5. ANGINA PECTORIS
SYMPTOM COMPLEX:
Constitutes A Clinical Syndrome Rather Than A Disease
Cause: Transient Myocardial Ischaemia
Occurs When Ever There Is An Inbalance Between Myocardial
Oxygen Supply And Demand
Comonest Cause: Atheromatous Disease Of Coronary Arteries
May Also Be A Manifestation Of Other Forms Of Heart Disease
e.g. Severe aortic valve disease, hypertrophic cardiomyopathy
6. Types of Angina ?Types of Angina ?
1. Stable Angina.
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2. Unstable Angina.
3. Variant Angina.
7.
8. Angina Pectoris ?
• Classic angina is characterized
• substernal squeezing chest pain,
• occurring with stress and
• relieved with rest or nitroglycerin.
• May radiate down the left arm
• May be associated with nausea, vomiting, or
diaphoresis.
9. Stable Angina
•Also called “Effort Angina”
•Discomfort is precipitated by
activity
•Minimal or no symptoms at rest
•Symptoms disappear after
rest/cessation of activity
10. HOME
1.1. Stable Angina ?.
Retrosternal painRetrosternal pain
Radiating to left arm &Radiating to left arm &
shouldershoulder
The commonest cause isThe commonest cause is ADVANCEDADVANCED
ATHEROSCELEROSISATHEROSCELEROSIS
Lasting less than 15 min.Lasting less than 15 min.
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12. Exercise ECG showing typical severe down sloping STExercise ECG showing typical severe down sloping ST
segment :segment :
Anginal pain is often associated with Depression ofAnginal pain is often associated with Depression of STST
segmentsegment
Standing 1 min. 3 min. 7 min. 9 min.
Stable Angina
In between attacksIn between attacks : ECG is entirely: ECG is entirely NORMALNORMAL
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13. UNSTABLE ANGINA
• Often occurs at rest
• Is more severe and lasts longer than stable angina
• Episodes of pain tend to be changing in the
character,i.e. increasing severity (cresendo angina) ,
frequency, duration as well as precipitating factors
14. 2.2. Unstable Angina ? .
Increased frequencyIncreased frequency,, severity or duration of painseverity or duration of pain
in a patient of Stable Anginain a patient of Stable Angina
Myocardial infarction may occur in 10-20% of patients.Myocardial infarction may occur in 10-20% of patients.
N.B.N.B.
Pain occurs with less exertion orPain occurs with less exertion or
at restat rest
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15. The underlying cause isThe underlying cause is
•Atheroscelerotic changesAtheroscelerotic changes
Fissuring of atheroscelerotic plaquesFissuring of atheroscelerotic plaques
Platelet aggregationPlatelet aggregation
ThrombosisThrombosis
Coronary artery spasmCoronary artery spasm
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16. Prinzmetal, Variant ,vasospastic angina
• Usually occurs at rest
• Tend to be severe
• Is caused by a transient spasm in a coronary artery
• Is relieved by anti-anginal drugs
17. 3.3. Variant Angina ? .
(Prinzmetal)
Chest pain at rest due to coronaryChest pain at rest due to coronary
artery spasmartery spasm
ECG changes:ECG changes:
Acute elevation ofAcute elevation of STST segmentsegment
The baseline ECG
With chest pain , marked ST
segment elevation
Return of the ST segment to the
baseline after nitroglycerin
administration
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18. Management of Angina ?
Management of Stable Angina
Management of UnstableManagement of Unstable AnginaAngina
Management of Variant Angina
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19. Management of Stable
Angina ?
1-1- General measures.General measures.
2-2- Drug Treatment.Drug Treatment.
3-3- Coronary artery revascularization.Coronary artery revascularization.
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20. Stop smokingStop smoking Reduce weightReduce weight
Treat Hypertension ,Treat Hypertension ,
Hypercholestrolimia andHypercholestrolimia and
DiabetesDiabetes
AVOIDAVOID
SevereSevere
exertionexertion Heavy mealHeavy meal EmotionsEmotions Cold WeatherCold Weather
General measures
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•Graduated exercise may open new
collaterals
21. a. For an acute attacka. For an acute attack
b. For immediate pre-exertionalb. For immediate pre-exertional
prophylaxisprophylaxis
c. For long-term prophylaxisc. For long-term prophylaxis
d. Antiplatelet therapy.d. Antiplatelet therapy.
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22. Treatment of an acute attack of angina
Sublingual nitroglycerin (0.5 mg ) or isosorbideSublingual nitroglycerin (0.5 mg ) or isosorbide
dinitrate (5 mg )dinitrate (5 mg ) or
Oral spray nitroglycerin (0.4 mg/metered dose),Oral spray nitroglycerin (0.4 mg/metered dose),
isosorbide dinitrate(1.25 mg/metered dose)isosorbide dinitrate(1.25 mg/metered dose)
Relief within 1-3 min. Persistence of pain
Repeat nitroglycerin at 5 min.Repeat nitroglycerin at 5 min.
interval (3 tab. max.)interval (3 tab. max.)
Relief not relieved
InfarctionHOSPITALIZATION
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23. Immediate pre-exertional prophylaxis of AnginaImmediate pre-exertional prophylaxis of Angina
Sublingual nitroglycerin (0.5 mg) or isorbide
dinitrate (5 mg) should be taken 5 min. before effort.
For Long term prophylaxis:For Long term prophylaxis:
Long acting nitrates, Ca++
channel blockers,
β-blockers or combinations of these drugs.
Antiplatelet therapy:Antiplatelet therapy:
Aspirin in small dose (75-150 mg daily orally)Aspirin in small dose (75-150 mg daily orally)
or Dipyridamole (75 mg t.d.s orally)or Dipyridamole (75 mg t.d.s orally)
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24. Coronary artery bypass graftingCoronary artery bypass grafting
(CABG)(CABG)
Percutaneous Transluminal coronaryPercutaneous Transluminal coronary
Angioplasty (PTCA)Angioplasty (PTCA)
For patients not responding to adequateFor patients not responding to adequate
medical therapymedical therapy
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25. Management of Unstable Angina
NitrateNitrate
++
ββ-blocker-blocker
++
Aspirin (low dose) and/orAspirin (low dose) and/or
Heparin orHeparin or
Thrombolytic (stryptokinase)Thrombolytic (stryptokinase)
to minimize risk of infarctionto minimize risk of infarction
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26. Management of Variant
Angina
Nitrates and/or Ca++Nitrates and/or Ca++
Channel blockersChannel blockers
For the acute attack &For the acute attack &
prophylaxisprophylaxis
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27. Benefit of Drug Therapy ?
• .
Normal
supply demand
Angina
supply
demand
Drug Therapy
supply
demand
28. Treatment
• Aims:
Relief of symptoms
Slowing progression of the disease
Reduction of future events like myocardial
infarction
29. What are the antianginal drugs?
Organic nitrates.
Calcium channel blockers.
β- adrenoceptor blockers.
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30.
31. P-treatment ?:
1- Bed rest.
2- Diet control ( low fat ).
3- Quit smoking.
4- Drug treatment.
5- follow up
Hyperzahranism WWW.SMSO.CC 31
34. Organic nitrates
Pro drugs release NO
↑ Levels of intracellular cGMP
Dephosphorylation of mysosin light chain
↓ Cytosolic calcium
Relaxation of smooth muscle
EDRF –endothelium derived relaxing factor is NO
35.
36. Cellular Mechanism of Vasodilatation
NitratesNitrates Formation of NitricFormation of Nitric
oxide (NO)oxide (NO)
Activation of GuanylateActivation of Guanylate
cyclasecyclase
Synthesis ofSynthesis of
cyclic GMPcyclic GMP
Relaxation of Vascular smoothRelaxation of Vascular smooth
musclesmuscles
36
N.B. (-SH) groups are required
for formation of NO.
37. Effect of Nitrates :Effect of Nitrates :
On Stable Angina :On Stable Angina :
Venodilatation Arteriolar
dilatation
PreloadPreload AfterloadAfterload
Myocardial OxygenMyocardial Oxygen
demanddemand
2- Redistribution of coronary flow towards subendocardium
3- Dilatation of coronary collateral vessels.
1-1-
38. On Variant Angina :On Variant Angina :
Relax smooth muscles of the epicardial
coronaries → relieve coronary artery
spasm
On Unstable Angina :On Unstable Angina :
Dilatation of epicardial coronary arteries +
reducing O2 demands
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39. Preparations :
Short actingShort acting
For acute attacksFor acute attacks
Long actingLong acting
For antianginal prophylaxisFor antianginal prophylaxis
NitroglycerinNitroglycerin
(sublingual, buccal(sublingual, buccal
spray)spray)
IsosorbideIsosorbide
dinitrate(sublingual,dinitrate(sublingual,
buccal spray)buccal spray)
NitroglycerinNitroglycerin
oral SR (6.25-12mg) 2-4 times/daoral SR (6.25-12mg) 2-4 times/da
- 2% ointment (1-1.5 inch/4hrs)- 2% ointment (1-1.5 inch/4hrs)
- patches (1 patch=25mg)/day- patches (1 patch=25mg)/day
Isosorbide dinitrate (oral) 10-40mgIsosorbide dinitrate (oral) 10-40mg
t.d.s.t.d.s.
Isosorbide mononitrate (oral)Isosorbide mononitrate (oral)
20mg/12 hrs.20mg/12 hrs.
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40. Duration of Action of Various Preparations of
Organic Nitrates
Preparation
Duration of
action
" Short-acting"
1-Nitroglycerin
2- Isosorbide dinitrate
a) Sublingual
b) Spray
a) Sublingual
b) Spray
10-30 min
10-30 min
Up to 60 min.
1.5 hours
" Long-acting"
1-Nitroglycerin
2- Isosorbide dinitrate
3-Isosorbide mononitrate
a) Oral; sustained release
b) Ointment
c) Transdermal patches
Oral
Oral
4-8 hours
3-6 hours
8-12 hours
4-6 hours
6-10 hours
41. How does it occur?
The main limitation of chronic nitrate therapy is
TOLERANCE
SH groups in vessel wall
oxidized by constant exposure to nitrates,
this prevents the production of NO
hence stimulation of Guanylate cyclase.
Tolerance to the antianginal effect occurs as a result of
chronic administration
41
“NITRATE FREE INTERVAL” of 8-10 hrs reduces or prevents development
of nitrate tolerance.
42. Adverse Reactions :Adverse Reactions :
1- Postural Hypotension &1- Postural Hypotension &
SyncopeSyncope
2- Tachycardia2- Tachycardia
5- Throbbing Headache5- Throbbing Headache
4- Facial Flushing4- Facial Flushing
3- Drug Rash3- Drug Rash
6- Prolonged high dose6- Prolonged high dose
MethaemoglobinaemiaMethaemoglobinaemia
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46. β-blockers are effective in STABLE & UNSTABLE angina
In contrast they are not useful for
vasospastic angina (Variant) {Prinzmetal}& may
worsen the condition. This deleterious effect is likely
due to an increase in coronary resistance caused by the
unopposed effects of catecholamines acting at α-
adrenoceptors.
47. ∀↑ Heart rate
∀↑ Contractility
∀↑ Preload
∀↑ Afterload
∀↓ Coronary flow
∀↓ Regional
myocardial blood flow
↑
O2
De
ma
n d
↓
O2
S
u p
p
l y
β-Blockers/Ca2+
channel
blockers
Nitrates/Ca2+
channel
blockers
Nitrates/Ca2+
channel
blockers/antithrombotics/
statins
HEART
48. The effectiveness ofThe effectiveness of ββ-adrenoceptor blockers in the treatment-adrenoceptor blockers in the treatment
of exertional angina is attributable to a fall in myocardial Oof exertional angina is attributable to a fall in myocardial O22
requirement at rest & during exertion due to :requirement at rest & during exertion due to :
1- A -ve chronotropic effect (particularly during exercise).1- A -ve chronotropic effect (particularly during exercise).
2- A -ve inotropic effect.2- A -ve inotropic effect.
3- A reduction in arterial blood pressure (particularly systolic3- A reduction in arterial blood pressure (particularly systolic
pressure) during exercise.pressure) during exercise.
Mechanism of antianginal action:Mechanism of antianginal action:
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49. 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
50. Adverse ReactionsAdverse Reactions ::
CHFCHF A-V blockA-V block BronchospasmBronchospasm
ColdCold
extremitiesextremities Worsening symptomsWorsening symptoms
of PVDof PVD
HypotensionHypotension
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51. Fatigue &Fatigue &
weaknessweakness
Mask signs ofMask signs of
HypoglycemiaHypoglycemia
Nightmares , Hallucinations ,Nightmares , Hallucinations ,
Depression.Depression.
Plasma Triglycerides & HDLPlasma Triglycerides & HDL
CholesterolCholesterol Discontinuation after longDiscontinuation after long
ttt exacerbates Anginattt exacerbates Angina
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Adverse ReactionsAdverse Reactions ::
52. CHFCHF A-V blockA-V block
PeripheralPeripheral
Vascular diseaseVascular disease
HypotensionHypotension
Contraindications :Contraindications :
BronchialBronchial
asthmaasthma
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53. Verapamil (80-160 mg) /8 hr(80-160 mg) /8 hr
Diltiazem (60-120 mg) /8 hr(60-120 mg) /8 hr
Dihydropyridine group
Nifedipine (10-40mg) /8 hr
Amlodipine 5mg/day
Used in treatment of all types of angina.
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54.
55.
56. BlockBlock
Voltage -dependent calcium channelsVoltage -dependent calcium channels
(L-type) in cardiac and smooth muscles.(L-type) in cardiac and smooth muscles.
CC
AA
LL
CICI
UU
MM
57. Mechanism of anti-anginal action :Mechanism of anti-anginal action :
1 - Coronary artery dilatation and relief of
coronary spasm (variant angina)
•(Verapamil & Diltiazem)
•Decrease HR.
•Decrease contractility
•Decrease AV conductivity
•Arteriolar dilatation Vascular
resistance
Afterload
2 -Decrease myocardial O2 demand due to:
58.
59. 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
63. Misc. Antianginal Drugs
• Potassium channel openers:
• Types of K ch: Voltage gated , Ca activated, ATP activated
• Nicorandil: Newer agent, Activates ATP sensitive K ch ( K ATP ) &
hyperpolarizes VSM.
• Decreases pre- & afterload & produce coronary dilation. Has
nitrate –like moiety, also exerts nitrate like effect. Thus
arteriodilator + venodilator. But no tolerance.
64. Ranolazine:
-Reserve agent for treatment of chronic, resistant angina
-Inhibits cardiac late Na+
current
Decreases cardiac contractility
-No change in HR, BP
-Prolongs QT interval so it is contraindicated with drugs
that increase QT interval
65.
66. Ivabradine
Direct bradycardic agent or ‘pure’ HR lowering agent
• Blocks hyperpolarization activated current (If ) through Na ch‐
present in SA node which get activated during early part of slow
diastolic depolarization (Ph4) during ischaemic episodes .
HR decreased and oxygen demand decreases.
No negative inotropic or lusitropic effect
No fall in BP
67.
68. Cytoprotective agents
Trimetazidine:
Acts non haemodynamically prevents degradation of‐
membrane unsaturated fatty acids by lipid
peroxidation
Reduces myocardial O2 demand
Also inhibits superoxide cytotoxicity protects heart‐
from harmful effects of ischaemia.
70. Define angina pectoris:
Chest pain resulting from a myocardial oxygen
demand that is not met by adequate oxygen
supply; seen in patient with myocardial ischemia
71. What type of angina is caused by
spontaneous coronary vasospasm?
Prinzmetal (variant) angina
72. What type of angina is caused by
atherosclerosis of coronary vessels
and is precipitated by exertion?
Classic angina
73. What type of angina can be acute in
onset and is caused by platelet
aggregation?
Unstable angina
74. What two mechanistic strategies are
used in the treatment of angina?
Increase oxygen supply to the myocardium
Decrease myocardial oxygen demand
75. What types of drugs can increase oxygen
supply?
Nitrates; calcium channel blockers (CCBs)
76. What types of drugs can decrease
oxygen demand?
Nitrates; CCBs; β-blockers
77. What is the drug of choice for immediate
relief of anginal symptoms?
Sublingual nitroglycerin (NT G)
78. What is the mechanism of action of
nitrates?
Nitrates form nitrites; nitrites form nitric oxide (NO);
NO activates guanylyl cyclase to increase cGMP;
increased cGMP leads to increased relaxation of
vascular smooth muscle
79. How does cGMP lead to relaxation of
vascular smooth muscle?
Causes dephosphorylation of myosin light chains
80. How do nitrates increase oxygen
supply?
Dilation of coronary vessels which leads to increased
blood supply
81. How do nitrates decrease oxygen
demand?
Dilation of large veins which leads to preload
reduction; decreased preload reduces the amount
of work done by the heart; decreased amount of
work results in decreased myocardial oxygen
requirement
82. What are the adverse effects of
nitrates?
Headache; hypotension; reflex tachycardia; facial
flushing; metnemoglobinemia
83. Why must patients have at least a 10- to 12-
hour “nitrate -free” interval every day?
Tolerance (tachyphylaxis) develops to nitrates if given
on a continuous (around-the-clock) basis
86. What are the common formulations
of nitrates?
NTG; isosorbide mononitrate; isosorbide dinitrate
87. What is the time to peak effect of
sublingual NTG?
2 minutes
88. What is the dosing frequency of sublingual
NTG during an anginal episode?
Every 5 minutes for a maximum of three doses
89. How do β-blockers work in the treatment of
angina?
Inhibition of α1-adrenoceptors which leads to
decreased CO, HR, and force of contraction,
thereby reducing the workload of the heart and
oxygen demand
91. New mechanistic approaches to
chronic stable angina
Sinus node inhibition (ivabradine)
Late INa inhibition (ranolazine)
Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine)
Preconditioning (nicorandil)
O
H3C O
H3C O
N
CH3
O CH3
O CH3
N
O
N
CH3
H
CH3
CH3
O
O H
N
SO2 NHN
O
O NO2
H
N
O
OHCH3
CH3
OCH3
H
N N N O
N
N
92. For each of the following CCBs, state
whether their primary effects are on
the myocardium or peripheral
vasculature
Verapamil
Myocardium (greater negative inotropic effects)
94. How do CCBs work in the treatment
of angina?
Block vascular L-type calcium channels which leads to
decreased heart contractility and increased
vasodilation
How does it occur?
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.e.g. isosorbide dinitrate is given at 7am, noon and 5pm; trnsdermal patches should be used for about 12 hrs daily
In contrast they are not useful for
vasospastic angina (Variant) {Prinzmetal}& may worsen the condition. This deleterious effect is likely due to an increase in coronary resistance caused by the unopposed effects of catecholamines acting at -adrenoceptors.
Voltage gated {vasular & other SM}, Ca activated, ATP activated{ cardiac ms & Beta cells of pancreas: opening causes hyperpolarization & relaxation of cardiac SM; others
Effects the Na+ dependent Ca2+ channels and prevents Ca2+ overload that causes cardiac ischemia
• PK: Absb PO, partly metab in liver , mainly
excreted unchanged in urine.
• A/E : GI irritation,fatigue,dizziness,reversible
parkinsonism in elderly.Use : stable angina
The following slides will present results of clinical trials with new antianginal drugs shown here.1-5