[Year]

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 .

It is a prodrug which must

undergo denitration to
give the active moiety
which is NO .
(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, bluish-

colored 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.

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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 1,4-
dihydropyridine 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: It’s the only member of this

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

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 (long-
term) 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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 It’s a hydrophilic drug
2- Nadolol (Corgard®) 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- ItNicotinyl
is a prodrug alcohol (pyridylcarbinol)
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 3-
Hydroxy-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
The exact way in which this medicine called
works is high
not blood
known.
Amlodipine is a type of medicinepressure
known asmedicines.
a calciumIt is channel
used to
treat high
blocker. Benazepril is a type of medicine blood
known as pressure.
an Angiotensin-
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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