drugs for angina

1. Dr. Mani Bharti
Assistant prof.
Department Of Pharmacology
North DMC Medical college &
HRH, Delhi
PH1.28
Describe the mechanisms of action, types, doses, side
effects, indications and contraindications of the
drugs used in ischemic heart disease (stable,
unstable angina and myocardial infarction),
peripheral vascular disease

2. Learning Objectives
• Define angina pectoris & explain the various types of angina pectoris
describing their underlying pathology.
• Classify anti-anginal drugs, describe the mechanism of action,
pharmacological actions, adverse effects and therapeutic uses of nitrates
• Describe the routes of administration, doses and preparations of Nitrates
• Classify Calcium channel blockers, describe the mechanism of action,
pharmacological actions, adverse effects and therapeutic uses of calcium
channel blockers
• Describe the anti-anginal actions, adverse effects and contra-indications to
beta blockers
• Describe the mechanism of action, anti-anginal actions, adverse effects and
the indication for the use of potassium channel openers (nicorandil) in
angina pectoris
• Describe the anti-anginal actions and indications for the use of Ivabradine in
angina pectoris

4. pathophysiology

11. Stable angina:
•Also called “Effort
Angina”
•Discomfort is
precipitated by activity
•Minimal or no
symptoms at rest
•Symptoms disappear
after rest/cessation of
activity

12. Unstable angina:
•Also called “Crescendo
angina”
•Acute coronary syndrome in
which angina worsens
•Occurs at rest
•Severe and of acute onset
•Crescendo pain- pain
increases every time

14. Prinz metal's angina
•Prinz metal's angina is a variant form of angina with
normal coronary vessels or minimal atherosclerosis
•It is probably caused by spasm of coronary artery

15. •Symptoms
•What is the cause of
ischemia ?
either  oxygen
demand or  oxygen
supply
•Inadequate blood
supply and decreased
oxygen supply are
directly related to
blockade or narrowed
vessels

16. management

17. •Aim:
Relief of symptoms
Slowing progression of the disease
Reduction of future events like
myocardial infarction

18. Drugs:
1. For treatment of acute attacks:
Organic nitrates/nitrites
2. For prophylaxis:
Organic nitrates
Beta blockers
Calcium channel blockers
Ranolazine
K+ channel opener- Nicorandil

21. • Heart rate
• Contractility
• Preload
• Afterload
• Coronary flow
• Regional
myocardial blood
flow

O2
D
e
m
a
n
d

O2
S
u
p
p
l
y
-Blockers/Ca2+ channel
blockers
Nitrates/Ca2+ channel
blockers
Nitrates/Ca2+ channel
blockers/antithrombotics/
statins
HEART

22. Nitrates
(a) Short acting:
• Glyceryl trinitrate (GTN, Nitro-
glycerine)
(b) Long acting:
• Isosorbide dinitrate
• Isosorbide mononitrate,
• Erythrityl tetranitrate,
• Pentaerythritol tetranitrate

24. Organic nitrates
Pro drugs release NO
 Levels of intracellular cGMP
Dephosphorylation of mysosin light chain
 Cytosolic calcium
Relaxation of smooth muscle

25. •Relaxation of vascular smooth muscles-
vasodilatation
•NO-mediated guanylyl cyclase activation
inhibits platelet aggregation
•Relaxation of smooth muscles of bronchi
and GIT

26. L-Arginine
NO
NO Synthases
Neurotransmission
Vasomotor
effects
Immunomodulation
Endogenous NO pathway
nNOS
eNOS
iNOS

27. Three different forms of NO synthase are
found in humans:
1. Neuronal NOS (nNOS or NOS1)
2. Inducible NOS (iNOS or NOS2)
3. Endothelial NOS (eNOS or NOS3 or
cNOS) found in endothelium- responsible for
vasodilation

28. CVS Effects:
•Vasodilatation
•Venodilatation  decreases venous return
•Decreased chamber size &end-diastolic pressure
•Systemic vascular resistance changes minimally
•Systemic BP may fall slightly
•Dilatation of meningeal vessels can cause
headache

29. •HR-unchanged or may increase slightly
(reflex tachycardia)
•CO slightly reduced
•Even low doses can cause flushing.
•Higher doses-fall in BP
•Reflex tachycardia -restore the systemic BP

30. •Coronary blood flow may initially increase transiently
•Subsequently, due to decreased BP, may decrease
•Nitrates have dilating effect on large coronary vessels
•Increase collateral flow to ischemic areas
•Tend to normalize blood flow to subendocardial
regions of heart- redistribution of blood
•Dilate stenose and reduce vascular resistance in
ischemic areas

31. •Reduction in myocardial O2 consumption is caused by:
Reduced preload
Reduced afterload
  in end diastolic volume and LV filling pressure
•In platelets increases cGMP- inhibits aggregation
•Strongest factor for nitrate effect is peripheral pooling
Nitrates infused into coronary artery- no effect
Sublingual- produces effect

32. How myocardial O2 consumption can be determined?
Double product: HR  aortic pressure- approximate
measure of myocardial O2 consumption
Triple product: Aortic pressure  HR  Ejection time-
roughly proportional to myocardial O2 consumption
•Angina occurs at the same value of triple product
with or without nitrates, therefore;
•The beneficial effects of nitrates appear to be due to
decrease in oxygen consumption rather than increase
in oxygen supply

33. Pharmacokinetics:
•High first pass metabolism
•Administered sublingually.
Tolerance:
•Repeated doses lead to tolerance
•Dose spacing is necessary
•Reasons for tolerance:
 Capacity of vascular smooth muscle to convert
nitrates to NO – called true vascular tolerance

34. Uses:
A- Angina pectoris
B- Biliary cholic
C- Cyanide poisoning
D- MI(Dil ka daura)
E- Esophageal spasm
F- Failure (heart)

35. ADRs:
T-Tolerance, throbbing headache
D-dependance
S- skin rashes
R-reflex tachycardia
O-orthostatic hypotension
M-methhemoglobinia

36. •Headache
May disappear after continued use or,
Decrease dose
•Transient episodes of dizziness, weakness,
pallor etc- symptoms of postural hypotension
•Rash
•PDE5 inhibitor (sildenafil) and nitrates given
simultaneously can produce severe
hypotension

37. Cyanide poisoning

38. Administration of nitrates:
•Sublingual
•Oral: For prophylaxis, require high doses due to first
pass metabolism, isosorbide dinitrate (20 mg or more)
every 4 h or mononitrate (20 mg or more) OD or BD
•Cutaneous:
Ointment (2%) applied to 2.5-5 cm patch of skin

40. Transdermal nitrogycerine discs impregnated with
nitroglycerine polymer- gradual absorption and 24 h
plasma nitrate concentration
Onset is slow
Peak concentration in 1-2 h
Interrupt therapy for at least 8 h a day to prevent
tolerance

41. Calcium channel blockers
(a) Phenyl alkylamine: Verapamil
(b) Benzothiazepine: Diltiazem
(c) Dihydropyridines: Nifedipine, Felodipine,
Amlodipine, Nitrendipine, Nimodipine, Lacidipine,
Lercanidipine, Benidipine

43. MOA
 Ca2+ influx
Negative iono and chronotropic effects
Peripheral vasodilatation

44. Uses
• variant angina (spasm),
• exertional angina,
• unstable angina,
• MI,
• Hypertension,
• Arrhythmia

47. -Blockers:
 Effective in reducing severity and frequency of
exertional angina
 May worsen vasospastic angina- contraindicated
 Reduce myocardial O2 demand by reducing cardiac
work (-ve iono and chrono effects; decrease in BP
during rest and exercise)
 All -blockers are equally effective

49. Nicorandil
 Vasodilatory drug used to treat angina pectoris
 It has dual properties of a nitrate and ATP
sensitive K+ channel opener
 Nitrate action dilates the large coronary arteries
at low plasma concentrations

50.  At high concentrations it reduces coronary artery
resistance which is associated with opening of ATP
sensitive K+ channels
 Nicorandil has cardioprotective effect which
appears to be due to activation of ATP sensitive K+
channels
 ADRs: Flushing, palpitation, headache, mouth
ulcers, nausea and vomiting

51. Ranolazine:
 Reserve agent for treatment of chronic, resistant
angina
 Inhibits cardiac late Na+ current
 Effects the Na+ dependent Ca2+ channels and
prevents Ca2+ overload that causes cardiac
ischemia

52.  Decreases cardiac contractility
 No change in HR, BP
 Prolongs QT interval so it is contraindicated with
drugs that increase QT interval

53. Combination therapy
Nitrates and β-adrenoceptors blockers.
Calcium channel blockers and β-adrenoceptor
blockers .? ?
Calcium channel blockers and nitrates.
Calcium channel blockers, β-adrenoceptor
blockers, nitrates.

55. DRUG THERAPY IN MYOCARDIAL INFARCTION
• According to severity, the acute coronary syndromes (ACS) may be
graded into:
• Unstable angina (UA): Vascular obstruction is incomplete,
• Non-ST segment elevation myocardial infarction (NSTEMl): Vascular
obstruction is incomplete, but is attended by partial thickness and
relatively smaller area or myocardial necrosis; biochemical markers
appear in blood, but ST segment is not elevated.
• ST segment elevation myocardial infarction (STEM/) : Vascular
obstruction is complete, full thickness of ventricular wall and larger
area of myocardium is necrosed, biochemical markers are prominent
and ST segment in ECG is elevated.

56. • I. Pain, anxiety and apprehension- After pain is not relieved by 3
doses of GTN given 5 min apart, an opioid analgesic (morphine) or
diazepam is administered parenterally.
• 2. Oxygenation- By 02 inhalation and assisted respiration, if needed.
3. Maintenance of blood volume, tissue perfusion and
microcirculation -Slow i.v. infusion of saline/dextrose (avoid volume
overload).
• 4. Correction of acidosis- Acidosis occurs due to lactic acid
production; can be corrected by i.v. sod. bicarbonate infusion.
• 5. Prevention and treatment of arrhythmias- If there are no
contraindications, prophylactic administration (i.v. or oral) of a beta
blocker

57. 6. Pump failure-
(a)Furosemide: indicated if pulmonary wedge pressure is >
20 mm [ lg. It decreases cardiac pre load.
(b)Vasodilators: Venodilator (GTN slow i.v infusion) is
mainly used.
(c)inotropic agents: dopamine or dobutamine
7. Prevention of thrombus extension, embolism, venous
thrombosis-
• Aspirin ( 162- 325 mg). This is continued at 80- 160
mg/day.
• Clopidogrel/ prasugrel/ticagrelor may be given as
alternative.
• Anticoagulants (heparin/fondaparinux followed by oral
anticoagulants)

58. 8. Thrombolysis and reperfusion- Fibrinolytic agents,
i.e. plasminogen activators- alteplase/ tenecteplase to
achieve reperfusion of reinfarcted area
9. Prevention of remodeling and subsequent CHF ACE
inhibitors/ARBs
10. Prevention of future attacks
(a) Plate let inhibitors aspirin or clopidogrel
(b) blockers-
(c) Control of hyperlipidemia-dietary substitution
with unsaturated fats, hypolipidemic drugs
especially statins are routinely prescribed,
irrespective of blood cholesterol level.

59. Peripheral vascular
disease
•Peripheral Vascular
Disease.
•Pulmonary Embolism.
•Raynaud's
Phenomenon.
•Renal Vascular Disease.
•Thoracic Aortic
Aneurysm.
•Varicose Veins.

61. DRUGS FOR PERIPHERAL VASCULAR DISEASE
Pentoxiphylline (oxypentifylline):
MOA- inhibits phospho-diesterase enzyme.
It is a blood viscosity reducing agent and improves blood flow in ischaemic
area through microcirculation.
Oral doses do not affect HR, total peripheral resistance and BP. It does not
exhibit "coronary steal phenomenon". However, the overall benefits in
anginal patients are only limited.
Its other uses are
To reduce peripheral claudication, non-haemorrhagic stroke; chronic
cerebrovascular insufficiency; to improve symptoms like vertigo and
memory

62. Side effects -are mild and well tolerated.
Dose: 400 mg BD orally.
Drug interactions: It may increase anticoagulatory
effects of warfarin and may increase serum levels
of theophylline.
Other therapies include: Cilostazole,
Naftidofuryl (SHT2, receptor antagonist) and
Levo-Carnitine -(which improves the metabolic
status of skeletal muscle).
These can be supplemented with statins for more
beneficial results