A presentation outlining the causes of angina, mechanism of action of various anti-anginal drugs, their uses and side effects alongwith contraindications

1. ANTI-
ANGINAL
DRUGS
DR. KARUN KUMAR
JUNIOR RESIDENT-I
DEPARTMENT OF PHARMACOLOGY

2. What is Angina ?
▪Symptom complex caused by transient myocardial ischemia
and constitutes a “clinical syndrome” rather than a disease.
▪The term derives from the Latin angina ("infection of the
throat") from the Greek ankhonē ("strangling"), and the
Latin pectus ("chest"), and can therefore be translated as "a
strangling feeling in the chest".

3. ▪Intermittent chest pain
caused by transient,
reversible, myocardial
ischemia
▪Pain is relieved by rest or by
taking nitrates.

4. PATHOPHYSIOLOGY
▪Imbalance between
myocardial oxygen
supply and demand
▪Most common cause
 Coronary atheroma
(esp. in Left anterior
descending artery)

5. Due to inadequacy of ischemic
left ventricle, the end diastolic
left ventricular pressure rises
from about 5 to 25 mm Hg-
produces subendocardial
‘crunch’ during diastole and
aggravates the ischemia in this
region.

6. SITE OF PAIN
▪Pain is typically substernal
▪It is described as a constricting
sensation, pressure like feeling or
tightness in the chest and is
frequently transmitted to the neck,
left shoulder, left arm or lower jaw.
▪Occasionally, it radiates to the
back or down the right arm.

7. TYPES
▪Typical/stable angina
▪Prinzmetal/Variant angina
▪Unstable/Crescendo angina
▪Angina with normal coronary
arteries
▪Microvascular angina

8. STABLE ANGINA
▪Also known as effort angina
▪It is usually associated with a fixed atherosclerotic
narrowing (>=75%) of one or more coronary arteries
▪With this degree of critical stenosis, myocardial oxygen
supply may be sufficient under basal conditions but cannot
be adequately augmented to meet increased requirements

9. ▪Attacks are predictably provoked by exercise, emotion
(anger, fear), sexual intercourse, and subside when the
increased energy demand is withdrawn.
▪Stress test shows ST segment depression
▪Pain lasts from 30 seconds to 30 minutes and is relieved by
rest or nitroglycerine

10. VARIANT ANGINA (VA)
▪Temporary increase in coronary vascular tone (vasospasm)
causing a marked, but transient reduction in luminal
diameter[1]
▪Patients are predominantly younger women[1]
▪It has been associated with vasospastic disorders such as
Raynaud's phenomenon and migraine headaches.[1]
1. Keller KB, Lemberg L. Prinzmetal’s angina. Am J Crit Care. 2004;13(4):350-4

11. ▪As it is not a "demand"- induced symptom, but rather a
supply (vasospastic) abnormality, exercise treadmill stress
testing is of no value in the diagnosis of VA.
▪The most sensitive and specific test for VA is the
administration of ergonovine intravenously.
▪50 micrograms of Ergonovine is given at 5-minute intervals
until a positive result or a maximum dose of 400 microg
has been administered.
▪When positive, the symptoms and associated ST-segment
elevation should be present.

12. ▪Nitroglycerin rapidly reverses the effects of ergonovine if
refractory spasm occurs.
▪Medical therapy classically employs vasodilator drugs,
which include nitrates and calcium channel blockers.
▪Beta-Blockers and large doses of aspirin are contraindicated
in VA.

13. UNSTABLE ANGINA
▪ Also known as crescendo angina or pre-infarction angina
▪ It has at least one of these three features:[2]
1) It occurs at rest (or minimal exertion), usually lasting >10 min;
2) It is severe and of new onset (i.e., within the prior 4–6 weeks);
3) It occurs with a crescendo pattern (i.e., distinctly more severe,
prolonged, or frequent than previously).
2. Daniel, 2010. http://kardzmed.com/kardz/health-life/item/240-angina-pectoris

14. ▪It is characterized by increased frequency of pain,
precipitated by progressively less exertion; the episodes also
tend to be more intense and longer lasting than stable
angina
▪It is associated with plaque disruption
▪64% of all episodes occurring between 10 PM and 8 AM,
this nocturnal preponderance being evident for episodes
with or without a preceding increase in heart rate. [3]
3. Patel DJ, Knight CJ, Holdright DR, Mulcahy, Clarke D, Wright C et al. Pathophysiology of
Transient Myocardial Ischemia in Acute Coronary Syndromes. 1996.

15. ANGINA WITH NORMAL CORONARY
ARTERIES
▪ Normal or nonobstructive coronary disease at angiography is not
uncommon and occurs in 10% of women presenting with ST-
segment elevation myocardial infarction compared with 6% in
men.[4]
▪ Randomized placebo-controlled studies have demonstrated that
tricyclic antidepressants, beta-blockers, angiotensin-converting
enzyme inhibitors, L-arginine, statins, and exercise may relieve
symptoms, vascular dysfunction, or both; however, longer-term
studies evaluating cardiac event rates need to be performed.[4]
4. Bugiardini R, Bairy CNM. Angina with “normal” coronary arteries:a changing philosophy. JAMA.
2005;293(4):477-84.

16. MICROVASCULAR ANGINA
▪Also known as angina syndrome X.
▪Cardiac syndrome X defines patients with typical chest pain,
transient ischaemic ST segment changes during effort and
normal coronary angiograms[5]
▪It appears to be due to spasm in the tiny blood vessels of
the heart arms, and legs[6]
▪Patients cope well with this type of angina and have very
few long-term side effects[6]
5. Kaski JC, Perez RF. Rev Esp Cardiol. 2002;55 Suppl 1:10-6.
6. http://www.texasheartinstitute.org/hic/topics/cond/angina.cfm

17. MANAGEMENT
NON-PHARMACOLOGIC MEASURES
A)Explanation and reassurance
B)Do not smoke
C)Aim for ideal body weight
D)Take regular exercise (May promote
collateral vessels)
E) Avoid severe exertion and vigorous
exercise
F) Correction of established risk factors

18. PRINCIPAL THERAPEUTIC GOAL
Heart rate
Contractility
Preload
Afterload
Beta blockers
Calcium channel
blockers (CCBs)
Organic nitrates
Calcium channel
blockers
Coronary blood
flow
Regional
myocardial
blood flow
Vasodilators (esp.
CCBs), statins, anti-
thrombotics, stents,
angioplasty, CABG
surgery
Oxygen
demand
Oxygen
supply
Balance
Ischemia
=
>
Agents decreasing myocardial oxygen
demand Agents increasing myocardial blood flow

19. MEDICAL MANAGEMENT
▪1) ACUTE ATTACK:- NITROGLYCERIN AND ISOSORBIDE
DINITRATE
▪2) FIRST LINE DRUGS:- NITRATES AND BETA BLOCKERS
▪3) SECOND LINE DRUGS:- CALCIUM CHANNEL BLOCKERS
AND POTASSIUM CHANNEL OPENERS

20. NITRATES
▪A) CLASSIFICATION:-
▪i) Short acting:- Glyceryl trinitrate[GTN] (sublingual),
Isosorbide dinitrate[IDN] (sublingual), Amyl nitrite (shortest
acting)
▪ii) Long acting:- Isosorbide dinitrate (oral), Isosorbide
mononitrate, Erythritol tetranitrate, Pentaerythritol
tetranitrate (longest acting)
B) PREPARATION AND DOSE:- GTN (Angised)-0.5 mg tab.; IDN
(Sorbitrate) -5, 10 mg tab.

21. MECHANISM OF ACTION
Rapidly denitrated in smooth muscle cell
Nitric oxide released
Activation of guanylyl cyclase
Increased cyclic guanosine monophosphate (cGMP)
Dephosphorylation of myosin light chain kinase (MLCK)

23. CORONARY STEAL PHENOMENON

24. ADVERSE EFFECTS
▪These are mostly due to vasodilatation[7]
▪Headache is the most common side effect of nitrates; often
dose-related and reported by up to 82% of patients in
placebo-controlled trials[8]
▪Nearly 10% of patients are unable to tolerate nitrates due to
disabling headaches or dizziness[8]

25. ▪Other adverse effects are tachycardia, orthostatic
hypotension and methemoglobinemia[7]
▪Rashes are rare, though relatively more common with
pentaerythritol tetranitrate[7]
7. Tripathi KD. Antianginal and other anti-ischaemic drugs. In: Tripathi M, editor. Essentials
of Medical Pharmacology. 7th ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd;
2013. p. 542.
8. Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf.
2006;5(5):667-74.

26. TACHYPHYLAXIS AND CONTRAINDICATIONS
▪Tolerance can develop to nitrates on chronic use (NOT seen
with sublingual use). Thus, for clinical use, at least 8 hours
of drug free period per day is required.
▪Administration of nitrates is contraindicated with
concomitant use of phosphodiesterase-5 inhibitors used for
the treatment of erectile dysfunction, as combination
therapy may lead to profound hypotension and even
death.[8]

27. BETA BLOCKERS
A) CLASSIFICATION:-
i) Non-selective:-Propranolol, Sotalol, Timolol, Pindolol,
Labetalol, Carvedilol
ii) Cardioselective:-Metoprolol, Atenolol, Acebutolol,
Bisoprolol, Esmolol, Betaxolol, Celiprolol, Nebivolol
B) Preparation and Dose:-Pindolol(Visken)-10, 15 mg tab.;
Dose-10-30 mg per day; Metoprolol(Betaloc)-25, 50, 100 mg
tab.; Dose-100-400 mg day

28. MECHANISM OF ACTION
▪Reduction of heart rate and blood pressure  Decreased
myocardial oxygen consumption  Improved exercise
tolerance
▪Beta-Blockers provide similar clinical outcomes and are
associated with fewer adverse events than calcium
antagonists in randomized trials of patients who have stable
angina.[9]
9. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, et al., 1999. Meta-
analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable
angina. JAMA. 1999;281(20):1927-36

29. ADVERSE EFFECTS
1. Bradycardia
2. Bronchoconstriction
3. Claudication
4. Plasma lipid profile altered
5. Vivid dreams and nightmares
6. Reduced sensitivity to hypoglycemia
7. Fatigue
8. Erectile dysfunction

30. CONTRAINDICATIONS
1. Asthma
2. Chronic obstructive
pulmonary disease
3. Diabetes mellitus
4. Severe bradycardia
5. Bradycardia-tachycardia
syndrome (variant of sick
sinus syndrome)
6. Atrioventricular
blockade
7. Unstable left
ventricular failure
8. Prinzmetal’s angina
9. Peripheral vascular
disease

31. CALCIUM CHANNEL BLOCKERS
A) CLASSIFICATION:-
i) Phenylalkylamine:-Verapamil
ii) Benzothiazepine:-Diltiazem
iii) Dihydropyridines:- Nifedipine, Felodipine, Amlodipine,
Nitrendepine, Nimodipine, Lacidipine, Lercanidipine,
Benidipine, Isradipine, Nicardipine, Nisoldipine
B) Preparations and Dose-Verapamil(Calaptin)–40, 80 mg
tab., Dose – 40-160 mg TDS oral; Diltiazem(Dilzem) – 30, 60
mg tab., Dose – 30-60 mg TDS-QID oral

32. MECHANISM OF ACTION
Block voltage gated L-type calcium channels
Drugs bind more effectively to open channels and inactivated channels
Reduces the frequency of opening in response to depolarization
Decrease in transmembrane calcium current
Decrease in contractility throughout the heart and decrease in sinus
node pacemaker rate and atrioventricular node conduction velocity

34. ADVERSE EFFECTS
▪Well tolerated, associated with few side effects.
▪In recent trials
▪Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT)
▪International Verapamil Slow-Release/Trandolapril Study
(INVEST)
▪Controlled Onset Verapamil Investigation of Cardiovascular
Endpoints (CONVINCE) study
no association with precipitation of cardiovascular events
found. [10]

35. ▪Dihydropyridines may cause reflex tachycardia, flushing,
headache, and ankle swelling. Diltiazem and verapamil
depress cardiac conduction and cause bradycardia, and
should not be given to people with heart block or treated
with a β blocker. Verapamil may cause constipation.[11]
10. Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med.
2004;116(1):35-43.
11. NICE Clinical Guidelines, No. 126. National Clinical Guidelines Centre (UK). Royal College
of Physicians (UK); 2011.

36. CONTRAINDICATIONS
▪ In patients with unstable angina, immediate-release short-acting
calcium channel blockers can increase the risk of adverse cardiac
events and therefore are contraindicated.[12]
▪ Calcium channel blockers do not reduce the risk of initial or
recurrent infarction or death when given routinely to patients with
acute myocardial infarction or unstable angina.[13]
12. Katzung BG. Vasodilators and the treatment of angina pectoris. In: Katzung BG, Masters
SB, Trevor AJ, editors. Basic and Clinical Pharmacology. 12th ed. India: McGraw-Hill; 2012. p.
205.
13. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction
and unstable angina: an overview. BMJ. 1989;299(6709):1187-92.

37. POTASSIUM CHANNEL OPENERS
A) CLASSIFICATION:- Nicorandil, Pinacidil, Cromakalim,
Minoxidil, Diazoxide
B) Preparation:-Nicorandil(Nikoran)5,10mg tabs.;Dose–5-20
mg BD
Nicorandil inhibits rest and effort angina unresponsive to
usual doses of calcium antagonist and oral nitrate.[14]

38. Use
Resistant angina
Adverse effects
Flushing, palpitation, weakness, headache, dizziness,
nausea, vomiting
Drug interactions
Sildenafil

39. MECHANISM OF ACTION
▪ Activation of ATP sensitive potassium channels 
Hyperpolarization of vascular smooth muscle
▪ NO donor  Increased cGMP  Relaxation of blood vessels
▪ Nicorandil is believed to exert cardioprotective action by stimulating
‘ischaemic preconditioning’ as a result of activation of
mitochondrial KATP channels (Ischaemic preconditioning is a
phenomenon in which brief periods of ischaemia and reperfusion
exert a cardioprotective effect on subsequent total vascular
occlusion)
14. Araki H, Hayata N, Matsuguchi T, Nakamura M. Effects of nicorandil on rest and effort angina unresponsive
to combination therapy with a calcium antagonist and oral nitrate. Clin Ther. 1987;9(2):174-82.

40. OTHER ANTI-ANGINAL DRUGS
1. DIPYRIDAMOLE:-
It inhibits platelet aggregation by potentiating
PGI2 and increasing cAMP in platelets.
It is not useful as an anti-anginal drug
(“coronary steal”) but is being employed for prophylaxis of
coronary and cerebral thrombosis in post-MI and post-
stroke patients, as well as to prevent thrombosis in
patients with prosthetic heart valves.
Preparation is Persantin (25, 75, 100 mg tab.)
and dose is 25 - 100 mg TDS

41. 2. TRIMETAZIDINE
It is used as an add on medication to conventional
therapy in angina and post-MI patients.
Mechanism of action
It causes inhibition of mitochondrial enzyme long
chain 3-ketoacyl thiolase (LC-3KAT)  Reduces fatty acid
metabolism in myocardium and increases glucose
metabolism  Shift back of substrate to glucose decreases
oxygen demand.

42. Side effects are gastric burning, dizziness, fatigue,
muscle cramps.
Other uses are visual disturbances, tinnitus,
Meniere’s disease.
Preparation:-Flavedon 20 mg tabs.; Dose- 20 mg
TDS

43. 3. RANOLAZINE
It is a newer antianginal drug used in prophylaxis of
angina
Mechanism of action-It acts by reducing a late
sodium current (INa) that facilitates calcium entry via the
sodium-calcium exchanger  Decreased intracellular
calcium concentration  Decreased cardiac contractility and
work
It also inhibits LC-3KAT

44. Adverse effects - Dizziness, weakness, constipation,
postural hypotension, headache and dyspepsia.
Drug interactions – Avoided in patients taking
CYP3A4 inhibitors.
Preparation - Ranozex 0.5 g SR tab.; Dose – 0.5 – 1
gm BD as SR tab

45. 4. IVABRADINE
It has been introduced recently.
Uses-
a) Chronic stable angina with sinus rhythm (patients in whom
beta blockers are contraindicated or they are intolerant to
beta blockers)
b) Inappropriate sinus tachycardia

46. Mechanism of action-Relatively selective If sodium
channel blocker that reduces cardiac rate by
inhibiting the hyperpolarization-activated sodium
channel in the sinoatrial node
Preparation – Ivabrad (5, 7.5 mg tab.)
Dose – Initially 5 mg BD, increase if needed to 7.5
mg BD

47. 5. OXYPHEDRINE
It improves myocardial metabolism so that heart can
sustain hypoxia better.
Preparation – Ildamen (8, 24 mg tab.)
Dose – 8-24 mg TDS oral
6. FASUDIL
Rho-kinase plays an important role in calcium
sensitization for vascular smooth muscle (VSMC) contraction and
may be involved in the inappropriate coronary vasoconstriction
during exercise-induced myocardial ischemia.[15]

48. It is an inhibitor of smooth muscle Rho kinase
which reduces coronary vasospasm in experimental animals.
In clinical trials in patients with coronary artery
disease, it has improved performance in stress tests.
15. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H et al. Anti-anginal
effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter
study. J Cardiovasc Pharmacol. 2002;40(5):751-61.

49. 7. ALLOPURINOL
Experimental evidence suggests that xanthine oxidase inhibitors reduce
myocardial oxygen consumption. Due to this fact, this class of inhibitors could
become a new treatment for ischaemia in patients with angina pectoris.[16]
The mechanism of the anti-ischemic effect of allopurinol could be
related to its reducing xanthine oxidase-induced oxidative stress.[17]
16. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on
exercise in patients with chronic stable angina: a randomised, placebo controlled crossover
trial. Lancet. 2010;375(9732):2161-7.
17. Rajendra NS, Ireland S, George J, Belch JJ, Lang CC, Struthers AD. J Am Coll Cardiol.
2011;58(8):820-8.

50. SURGICAL INTERVENTION
▪PCI (Percutaneous Coronary
Intervention)
▪CABG (Coronary Artery Bypass
Graft)

51. STABLE ANGINA
▪Drug of choice depends on individual patient’s response
▪In hypertensive patients, monotherapy with either slow-
release or long-acting calcium channel blockers or β
blockers may be adequate
▪In normotensive patients, long-acting nitrates may be
suitable.
▪Combination therapy has been found to be more effective
than monotherapy as can be clearly seen in the below
mentioned clinical trials:-

52. a) The combination of a calcium antagonist and a beta-
blocker is statistically more effective than either
monotherapy.[18]
b) The combination of trimetazidine with beta-blockers or
long-acting nitrates significantly improves exercise stress test
parameters and angina symptoms compared with
placebo.[19]
c) Trimetazidine is useful for combination therapy in patients
with stable angina insufficiently controlled by monotherapy
with a beta-blocker.[20]

53. 18. Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined
antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis. Coron
Artery Dis. 2002;13(8):427-36.
19. Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, Rumiantzeva EG, Fitileva TB.
Trimetazidine in Angina Combination Therapy--the TACT study: trimetazidine versus
conventional treatment in patients with stable angina pectoris in a randomized, placebo-
controlled, multicenter study. Am J Ther. 2005;12(1):35-42.
20. Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, et al.
Combination treatment in stable effort angina using trimetazidine and metoprolol: results
of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur
Heart J. 2001;22(24):2267-74.

54. VARIANT ANGINA
▪ Calcium channel blockers are extremely effective in preventing
coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinase
inhibitor are also useful for inhibiting coronary artery spasm.[21]
▪ Stent implantation in patients with recurrent variant angina
refractory to medical treatment may be an alternative treatment in
carefully selected, clinically unstable patients.[22]
21. Kusama Y, Kodani E, Nakagomi A, Otsuka T, Atarashi H, Kishida H, et al. Variant angina
and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J
Nippon Med Sch. 2011;78(1):4-12
22. Martí V, Ligero C, García J, Kastanis P, Guindo J, Domínguez de Rozas JM. Stent
implantation in variant angina refractory to medical treatment. Clin Cardiol.
2006;29(12):530-3.

55. UNSTABLE ANGINA
▪Aggressive antiplatelet therapy with Aspirin and Clopidogrel
is indicated.
▪In nonprior aspirin users, combination antithrombotic
therapy with aspirin plus anticoagulation significantly
reduces recurrent ischemic events in the early phase of
unstable angina[23]
▪If PCI with stenting is required, glycoprotein (GP) IIb/IIIa
inhibitors such as Abciximab, Eptifibatide or Tirofiban
should be added.

56. ▪In addition, therapy with nitroglycerin and β blockers should
be considered
▪Calcium channel blockers should be added in refractory
cases
▪Primary lipid-lowering and angiotensin converting enzyme
(ACE) inhibitor therapy should also be initiated.
23. Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I, et al. Combination
antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin
users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute
Coronary Syndromes Research Group. Circulation. 1994;89(1):81-8.

57. ▪ Consideration should be given to measuring serum levels of a
cardiac troponin (either T or I) and using intravenous GP IIb-IIIa
inhibitors and low-molecular-weight heparin in the standard
management of patients with unstable angina.[24]
▪ Nondrug therapies for unstable angina include intra-aortic balloon
counterpulsation, percutaneous transluminal coronary angioplasty,
and coronary-artery bypass surgery.[25]
24. Braunwald E, Califf RM, Cannon CP, Fox KA, Fuster V, Gibler WB, et al. Redefining
medical treatment in the management of unstable angina. Am J Med. 2000;108(1):41-53.
25. Spinler SA, Davis LE. Advances in the treatment of unstable angina pectoris. Clin Pharm.
1991;10(11):825-38.

58. REFRACTORY ANGINA
▪Clinical trials have shown that combined haemodynamic
and metabolic treatment is more effective than combined
haemodynamic therapy and is well tolerated.[26]
▪Haemodynamic agents are nitrates, β blockers and calcium
channel blockers.
▪Metabolic agents such as Trimetazidine or L-carnitine are a
new class of drugs that directly modify the use of energy
substrates in the heart, lessening ischaemic injury and
improving cardiac performance during ischaemia.[26]

59. ▪For patients with severe angina pectoris not responding to
combination therapy of a β-blocker with a nitrate, triple
therapy may be of advantage, although the number of
patients studied has been small.[27]
26. Jackson G. Combination therapy in angina: a review of combined haemodynamic
treatment and the role for combined haemodynamic and cardiac metabolic agents. Int J
Clin Pract. 2001;55(4):256-61.
27. W.E.M. Kok, F.C. Visser, and C.A. Visser. Combination and triple therapy in patients with
stable angina pectoris not adequately controlled by optimal β-blocker therapy. Neth Heart J.
2002;10(11):455-461.

60. THANK YOU