European society guidelines 2013 on disease . Antianginal drugs Stable coronary artery disease Mchanism of action of antianginal drug

2. WHAT SAY NEW GUIDELINES ?
Many alternatives for treating angina :
How to choose ?

4. A new name for the Guidelines that can be applied
to a wider and more realistic range of patients
“Stable angina pectoris”
2006
“Stable Coronary Artery Disease”
2013
This much broader term intended to include both symptomatic
and asymptomatic patients with a previous or present history
of confirmed or suspected stable CAD.

5. (i) Those having stable angina pectoris or other symptoms
felt to be related to CAD such as dyspnoea
(ii) Those previously symptomatic with known obstructive
or non-obstructive CAD, who have become asymptomatic
with treatment and need regular follow-up
(iii) Those who report symptoms for the first time and are
judged to already be in a chronic stable condition (for
instance because history-taking reveals that similar
symptoms were already present for several months).
Stable coronary artery disease

7. Meets all three of the following characteristics:
• substernal chest discomfort of characteristic
quality and duration;
• provoked by exertion or emotional stress;
• relieved by rest and/or nitrates within minutes.
Typical angina
Meets two of these characteristicsAtypical angina
(probable)
Lacks or meets only one or none of the
characteristics
Non-anginal
chest pain
(Definite)
Traditional clinical classification of chest pain

8. Ordinary activity does not cause angina such as walking and climbing
stairs. Angina with strenuous or rapid or prolonged exertion at work or
recreation.
Class I
Slight limitation of ordinary activity.
Angina on walking or climbing stairs rapidly, walking or stair climbing
after meals, or in cold, wind or under emotional stress, or only during
the first few hours after awakening. Walking more than two blocks on
the level and climbing more than one flight of ordinary stairs at a normal
pace and in normal conditions.
Class II
Marked limitation of ordinary physical activity.
Angina on walking one to two blocks (~100–200 m)on the level or one
flight of stairs in normal conditions and at a normal pace.
Class III
Inability to carry on any physical activity without discomfort' –
angina syndrome may be present at rest'.
Class IV
Classification of angina severity according to the Canadian Cardiovascular Society

9. Antianginal Drug
Relief of symptoms Improving prognosis
(Prevent cardiovascular events)
Feel better Live longer

10. Medical management of SCAD patients
“We recommend the old drugs as first
line treatment because they are cheap,
effective and available everywhere.”
“We have roughly the same level of evidence for all of the second line drugs and we
recommend that physicians also choose according to what is available in their
country.”
Angina relief Event prevention
• β-blockers and/or CCB
 Ivabradine
 Long-acting nitrates
 Nicorandil
 Ranolazine
 Trimetazidine
• Lifestyle management
• Control of risk factors
• Aspirin (if intolerance, consider clopidogrel)
• Statins
• Consider ACE inhibitors or ARBs
+ consider angio → PCI-stenting or
CABG
Short-acting nitrates, plus
1st line
2nd line

11. Medical management of SCAD
patients
Angina relief Event prevention
• β-blockers and/or CCB
Ivabradine
Long-acting nitrates
Nicorandil
Ranolazine
Trimetazidine
• Lifestyle management
• Control of risk factors
• Aspirin (if intolerance, consider clopidogrel)
• Statins
• Consider ACE inhibitors or ARBs
+ consider angio → PCI-
stenting or CABG
Short-acting nitrates, plus
1st line
2nd line
About revascularization,
chairmen hopes that “guidelines
will shift physicians’ practice so
that they consider optimal
medical treatment as their first
course of action in stable CAD
patients”.

12. Stable coronary artery
disease
Old and New Anti-anginal
Drugs

13. Old ( traditional ) anti-anginals
Drug class Vasodilation Heart rate Myocardial
contractility
Short acting
nitrate -
sublingual
Beta-blockers
Long-acting
nitrates
Calcium channel
blockers
DHP Amlodipine Non-DHP Diltiazem and Verapamil

14. Nitrates
Calcium channel blockers
Beta blockers
Calcium channel blockers

15. New mechanistic approaches to
myocardial ischemia
Metabolic modulation (trimetazidine)
Sinus node inhibition (ivabradine)
Late Na+ current inhibition (ranolazine)
Preconditioning (nicorandil)

16. Metabolic modulation (pFOX ) : trimetazidine
Trimetazidine : pFOX (partial fatty acid oxidation ) inhibitor

18. Ischemic Preconditioning
Myocardial Protection
There is general
consensus that
Mito K+
ATP channels
play a key role

19. Focus on ATP-sensitive K+ channels

20. MYOCARDIAL ISCHAEMIC
PRE-CONDITIONING
“Phenomenon by which a brief episode (s) of
myocardial ischaemia increases the ability of the
heart to tolerate a sbsequent prolonged period
of ischaemia”

21. IPC concept
Murry CE. Circulation 1986;74:1124-36
infarct surface
Control
Group
Preconditioning
Group
ischemia
brief ischemia
ischemia
reperfusion
induction
prolonged occlusion

22. Adenosine subtype 1 (A1) receptor
Ischemic stimulus
G protein and protein kinase C (PKC).
Opening of Mito K+
ATP channel
Cardio-protective effect
IPC involves a complex cascade of intracellular events
amplified
effector
?

23. Cardioprotective effect
Opening Mitochondrial ATP-K+ channels:
Mimic the cardioprotective effect of IPC without
inducing ischemia
Pharmacological preconditioning agents
Nicorandil mimics IPC

24. Preconditioning: Nicorandil
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
Activation of ATP-sensitive K+ channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
N O
O NO2
HN

25. Nicorandil :dual effects
The ATP-sensitive
K+ channels are
composed of
subunit proteins:
*an inwardly
rectifying K+
channel (KIR)
*a sulphonylurea
receptor (SUR)
Activation of ATP-sensitive K+ channels causes K+ efflux
and hyperpolarisation of the smooth muscle cell
membrane and closure of voltage-gated Ca2+ channels.
Closure of Ca2+ channels reduces intracellular levels of
Ca2+, resulting in relaxation of vascular smooth muscle
and dilation of systemic and coronary arterioles
The nitrate moiety produces
relaxation of vascular smooth
muscle with dilation of
systemic venous circulation
and epicardial coronary
arteries.

26. EFFECT OF MEDICATION
Preconditioning Preconditioning 
KATP channel blockersKATP channel openers
Sulfonylurea drugs:
Glibenclamide , gliclazide , glimepiride
NICORANDIL

27. Cardioprotective effects of
nicorandil

29. Adverse effects
Blood pressure and heart rate
Comorbidities & Contraindications
Drug costs & Drug-drug interactions
The ESC common strategy might be adjusted according to:-

30. Anti-anginal drugs.

31. Anti-anginal drugs.

32. Short-Acting Nitrates
SL Nitroglycerin & SL Isosorbide dinitrate
• Relief of pain, hemodynamic effect (10 mm Hg drop, ↑HR)
• Onset: 1-3 min, duration:10-30 min
• Prevention of attack: To be taken 5-10 min before the exertion
that possibly precipitate angina(activity after a meal, emotional
stress, sexual activity and in colder weather)
• Instructions to Patient:
o Sit immediately, place NTG/ISDN tablet under tongue
(standing promotes syncope, lying down enhances venous return
and heart work)
o Max three tablets over 15 min
o If pain persists >30 min →suspected ACS

33. Nitrate Tolerance Minimization
• Nitrate-free interval of 10-12 hours minimize
tolerance to therapeutic activity
• Lowest effective nitrate dose lower tolerance
• ß-blocker or CCB is given to provide anginal
protection during nitrate-free period
• Long-acting nitrates have no evidence of
causing tolerance to SL nitrates’ use

34. ISOSORBIDE DINITRATE & MONONITRATE
(ISDN & ISMN)
• ISDN oral formulation is used usually three
times a day especially in severe angina
Usually ISDN is taken at 7 AM, Noon & 5 PM to
allow 12 hr nitrate-free period
ISDN can be given twice/day in moderate
severity angina
• ISMN can be given once or twice/day
(early morning & 7 hrs later)
ISMN has better patient compliance

35. Sexual activity may trigger ischaemia, and
nitroglycerin prior to sexual intercourse
may be helpful as in other physical activity.
Sexual activity
Erectile dysfunction (ED)
Pharmacological therapy with PDE5 inhibitors
(sildenafil, tadalafil and vardenafil) are effective,
safe and well tolerated in men with stable CAD

36. All of the preparations of nitroglycerin
as well as isosorbide mononitrate and
isosorbide dinitrate, are absolute
contra-indications to the use of PDE5
inhibitors because of the risk of
synergistic effects on vasodilation,
causing hypotension and
haemodynamic collapse.
If a patient on a PDE5 inhibitor develops chest pain,
nitrates should not be administered in the first 24 hours
(sildenafil “viagra”, vardenafil “levitra”) to 48 hours
(tadalafil “cialis”).

37. Prostatic
problems
Erectile
dysfunction
Angina
α-adrenergic
blockers
PDE5 inhibitorsNitrates

38. β-Adrenergic Blockers
ß-blockers abrupt withdrawal can
be serious in severe CAD → ACS
*β - Blockers can be combined with CCBs ( DHPs:amlodipine ) to
control angina.
*Combination therapy of β -blockers with verapamil and diltiazem
(non-DHPs) should be avoided because of the risk of bradycardia or AV
block
Nevibolol and bisoprolol are partly secreted by the
kidney, whereas carvedilol and metoprolol are
metabolized by the liver, hence being safer in patients with
renal compromise.

39. Anti-anginal drugs should be started at very
low doses, with preferential use of drugs with
no- or limited impact on BP, such as
ivabradine (in patients with sinus rhythm),
ranolazine or trimetazidine.

40.  Although lowering the heart rate ,60 b.p.m. is an
important goal in the treatment of SCAD, patients
presenting with low heart rate should be treated
differently.
 Heart rate lowering drugs (β-blockers, ivabradine,heart
rate lowering CCBs) should be avoided or used with
caution and, if needed, started at very low doses.
 Anti-anginal drugs without heart lowering effects
should preferably be given.

41. Non-steroidal anti-inflammatory drugs
(NSAIDs) has been associated with an
increased risk for CV events
 In patients at increased CV risk in need of pain relief, it is
therefore recommended to commence with acetaminophen or
aspirin at the lowest efficacious dose, especially for short-term
needs.
 If adequate pain relief requires the use of NSAIDs, these agents
should be used in the lowest effective doses and for the shortest
possible duration.

43. BIShort-acting nitrates are recommended
AIFirst-line treatment is indicated with ß-blockers and/or
calcium channel blockers to control heart rate and
symptoms.
BIIaFor second-line treatment it is recommended to add
long-acting nitrates or ivabradine or nicorandil or
ranolazine,
according to heart rate, blood pressure and tolerance.
BIIbFor second-line treatment, trimetazidine may be
considered
CIAccording to comorbidities/tolerance it is indicated to
use second-line therapies as first-line treatment in
selected patients
Angina/ischaemia relief Class Level
2013 ESC guidelines on the management of SCAD

44. AILow-dose aspirin daily is recommended in all
SCAD patients.
BIClopidogrel is indicated as an alternative in case of
aspirin intolerance.
AIStatins are recommended in all SCAD patients.
AIIt is recommended to use ACE inhibitors (or ARBs)
if presence of other conditions (e.g. heart failure,
hypertension or
diabetes).
Event prevention Class Level
2013 ESC guidelines on the management of SCAD