NITRATES IN THE MANAGEMENT OF ANGINA PECTORIS

Pharm. Jimmy AidenPharmacy Department, Federal Teaching Hospital,

GombeJune 24th , 2015

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

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

OVERVIEW

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

• 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

• 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

• 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

PATHOPHYSIOLOGY

• O2

demand

O2

supply>An imbalance between the myocardial oxygen supply and demand.

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.

PATHOPHYSIOLOGY

• 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

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

• 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

• 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

NITRATES

• 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

• Short acting: Glyceryl trinitrate (GTN, Nitro glycerine)

• Long acting: Isosorbide dinitrate (short acting by S.L route), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythrityl tetranitrate

EXAMPLES

MODE OF ACTION

• 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 ACTIONGlutathione S-transferase

STRUCTURAL ACTIVITY RELATIONSHIP

STRUCTURAL ACTIVITY RELATIONSHIP

Eritrityl tetranitrate

• 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

• 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

SYSTEMIC EFFECTS OF NITRATESa. 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

• Angina pectoris• Myocardial infarction• Congestive Heart Failure

INDICATIONS

• 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

• 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

• 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

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 dinitrateISMN: Isosorbide mononitrate

• 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

• 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

• Alcohol• Phosphodiesterase inhibitors e.g. Sildenafil,

Tadalafil, Vardenafil• Riociguat ( Soluble guanylate cyclase

stimulator)• Disopyramide

INTERACTIONS

• 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 nitratesi. Neurohormonal activation (Maxwell SRJ, 1992)ii. Plasma volume expansion (Parker JD, 1998)iii. Intracellular sulfhydryl group depletion

(Maxwell SRJ, 1992)

NITRATE TOLERANCE

• 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

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

• 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

• 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

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

CONCLUSION1. Nitrates + -blockers :- in stable angina2. Ca++ channel blockers + -blockers :-in stable angina

when the treatment with nitrates and -blockers has failed.

3. Ca++ channel blockers + Nitrates :- in unstable angina4. All 3 together:- when the combinations of 2 drugs has

failed, where:-1. Nitrates:- decrease Preload2. Ca++ channel Blockers:- decrease Afterload3. -blockers:- decrease heart rate and myocardial

contractions

• 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

• 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

Questionsi. 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

• 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

QUESTIONS, COMMENTS & CONTRIBUTIONS

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