WHAT IS ANGINA???

Angina

pectoris is a characteristic
sudden severe pressing chest pain or
heaviness radiating to the neck, jaw,
back and arms. It is often associated
with diaphoresis, tachypnea and
nausea.

WHAT IS ANGINA???
Angina

is caused by coronary flow

that is insufficient to meet oxygen
demands of the myocardium.
Angina can be precipitated by any
activity/process that creates an
imbalance in O2 supply and demand.

Angina
The

discomfort abates when supply

becomes adequate for demand.
Typically angina lasts for seconds to
minutes, up to 15 minutes.

Types of Angina

Angina occurs in
three overlapping
patterns:
Stable angina

Unstable angina
Prinzmetal (variant)

angina

Stable Angina

Stable angina is also known as:

Exertional angina, Typical or classic angina
Angina of effort, Atherosclerotic angina

Therapeutic goals: Increase myocardial

blood flow by dilating coronary arteries and
arterioles (increase oxygen delivery),
decrease cardiac load (preload and afterload;
decrease oxygen demand), decrease heart
rate (decrease oxygen demand), [alter
myocardial metabolism?]

Unstable Angina

Unstable angina is also known as:Preinfarction angina, Angina at rest

Caused by recurrent episodes of small platelet clots at the site of a
ruptured atherosclerotic plaque which can also precipitate local
vasospasm
May be associated with myocardial infarction
Therapeutic rationale: Inhibit platelet aggregation and thrombus
formation (increase oxygen delivery), decrease cardiac load (decrease
oxygen demand), and vasodilate coronary arteries (increase oxygen
delivery)

Vasospastic Angina

Vasospastic angina is also referred to as:

Variant angina
Prinzmetal's angina

Caused by transient vasospasm of the

coronary vessels
Usually associated with underlying
atheromas

What is antianginal
drugs???
Antianginal drugs are those drugs
which improves the oxygen supply to
myocardium and reduce the oxygen
demand.
Those drugs which are used to treat the
episodes of angina.

Classification of
antianginals

Three major classes of agents are used

individually or in combination to treat angina:
Organic nitrates
Vasodilate coronary arteries
Reduce preload and aferload
Calcium channel blockers
Vasodilate coronary arteries
Reduce afterload
The non-dihydropyridines (verapamil and
diltiazem) also decrease heart rate and
contractility

Classification.

Beta-adrenergic blockers
Decrease heart rate and contractility
Decrease afterload 2 to a decrease in cardiac
output
Improve myocardial perfusion 2 to a
decrease in heart rate

A new class of drugs, pFox inhibitors, are in the

final stages of approval for chronic angina
Reduce myocardial oxygen consumption by
shifting metabolism from fatty acid to glucose
metabolism
No hemodynamic effects

Organic nitrates

Short acting : Sublingual : GTN (nitroglycerine)

Long acting : Oral : Isosorbide dinitrate, Isosorbide
mononitrate,

All of these agents are enzymatically converted to nitric

oxide (NO) in the target tissues

Veins and larger arteries appear to have greater enzymatic

capacity than resistance vessels, resulting in greater effects
in these vessels

Organic Nitrates

NO activates a cytosolic form of guanylate

cyclase in smooth muscle
Activated guanylate cyclase catalyzes the
formation of cGMP which activates cGMPdependent protein kinase
Activation of this kinase results in
phosphorylation of several proteins that
reduce intracellular calcium and hyperpolarize
the plasma membrane causing relaxation.

Effects of Nitrovasodilators

Peripheral vasodilation:
Dilation of veins predominates over that of arterioles

Increased coronary blood flow:

Collateral flow may be increased
Decreased preload improves subendocardial perfusion
Although organic nitrates can relax vasospastic coronary

arteries, they have little or no effect on total coronary blood

flow in patients with typical angina due to atherosclerosis

Inhibition of platelet function:

May contribute to their effectiveness in the treatment of

unstable angina

ORGANIC
NITRATES

Organic nitrates & nitrites are

simple nitric & nitrous esters
of glycerol.
These agents cause a rapid
decrease in myocardial
oxygen demand leading to
rapid resolution of symptoms.
Nitrates are effective for all
types of angina.
Activation of guanylate
cyclase increases cGMP
activating a cGMP kinase
leading to dephosphorylation
of myosin light chains
decreasing contractile force.

Requires normal
vascular
endothelium
Diffuses to local
vascular smooth
muscle

Indications

Angina Pectoris Nitrates are effective in classical

as well as variant angina. Nitrates increase exercise
tolerance and postpone ECG changes of ischemia.
CCF and LVF- Nitrates afford relief by venous
pooling of blood >Reduced venous return
>Decrease end diastolic volume >Improvement in
left ventricular function and regression of pulmonary
congestion.
Myocardial infarction -GTN is frequently used during
evolving MI with the aim of relieving chest pain,
pulmonary congestion and limiting the area of
necrosis by favorably altering O2 balance in
marginally partially ischemic zone.

Indications
Cyanide poisoning- Nitrates generate methhemoglobin which

Excreted in
urine
solution IV)

Thiosulphate
mlof
25%
Sod.
(50

Cyanide

has strong affinity for cyanide radical and form cyanomethemoglobin .This
may again dissociate to release cyanide .Therefore sod.thiosulphate is
given to form sod. Thiocyanate which is excreted in urine.

Sod.
Nitrate(10m
l of 3%
solution IV

NITRATES
CONTRAINDICATIONS

Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

WITH CAUTION:

Constrictive pericarditis
Intracranial hypertension
Hypertrophic cardiomyopathy

Pharmacokinetics
The difference between nitrate preparations
is mainly in time of onset of action.
1. Nitroglycerin suffers marked 1st pass
metabolism so administration is
sublingual (rapid absorption and onset
(<1 minute), t1/2 ~10 minutes.
Occasionally as nitroglycerin is
metabolized anginal symptoms will
return.
Transdermal administration either as
patch or paste provides a depot of agent
for a steady availability. Nitro-Bid is an
oral or topical preparation which
saturates the hepatic catabolic
pathways allowing a prolonged level of
nitroglycerine.

 Isosorbide

mononitrate &
isosorbide dinitrate
are long acting
nitrates that are
relatively resistant
to hepatic
catabolism t1/2 ~ 1
hour.

Mechanism of Action
Nitrates decrease myocardial oxygen demand:
1. The primary effect is a reduction in venous tone
which results in venous pooling decreasing
venous return (decreased preload).
2. Arteriolar tone is less effectively reduced resulting
in a decrease in PVR (decreased afterload ) and
decreased blood pressure.
3. #s 1 & 2 decrease myocardial wall stress reducing
O2 demand.
4. Dilation of coronary vessels or exerts a ~minor
effect on increasing O2 supply.

Pharmacokinetic Properties of
Organic Nitrates
Hepatic first-pass metabolism is high and oral
bioavailability is low for nitroglycerin (GTN) and
isosorbide dinitrate (ISDN)
Sublingual or transdermal administration of these agents

avoids the first-pass effect

Isosorbide mononitrate (ISMN) is not subject to firstpass metabolism and is 100% available after oral
administration
Hepatic blood flow and disease can affect the
pharmacokinetics of GTN and ISDN

Property
Half-life (min)
Plasma clearance (L/min)
Apparent volume of distribution (L/kg)
Oral bioavailability (%)

GTN

ISDN

3
50
3
<1

10
4
4
20

ISMN
280
0.1
0.6
100

Routes of Administration

Amyl nitrate is a gas at room temperatures and

can be administered by inhalation
Rapid onset, short duration (3-5 min)

GTN and ISDN have a rapid onset of action (1-3

min) when administered sublingually, but the
short duration of action (20-30 min) is not
suitable for maintenance therapy
IV nitrogylcerin can be used to treat severe
recurrent unstable angina
Slowly absorbed preparations of
nitrovasodilators (oral, buccal, transdermal) can
be used to provide prolonged prophylaxis
against angina (3-10 hrs), but can lead to
tolerance.

Dosage
DRUG

DOSE AND ROUTE

DURATION OF ACTION

GTN(nitroglycerine)

0.5mg sublingual
5-15 mg oral
0.4-0.8 mg s.l. spray

10-30 min
4-8 hrs
10-30 min

Isosorbide dinitrate

5-10 mg sublingual
10-20 mg Oral
20-40 mg Oral(SR)

20-40 min
2-3 hrs
6-10 hrs

Isosorbide 5 mononitrate

20-40 mg Oral

6-10 hrs

Erthrityl-tetranitrate

15-60 mg Oral

4-6 hrs

Pentaerthyritol-tetranitrate 10-40 mg Oral

80 mg Oral

3-5 hrs
8-12 hrs

Tolerance and Dependence with

Nitrovasodilators

Continuous or frequent exposure to nitrovasodilators can

lead to the development of complete tolerance
Transdermal GTN may provide therapeutic levels of

drug for 24 hours or more, but efficacy only lasts 8-10

hrs
Nitrate-free periods of at least 8 hrs (e.g.- overnight) are

recommended to avoid or reduce tolerance.

The mechanism of tolerance is not completely understood

but appears to relate to the enzymes involved in
converting the nitrates to NO, or to the enzyme that
produces cGMP

Adverse Effects of
Nitrovasodilators

The major acute adverse effects of

nitrovasodilators are due to excessive
vasodilation

Orthostatic hypotension
Tachycardia
Severe throbbing headache
Dizziness
Flushing
Syncope

Organic nitrates are contraindicated in

patients with elevated intracranial pressure

Adverse effects
1.
2.
3.

4.

5.

The most common side effect of nitrates is

headache due to veno-dilation.
Postural hypotension & syncope particularly with
sublingual use.
Tachycardia induced by decreased PVR may itself
induce anginal symptoms especially with unstable
symptoms.
Methemaglobinemia can occur with chronic use of
long term agents, this may occur when sublingual
use is combined with long acting agents.
Withdrawal symptoms may occur (an indication of
tolerance) when nitrate agents are tapered or
discontinued, this may precipitate anginal attacks.

-Blockers

-Blockers decrease O2 demands of the

myocardium by lowering the heart rate and
contractility (decrease CO) particularly the
increased demand associated with exercise. They
also reduce PVR by direct vasodilation of both
arterial & venous vessels reducing both pre- and
after load.
These effects are caused by blocking 1 receptors,
selective 1 antagonists (atenolol, metoprolol and
acebutolol) lose their selectivity at high doses and
at least partially block 2 receptors (a concern for
bronchospastic disease).

antagonists reduce the frequency

and severity of anginal episodes
particularly when used in combination
with nitrates.
There are a number of
contraindications for blockers:
asthma, diabetes, bradycardia, PVD
& COPD.
-Blockers in combination with
nitrtates can be quite effective.

MECHANISM OF ACTION

Beta-adrenoceptor antagonists competitively inhibit the binding of

endogenous catecholamines to 1-adrenoceptors in the heart.

Decrease the heart rate, resulting in decreased myocardial oxygen

demand and increased oxygen delivery to heart.

Decrease myocardial contractility helping to conserve energy or

decrease demand

b-Adrenergic Blockers in the

Treatment of Angina

Desired effects of beta-blockers

Reduce myocardial oxygen consumption by
reducing contractility and heart rate
Reducing cardiac output also reduces

afterload
Some b-blockers can cause vasodilation
directly or by acting as a-blockers
Improve myocardial perfusion by slowing heart rate

(more time spent in diastole)

Adverse Effects and

Contraindications for b-Blockers
May exacerbate heart failure
Contraindicated in patients with asthma
May depress contractility and heart rate
and produce AV block in patients
receiving non-dihydropyridine calcium
channel blockers (i.e. verapamil and
diltiazem)

Ca+2 Channel Blockers

Ca+2 channel blockers protect tissue by inhibiting
the entrance of Ca+2 into cardiac and smooth
muscle cells of the coronary and systemic arterial
beds.
All Ca+2 channel blockers produce some
vasodilation ( PVR) and (-) inotropes.
Some agents also slow cardiac conduction
particularly through the AV node thus serving to
control cardiac rhythm.
Some agents have more effect on cardiac muscle
than others but all serve to lower blood pressure.
CHF patients may suffer exacerbation of their
failure as these are (-) inotropes.
They are useful in Prinzmetal angina in
conjunction with nitrates.

Chemistry of Ca++ Channel

Blockers

Five major classes of Ca++ channel

blockers are known with diverse
chemical structures:
Benzothiazepines: Diltiazem
Dihydropyridines: Nicardipine, nifedipine,

nimodipine, amlodipine, and many others

Phenylalkylamines: Verapamil
Diarylaminopropylamine ethers: Bepridil
Benzimidazole-substituted tetralines:
Mibefradil

Desired Therapeutic Effects of

Calcium Channel Blockers for
Angina

Improve oxygen delivery to ischemic

myocardium
Vasodilate coronary arteries
May inhibit platelet aggregation
Particularly useful in treating vasospastic

angina

Reduce myocardial oxygen consumption

Decrease afterload (no effect on preload)
Non-dihydropyridines also lower heart rate

and decrease contractility

Relative Cardiovascular Effects of Calcium Channel

Blockers
(adapted from Goodman & Gilman, 9th ed.)

Compound

Coronary
vasodilation

Suppression
of cardiac
contractility

Suppression
of
SA node

Suppression
of
AV node

Verapamil

++++

++++

+++++

+++++

Diltiazem

+++

++

+++++

++++

Nifedipine

+++++

Nicardipine

+++++

DOSAGE
Name of
drug

Action

Dose and
route

VERAPAMIL

DILATES ARTERIOLES AND HAS ADRENERGIC

BLOCKING ACTIVITY.HR GENERALLY DECREASES,AV
CONDUCTION IS SLOWED BUT CO IS MAINTAINED BY
SYMPATHETIC STIMULATION

DILITIAZEM

DIRECT NEGATIVE IONOTROPIC EFFECT.CLINICAL 30-60 MG ORAL

DOSES PRODUCE CONSISTENT FALL IN BP WITH
LITTLE CHANGE OR DECREASE IN HR

NIFEDIPINE

OVERRIDING ACTION IS ARTERIOLAR DILATATION

.THE DIRECT DEPRESSANT EFFECT ON HEART
REQUIRES MUCH HIGHER DOSES .

5-20 MG ORAL

FELODIPINE

GREATER VASCULAR SELECTIVITY,LARGER TISSUE

DISTRIBUTION AND LONGER T1/2 .

5-10 MG ORAL

AMLODIPINE

AMLODIPINE IS A DILATOR OF PERIPHERAL ARTERIES 5-10 MG ORAL

AND ARTERIOLES WHICH REDUCES THE TOTAL
PERIPHERAL RESISTANCE AND, REDUCES THE
WORKLOAD OF THE HEART. THE UNLOADING OF THE
HEART DECREASE ISCHEMIA AND RELIEVE ANGINA
BY REDUCING MYOCARDIAL ENERGY OXYGEN
CONSUMPTION
.

40-60 MG ORAL
5 MG BY SLOW
IV INJ.

Ca++ Channel Blockers: Toxicities

Adverse effects are typically direct extensions of their therapeutic

effects and are relatively rare
Major adverse effects:
Depression of contractility and exacerbation of heart failure
AV block, bradycardia, and cardiac arrest

Minor adverse effects

Hypotension, dizziness, edema, flushing

Patients with ventricular dysfunction, SA node or AV conduction

disturbances, WPW syndrome, and systolic blood pressures below 90
mm Hg should not be treated with verapamil or diltiazem

Partial Fatty Acid Oxidation (pFox)

Inhibitors
Ranolazine (Ranexa, piperazine acetamide) is under

review by the FDA for the treatment of chronic angina,

acute coronary syndromes (ACS) , and long-term
prevention of ACS
Acts by partially inhibiting fatty acid oxidation in the
myocardium, thus shifting metabolism to glucose
which requires less oxygen to metabolize
No hemodynamic effects
FDA advisory committee (12/9/2003) recommended
use only in refractory cases of angina until safety
concerns have been addressed
QT prolongation and testicular toxicity are the
among the possible toxicities so far

Antianginal Agents: Nursing Implications

Perform a complete health history to determine presence of

conditions that may be contraindications for use

Obtain baseline VS, including respiratory patterns and rate.
Assess for drug interactions.
Patients should not take OTC medications.
Patients should report blurred vision, persistent headache, dry
mouth, dizziness, edema, fainting episodes, weight gain of 2
pounds in 1 day or 5 or more pounds in 1 week, pulse rates under
60, and any dyspnea
Alcohol consumption and hot baths, hot tubs, or saunas will result
in vasodilation, hypotension, and the possibility of fainting

Antianginal Agents: Nursing Implications

Teach patients to change positions slowly to avoid postural BP

changes.
Encourage patients to keep a record of their anginal attacks,
including precipitating factors, number of pills taken, and
therapeutic effects.
Monitor for adverse reactions
Allergic reactions, headache, light-headedness, hypotension,
dizziness
Monitor for therapeutic effects
Relief of angina, decreased BP, or both

Antianginal Agents: Nitroglycerin

Nursing Implications

Instruct

patients in proper technique and

guidelines for taking sublingual NTG for anginal
pain.
Instruct patients never to chew or swallow the SL
form.
Instruct patients that a burning sensation felt with
SL forms indicates that the drug is still potent.

Antianginal Agents: Nitroglycerin

Nursing Implications
Monitor VS frequently during acute exacerbations of angina

and during IV administration.

IV forms of NTG must be contained in glass IV bottles and
must be given with infusion pumps.
Discard parenteral solution that is blue, green, or dark red.
Follow
specific manufacturers instructions for IV
administration.

Antianginal Agents: Beta Blockers

Nursing Implications
Patients taking beta blockers should monitor pulse rate daily

and report any rate lower than 60 beats per minute.

Dizziness or fainting should also be reported.
Instruct patients to take in adequate fluids and eat high-fiber
foods to prevent constipation
These medications should never be abruptly discontinued
due to risk of rebound hypertensive crisis.
Inform patients that these medications are for long-term
prevention of angina, not for immediate relief.