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University of Alexandria Faculty of pharmacy Pharmaceutical chemistry department.

ANTIANGINAL DRUGS

Antianginal drugs
These drugs are used to treat angina pectoris which is myocardial disease.

What is Angina pectoris?
Angina (angina pectoris - Latin for squeezing of the chest).It’s used to describe the pain, breathlessness, and choking feeling that can be caused by restricted blood flow in arteries that supply the heart .It’s the principle symptom of an ischemic heart disease which may develop into myocardial infarction. In most cases, the lack of blood supply is due to a narrowing of the coronary arteries as a result of arteriosclerosis. A typical attack of angina usually starts during exercise Angina is usually felt as: pressure, tightening, squeezing, or aching across the chest, particularly behind the breastbone. The pain usually lasts for a short time and usually goes away fairly quickly after rest. The patient may also suffer breathlessness, sweatiness & a sense of fear. Patients may also suffer: indigestion heartburn, weakness, nausea, cramping.

Causes of Angina ?
The majority of angina cases are caused by disease of the coronary arteries (CAD) that occurs when the arteries become blocked by fatty

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deposits. This narrowing of the arteries means the heart cannot receive enough blood.

CAD occurs when a fatty material called plaque builds up on the inner walls of the coronary arteries.

Other causes of angina include:
- Narrowing of the aortic heart valve. - Anemia. - Fast, abnormal heart rhythms. -. Diseases of the heart muscle

Types of Angina.
(a)Stable angina: It’s also known as typical or classic angina, angina of effort and atherosclerotic angina. This type is usually due to atherosclerosis, develops when your heart works harder, such as when you exercise or climb stairs Causes of Stable angina: Stable angina is usually triggered by physical exertion. When someone climbs stairs, exercises or walks, his heart demands more blood, but it's harder for the muscle to get enough blood when the arteries are narrowed. Besides physical activity, factors such as emotional stress, cold temperatures, heavy meals and smoking also can narrow arteries and trigger angina. (b) Unstable angina: It’s also known as preinfarction angina and angina at rest. It has different pathology and results from fissuring or erosion of an atherosclerotic plaque with subsequent platelet aggregation. Causes of Unstable angina: If fatty deposits (plaques) in a blood vessel rupture or a blood clot forms, it can quickly block or reduce flow through a narrowed artery, suddenly and severely decreasing blood flow to your heart muscle. Unstable angina can also be caused by conditions such as severe anemia, especially if you already have narrowed coronary arteries.
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(c) Variant angina: It’s also known as vasospastic angina and Prinzmetal's angina. Causes of variant angina: Caused by a spasm in a coronary artery in which the artery momentarily narrows. This narrowing reduces blood flow to your heart, causing chest pain. Variant angina accounts for about 2 percent of angina cases.

Treatment strategy.
The main goal is to restore the balance between oxygen demand and supply, and this can be done by several techniques like: (a)Decrease oxygen demand. (b)Increase oxygen delivery to ischemic tissue. (c)Modify risk factors associated with atherosclerosis as smoking, hypertension, diabetes, and hyperlipidemia.

Surgery
When medicines and other treatments don't control angina, you may need a medical procedure to treat the underlying heart disease. Angioplasty and coronary artery bypass grafting (CABG) are both commonly used to treat angina. Angioplasty opens blocked or narrowed coronary arteries. It can improve blood flow to your heart, relieve chest pain, and possibly prevent a heart attack. Sometimes a small mesh tube called a stent is placed in the artery to keep it open after the procedure.

Therapeutic classes:
(a) Organic nitrates They are first line drugs; they are effective in stable, unstable, and variant angina. They are simple nitrous and nitric acid esters of alcohols. They are used in both treatment and prophylaxis against angina attacks. Mechanism:

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Organic nitrates interact with tissue thiols and release Nitric Oxide which stimulates the guanyl cyclase which increase the intracellular concentration of cGMP which cause vasodilatation in large veins, resulting in pooling of the blood in the vines and decreased venous return to the heart (which means decreased preload) also they dilate the arteries resulting in decrease in the resistance of the peripheral tissues (which means decreased after load) that’s results in general decrease in cardiac work. Therefore organic nitrates restore the balance between oxygen demand (by decreasing the cardiac work) and oxygen supply (by vasodilating the coronary artery). Repeated exposure to organic nitrates will deplete tissue thiols and render drug inactive that’s why patient should have a nitrate free period which is about 6 to 8 hours to allow the regeneration of tissue thiols. This class of drugs has some common adverse effects: - Headache. - Postural hypotension (so patient should be advised to set down when taking the drug). - Reflex tachycardia.

Drugs
(1)Amyl Nitrite, Isopentyl Nitrite:

Amyl nitrite is a rapidly acting vasodilator administered by inhalation. 0.35ml is supplied in a covered thin glass capsule which is easily crushed between the fingers. Amyl nitrite is a clear, yellowish liquid having a peculiar ethereal, fruity odor. It is volatile, even at low temperatures, and is flammable.The molecular formula of amyl nitrite is: (CH3)2CHCH2CH2ONO,there are a variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly
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due to the nitrite group, it also has a psychoactive effect, which has led to its recreational use. (2)Nitroglycerin, Glyceryl Trinitrate: It has been used to treat angina and heart failure since at least 1870.It has moderate volatility . it can be prepared as rapid acting preparation as sublingual tablets or spray of glyceryl trinitrate for treatment of acute attacks or can be prepared as long acting preparation (sustained released) as transdermal patches and buccal tablets and ointments of glyceryl trinitate for prevention therapy.one dose of glyceryl trinitrate usually eases the pain within 2-3 minutes. If the first dose does not work, a second dose can be taken after five minutes, and a third dose after a further five minutes. If no effect seems to appear after the third dose, the patient must be hospitalized .

(3)Isosorbid Dinitrate : It presents in solid form at room temperature. It has a long duration of action that’s why it’s used in a sustained released form for prophylaxis. They are used in three ways: to relieve an attack that is occurring by using the medicine when the attack begins; to prevent attacks from occurring by using the medicine just before an attack is expected to occur; or to reduce the number of attacks that occur by using the medicine regularly on a long-term basis. It may have some side effects like: Blurred vision, dryness of mouth, headache, skin rash, bluishcolored lips, fingernails, or palms of hand , dizziness or fainting, feeling of extreme pressure in head, shortness of breath, unusual tiredness or weakness, weak and fast heartbeat, fever, or convulsions.

It is a prodrug which must undergo denitration to give the active moiety which is NO .

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(b)Calcium channel blockers (CCBs) They are four types of calcium channels according to their location and function, and three types according to receptors operated, Na/Ca exchanger, stretch operated and voltage operated which are T (transient), N (neuronal), and L (long duration, slowly acting) and the one we can block is the L-type of voltage operated Ca channels which are located in the cellular membrane of the heart and smooth muscles.

Mechanism: Influx of Ca ions through these channels leads to membrane depolarization and initiates or strengthens muscle contraction. CCBs block the inward movement of Ca2+ by binding to the L-type Ca channels. This causes muscle relaxation and suppresses cardiac or blood vessels activity. The channel can exist in one of the three conformations: (a)Resting state: In normal tissue an ion channel will most likely be in this state. The channel blocker cannot reach its receptor site. Open (activated) state: Ca2+ can pass; also the blocker now has access to its binding site. (b)Inactive state: This is refractory to further depolarization. Ca2+ cannot pass through the channel, nor will the drug. Depending on the lipid solubility of the drug, it can still have access to its binding site through the phospholipids bilayer. Differences among them: CCBs differ in their duration of action, the process by which they are eliminated from the body (The common ending for most of the calcium channel blockers is – IPINE.), and, most importantly, in their ability to affect heart rate and contraction. Some CCBs [for example, amlodipine (Norvasc)] have very little effect on heart rate and contraction so they are safer to use in
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individuals who have heart failure or bradycardia (a slow heart rate). Verapamil (Calan, Isoptin) and diltiazem (Cardizem) have the greatest effects on the heart and reduce the strength and rate of contraction. Therefore, they are used in reducing heart rate when the heart is beating too fast. Common side effects: constipation, nausea, headache, rash, edema (swelling of the legs with fluid), low blood pressure, drowsiness, and dizziness. Classes: (a)Dihydropyridines: Nifedipine is the prototype of this group. Amlodipine and 3-Felodipine are second generation of 1,4dihydropyridine derivatives. They have greater selectivity for vascular smooth muscles than myocardial tissue than Nifedipine. SAR: --1,4-dihydropyridine ring is essential for the activity -C2 and C6 are substituted with alkyl group (have a. role in duration of action). -C3 and C5 have carboxylic groups that must be protected with ester functional groups. -C4 has an aromatic ring with electron withdrawing group. 1-Nifedipine : It reduces the heart’s workload by relaxing the smooth muscles and widening the lumen of the blood vessels (arteries and veins). It is used to treat hypertension or high blood pressure and angina pectoris (chest pain). Drug interactions: cimetidine (Tagamet, Tagamet HB); another heart medication to treat the same or another condition; erythromycin (E-Mycin and
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others); itraconazole (Sporanox) or ketoconazole (Nizoral); carbamazepine (Tegretol); phenytoin (Dilantin) and rifampin (Rifadin, Rimactane) or rifabutin (Mycobutin). Avoid grapefruit or grapefruit juice when taking nifedipine because of a possible interaction that may have dangerous effect. Be careful in changing positions since you may become dizzy especially when you stand or sit up from a lying position or if you wake up during the night. Special precautions: It’s contraindicated with kidney disease; liver disease; another disease of the heart or blood vessels such as sick sinus syndrome, aortic stenosis, heart failure, low blood pressure, or coronary artery disease. Serious adverse effects: Allergic reaction (difficulty of breathing, closing of the throat, swelling of the lips, tongue, face or hives; fast or slow heartbeats; severe dizziness or fainting; psychosis; jaundice (yellowing of the skin or eyes); swelling of the legs and ankles. 2-Amlodipine : Amlodipine affects the movement of calcium in the heart and blood vessels. As a result, it relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload

Indications: Used to treat hypertension (high blood pressure) and angina pectoris (chest pain). Overdose symptoms:

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Dizziness, weakness, chest pain, shortness of breath, fainting, unusually fast or slow heartbeat, coma, slurred speech, and confusion. Serious side effects: Allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); fast or slow heartbeat; chest pain; severe dizziness or fainting; psychosis; yellowing of the skin or eyes (jaundice); or leg and ankle swelling. It also has gastrointestinal side effects including constipation, loss of appetite, indigestion, diarrhea and gas 3-Felodipine : It’s used to increase the supply of blood and oxygen to the heart by relaxing blood vessels. It may be used to relieve and control angina or to control high blood pressure. Patients may get a headache after taking a dose of this medicine. This usually fades the longer they take

the medication.
(b) Benzothiazepines: Diltiazem It’s the only member of this class. it’s action is due to its water solubility as it reaches binding sites by hydrophilic pathway when the Ca channel is open.It has direct –ve inotropic effect and +ve chronotropic effect on the heart (decrease oxygen demand); so it has antianginal, antiarrhythmic and antihypertensive activity like phenylalkylamines.

Contraindications: In case of any allergic reaction to any form of diltiazem in the past, kidney disease, liver disease and other disease of heart or blood
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vessel. Diltiazem can interact with grapefruit and grapefruit juice and the interaction may have dangerous effects. Diltiazem passes into breast milk and may affect a nursing infant. Side effects: Diltiazem may cause dizziness or drowsiness (c)Phenylalkylamines: 1-Verapamil It’s the prototype of this class. Its water solubility that makes it reaches their binding sites by hydrophilic pathway when the channel is open. It has direct –ve inotropic effect and +ve chronotropic effect on the heart (decrease oxygen demand)

Contraindications:

It has antianginal, antiarrhythmic and antihypertensive activity. In patient with congestive heart failure due to its negative inotropic effect on heart.

Side effects:
2- Bepridil (Vascor®). As in Benzothiazepines.

.
It’s a second generation phenylalkylamine derivative.

(c)Beta-adrenergic antagonists (Beta-blockers) Beta-blockers are the preferred first choice treatment for helping to prevent angina. They make the heart beat slower and with less force. This means that the heart needs less blood and oxygen after exercise, so angina is prevented, or occurs less frequently. Most common side effects of beta-blockers include: -Tiredness.
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- Cold hands and feet. - Slow heartbeat. - Diarrhea and nausea. Less common side effects of beta-blockers include: -Sleep disturbances. -Nightmares and impotence Contra-indications: B-blockers are not suitable for patients of asthma or chronic pulmonary obstruction disorder (COPD) which is chronic (longterm) lung diseases. Drugs (a)Non-selective Beta Blocker This class is contraindicated in patient with bronchospastic disease (asthma) and diabetes as it suppresses insulin release. They have negative inotropic effect (reduce contractility of the myocardium) and negative chronotropic effect (decrease heart rate.). 1-Propranolol (Inderal) It’s the prototypical beta-blocker. Propranolol is mainly used in the treatment of hypertension. It is lipid soluble so have CNS side effects as dizziness, confusion and depression. SAR: 1-OH gp is essential for H bonding. 2-secondary amino gp is essential for ionic bonding. 3-The branching and the extention of the carbon chain are beneficial for fitting in hydrophobic pocket.

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2- Nadolol (Corgard®)

It’s a hydrophilic drug used to overcome CNS side effects of propranolol.

(b)Beta1-Selective Blockers This class has some adverse Effects as cold hands, impotence, mental depression & sleep disturbance. SAR: Atenolol is the prototype of this class. One common feature of this class is the presence of p-substituent of sufficient size on the aromatic ring along with the absebce of m-substituents. 1-Atenolol Atenolol is used in the treatment of high blood pressure, used to relieve angina, and in heart attack patients to help prevent additional heart attacks. It is also used to correct irregular heartbeat, prevent migraine headaches, and to treat tremors. 2- Metoprolol It’s available as 50- and 100-mg tablets for oral administration and in 5-ml ampuls for intravenous (d)Other types of antianginal drugs: 1- Nicorandil(Icorel) Nicorandil is a vasodilator drug used to treat angina. It is marketed Mechanism: Cause relaxation of the smooth muscle of the blood vessels, especially those of the venous system. Firstly, by activating potassium channels, and secondly by donating nitric oxide to
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activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of GMP leading to both arterial and venous vasodilatation 2- Dipyridamole(Persantin) It is a drug that inhibits thrombus formation when given chronically and causes vasodilatation when given at high doses over short time it Inhibits Thromboxane synthase, therefore lowering the levels of TXA2 and thus stops the effects of TXA2 (platelet aggregation, bronchoconstriction and vasoconstriction), leading to vasodilatation.

3- It is a prodrug alcohol (pyridylcarbinol) Nicotinyl which is converted in vivo into its active form ‘’Nicotinic acid’’. Nicotinyl alcohol →active nicotinic acid, in vivo. Nicotinyl alcohol (pyridylcarbinol) is a niacin derivative used as a hypolipidemic agent and as a vasodilator. 4- Pravachol , is used to lower levels of cholesterol and other fats in the blood. Pravachol belongs to the group of medicines called 3Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors. They work by blocking an enzyme that is needed to make cholesterol.

5- Lotrel Combination of Amlodipine and Benazepril, it belongs to the class of medicines called not known. The exact way in which this medicine works is high blood Amlodipine is a type of medicinepressure as a calcium channel known medicines. It is used to treat known as an Angiotensinblocker. Benazepril is a type of medicinehigh blood pressure. Converting Enzyme (ACE) inhibitor. It blocks an enzyme that is necessary to cause blood vessels to tighten. The action of both medicines together is to relax blood vessels, lower blood pressure, and increase the supply of blood and oxygen to the heart.
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Clinical case
A 63 year old woman presented to the emergency room with pain in her left shoulder that radiated to the breastbone and to the pit of her stomach. With ITTP guidance, the medical student took a very thorough history. The following was discovered. The woman has had many attacks of pain for ten years, with lengthy intervals between them. However, the attacks have occurred everyday for the past two weeks, forcing her to stop working. Exertion in the form of gardening or exercising precipitates the attacks. The pain is not severe, and it is always relieved by rest. Exam revealed: -Shoulder joint within normal limits, range of motion free. -Heart slightly enlarged, otherwise within normal limits.

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-No elevation of cardiac enzymes.

Administration of sublingual nitroglycerin resulted in pain relief. She was diagnosed with angina pectoris and discharged until further tests could be performed. The woman showed up at the emergency room again, one week later. Her pain was more severe, lasted more than an hour, and was unrelieved by rest or nitroglycerin. She is diagnosed with myocardial infarction, and admitted immediately. Surgically treatment is recommended either angioplasty or coronary artery bypass grafting (CABG) are both commonly used to treat angina. In this case the patient has chosen CABG in which healthy arteries or veins taken from other areas in your body are used to bypass (go around) the narrowed coronary arteries. Bypass surgery can improve blood flow to the heart, relieve chest pain, and possibly prevent a heart attack.

A proposed exam question on antianginal drugs :

B A
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C
Study the shown structures then answer he following questions In questions ( A,B,C,D and E ) choose one from this drugs for each answer each drug can be used once , more or none . A) …………………… is a prodrug must undergo de-nitration to give NO which is the active moiety. B) …………………. Used as inhaled antianginal drug but it also has a psychoactive effect, which has led to its recreational use. C) Angina may be ………… (1)…………(2)……….or ……(3) ……… (Complete). D)…………… used to provide immediate relief from the symptoms in treatment for stable angina. E) Antiplatlets as ………………..can be used to prevent symptoms in treatment for stable angina. GOOD LUCK

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