Antianginal Drugs Zhu Yi Zhun, Dept. of Pharmacology, SPFDU Email: zhuyz@fwww.book118.com Hypertension Complications of untreated hypertension Hypertensive cardiovascular disease Hypertensive cerebrovascular disease and dementia Hypertensive renal disease Aortic dissection Atherosclerotic complication Myocardial infarction ( MI ) is one of the most common diagnoses occurring in the world. Its mortality is approximately 30%. Although the survival following treatment has improved in the last two decades, the morbidity and mortality of MI still remain high. LEADING CAUSES OF MORTALITY IN WHO REPORT MYOCARDIAL INFARCTION Myocardial Infarction generally occurs with the abrupt decrease in coronary blood flow that follows a thrombotic occlusion of a coronary artery leads to irreversible myocardial cells damage and necrosis. Angina pectoris Is the most common condition involving in tissue ischemia Vasodilators Calcium channels blockers: arteriodilator (e.g. Nifedipine 硝苯地平, verapamil 异搏定, diltiazem 硫氮卓酮) Cause Atheromatous obstruction—most frequent Primary cause: imbalance between the oxygen required by the heart and oxygen supplied to it by the coronary artery. Drugs used to treat Angina Nitrates: Nitroglycerin (glyceryl trinitrate) Nitrites: Amyl Nitrite Indications Short-acting nitrates for acute effort angina: sublingual nitroglycerin (0.3 to 0.6 mg) every 5 minutes until pain goes or a max. of 4 to 5 tablets to be taken. Nitroglycerin spray is an alternative mode of oral administration. Side-effects of Nitrates Headache--most common side-effect Other drugs used to treat angina Calcium channel blockers Indications: 	chronic stable angina, unstable angina 	Hypertension 	Superaventricular Arrhythmias 	Others: hypertrophic cardiomyopathy, migraine and atherosclerosis. Side-effects 	Headache, facial flushing, dizziness, and constipation (but Nifedipine not ) Indications: 	Ischemic heart disease 	Hypertension 	Cardiac arrhythmias 	Others cardiovascular disorders: increasing stroke volume (in patients with obstructive cardiomyopathy), congestive heart failure (in certain carefully selected patients) 	Glaucoma, Hyperthroidism, Neurologic diseases. Side-effects 	Worsening of preexisting asthma and other forms of airway obstruction (nonselective agents due to 2 blockade); 	Rash, fever, sedation, sleep disturbance, and even depression  Drugs for Atherosclerosis Zhu Yi Zhun, Dept. of Pharmacology, SPFDU Email: zhuyz@www.book118.com Agents for hyperlipidemia Cholesterol level Metabolism of cholesterol Lovastatin Vasodilators Calcium channels blockers: arteriodilator (e.g. Nifedipine 硝苯地平, verapamil 异搏定, diltiazem 硫氮卓酮) Indications Short-acting nitrates for acute effort angina: sublingual nitroglycerin (0.3 to 0.6 mg) every 5 minutes until pain goes or a max. of 4 to 5 tablets to be taken. Nitroglycerin spray is an alternative mode of oral administration. Metabolism of cholesterol  * Therefore, it is important to treat hypertension and reduce mortality and morbidity of these conditions End organ damage is associated with increased risk from ischemic heart disease, cerebrovascular accidents, heart and renal failure.  MYOCAIDIAL INFARCTION The mortality of ischaemic heart disease is ranked first among other diseases in the WHO statistics Vasodilator drugs are commonly used (e.g. nitroglycerin, calcium channel blocker) -blockers are also useful Nitrites (increase NO): venodilator (+++), Arterioles (+), ischemic zone (+). ACE inhibitors (e.g. Captopril 开普通) and angiotensin II receptor antagonists (Losartan 氯沙坦): mixed O2 required O2 supplied Nitrates & Nitrites ( 硝酸盐& 亚硝酸盐) Mechanisms of action in Angina: * Endothelial-derived relaxation factor (EDRF 内皮衍生的松弛因子)—nitric oxide (NO ): induces coronary vasodilation  * Nitrates dilate coronary arteries to: 1) redistribute blood flow from epicardial to endocardial regions. 2) relieve coronary spasm and dynamic stenosis * Reduce oxygen demand Nitrates/Nitrites NO  Relaxation Pentaerythritol tetranitrate Isosorbide dinitrate  硝酸甘油硝酸异山梨酯硝酸戊四醇酯Drugs used to treat Angina ( 戊基亚硝酸盐) Long acting nitrates for angina prophylaxis: Oral preparation of nitrate is frequently given for the prophylaxis of angina. Long-acting nitrates are not continuously effective if regularly taken over a prolonged period, unless allowance is made for a nitrate-free or -low interval. 	with long-acting preparations: the development of tolerance, worsening of the underlying diseases process.  Failure of nitrate therapy 	with short-acting preparations: noncompliance (headache), loss of potency of the tablets, and incorrect timing Hypotension--most serious side-effect -blockers Calcium channel blocking drugs Effects of calcium channel blocking drugs -adrenoceptor blocking drugs Hyperlipidemia: Lipoprotein  Acute pancreatitis Atherosclerosis (LDL↑) (HDL↓) [mg/dL(mmol/L)] 3-hydroxy-3-methyl- glutaryl-coenzyme A 3- 羟-3- 甲戊二酰辅酶-statin Lovasatin Atorvastatin Fluvastatin Pravastatin Simvastatin Rosuvastatin LDL Oxidative stress Prodrug Active form Daily dose: 10-80 mg, evening administration Absorbtion: 40-75% T1/2: 1-3 h Other cholesterol lowing agents: Niacin, Ezetimibe etc. Nitrites (increase NO): venodilator (+++), Arterioles (+), ischemic zone (+). ACE inhibitors (e.g. Captopril 开普通) and angiotensin II receptor antagonists (Losartan 氯沙坦): mixed Nitrates & Nitrites ( 硝酸盐& 亚硝酸盐) Mechanisms of action in Angina: * Endothelial-derived relaxation factor (EDRF 内皮衍生的松弛因子)—nitric oxide (NO ): induces coronary vasodilation  * Nitrates dilate coronary arteries to: 1) redistribute blood flow from epicardial to endocardial regions. 2) relieve coronary spasm and dynamic stenosis * Reduce oxygen demand Nitrates/Nitrites NO  Relaxation Long acting nitrates for angina prophylaxis: Oral preparation of nitrate is frequently given for the prophylaxis of angina. Long-acting nitrates are not continuously effective if regularly taken over a prolonged period, unless allowance is made for a nitrate-free or -low interval. Nitrates & Nitrites Mechanisms of action in Angina: * Endothelial-derived relaxation factor (EDRF)—nitric oxide (NO ): induces coronary vasodilation  * Nitrates dilate coronary arteries to: 1) redistribute blood flow from epicardial to endocardial regions. 2) relieve coronary spasm and dynamic stenosis * Reduce oxygen demand Nitrates/Nitrites NO  Relaxation 3-hydroxy-3-methyl- glutaryl-coenzyme A 3- 羟-3- 甲戊二酰辅酶-statin Lovasatin Atorvastatin Fluvastatin Pravastatin Simvastatin Rosuvastatin LDL Oxidative stress *  Sheet3
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Compound
Route
Preparation and dose
Duration of effects and comments
Nitroglycerin
(a) sublingual
0.3-0.6 mg up to 1.5 mg
Peak blood level at 2 min; t1/2 7 min;
 for acute therapy of effort and rest angina
(b) Spray
0.4 mg/ metred dose, as needed
Similar to tablets at same dose
2.5-13 mg 1-2 tablets 3 x daily
4-8 h after first dose, no efficacy data for 
chronic therapy
(d) i.v.
5-200 ug/min
in unstable angina, increasing dose are often 
needed to overcome tolerance
(e) Ointment
2%, 15x15cm or 7.5-40mg
Apply 2 x daily; 6 h interval, effect up to 7 h 
tablets
after 1st dose, no data for chronic use
(c) Oral, sustained
release
(f) Transdermal
patches
0.2-0.8 mg/h patch on for 12 h 
patch off for 12 h
Effects start within 1-2 h, last 8-12 h during 
intermittent therapy. Not effective during 
continuous patch-on therapy
(g) Buccal
1-3 mg tablets 3x daily
Effects start within minutes and last 3-5 h
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Compound
Route
Preparation and dose
Duration of effects and comments
(a) sublingual
(b) Spray
(e) Ointment
release
Isosorbide 
dinitrate
2.5-15 mg
Onset 5-10 min, effect up to 60 min
1.25 mg on tongue
Rapid action 2-3 min
(c) Oral tablets
5-80 mg 1-2 tablets 2-3 x daily
Up to 8 h (first dose then tolerance with 3x 
or 4x daily