afterload

Myocardial Myocardial oxygen supply oxygen supply is is increasedincreased by:by:• 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)

Treatments:• Non-drug treatment:经皮冠状动脉成形术 (percutaneous transluminal coronary angioplasty, PTCA), 冠脉搭桥术 ( coronary artery bypass graft surgery, CABG )• Drug treatment

Wall tension Wall tension

OverviewOverview

Antianginal DrugsAntianginal Drugs

Antianginal drugs:Antianginal drugs:• Organic nitratesOrganic nitrates• receptor blockersreceptor blockers

• Calcium channel blockersCalcium channel blockers • Anti-platelet agents• ACEIs• Fish oil

Effects of antianginal drugs:Effects of antianginal drugs:

• Reducing oxygen demandsReducing oxygen demands

• Increasing oxygen supplyIncreasing oxygen supply

• Others:Others: Anti- platelet coagulation and thr Anti- platelet coagulation and thrombus formation ombus formation

Nitrates & Nitrites

• Quick tolerance and cross-tolerance;• Pharmacokinetic factors determine the selection;

nitroglycerin

- Pharmacokinetics• Low oral bioavailability (eg, nitroglycerin and isosorbide dini

trate, typically < 10–20%).• Sublingual is normally used. Transdermal and buccal absorpt

ion from slow release preparations.• Amyl(戊基 ) nitrite and related nitrites can be used with inhal

ation route.• Duration of effect is very brief (Unchanged nitrate t1/2=2-8 minu

tes, partially denitrated metabolites longer t1/2= 3 hrs). So micro-pump is very common in hospital usage.

Nitrates & Nitrites

- Pharmacological actions- Pharmacological actions• Dilating vessels and reducing heart loadsDilating vessels and reducing heart loads wall tension wall tension ; reflex tachycardia; reflex 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 • Alleviating  ischemic injuryAlleviating  ischemic injury• Anti- platelet coagulationAnti- platelet coagulation

Nitrates: Nitrates: NitroglycerinNitroglycerin (( 硝酸甘油硝酸甘油 ))

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

Nitrates: Nitrates: NitroglycerinNitroglycerin (( 硝酸甘油硝酸甘油 ))

Intracellular Ca2+ release↓ ， extracellular Ca2+ influx↓

Intracellular [Ca2+] ↓

The production of PGE or PGI2 and membrane hyper-polarization may also be involved.

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

- Clinical uses- Clinical uses• Angina pectoris: Angina pectoris: all kinds, especially stable typeall kinds, especially stable type• Heart failureHeart failure

- Adverse reactions- Adverse reactions• Symptoms due to vasodilation:Symptoms due to vasodilation: headache, postural headache, postural hypotension, hypotension, etcetc..• Increase in heart rate and contractilityIncrease in heart rate and contractility• 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 –SHsupplement of agents containing –SH (captopril, NAC), VitC(captopril, NAC), VitC

Nitrates: Nitrates: NitroglycerinNitroglycerin (( 硝酸甘油硝酸甘油 ))

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

NitratesNitrates

- Pharmacological action- 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 Increase oxygen supplyIncrease oxygen supply Inhibiting coagulation of plateletsInhibiting coagulation of platelets

receptor blockersreceptor blockers

- Clinical uses- Clinical uses stablestable and and unstableunstable pectoris, pectoris, 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

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

• Cardiac depressionCardiac depression• Inducing asthmaInducing asthma• Combination with nitroglycerinCombination with nitroglycerin

receptor blockersreceptor blockers

- Pharmacological actions- 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• Inhibiting coagulation of plateletsInhibiting coagulation of platelets• Protecting ischemic myocardial cellsProtecting ischemic myocardial cells

- Clinical uses- Clinical uses

stable and variant type:stable and variant type: nifedipine, verapamil, diltiazemnifedipine, verapamil, diltiazem

unstable type:unstable type: verapamil, diltiazemverapamil, diltiazem

Calcium channel blockersCalcium channel blockers

- Toxicity• Cardiac depressionCardiac depression, including cardiac arrest, bradycardia, atriove

ntricular block, and heart failure.• Relatively short-acting calcium channel blockers have the potential

to enhance the risk of adverse cardiac events.• Slow-release and long-acting vasoselective calcium channel blocke

rs are usually well tolerated.

• Patients receiving -adrenoceptor-blocking drugs are more sensitive to

the cardiodepressant effects of calcium channel blockers.

• Tolerable toxicity: flushing, dizziness, nausea, constipation, and peripheral edema.

Calcium channel blockersCalcium channel blockers

Other drugsOther drugsAngiotensin converting enzyme inhibitors (ACEI)Angiotensin converting enzyme inhibitors (ACEI)

Nicorandi Nicorandi ((尼可地尔尼可地尔 ))

• a potassium channel opener

Molsidomine Molsidomine （吗多明）（吗多明）• Producing NO → stimulate guanylyl cyclase (GC) →increase cGMP → relaxes vascular smooth muscle

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

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

Summary of antianginal drugsSummary of antianginal drugs

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