Drug therapy of Drug therapy of cardiovascular diseasescardiovascular diseases

Angina pectorisAngina pectoris is a clinical syndrome

characterized by episodes of chest pain. It occurs when there is a deficit in myocardial oxygen supply (myocardial ischemia) in relation to myocardial oxygen demand. It is most often caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm. The development and progression of atherosclerotic plaque is called coronary artery disease.

Risk factors for coronary artery diseaseRisk factors for coronary artery diseaseSmokingSmokingHypertensionHypertensionHyperlipidaemiaHyperlipidaemiaDiabetes mellitusDiabetes mellitus

AntianginalAntianginal ((coronary coronary activeactive)) drugsdrugs

a group of drugs that a group of drugs that relieve anginal pain by reducing myocardial oxygen demand or increasing blood supply to the myocardium.

Clinically it is manifested by removalClinically it is manifested by removal or or prevention of stenocardia attacks prevention of stenocardia attacks (improvement of disease current) and (improvement of disease current) and increasing of patients’ tolerance to physical increasing of patients’ tolerance to physical loadload

ANTIANGINALANTIANGINAL ( (CORONARY CORONARY ACTIVEACTIVE) ) DRUGSDRUGS

І. І. Nitrates and sidnonims Nitrates and sidnonims

ІІ. ІІ. BetaBeta--adrenoblockersadrenoblockers

ІІІ. ІІІ. Calcium channel blockersCalcium channel blockers

ІУ. ІУ. Activators of potassium channelsActivators of potassium channels

NITRATESNITRATES

Glyceryl trinitrateGlyceryl trinitrate

isosorbidisosorbid dinitratedinitrate isosorbidisosorbid-5--5-mononitratemononitrate

INDICATIONSINDICATIONSTreatment and prevention of angina.Treatment and prevention of angina.Treatment of acute left ventricular Treatment of acute left ventricular failure.failure.

NITRATESNITRATES

1.1. Nitrates are first-line treatments for the symptoms of Nitrates are first-line treatments for the symptoms of angina but do not affect the course of the underlying angina but do not affect the course of the underlying disease.disease.

2.2. They cause vasodilatation; this can be hazardous in They cause vasodilatation; this can be hazardous in some patients:some patients:Patients who are hypovolaemic (severe Patients who are hypovolaemic (severe hypotension).hypotension).Patients with cardiac disease such as hypertrophic Patients with cardiac disease such as hypertrophic cardiomyopathy or mitral stenosis.cardiomyopathy or mitral stenosis.Patients with bleeding (e.g. following head trauma or Patients with bleeding (e.g. following head trauma or cerebral haemorrhage).cerebral haemorrhage).No dosage adjustment is usually required in renal or No dosage adjustment is usually required in renal or hepatic insufficiency.hepatic insufficiency.Avoid these drugs during pregnancy; the effects on Avoid these drugs during pregnancy; the effects on blood pressure can affect placental blood flow.blood pressure can affect placental blood flow.

NITROGLYCERINENITROGLYCERINETabletsTablets ( (under the tongueunder the tongue))

1 % 1 % alcohol or oil alcohol or oil solutionsolution ((under the tongueunder the tongue))

aerosolaerosol

Latent periodLatent period - - 2-3 2-3 minmin

Duration of actionDuration of action - 20-30 - 20-30 minmin

ampoulesampoules 1 % 1 % solutionsolution – – intravenously intravenously dropply 0,01%dropply 0,01% solutionsolution

prolongedprolonged forms of nitroglycerineforms of nitroglycerine: : trinitrolongtrinitrolong, , sustaksustak, , nitrongnitrong, , ointmentointment, , plasterplaster

Contraindications for Contraindications for nitroglycerine usenitroglycerine use

Close-angled form of glaucomaClose-angled form of glaucoma

IIncreasing of intracranial pressure, ncreasing of intracranial pressure, insultinsult

AAcute myocardium infarctioncute myocardium infarction ((in case in case of presence of hypotension and of presence of hypotension and

collapsecollapse))

PROLONGED FORMS OF PROLONGED FORMS OF NITROGLYCERINENITROGLYCERINE

TrinitrolongTrinitrolong – – polymer filmspolymer films ( (0,001 0,001 gg oror 0,002 0,002 gg of of nitroglycerinenitroglycerine)) action develops immediately, lasts for action develops immediately, lasts for 3-3-5 5 hourshours

SustacSustac Sust Sustaaс-mite (с-mite (containscontains 0,0026 0,0026 g of g of nitroglycerinenitroglycerine) ) andand Sustac-forte (0,0064 Sustac-forte (0,0064 g of g of nitroglycerine)nitroglycerine)

beginning of action beginning of action – – after after 10 10 min,min, maximal action maximal action – – after after 1 1 hourhour, , duration of actionduration of action – 4-5 – 4-5 hourshours

Nitrong Nitrong – – microcapsule form of nitroglycerine of microcapsule form of nitroglycerine of prolonged actionprolonged action

latent periodlatent period – 30-60 – 30-60 minmin, , maximal effectmaximal effect - - afterafter 3-4 3-4 hourshours,,

action durationaction duration - - 6-86-8 hours hours

Other nitratesOther nitratesNitrosorbid Nitrosorbid – – isosorbid dinitrateisosorbid dinitrate

latent periodlatent period 30-50 30-50 minmin, , duration of actionduration of action – 4-6 – 4-6 hours and morehours and more

With sublingual administration of the drug latent period grows With sublingual administration of the drug latent period grows short toshort to 3-5 3-5 minmin

buccal formbuccal form ( (DinitrolslrbilongDinitrolslrbilong))tablets of prolonged actiontablets of prolonged action ( (Isoket-retardIsoket-retard) )

ointmentointment aerosolaerosol

drugs for intravenous introductiondrugs for intravenous introduction

IsosorbidIsosorbid-5--5-mononitratemononitrate - - pharmacologically active metabolite of isosorbid dinitratepharmacologically active metabolite of isosorbid dinitrate

duration of actionduration of action - - fromfrom 6 6 tilltill 24 24 hourshours

The adverse effects of nitratesThe adverse effects of nitrates are related to are related to their vasodilator propertiestheir vasodilator properties

The most common is a throbbing headache; The most common is a throbbing headache; this may improve with time.this may improve with time.Other common adverse effects include Other common adverse effects include dizziness, postural hypotension, and dizziness, postural hypotension, and tachycardia.tachycardia.Hypotension is the most serious adverse Hypotension is the most serious adverse effect; take care to titrate the dose to minimize effect; take care to titrate the dose to minimize the risk of falls.the risk of falls.Prolonged intravenous administration can Prolonged intravenous administration can cause methaemoglobinaemia; this is rare.cause methaemoglobinaemia; this is rare.Avoid prolonged intravenous administration; Avoid prolonged intravenous administration; the patient will become tolerant to the effects of the patient will become tolerant to the effects of the drug.the drug.

SYDNONIMSSYDNONIMS

MolsydominMolsydomin – – corvatoncorvaton - - sydnopharmsydnopharm

2 2 mg of molsydominmg of molsydomin == 0,5 0,5 mg of mg of nitroglycerine nitroglycerine

MolsydominMolsydominlatent period latent period - - 20 20 minmin ( (5-10 5-10 minmin – – if administered if administered sublinguallysublingually)),, action durationaction duration - - 6 6 hourshours. .

can be used for prophylaxis and releasing can be used for prophylaxis and releasing stenocardia attacks in patients with glaucomastenocardia attacks in patients with glaucoma ( (doesn’t increase intraoccular pressuredoesn’t increase intraoccular pressure))

indicated for patients who make breaks in using indicated for patients who make breaks in using nitrates to decrease tolerance towards themnitrates to decrease tolerance towards them

doesn’t lead to development of tolerance (doesn’t doesn’t lead to development of tolerance (doesn’t need previous combining with sulfhydryl groupsneed previous combining with sulfhydryl groups))

absence of withdrawal syndromeabsence of withdrawal syndrome

Treatment of angina Treatment of angina

Glyceryl trinitrate is given as sublingual tablets or spray for the Glyceryl trinitrate is given as sublingual tablets or spray for the symptomatic relief of angina. It acts within a few minutes and symptomatic relief of angina. It acts within a few minutes and lasts for 20lasts for 20-30-30 minutes. minutes.

If the patient has predictable angina on exertion, they If the patient has predictable angina on exertion, they can take the glyceryl trinitrate beforehand to prevent angina.can take the glyceryl trinitrate beforehand to prevent angina.If the first dose of glyceryl trinitrate does not relive the angina, If the first dose of glyceryl trinitrate does not relive the angina, advise the patient to take a second dose after 5 minutes. If this advise the patient to take a second dose after 5 minutes. If this does not relieve their symptoms, they should seek urgent does not relieve their symptoms, they should seek urgent medical attention.medical attention.Glyceryl trinitrate can relieve symptoms of angina at rest or on Glyceryl trinitrate can relieve symptoms of angina at rest or on minimal exertion, but these are symptoms of unstable disease; minimal exertion, but these are symptoms of unstable disease; advise the patient to seek urgent medical attention.advise the patient to seek urgent medical attention.Glyceryl trinitrate is most useful for intermittent symptoms. Glyceryl trinitrate is most useful for intermittent symptoms. Glyceryl trinitrate is relatively unstable; the sublingual tablets Glyceryl trinitrate is relatively unstable; the sublingual tablets have a limited shelf-life. Advise the patient to dispose of any have a limited shelf-life. Advise the patient to dispose of any unused tablets after 3 months, and obtain a fresh supply. The unused tablets after 3 months, and obtain a fresh supply. The spray formulation lasts longer.spray formulation lasts longer.

Treatment of anginaTreatment of angina (cont’d) (cont’d)

If the patient has frequent symptoms, a modified-release If the patient has frequent symptoms, a modified-release formulation that acts over a longer period may be suitable. formulation that acts over a longer period may be suitable. Remember that nitrates do not affect the disease process; Remember that nitrates do not affect the disease process; ensure that the patient has been adequately investigated.ensure that the patient has been adequately investigated.If nitrates are given repeatedly, patients rapidly become tolerant If nitrates are given repeatedly, patients rapidly become tolerant to their effects (within 24 hours). It is important to have a nitrate-to their effects (within 24 hours). It is important to have a nitrate-free period of at least 4free period of at least 4-8-8 hours during the day. hours during the day.

Immediate-release formulations should usually be given at Immediate-release formulations should usually be given at 08.00 and 14.00, to give a nitrate-free period overnight. The 08.00 and 14.00, to give a nitrate-free period overnight. The timing of the doses can be altered to coincide with the patient's timing of the doses can be altered to coincide with the patient's symptoms, but they should not be given 12 hours apart.symptoms, but they should not be given 12 hours apart.

Modified-release formulations are usually formulated to provide Modified-release formulations are usually formulated to provide relief over an 18-hour period.relief over an 18-hour period.

Remove nitrate patches to provide a nitrate-free period(usually Remove nitrate patches to provide a nitrate-free period(usually overnight).overnight).

Avoid giving intravenous glyceryl trinitrate for long periods.Avoid giving intravenous glyceryl trinitrate for long periods.

Treatment of anginaTreatment of angina (cont’d) (cont’d)

Nitrates by intravenous infusion are used Nitrates by intravenous infusion are used in the treatment of acute coronary in the treatment of acute coronary syndromes for symptomatic relief and syndromes for symptomatic relief and because they lower blood pressure. because they lower blood pressure. Intravenous nitrates are sometimes given Intravenous nitrates are sometimes given to control severe hypertension before to control severe hypertension before thrombolysis.thrombolysis.

Treatment of angina Treatment of angina (cont’d)(cont’d)Angina is the symptom experienced when the myocardium is Angina is the symptom experienced when the myocardium is ischaemic, usually as a result of coronary artery disease. ischaemic, usually as a result of coronary artery disease. Classically, angina is a dull, tight, central chest pain that may Classically, angina is a dull, tight, central chest pain that may radiate to the neck and left arm. Some patients do not have radiate to the neck and left arm. Some patients do not have classical symptoms, but recognize other symptoms as angina.classical symptoms, but recognize other symptoms as angina.The first-line treatment for angina is a beta-blocker given The first-line treatment for angina is a beta-blocker given regularly, and a nitrate given as required to relieve the pain.regularly, and a nitrate given as required to relieve the pain.Coronary artery disease is usually the cause of angina; patients Coronary artery disease is usually the cause of angina; patients need to be advised how to adjust their lifestyle to modify their need to be advised how to adjust their lifestyle to modify their risk factors (e.g. smoking, diet, exercise). Patients with angina risk factors (e.g. smoking, diet, exercise). Patients with angina should also be given an antiplatelet drug (e.g. aspirin) and a should also be given an antiplatelet drug (e.g. aspirin) and a cholesterol-lowering drug (e.g. a statin).cholesterol-lowering drug (e.g. a statin).Once a diagnosis of angina has been made, the patient should Once a diagnosis of angina has been made, the patient should have their risk of myocardial infarction assessed. This is usually have their risk of myocardial infarction assessed. This is usually by means of an exercise tolerance test with electrocardiographic by means of an exercise tolerance test with electrocardiographic monitoring. An alterative is a cardiac nuclear perfusion scan.monitoring. An alterative is a cardiac nuclear perfusion scan.

Treatment of anginaTreatment of angina (cont’d) (cont’d)

Those at high risk should be assessed for coronary Those at high risk should be assessed for coronary angiography, with a view to percutaneous intervention or angiography, with a view to percutaneous intervention or bypass grafting. Some patients are at low risk, and others do bypass grafting. Some patients are at low risk, and others do not have lesions amenable to intervention. For these patients not have lesions amenable to intervention. For these patients optimization of pharmacotherapy, in combination with lifestyle optimization of pharmacotherapy, in combination with lifestyle changes, is indicated.changes, is indicated.Many patients are adequately treated with a beta-blocker and Many patients are adequately treated with a beta-blocker and nitrate alone. Beta-blockers are recommended as they have nitrate alone. Beta-blockers are recommended as they have beneficial effects on vascular growth and function.beneficial effects on vascular growth and function.Some patients are unable to take a beta-blocker, or their Some patients are unable to take a beta-blocker, or their symptoms are inadequately controlled. Consider a calcium symptoms are inadequately controlled. Consider a calcium channel blocker for these patients. The most commonly channel blocker for these patients. The most commonly prescribed are the dihydropyridines (e.g. amlodipine, nifedipine). prescribed are the dihydropyridines (e.g. amlodipine, nifedipine). Verapamil and diltiazem lower heart rate; this may be beneficial Verapamil and diltiazem lower heart rate; this may be beneficial if tachycardia is a feature. Verapamil should not be given to if tachycardia is a feature. Verapamil should not be given to patients taking beta-blockers (risk of severe hypotension and patients taking beta-blockers (risk of severe hypotension and asystole).asystole).

Antiarrhythmic agentsAntiarrhythmic agents are a group of  are a group of pharmaceuticalspharmaceuticals that are used to suppress  that are used to suppress abnormal rhythms of the abnormal rhythms of the heartheart ( (cardiac arrhythmiascardiac arrhythmias), such as ), such as atrialatrial fibrillation fibrillation, , atrialatrial flutter flutter, , ventricular tachycardiaventricular tachycardia, , and ventricular fibrillation. and ventricular fibrillation.

These drugs were classified into various groups These drugs were classified into various groups by SINGH VAUGHAN WILLIAMS as follows: by SINGH VAUGHAN WILLIAMS as follows:

I.I. Na+ channel blockers (membrane Na+ channel blockers (membrane stabilizing group). stabilizing group).

II.II. Beta- adrenergic blockers Beta- adrenergic blockers

III.III. K+ channel blockers (prolong K+ channel blockers (prolong repolarisation and action potential)repolarisation and action potential)

IV.IV. Ca2+ channel blockers L-typeCa2+ channel blockers L-type

Class I drugs are divided into three Class I drugs are divided into three subgroups:subgroups:

Subgroup I ASubgroup I A

Subgroup I BSubgroup I B

Subgroup I CSubgroup I C

Sinus Sinus tachycardiatachycardia (also colloquially known  (also colloquially known as as sinus tachsinus tach or  or sinus tachysinus tachy) is a heart ) is a heart rhythm with elevated rate of impulses rhythm with elevated rate of impulses originating from the originating from the sinoatrialsinoatrial node node, defined , defined as a rate greater than 100 beats/min (bpm) in as a rate greater than 100 beats/min (bpm) in an average adult. The normal heart rate in an average adult. The normal heart rate in the average adult ranges from 60–100 the average adult ranges from 60–100 beats/min. Note that the normal heart rate beats/min. Note that the normal heart rate varies with age, with infants having normal varies with age, with infants having normal heart rate of 110–150 bpm to the elderly, who heart rate of 110–150 bpm to the elderly, who have slower normals.have slower normals.

PainPainFeverFeverAnxietyAnxietyDehydrationDehydrationMalignant hyperthermiaMalignant hyperthermiaHypovolemia with hypotension and shockHypovolemia with hypotension and shockAnemiaAnemiaHeart failureHeart failureHyperthyroidismHyperthyroidismMercury poisoningMercury poisoningKawasaki diseaseKawasaki diseasePheochromocytomaPheochromocytoma

1. Palpitations, or sweating, dizziness, 1. Palpitations, or sweating, dizziness, vertigo, fatigue, or the performance of vertigo, fatigue, or the performance of primary disease.primary disease.

2. Can be induced by other arrhythmia or 2. Can be induced by other arrhythmia or angina.angina.

3. Heart rate for 100 to 150 times / min, 3. Heart rate for 100 to 150 times / min, heart sounds are mostly strong, or signs of heart sounds are mostly strong, or signs of primary heart disease.primary heart disease.

RateRate: Greater than or equal to 100.: Greater than or equal to 100.

RhythmRhythm: Regular.: Regular.

P wavesP waves: Upright, consistent, and normal : Upright, consistent, and normal in morphology (if no atrial disease)in morphology (if no atrial disease)

P–R intervalP–R interval: Between 0.12–0.20 seconds : Between 0.12–0.20 seconds and shortens with increasing heart rateand shortens with increasing heart rate

QRS complexQRS complex: Less than 0.12 seconds, : Less than 0.12 seconds, consistent, and normal in morphology.consistent, and normal in morphology.

Usually apparent on the EKG, but if heart rate is Usually apparent on the EKG, but if heart rate is above 140 bpm the P wave may be difficult to above 140 bpm the P wave may be difficult to distinguish from the previous T wave and one distinguish from the previous T wave and one may confuse it with a may confuse it with a paroxysmal paroxysmal supraventricularsupraventricular tachycardia tachycardia or  or atrialatrial flutter flutter with  with a 2:1 block. a 2:1 block. Ways to distinguish the three areWays to distinguish the three are::VagalVagal maneuvers maneuvers (such as carotid sinus  (such as carotid sinus massage or Valsalva's maneuver) to slow the massage or Valsalva's maneuver) to slow the rate and identification of P wavesrate and identification of P wavesadminister AV blockers (e.g., administer AV blockers (e.g., adenosineadenosine, , verapamilverapamil) to identify ) to identify atrialatrial flutter flutter with 2:1 block with 2:1 block

Not required for physiologic sinus tachycardia. Underlying causes are Not required for physiologic sinus tachycardia. Underlying causes are treated if present.treated if present.

Acute myocardial infarctionAcute myocardial infarction. . Sinus tachycardia can present in more Sinus tachycardia can present in more than a third of the patients with than a third of the patients with AMIAMI but this usually decreases over time.  but this usually decreases over time. Patients with sustained sinus tachycardia reflects a larger infarct that are Patients with sustained sinus tachycardia reflects a larger infarct that are more anterior with prominent left ventricular dysfunction, associated with more anterior with prominent left ventricular dysfunction, associated with high mortality and morbidity. Tachycardia in the presence of AMI can high mortality and morbidity. Tachycardia in the presence of AMI can reduce coronary blood flow and increase myocardial oxygen demand, reduce coronary blood flow and increase myocardial oxygen demand, aggravating the situation. aggravating the situation. Beta blockersBeta blockers can be used to slow the rate, but  can be used to slow the rate, but most patients are usually already treated with beta blockers as a routine most patients are usually already treated with beta blockers as a routine regimen for AMI.regimen for AMI.

Practically, many studies showed that there is no need for any treatment.Practically, many studies showed that there is no need for any treatment.Inappropriate sinus tachycardia and Postural tachycardia Inappropriate sinus tachycardia and Postural tachycardia syndromesyndrome. . Beta blockersBeta blockers are useful if the cause is sympathetic  are useful if the cause is sympathetic overactivity. If the cause is due to decreased vagal activity, it is usually overactivity. If the cause is due to decreased vagal activity, it is usually hard to treat and one may consider hard to treat and one may consider radiofrequency catheter ablationradiofrequency catheter ablation..

Atrial flutter is an abnormality of the heart Atrial flutter is an abnormality of the heart rhythm, resulting in a rapid and sometimes rhythm, resulting in a rapid and sometimes irregular heartbeat. Such abnormalities, irregular heartbeat. Such abnormalities, whether in the rate or regularity of the whether in the rate or regularity of the heartbeat, are known as arrhythmias.heartbeat, are known as arrhythmias.

Atrial flutter may be caused by abnormalities Atrial flutter may be caused by abnormalities of the heart, by diseases of the heart, or by of the heart, by diseases of the heart, or by diseases elsewhere in the body that affect diseases elsewhere in the body that affect the heart. Atrial flutter may also be caused the heart. Atrial flutter may also be caused by consuming substances that change the by consuming substances that change the way electrical impulses are transmitted way electrical impulses are transmitted through the heart. Atrial flutter can occur through the heart. Atrial flutter can occur after after open heart surgeryopen heart surgery. In a few people, no . In a few people, no underlying cause is ever found.underlying cause is ever found.

Heart diseases or abnormalities that can cause atrial Heart diseases or abnormalities that can cause atrial flutter include the following:flutter include the following:Decreased blood flow to the heart (Decreased blood flow to the heart (ischemiaischemia) due to ) due to coronary heart disease, coronary heart disease, hardening of the arterieshardening of the arteries ( (atherosclerosisatherosclerosis), and/or a ), and/or a heart attackheart attackHigh blood pressureHigh blood pressure (hypertension) (hypertension)Disease of the heart muscle (Disease of the heart muscle (cardiomyopathycardiomyopathy), ), especially associated with especially associated with congestive heart failurecongestive heart failure

Abnormalities of the Abnormalities of the heart valvesheart valves, especially the , especially the mitral valvemitral valveAn abnormally enlarged chamber of the heart An abnormally enlarged chamber of the heart (hypertrophy)(hypertrophy)

Some people have no symptoms with atrial Some people have no symptoms with atrial flutter. Others describe the following flutter. Others describe the following symptoms:symptoms:

Palpitations (a rapid heartbeat or a Palpitations (a rapid heartbeat or a pounding sensation in the chest)pounding sensation in the chest)

A fluttering feeling in the chestA fluttering feeling in the chest

Shortness of breathShortness of breath

AnxietyAnxiety

WeaknessWeakness

People with underlying heart or lung People with underlying heart or lung disease who experience atrial flutter may disease who experience atrial flutter may have these symptoms as well as the have these symptoms as well as the following more significant symptoms:following more significant symptoms:

Angina pectoris (chest or heart pains)Angina pectoris (chest or heart pains)

Feeling faint or light headedFeeling faint or light headed

Fainting (syncope)Fainting (syncope)