new anti anginal drugs

1. {
RECENT ADVANCES IN
ISCHEMIC HEART
DISEASES
By Dr. Sachin R. Choudhari
JR 2, Dept. of Pharmacology
SVNGMC , Yavatmal

2.  INTRODUCTION
 WHAT IS ANGINA PECTORIS ???
 AVAILABLE TREATMENT
 OTHER ANTIANGINAL DRUGS
 NEED FOR NEW AGENTS
 RECENTS ADVANCES
 SUMMARY
OUTLINE…..

3.  An imbalance between the supply of oxygen and the
myocardial demand resulting in myocardial ischaemia
 Most common cause of cardiovascular morbidity and mortality
 Peak incidence of symptomatic IHD is age 50-60 (men)
and 60-70 (women)
 M>F
 MC cause of death worldwide by 2020
 Consist of Angina and Myocardial Infarction
INTRODUCTION

4.  Angina :
 Stable Angina
 Unstable Angina
 Variant Angina / Vasospastic Angina
 Myocardial infarction :
 STEMI
 NSTEMI

5.  Principal symptoms of patient with ischemic heart disease
 Manifested by sudden, severe, pressing substernal pain
that often radiates to the left shoulder and along the flexor
surface of the left arm
 Usually precipitated by exercise, excitement or a heavy
meal

6. Type of Angina
Pectoris
typical Stable
Angina
↓ coronary flow
,Occurs on physical
Exertion
(five minutes or less)
Unstable angina
Epicardial coronary
spasm & formation of
non-occlusive thrombi
Can Occurs at rest Heart
attack
(emergency)
Variant ,
vasospastic or
prinzmetal angina ..
Reversible
coronaryspasm
.. Occurs at rest
2%

7. RISK
FACTORS

8. SYPMTOMS

9.  ACUTE ANGINA :
 Rest
 Sublingual Nitroglycerine
 CHRONIC ANGINA :
 Long acting nitrates
 Beta blockers
 CCBs
 K+ channel opener
 pFOX inhibitors
CURRENT TREATMRNT
STRATEGY

11. 1. Nitrates :
a. Short acting : Glyceryl trinitrate
b. Long acting : Isosorbide dinitrate
Isosorbide mononitrate
Erythrityl tetranitrate
Pentaerythritol tetranitrate
2. Beta blockers : propranolol
Metoprolol
Atenolol
Antianginal drug :

12. 3. Calcium channel blockers :
a. Phenyl alkylamine : Verapamil
Gallopamil
b. Benzothiazepines : Diltiazem
c. Dihydropyridines : Nifedipine
Felodipine
Amlodipine
Nitrendipine
Nimodipine
Lacidipine
Lercanidipine
Benidipine
4. Potassium channel opener : Nicorandil

13.  Others :
1. Dipyridamole
2. Trimetazidine
3. Ranolazine
4. Ivabradine
5. Oxyphendrine

14.  Organic nitrates & nitrites
are simple nitric & nitrous
esters of glycerol.
 Cause a rapid decrease in
myocardial oxygen demand
 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.
Nitrates :

15. Reduced venous return
(Due to dilatation of the veins)
Decrease left ventricular volume
Decrease preload
Decrease workload
Decrease oxygen consumption
1st mechanism of action

16. Reduction on peripheral resistance
(Secondary to dilatation of aorta)
Decrease blood pressure
Decrease after load
Decrease workload
Decrease oxygen consumption
2nd mechanism of action :

17. Coronary artery dilatation
Decrease coronary bed resistance
(Relieved coronary vasospasm)
Increase coronary blood flow
Increase oxygen supply
3rd mechanism of action :

19.  Throbbing headache
 Flushing of the face
 Dizziness
 Postural Hypotension
 Tolerance
 Dependence
 Methemoglobinemia
Adverse effects :

20.  Decrease oxygen demands of the myocardium by
lowering the HR and contractility (decrease CO)
 Reduce PVR by direct vasodilatations of both arterial &
venous vessels
 Reduce the frequency and severity of anginal episodes
(when used in combination with nitrates)
 Improve survival in post MI patients and decrease the
risk of subsequent cardiac events & complications
Beta blockers :

21. Decrease heart rate & Contractility
Increase duration of diastole
Decrease workload
Increase coronary blood flow
Decrease O2 consumption
Increase oxygen supply
MOA:

22.  Decompensated congestive heart failure
 Asthma
 Complete heart block
Contraindications :

24.  Inhibit the entrance of Ca+2 into cardiac and smooth muscle
cells of the coronary and systemic arterial beds
 Produce some vasodilation (↓ PVR) and (-) inotropes
 By acting on AV node thus serving to control cardiac
rhythm
 They are useful in Prinzmetal angina in conjunction with
nitrates
Calcium channel blockers :

25.  Works mainly on the arteriolar vasculature decreasing after
load it has minimal effect of conduction or HR.
 Metabolized in the liver and excreted in both the urine & the
feces
 Causes less flushing, headache, hypotension and peripheral
edema
 Induces less reflex sympathetic stimulation
DHP other than Nifedipine:

26.  Main effect on cardiac conduction decreasing HR and
thereby O2 demand
 It has much more (-) inotropic effect than other Ca+2 channel
blockers
 It is a weak vasodilator
 Because of its focused myocardial effects it is not used as an
antianginal unless there is a tachyarrhythmia
 It interferes with digoxin levels causing elevated plasma levels
Verapamil :

27.  This agent function similarly to Verapamil however it is
more effective against Prinzmetal angina
 Dilates coronaries
 It has less effect on HR
 It has similar metabolism and side effects as Verapamil
Diltiazem :

28.  Nausea and vomiting
 Dizziness
 Flushing of the face
 Tachycardia : Due to hypotension
Adverse effect :

29.  Cardiogenic shock
 Recent myocardial infarction
 Heart failure
 Atria-ventricular block
Contraindications :

30. 1 . Nitrates and B-blockers :
 The additive efficacy is primarily a result of one drug
blocking the adverse effect of the other agent on net
myocardial oxygen consumption
 B-blockers : Blocks the reflex tachycardia associated with
nitrates
 Nitrates : Attenuate the increase in the left ventricular end
diastolic volume associated with B-lockers by increasing
venous capacitance
Combination therapy :

31.  Useful in the treatment of exertional angina that is not
controlled adequately with nitrates and B-blockers
 B-blockers : Attenuate reflex tachycardia produce by
nifedipine
 These two drugs produce decrease blood pressure
Calcium channel blockers +beta
blockers :

32.  Useful in severe vasospastic or exertional angina
(particularly in patient with exertional angina with
congestive heart failure and sick sinus syndrome)
 Nitrates reduce preload and after load
 Ca channels reduces the after load
 Net effect is on reduction of oxygen demand
Calcium channel blocker + nitrates :

33.  Useful in patients with exertional angina not controlled
by the administration of two types of anti-anginal agent
 Nifidipine – decrease after load
 Nitrates – decrease preload
 B-blockers – decrease heart rate & myocardial
contractility
Triple drugs: Nitrates + calcium
channel blockers + beta blocker

35.  Nicorandil , Pinacidil :
 Minoxidil and Diazoxide : older Drugs used in hypertension
 MOA:
 Activation of ATP sensitive K+ channel – hyperpolarization of vascular
smooth muscle – relaxation of Smooth muscle
 Also acts as NO donor and increases cGMP : Arterio-venous relaxation
 Dilatation of all types of coronary vessels
Potassium Channel Openers :

36.  Benefits in angina
(equipotent to nitrates, beta blockers and Ca++ channel blockers)
 Reduced angina frequency
 Increased exercise tolerance
 Ischaemic preconditioning for Myocardial stunning ,
arrhythmia and infarct size
(Mitochondrial K+ATP channel opening)
 ADRs: Flushing, palpitation, nausea, vomiting, aphthous ulcer

37.  Dipyridamole :
 Powerful coronary dilator
 dilates resistance vessels and abolishes autoregulation , but has no effect
on larger conducting coronary vessels
 pharmacological success but therapeutic failure : coronary steal
phenomenon
 By potentiating PGI2 and increasing cAMP in platelets, it enhances
antiaggregatory influences
 Not useful as an antianginal drug
 Employed for prophylaxis of coronary and cerebral thrombosis in post-
MI and post stroke patients
Other antianginal drugs :

38.  Labelled as pFOX (fatty acid oxidation pathway) inhibitor
 Inhibiting mitochondrial long chain 3-ketoacyl-CoAthiolase
(LC3-KAT)
 Reduces fatty acid metabolism and increases glucose metabolism in
myocardium
 Since oxidation of fatty acid requires more O2, shift back of substrate to
glucose would reduce O2 demand
 Limiting intracellular acidosis and Na+, Ca2+ accumulation during
ischaemia
 Protecting against Oxygen free radical induced membrane damage.
Trimetazidine

39.  No effect on HR and BP , both at rest as well as during
exercise
 Absorbed orally, partly metabolized and largely excreted
unchanged in urine
 t ½ : 6 hr.
 Widely used in France, Spain, some other European
countries and India, but not in the UK or USA
 Mostly an add on medication to conventional therapy
 Side effects : gastric burning, dizziness, fatigue and muscle
cramps

40.  Acts by inhibiting a late Na+ current (late INa) in the myocardium which
indirectly facilitates Ca2+ entry through Na+/Ca2+ exchanger
 Decrease calcium level decreases contractility
(cardioprotective effect)
 Sparing of fatty acid oxidation
 No effect on HR and BP, but prolongs exercise duration in angina patient
 Side effects : dizziness, weakness, constipation, postural hypotension,
headache and dyspepsia
Ranolazine :

41.  Several trial :
 Aim : To see efficacy in decreasing frequency of anginal
attacks and in prolonging exercise duration
1. MARISA : (2004)
2. CARISA : (2004)
3. ERICA : (2005)
4. MERLIN TIMI 36 : (2007)
 It is metabolized in liver by CYP3A4 and excreted in urine

42.  ‘Pure’ heart rate lowering antianginal drug (alternative to β blockers.)
 Significant action : Blockade of cardiac pacemaker (sino-atrial) cell ‘f’ channels,
which are ‘funny’ cation channels
 Resulting inward current (If) determines the slope of phase 4 depolarization
 results in heart rate reduction without any other electrophysiological or negative
inotropic effect
 HR reduction decreases cardiac O2 demand and prolongation of diastole tends to
improve myocardial perfusion (O2 supply)
Ivabradine :

43.  40% bioavailable due to first pass metabolism; degraded
by CYP3A4 and excreted in urine
 Side effects : Excess bradycardia , visual disturbance
 Indicated in chronic stable angina in patients with sinus
rhythm who are intolerant to β blockers
 Contraindications : HR < 60/min , AF

44.  claimed to improve myocardial metabolism so that heart
can sustain hypoxia better
 Its efficacy and status in coronary artery disease is not
defined
 Can diminish or alter taste sensation.
Oxyphedrine :

45. 1. Non selectivity
2. Affect hemodynamic parameters
3. Do not protect heart from stress induced adrenergic
effects
4. Beneficial effect is short-lived
5. Tolerance
Need for new drugs ???

46. Recent advances :

47.  It’s a CCB and similar to verapamil
 It reduces AV conduction
 Can be used as adjuvant for prophylaxis of angina
 Did not find much favor for clinical use
 Side effect : Dyguesia
Ladoflazine :

48.  A Rho-kinase inhibitor
 Rho kinase, an intracellular signaling molecule involved in the vascular
smooth muscle contractile response to agonists such as acetylcholine,
angiotensin II, endothelin, norepinephrine, platelet-derived growth factor,
and serotonin
 In phase 2 dose-finding trials : in Japanese patients : increased maximum
exercise time and time to the onset of > 1 mm ST-segment depression
compared with baseline
 Well tolerated
 Minimal effects on blood pressure or heart rate at rest or during exercise
FASUDIL :

49.  A new class of CAs, which selectively blocks T-type of Ca2+ channels
 Trial shows : statistically significant but clinically modest improveinent in
total ETT duration
 Decreases all hemodynamic parameters
 Associated with a significantly larger reduction in the number of weekly
anginal attacks
 Combination of mibefradil 50 mg and long-acting nitrates was well
tolerated
Mibefradil : (phase 2)

50.  A new generation of CCBs
 A more vascular selective action than currently available agents
 A potent vasodilator in peripheral, coronary, and cerebral arterial
beds and has substantially less myocardial depressant effect than
nifedipine
 Acute administration : resulted in a larger increase in coronary
blood flow and myocardial oxygen supply
 In acute studies, it appears to increase the myocardial oxygen
supply to demand ratio
Nicardipine :

51.  First dehydropyridine available in both oral and intravenous
dosage forms
 No or minimal effect on hemodynamic parameters
 Minimal negative inotropic or dromotropic effects even in
patients with existing left ventricular dysfunction
 May be useful for the treatment of angina in patients with
coexisting left ventricular dysfunction or borderline heart
failure

52.  Inhibitory effect on SA node leads to decrease HR
 It has negative chronotropic effect but little effect on AV
node
 Causes less reflex tachycardia
 Slow onset of action and for longer duration
Isradipine :

53.  New DHP CCB with rapid onset of action but ultra
short action
 It has selectivity for arterial smooth muscle as
compared to vein or myocardium
 Useful for controlling severe HT
 Need to be evaluated more antianginal drugs
Clevidipine :

54.  It’s a CCB that blocks L and N type of calcium channels
 It dilates both arterioels and venules and thus reduces
capillary pressure & reduces reflex tachycardia
 Used for HT
 Also reduces platelet activation
 Side effect : peripheral oedema
Cilnidipine :

55.  New second generation dihydropyridine calcium antagonist
 Causes very similar hemodynamic changes at rest and during exercise
 Marked decrease in systemic vascular resistance, which was accompanied
by an increase in cardiac index and stroke volume
 Major MOA is lowering of systemic vascular resistance
 Improves systolic cardiac function in patients with chronic stable angina
 Data also suggest an improvement in coronary blood flow during exercise
Elgodipine : (phase 1)

56.  New sydnonimine compound in clinical development
 As a prodrug, it is transformed into a nitric oxide releasing
metabolite in vivo
 In human study :Compared with placebo, blood pressure, heart
rate during exercise, and cardiac output during exercise showed no
significant change
 pirsidomine is an effective anti ischemic and antianginal agent
 Safety and efficacy need to be evaluated in large population
Pirsidomine: (phase 2)

57.  IHDs : Most common cause of cardiovascular morbidity
and mortality
 Nitrates, CCB and Beta blockers are widely used agents for
the Rx of Angina
 Currently available drugs are associated with many adverse
effects
 In past 20 years , treatment strategies are not much changed
since non availability of new drugs
 We need newer effective drugs which are specific in action
with less adverse effects
Summary :

58.  Fkishman et al. Additional Antianginal and Anti-Ischemic Efficacy of
Mibefradil in Patients Concomitantly Treated with Long-Acting Nitrates
for Chronic Stable Angina Pectoris. Clin.Cardiol. 2000;Vol 21:483-490
 Kuhn A , Carlsson J, Miketic S, Tebbe U. Hemodynamic and anti ischemic
effects of intravenous elgodipine, a new dihydropyridine calcium channel
blocker, in patients with chronic stable angina. Cardiovasc Drugs Ther.
1995 Aug;9(4):595-600.
 C. pepine. Nicardipine, A New Calcium Channel Blocker: Role for
Vascular Selectivity. Clin. Cardiol. 12, 240-246 (1998)
References :

59.  Basics and clinical pharmacology-13th edition;BG
Katzung & AJ Trevor
 Pharmacology for MBBS – 1st edition ; S K shrivastav
 Principals of pharmacology - 2nd edition ; HL sharma
& KK sharma
 Essential of medical pharmacology- 7th edition; KD
Tripathi