Antianginal drugs

Submitted by :Ahmad al-jifri

Outlines:

Introduction of the Angina pectoris Definition symptoms Causes Types Risk factors & Complications Diagnosis & Treatment strategy

Classifications of antianginal drugs Mechanism of the drug Structure ( SAR ) Uses Adverse effect

What is the Angina ?

o "a strangling feeling in the chest“

oAngina pectoris is chest pain that can be caused by restricted blood flow in arteries that supply the heart

Symptoms:

Chest pain or discomfort (stabbing, pulsating)

Pain in your arms, neck, jaw, shoulder or back

Nausea Fatigue Shortness of breath Anxiety Sweating Dizziness

Causes of Angina include:The heart needs to be supplied be blood

or oxygen in that blood .. If no enough blood .. Cause ischemia

Reduced blood flow to the heart muscleCoronary artery disease (CAD ) is the

majority cause of angina cases .

Other : - Narrowing of the aortic heart valve.- Anemia.- abnormal heart rhythms.- Diseases of the heart muscle .

Type of Angina Pectoris

typical Stable Angina

↓coronary flow ,Occurs on

physical Exertion (five minutes or

less)

Unstable angina

Epicardial coronary spasm & formation of non-occlusive thrombi

Can Occurs at rest Heart attack(emergency)

Variant , vasospastic or

prinzmetal angina ..

Reversible coronary

spasm .. Occurs at rest

2%

Risk factors:

Tobacco use Diabetes High blood pressure High blood cholesterol or triglyceride levels Personal or family history of heart disease Older age. Men older than 45 and women

older than 55 have a greater risk than younger adults.

Lack of exercise Obesity Stress

Complications:

Pressure, fullness or a squeezing pain in the center of your chest that lasts for more than a few minutes

Pain extending beyond your chest to your shoulder, arm, back, or even to your teeth and jaw

Increasing episodes of chest pain Prolonged pain in the upper abdomen Shortness of breath Fainting

Diagnosis:

physical exam asking about your symptoms and

family history of heart disease Electrocardiogram (ECG) Stress test Chest X-ray other

Treatment strategy.

The main goal is to restore the balance between oxygen demand and supply ..

o Lifestyle changeso Antianginal drugo Surgery

o Angioplastyo coronary artery bypass grafting (CABG)

Lifestyle Changes (prevention): stop smoking. Avoid exposure to

secondhand smoke. Overweight >> weight-loss safe exercise plan Avoiding stress Avoid large meals. healthy diet

Antianginal drugs

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

Classification of drugs

Organic nitrates

(2)Nitroglycerin,

Glyceryl Trinitrate:

Calcium channel blockers

Dihydropyridines :

Nifedipine

Benzothiazepines

Diltiazem

Phenylalkylamines:

1-Verapamil

Beta-blockers

(a)Non-selective

Beta Blocker

Propranolol (Inderal)

(b)Beta1-Selective Blockers

Atenolol

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 of Action :

Organic nitrates interact with tissue thiols and release Nitric Oxide which stimulates the guanyl cycles 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.

Nitroglycerin, Glyceryl Trinitrate:

It has been used to treat angina and heart failure since at least 1870 .

it can be prepared as rapid acting preparation as sublingual tablets or spray of

glyceryl trinitrate for treatment of acute attacks or can be as long acting preparation (sustained released) as

transdermal patches and buccal tablets and ointments of glyceryl trinitate

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 .

for prevention therapy one dose of glyceryl trinitrate usually eases the pain within 2-3 minutes.

Example of organic nitrites :

Calcium channel blockers 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 of Action :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:

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. 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.

Common side effects:

constipation, nausea, headache, rash, edema (swelling of the legs with fluid), low blood pressure, drowsiness, and dizziness.

(a)Dihydropyridines: Nifedipine is the prototype of this group.

Amlodipine and 3-Felodipine are second generation of 1,4-dihydropyridine derivatives.

They have greater selectivity for vascular smooth muscles than myocardial tissue than Nifedipine.

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).

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. 

(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 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: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)

It has antianginal, antiarrhythmic and antihypertensive activity.

Contraindications: In patient with congestive heart failure due to

its negative inotropic effect on heart. 

 

(c)Beta-adrenergic antagonists (Beta- (blockersBeta-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.

- 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 (long-term) lung diseases.

(a)- Non selective BetaBlocker “

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.).

(a)- Non selective BetaBlocker

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.

(b)1- Beta SelectiveBlockers

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.

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..

Alternative Medicine:

Supplements that may help improve your angina treatment include:

L-arginine L-carnitine

ask the doctor first

References:

University of Alexandria, Faculty of pharmacy, Pharmaceutical chemistry department.

Thank you