Medical Management of Angina

Pectoris

Pharma. Dept. of Basic Medical School,
Jilin University

May 2014

Imbalance
The clinical pain syndrome of angina pectoris
results from a recurrent, transient imbalance
between cardiac oxygen requirement and
myocardial blood supply.
Exertion
Cardiac ischemia most frequently will result
from enhanced cardiac oxygen demand in
response to exertional stress in the presence
of atherosclerotic coronary artery obstruction.
Additionally, coronary arterial vasoconstriction
or spasm can occur spontaneously without
antecedent exertion leading to an
independent decrease in myocardial blood
flow.

How severe?
Prospective study has suggested that within 5
years of the onset of angina I in 4 men will suffer
a myocardial infarction. In addition, 30 percent
of patients over the age of 55 will be die within 8
years of clinical angina presentation and 44
percent of those deaths will be sudden.
Patients with angina pectoris, therefore,
represent a population that, in addition to being
subject to considerable discomfort, is at high risk
for additional complications.

Exercise induced classic angina pectoris
The pain of angina pectoris usually can be clinically
identified and diagnosed on the basis of
characteristic symptomatic criteria.
The pain or discomfort may be either localized to
the substernal area or more diffuse and generalized
to the anterior or lateral chest.
Angina is most frequently described as squeezing,
pressing, or burning in quality, may radiate to
the arm or the neck and may be associated with
shortness of breath, nausea, or diaphoresis.
Variant angina pectoris
however, cannot account for the clinically
recognized variant presentations of ischemic type
chest pain occurring at rest or nocturnally either
in the presence or absence of angiographically
demonstrable coronary artery stenosis.
Additional attention, therefore, must be directed to
factors affecting and regulating coronary artery
blood flow and myocardial oxygen supply.

nitroglycerin and long acting nitrates
It was first noted in the 19 century that amyl
nitrite and nitroglycerin were useful in the
treatment of acute episodes of angina pain, and
organic nitrates remain the primary therapeutic
agents in this condition to this day.

Mechanisms of Nitrates and nitrites

a. Nitrate and nitrites are polyol esters of
nitric acid(nitrates) or nitrous acid(nitrites)
that relax vascular smooth muscle.
b. Nitrates and nitrites activate guanylate
cyclase and increase cyclic guanine
nucleotides. This activates cGMP dependent
kinases that ultimately lead to
dephosphorylation of myosin light chain.

Pharmacological effects
These drugs dilate all vessels. Peripheral venodilation
decreases cardiac preload and myocardial wall tension;
arterial dilation reduces afterload. Both of these
actions lower oxygen demand by decreasing the work
of the heart. Coronary vessels may also be dilated,
and coronary blood flow to ischemic regions is
increased.
d. Nitrates and nitrites ameliorate the symptoms of
classic angina predominantly through the
improvement of hemodynamics.
Variant angina is relieved through effects on coronary
circulation.

Bioavailability
These drugs have a large first pass effect due
to the presence of high capacity organic
nitrate reductase in the liver, which inactivates
drugs.
Nitrates have a t1/2 of less than 10 min.

Preperations of Nitroglycerin
Nitroglycerin is preferably administered
sublingually for rapid delivery and short duration.
Sustained delivery systems are available and are
used to maintain blood levels. Aerosol, topical,
intravenous, and oral preparations are also
available.
Amyl nitrite is a volatile liquid that inhaled. An
unpleasant odor and extensive cutaneous
vasodilation render it less desirable than
nitroglycerin.


Isosorbide dinitrate
Isosorbide dinitrate has active initial
metabolites.
This drug is administered orally or
sublingually; it has better oral bioavailability
and longer half life than nitroglycerin. Timed
release oral preparations are available with
durations of action up to 12 hr.

Therapeutic uses
Sublingual nitroglycerin is most often used
for severe, recurrent Prinzmetals angina.
Continuous infusion or slowly absorbed
preparations of nitroglycerin (including the
transdermal patch) or derivatives with longer
half lives have been used for unstable angina
and for CHF in the presence of MI.

Adverse effects
Nitrates and nitrites produce vasodilation,
which can lead to orthostatic hypotension,
reflex tachycardia, throbbing headache (may
be dose limiting), blushing, and a burning
sensation. Continuous exposure may lead to
tolerance.
Large doses produce methemoglobinemia and
cyanosis.

Beta adrenoceptor antagonists
Beta blockers decrease heart rate, blood
pressure, and contractility, resulting in
decreased myocardial oxygen requirements.
Combined therapy with nitrates is often
preferred in the treatment of angina pectoris
because of the decreased adverse effects of
both agents.

CCBs
Mechanism: CCBs produce a blockade of L-type
(slow) calcium channels, which decreases
contractile force and oxygen requirements.
Agents cause coronary vasodilation and relief
of spasm, they also dilate peripheral
vasculature and decrease cardiac afterload.
Pharmacologic properties
CCBs channel blocking agents can be
administered orally. When administered
intravenously, they are effective within
minutes.
The therapeutic use of these drugs in angina is
generally reserved for instances in which
nitrates are ineffective or when beta blockers
are contraindicated.
Serum lipids are not increased.

Selected drugs (1)
a. Verapamil
(1) Verapamil produces slowed conduction through
the AV node (predominant effect); this may be an
unwanted effect in some situations (especially in the
treatment of hypertension).
(2) Verapamil may produce AV block when used in
combination with beta blockers. The toxic effects of
verapamil include myocardial depression, heart failure,
and edema.
(4) The peripheral effects of verapamil can produce
headaches, reflex tachycardia, and fluid retention.



Selected drugs (2)
b. Nifedipine, isradipine, nisoldipine, and
nicardipine
These dihyopyridine CCBs have predominant
actions in the peripheral vasculature, they
decrease afterload and to a lesser extent
preload and lower blood pressure.
These drugs have significantly less direct effect on
the heart than verapamil.

Selected drugs (3)
c. Diltiazem
Diltiazem, a benzothiazepine, is
intermediated in properties between
verapamil and the dihyropyridines.
Diltiazem is used to treat variant angina,
either naturally occurring or durg induced and
stable angina.