This document provides an overview of nitrates in the management of angina pectoris. It defines angina pectoris and its types, and describes the pathophysiology and rationale for using nitrates. It discusses the class and examples of nitrates, their mechanisms of action, effects, dosages, and interactions. It describes nitrate tolerance and the benefits of nitrate combinations with beta-blockers or calcium channel blockers. In conclusion, the document states that nitrates decrease preload while calcium channel blockers decrease afterload, and beta-blockers decrease heart rate and contractions, making all three drugs beneficial when used together for treating angina.

1. NITRATES IN THE MANAGEMENT
OF ANGINA PECTORIS
Pharm. Jimmy Aiden
Pharmacy Department, Federal Teaching Hospital,
Gombe
June 24th , 2015

2. TABLE OF CONTENTS
• OVERVIEW OF ANGINA PECTORIS
- Definition of Angina pectoris
- Types of Angina pectoris
- Pathophysiology of Angina pectoris
- Rationale for the use of Nitrates in Angina Pectoris
- Therapeutic objectives
• NITRATES
- Definition of class
- Examples
- Mechanism of action
- Structural Activity Relationship

3. TABLE OF CONTENTS
- Systemic effects of Nitrates
- Indications
- Dosages
- Pharmacokinetic profile
- Side effects
- Contraindications
- Interactions
- Nitrates Tolerance
• Nitrates + B-blocker/Calcium channel blocker
combination therapy
• Conclusion
• Case Study
• References

4. OVERVIEW

5. DEFINITION OF ANGINA PECTORIS
• Angina pectoris is a Syndrome
characterized by sudden severe
pressing substernal chest pain or
heaviness radiating to the neck, jaw,
back and arms. It is often associated
with diaphoresis, tachypnea and
nausea
• Occurs when there is a deficit in
myocardial oxygen supply in relation
to myocardial oxygen demand.
• This may be due to a fixed obstruction
in the coronary arteries,
vasoconstriction, thrombus formation,
or platelet aggregation

6. • Stable Angina
- Predictable
- Exertion or Exercise induce
- Due to artherosclerosis
- Frequency, intensity and duration attacks are stable
- Relief by rest or nitroglycerin
• Unstable Angina
- Acute coronary syndrome/insufficiency
- Due to rupture of an atheromatous plaque attracting
platelet deposition and progressive occlusion of the
coronary artery
- unpredictable
-Increase pattern of frequency, intensity and duration
of attacks
- Occurs even at rest
- Not relief by rest or nitroglycerin
TYPES OF ANGINA PECTORIS

7. • Prinzmetal Angina
- Variant or Vasospastic angina
- Occurs due to coronary vasospasm and is
often associated with artherosclerosis
- It occurs spontaneously at rest and with
greater frequency during the night or early
hours of the morning
- It is associated with transient ST-segment
elevation and carries a risk of progression to
myocardial infarction.
- Prolonged vasospasm may also lead to
ventricular arrhythmias, heart block, or
death.
TYPES OF ANGINA PECTORIS

8. • Syndrome X
- This is formally known as microvascular
angina characterized by angina-like chest
pain, in the context of normal epicardial
coronary arteries.
- Typical , exertional angina with positive
exercise stress test
- Anatomically normal coronary arteries
- Product of microvascular dysfunction
- Reduced capacity of vasodilation in
microvasculature hence reduce bood flow.
TYPES OF ANGINA PECTORIS

9. PATHOPHYSIOLOGY
• O2
demand
O2
supply>
An imbalance between the myocardial oxygen supply and demand.

10. PATHOPHYSIOLOGY
• This imbalance can result from an increase in
demand (e.g., during exercise) without a
proportional increase in supply (e.g., due to
obstruction or atherosclerosis of the coronary
arteries)
• Myocardial oxygen supply depends upon
coronary blood flow, which normally increases
to meet increased oxygen demands. Ischaemia
occurs when blood flow either cannot be
increased, or is reduced; this may be due to a
fixed obstruction in the coronary arteries,
vasoconstriction, thrombus formation, or
platelet aggregation.

11. PATHOPHYSIOLOGY

12. • The major determinants of myocardial
oxygen consumption include:
– Ventricular wall stress
• Both preload (end-diastolic pressure)
and afterload (end-systolic pressure)
affect ventricular wall stress
– Heart rate
– Inotropic state (contractility)
– Myocardial metabolism (glucose vs fatty
acids)
PATHOPHYSIOLOGY

13. PATHOPHYSIOLOGY
• Coronary artery blood flow is the primary
determinant of oxygen delivery to the myocardium.
Coronary blood flow is essentially negligible during
systole and is therefore determined by:
– Perfusion pressure during diastole (aortic
diastolic pressure)
– Duration of diastole
– Coronary vascular resistance: Coronary vascular
resistance is determined by numerous factors
including:
• Atherscelorosis, Intracoronary thrombi
• Metabolic products that vasodilate coronary
arterioles
• Autonomic activity
• Extravascular compression

14. • Venodilation results in decreased preload (
decreased ventricular chamber size, end-
diastolic volume, fiber tension) = decreased
work by the heart.
• Nitrates at higher doses produce arterial
vasodilation (decreased afterload)
• Nitrates selectively increase blood flow to
ischaemic area
• Nitrates are shown to reverse coronary
vasospasm
• Inhibition of platelet aggregation
RATIONALE FOR THE USE OF NITRATES

15. • Increase blood flow to ischemic heart muscle
and/or decrease myocardial oxygen demand
• Minimize the frequency of attacks and decrease
the duration and intensity of anginal pain
• Improve the patient’s functional capacity with
as few side effects as possible
• Prevent or delay the worst possible outcome,
MI
THERAPEUTIC OBJECTIVES

16. NITRATES

17. • Nitrates are drugs that mimic the actions of
endogenous Nitric oxide by releasing nitric
oxide or forming Nitric oxide within tissues.
• Nitric oxide is an intracellular and paracrine
autocoid synthesized from arginine by Nitric
oxide synthase in the endothelial and smooth
muscles cells through out the vasculature.
• Nitrates are peripheral and coronary
vasodilators used in the management of angina
pectoris, heart failure, and myocardial infarction
• These drugs acts directly on the vascular
smooth muscles to cause relaxation and
therefore serve as an independent vasodilator.
DEFINITION OF CLASS

18. • Short acting: Glyceryl trinitrate (GTN, Nitro-
glycerine)
• Long acting: Isosorbide dinitrate (short
acting by S.L route), Isosorbide mononitrate,
Erythrityl tetranitrate, Pentaerythrityl
tetranitrate
EXAMPLES

19. MODE OF ACTION

20. • Nitrates Nitric Oxide
• Nitric oxide is an effective activator of soluble
guanylyl cyclase.
• Exact their vasodilator effect through the release of
nitric oxide which causes stimulation of guanylyl
cyclase in the vascular smooth muscles cells
• Activated guanylyl cyclase* converts GTP to cGMP
resulting in an increase level of cGMP
• cGMP facilitates the dephosphorylation of myosin
light chains, preventing the interaction of myosin
with actin, and hence causing relaxation of
myocardial smooth muscles.
MODE OF ACTION
Glutathione S-transferase

21. STRUCTURAL ACTIVITY RELATIONSHIP

22. STRUCTURAL ACTIVITY RELATIONSHIP
Eritrityl tetranitrate

23. • In a cell free system, the potency of organic
nitrate for guanylate cyclase activation is
mainly determined by the number of nitrate
groups.
• Since nitrate induced activation of guanylate
cyclase involve the formation of nitric oxide
free radicals, potency therefore increases as
nitric group increases in the group
• Increase in lypophilicity due to esterification of
the free OH group in isosorbide mononitrate
had no major influence on guanylate cyclase
activation
STRUCTURAL ACTIVITY RELATIONSHIP

24. • In their action on vascular muscles, venous
dilatation predominates over dilatation of the
arterioles. Venous dilatation decreases venous
return as a result of venous pooling, and lowers
left diastolic volume and pressure ( preload )
• The smaller or less important dilatation of
arterioles reduces both peripheral vascular
resistance and left ventricular pressure at
systole ( afterload ). The effect on preload is
not shared by ß-blockers or Calcium channel
blockers.
• Also have a coronary vasodilator effect which
improves regional coronary blood flow to
ischaemic areas resulting in improved oxygen
supply to the myocardium
SYSTEMIC EFFECTS OF NITRATES

25. SYSTEMIC EFFECTS OF NITRATES
a. At minimal effective dose
dilate veins bood returning to the
heart
preload
Ventricular volume Wall tension
Myocardial O2
consumption
b. At higher dose
dilate arteries Peripheral resistance
After load Wall tension

26. • Angina pectoris
• Myocardial infarction
• Congestive Heart Failure
INDICATIONS

27. • Glyceryl trinitrate
- Sublingual tablet: 0.5- 1mg repeated as required
(NOTE: they are unstable, should be dispensed in
glass or stainless steel containers, and closed with a
foil-lined cap which contains no wadding. No more
than 100 tablets should be dispensed at one time,
and any unused tablets should be discarded 8 weeks
after opening the container)
- Buccal tablet: 1-5mg three times daily (NOTE: The
tablets are retained in the buccal cavity; the rate of
dissolution of the tablet can be increased by
touching the tablet with the tongue or drinking hot
liquids. Also patients using buccal tablets should be
advised to alternate placement sites and pay close
attention to oral hygiene to reduce the risk of dental
caries. The tablets are not intended to be chewed; if
the buccal tablet is inadvertently swallowed,
another may be placed in the buccal cavity. )
DOSAGES

28. • Isosorbide dinitrate
- The usual dose in acute angina is 2.5 to
10 mg sublingually. As an alternative, one to
three sprays (1.25 mg/spray) may be
directed under the tongue
- Anginal prophylaxis : 20-240 mg daily in
divided doses
- To be taken on an empty stomach, 30
minutes before meal
DOSAGES

29. • Isosorbide mononitrate
- The usual oral dose is 20 mg two or three times
daily, although doses ranging from 20 to 120 mg
daily have been given
DOSAGES

30. PHARMACOKINETIC PROFILE
• Pharmacokinetic
comparison:
• Bioavailability:
– NG: Below 1%
– IDN: 20%
– ISMN: 100%
• Plasma
clearance:
– NG: 50L/min
– IDN: 4L/min
– ISMN: 0.6L/min
NG: Nitroglycerine
IDN: Isosorbide dinitrate
ISMN: Isosorbide mononitrate

31. • Headache ( dilatation of meningeal artery,
disappears with continued use)
• Flushing (Cutaneous dilatation of arterioles
of the face and neck)
• Orthostatic hypotension,
• Dizziness
• Reflex tachycardia (activation of
baroreceptor reflex mechanism)
• Salt and water retention
SIDE EFFECTS

32. • Severe anaemia (Risk of methaemoglobinemia
in patients with NADH deficiency )
• Hypotension (less than 80 mmHg)
• Hypovolaemia
• Raised intraocular or intracranial pressure (
increased intraocular and cerebrospinal fluid
pressure)
• Hypertrophic obstructive cardiomyopathy
• Cardiac tamponade (Cardiac output in
dependent on venous return)
CONTRAINDICATIONS

33. • Alcohol
• Phosphodiesterase inhibitors e.g. Sildenafil,
Tadalafil, Vardenafil
• Riociguat ( Soluble guanylate cyclase
stimulator)
• Disopyramide
INTERACTIONS

34. • Also known as Tachyphylaxis or Monday disease
• Tolerance is the attenuation, or loss of one or
several of the effects of organic nitrates after
long term administration.
• There are 3 proposed mechanism which
contributes to the development of tolerance to
nitrates
i. Neurohormonal activation (Maxwell SRJ,
1992)
ii. Plasma volume expansion (Parker JD, 1998)
iii. Intracellular sulfhydryl group depletion
(Maxwell SRJ, 1992)
NITRATE TOLERANCE

35. • The magnitude of tolerance is a function of dosage
and frequency of use.
• Therefore, it is necessary to provide a 8-10 hrs a day
“Nitrate-Free” period
• Others methods of preventing tolerance includes:
- Sulfhydryl donor such as acetylcysteine,
methionine
- Captopril, and hydralazine, which may act by
reducing neurohormonal activation, although
none have found favour in clinical practice.
- Antoxidant effects of drugs, including carvedilol
and ascorbic acid,are being studied (Watanabe,
H. et al, 1998) & (Daniel TA, Nawarskas JJ, 2000)
NITRATES TOLERANCE

36. NITRATES + ß-BLOCKERS COMBINATION
THERAPY
• Beta Blockers prevent reflex tachycardia and contractility
produced by nitrate-induced hypotension.
• Nitrates prevent any coronary vasospasm produced by
Beta Blockers.
• Nitrates prevent increases in left ventricular filling
pressure or preload resulting from the negative inotropic
effects produced by Beta Blockers.
• Nitrates and Beta Blockers both reduce myocardial
oxygen consumption by different mechanisms.
• Nitrates and Beta Blockers both increase subendocardial
blood flow by different mechanisms

37. • Vasodilation is largely responsible for anti-
ischaemic effects of both nitrates and calcium
channel blockers
• The nitrates, however, acts principally on the
venous circulation, whereas the calcium channel
blockers are primarily arterial vasodilators
• However, both nitrates and dihydropyridine
calcium channel blockers can produce reflex
tachycardia, and hence, diltiazem or verapamil
are more appropriate choice than nifedipine or
nicardipine for use in combination with nitrate
compounds (Thadani, U., 1991)
NITRATES + CALCIUM BLOCKERS
COMBINATION THERAPY

38. • The discomfort associated with angina pectoris
abates when supply becomes adequate for
demand. Typically angina lasts for seconds to
minutes, up to 15 minutes. Classically angina is not
associated with ischemic cell death.
• The most common form of angina ( exertional
angina) is caused by formation of artheroscloretic
plaques in large coronary blood vessels resulting in
stenosis.
• Distal resistance vessels are usually plaques free,
and can adjust their vasomotor tone in respond to
metabolic need.
• When a stenosis develops to the extend that the
lumen diametre is narrowed by ̴ 70%, lood flow
when the body is at rest will be normal and
sufficient, but maximal blood flow during exertion
will be reduced even when distal resistance vessels
become fully dilated. In this situation coronary flow
will be inadequate and ischaemia with chest pain
results (Rhee et al., 2001)
CONCLUSION

39. CONCLUSION
Nitrates Alone
Reflex Increase
Decrease
Decrease
Reflex increase
Decrease
Beta or Calcium
Channel Blockers
Alone
Decrease*
Decrease
Increase
Decrease*
Increase
Nitrates Plus
Beta or Calcium
Blockers
Decrease
Decrease
None or decrease
None
None
Undesireable effects are shown in italics and RED
* Dihydropyridines may cause the opposite effect due to a reflex increase
in sympathetic tone
Heart Rate
Afterload
Preload
Contractility
Ejection time
Effect

40. CONCLUSION
1. Nitrates + -blockers :- in stable angina
2. Ca++ channel blockers + -blockers :-in stable angina
when the treatment with nitrates and -blockers has
failed.
3. Ca++ channel blockers + Nitrates :- in unstable angina
4. All 3 together:- when the combinations of 2 drugs has
failed, where:-
1. Nitrates:- decrease Preload
2. Ca++ channel Blockers:- decrease Afterload
3. -blockers:- decrease heart rate and myocardial
contractions

41. • ASM is a 53 years old man married man, civil servant by
occupation, Hausa by tribe and a residence of Bomala
Qrts Gombe. Came to the GOPD Clinic of the Hospital on
the 14th of May with complains of
- chest pain recurrent for 7 yrs
- feeling of indigestion
- anxiety
weight = 54kg; BP: 100/70 mmHg
Presumptive diagnosis was Peptic ulcer disease.
• Plan: Electrocardiogram, PCV, Chest X-ray
• Medication: Tabs. PCM 1g tds X 3/7
Caps. Ulcostop 20mg OD X 1/52
Tabs. Imipramine 50mg nocte x 5/7
CASE STUDY

42. • Came back on the 21st of May.
Weight = 55kg, Height = 1.61m, BMI=
21kg/m², BP: 110/80 mmHg, HR= 68 bpm
PCV= 40%
• ECG revealed Left ventricular hypertrophy
with interior wall ischaemia
• Diagnosis: Ischaemic Heart Disease
• Medication: Tabs. Isordil 10mg bd x 1/12
Tas. Propranolol 40mg od x 1/12
CASE STUDY

43. Questions
i. Why is pain associated with angina pectoris
usually felt around the neck, left arm, and
jaw?
ii. What benefit could the patient derived from
the nitrate and beta blocker combination
therapy?
iii. Could there be any need for any drug
addition? If yes, what drug?
iv. what advice will you give the patient with
regards to the use of nitrate?
CASE STUDY

44. • Parker JD, Parker JO. Nitrate therapy for stable angina
pectoris. N Engl J Med 1998; 338: 520–31. PubMed
• Maxwell SRJ, Kendall MJ. An update on nitrate tolerance:
can it be avoided? Postgrad Med J 1992; 68: 857–66.
PubMed
• Watanabe H, et al. Randomized, double-blind, placebo-
controlled study of carvedilol on the prevention of
nitrate tolerance in patients with chronic heart failure. J
Am Coll Cardiol 1998; 32: 1194–1200. PubMed
• Daniel TA, Nawarskas JJ. Vitamin C in the prevention of
nitrate tolerance. Ann Pharmacother 2000; 34: 1193–7.
PubMed
• Thadani, U: Medical therapy of stable angina pectoris.
Cardiol Clin., 9, 73-87 (1991)
REFERENCES

45. QUESTIONS, COMMENTS & CONTRIBUTIONS

46. THANK YOU