Pharmacology of Antianginal

Drugs

Tri Widyawati
M. Ichwan

Pharmacology & Therapeutic Dept.

Medical Faculty
University of Sumatera Utara
 Angina

• Chest pain due to an inadequate supply of

oxygen to the heart muscle (www.medicine.net)
• Not a disease.
• It is a symptom of an underlying heart
problem, usually coronary heart
disease (CHD) (www.heart.org)
Relationship between Vascular Tone and Parameter of
Cardiovascular Physiology
Vessel Type Parameter of Cardiovascular Physiology
Coronary arteries Myocardial O2 supply
Arterioles Afterload
Myocardial O2 demand
Regional myocardial perfusion
Capacitance veins Venous pooling
Preload
Myocardial O2 demand

Shu & Mayer, 2004

 Treatment of angina
Lifestyle changes
Nitrates
Medication β-blockers
Calcium channel blockers

Surgery : CABG ( coronary artery bypass graft)

PTCA (percutaneous transluminal
coronary angioplasty)
 Angina – Basis of Drug Therapy
Drugs can help to correct imbalance by:

 Decreasing myocardial oxygen demand by

reducing cardiac workload

• Reducing heart rate

• Reducing force of myocardial contraction
• Reducing after load

 Increasing the supply of oxygen to

ischemic myocardium

 Antiplatelet、antithrombosis
What are the antianginal drugs?

Organic nitrates.

- adrenoceptor blockers.

Calcium channel blockers.

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 NITRATES

Relaxation of smooth Veins

muscles Dilatation

Arteries
Note:
= Dilatation does not occur on sclerotic blood
vessel ***
= = nitrate decrease TPR---- cardiac work
decrease == O2 need decrease.
11
remember Dr.Dutton
Organic nitrates.
 Effect of Nitrates
On Stable Angina :
Arteriolar
1- Venodilatation
dilatation
Preload Afterload

Myocardial Oxygen demand

2- Redistribution of coronary flow towards subendocardium
3- Dilatation of coronary collateral vessels.
 Preparations :
Short acting Long acting
For acute attacks For antianginal prophylaxis

Nitroglycerin Nitroglycerin
oral SR (6.25-12mg) 2-4
(sublingual, buccal times/day
spray) - 2% ointment (1-1.5
inch/4hrs)
Isosorbide - patches (1
dinitrate(sublingual, patch=25mg)/day
buccal spray) Isosorbide dinitrate (oral)
10-40mg t.d.s.
Isosorbide mononitrate
(oral) 20mg/12 hrs.
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 Duration of Action of Various Preparations of
Organic Nitrates

Duration of
Preparation
action
" Short-acting"
1-Nitroglycerin a) Sublingual 10-30 min
b) Spray 10-30 min

2- Isosorbide dinitrate a) Sublingual Up to 60 min.

b) Spray 1.5 hours

" Long-acting" a) Oral; sustained release 4-8 hours

1-Nitroglycerin b) Ointment 3-6 hours
c) Transdermal patches 8-12 hours

2- Isosorbide dinitrate Oral 4-6 hours

3-Isosorbide mononitrate Oral 6-10 hours
 Adverse Reactions :
1- Postural Hypotension & 2- Tachycardia
Syncope

3- Drug Rash

4- Facial Flushing

6- Prolonged high dose

Methaemoglobinaemia
5- Throbbing Headache
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 The main limitation of chronic nitrate therapy is
TOLERANCE
“Monday morning headache”

As a result of chronic administration

It develops as SH groups in vessel wall become oxidized by constant
exposure to nitrates, this prevents the production of NO & hence
stimulation of Guanylate cyclase which is believed to be fundamental
to smooth muscle relaxation produced by the drugs.

“NITRATE FREE INTERVAL” of 8-10 hrs reduces or prevents

development of nitrate tolerance

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-blockers are effective in STABLE & UNSTABLE angina

•not useful for vasospastic angina (Variant) {Prinzmetal} & may

worsen the condition due to an increase in coronary
resistance caused by the unopposed effects of catecholamines
acting at a-adrenoceptors.
 Mechanism of antianginal action:
The effectiveness of -adrenoceptor blockers in the
treatment of exertional angina is attributable to a fall
in myocardial O2 requirement at rest & during exertion
due to :
1- A -ve chronotropic effect (particularly during
exercise).
2- A -ve inotropic effect.
3- A reduction in arterial blood pressure (particularly
systolic pressure) during exercise.
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 Disadvantage
1. decrease contractility eject time
ventricular volume O2consumption

2. block β2- R on coronary artery

coronary artery contract coronary
blood flow
However the net effect of -blockers is to  myocardial
O2 requirement particularly during exercise; their
potentially deleterious effects can be balanced by
concomitant use of nitrates
anti-ischemic effects of
β-blocker
 Dosage and Route of Administration

Drug Route Dosage

Propranolol Oral 30-360 mg/day in 2-4 divided

doses
Nadolol Oral 40-80 mg ONCE daily

Atenolol Oral 50-100 mg ONCE daily

Metoprolol Oral 50-100 mg TWICE daily

 Adverse Reactions :

Bronchospasm
CHF A-V block

Cold
extremities Worsening Hypotension
symptoms of PVD
23
 Adverse Reactions :

Fatigue & Mask signs of Nightmares , Hallucinations ,

weakness Hypoglycemia Depression.

Plasma Triglycerides & HDL

Cholesterol Discontinuation after
long ttt exacerbates
Angina
24
Used in treatment of all types of angina.
Verapamil (80-160 mg) /8 hr
Diltiazem (60-120 mg) /8 hr
Dihydropyridine group
Nifedipine (10-40mg) /8 hr
Amlodipine 5mg/day

25
 Block
Voltage -dependent calcium
channels (L-type) in cardiac and
smooth muscles.

CA
LC
IU
M
Mechanism of anti-anginal action :
1 - Coronary artery dilatation and relief of
coronary spasm (variant angina)

2 -Decrease myocardial O2 demand due to:

•Arteriolar Vascular
dilatation resistance Afterload
 Calcium Antagonist
 Derivat DIHYDROPYRIDINE
– Masa kerja singkat : nifedipin
– Masa kerja panjang : amlodipin, felodipin
 Derivat BENZOTHIAZEPINE (ex. diltiazem)
 Derivat DIPHENYLALKYLAMINE (ex. verapamil, gallopamil)

Basic Actions of Ca Antagonist on CVS

Vaso- Suppression
Drug dilation automaticity conductivity
contractility (SA) (AV)
Nifedipine 5 1 1 0
Diltiazem 3 2 5 4
Verapamil 4 4 5 5
CCBs - Pharmacokinetics
• High oral absorption, but high first pass metabolism (except amlodipine) –
individual variation and highly plasma protein bound
• Extensively distributed in tissues and metabolized in liver and excreted in
urine, eliminated in 22-6 Hrs (except amlodipine)

Drug Bioavailability Vd (L/kg) Active Elim half life(hr)

% metabolite
Verapamil 15-30 5.0 Y 4-6

Diltiazem 40-60 3.0 Y 5-6

Nifedepine 30-60 0.8 M 2-5

Felodipine 15-25 10.0 None 12-18

Amlodipine 60-65 21.0 None 35-45

 Dosage and Route of Administration

Drug Route Dosage

Verapamil Oral 80-160 mg every 8 hours

Nifedipine Oral 10-40 mg every 8 hours

Diltiazem Oral 60-120 mg every 8 hours

 Adverse reactions :

Ankle
Dizziness edema
Headache Hypotension

Constipation Reflex
Flushing A-V block & HF only Tachycardia with
with Verapamil & Nifedipine
Diltiazem
 Contraindications of
Verapamil & Diltiazem:

2 - Sinus or A-V node

disease.
1 - HF

3 - Bradycardia.
 Antiplatelet Agents

• Low dose ASPIRIN (75-150 mg)

• The formation of platelet aggregates are

important in the pathogenesis of angina,
unstable angina and acute MI

• Aspirin is a potent inhibitor of platelet

thromboxane production

• Thromboxane stimulates platelet aggregation

and vasoconstriction
 DUAL ANTIPLATELET THERAPY AND
INCREASED RISKS OF BLEEDING
• In a meta-analysis of 18 randomized trials which
included 129,314 patients

– Those assigned to dual antiplatelet therapy have about a 50% increase

in risks of major bleeding compared with those given single agent
therapy

– The magnitude of these excess risks are about as high as the

approximately 60% increase observed in the trials comparing single
antiplatelet agents to placebo

– These excess risks of major bleeding should be considered in relation

to the benefits on occlusive CVD events in choosing the optimal
antiplatelet strategy, especially for long-term treatment of patients
with prior events or those at high risk of developing CVD.

Fund Clin Pharm 2008; 22:315-321

 Medical Therapy in
Acute Myocard Infarction

MONA + BAH
• Morphine (class I, level C)
• Analgesia
• Reduce pain/anxiety—decrease sympathetic tone,
systemic vascular resistance and oxygen demand
• Careful with hypotension, hypovolemia, respiratory
depression

• Oxygen (2-4 liters/minute) (class I, level C)

• Up to 70% of ACS patient demonstrate hypoxemia
• May limit ischemic myocardial damage by increasing
oxygen delivery/reduce ST elevation
• Nitroglycerin (class I, level B)
• Analgesia—titrate infusion to keep patient pain free
• Dilates coronary vessels—increase blood flow
• Reduces systemic vascular resistance and preload
• Careful with recent ED meds, hypotension, bradycardia,
tachycardia, RV infarction

• Aspirin (160-325mg chewed & swallowed) (class I, level A)

• Irreversible inhibition of platelet aggregation
• Stabilize plaque and arrest thrombus
• Reduce mortality in patients with STEMI
• Careful with active PUD, hypersensitivity, bleeding
disorders
• Beta-Blockers (class I, level A)
• 14% reduction in mortality risk at 7 days at 23% long
term mortality reduction in STEMI
• Approximate 13% reduction in risk of progression to MI
in patients with threatening or evolving MI symptoms
• Be aware of contraindications (CHF, Heart block,
Hypotension)
• Reassess for therapy as contraindications resolve

• ACE-Inhibitors / ARB (class I, level A)

• Start in patients with anterior MI, pulmonary
congestion, LVEF < 40% in absence of
contraindication/hypotension
• Start in first 24 hours
• ARB as substitute for patients unable to use ACE-I
• Heparin (class I, level C to class IIa, level C)
– LMWH or UFH (max 4000u bolus, 1000u/hr)
• Indirect inhibitor of thrombin
• less supporting evidence of benefit in era of reperfusion
• Adjunct to surgical revascularization and thrombolytic /
PCI reperfusion
• 24-48 hours of treatment
• Coordinate with PCI team (UFH preferred)
• Used in combo with aspirin and/or other platelet
inhibitors
• Changing from one to the other not recommended
 Additional medication therapy
• Clopidodrel (class I, level B)
• Irreversible inhibition of platelet aggregation
• Used in support of cath / PCI intervention or if
unable to take aspirin
• 3 to 12 month duration depending on scenario

• Glycoprotein IIb/IIIa inhibitors

(class IIa, level B)
• Inhibition of platelet aggregation at final common
pathway
• In support of PCI intervention as early as possible
prior to PCI
 Beta Blockers
 Prescribed for  Therapeutic effect
– Hypertension – 1 Cardiac influence
– Angina – 2 Peripheral influence

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