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PHARMACOLOGICAL TREATMENT OF ISCHAEMIC HEART DISEASE 1. Definition of myocardial ischaemia "The blood supply to the myocardium is inadequate" (Opie) "The absence of arterial blood flow" (Jennings) "Supply-demand imbalance" (Schelbert) "Ischo" = "to hold back""haima" = "blood" - PowerPoint PPT Presentation
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PHARMACOLOGICAL TREATMENT OF ISCHAEMIC HEART DISEASE
1. Definition of myocardial ischaemia"The blood supply to the myocardium is inadequate" (Opie)"The absence of arterial blood flow" (Jennings)"Supply-demand imbalance" (Schelbert)
"Ischo" = "to hold back" "haima" = "blood"
The fundmental concept:
Imbalance between blood supply and blood demand of the myocardium (the oxygen supply is not able to keep up with the oxygen demand of the myocardium)
"Reversible" phase - when it is sufficiently severe to cause characteristic metabolic, mechanical, electrocardiographic changes that are diminished when the ischaemia ceases
"Irreversible" phase - as ischaemia progresses infarction (= stuffed in) cell death (= necrosis; "necro" = death)
Reperfusion (eg. thrombolysis) as early as possible - benefit for cells that are reversibly damaged
CAD(stenosis, spasm)
Blood supply (oxygen supply)
Impaired perfusion
“Litle blood, little work”
Impaired contractility
Metabolic changes
aerobic anaerobic(lactate , inorganic P , H+, adenosine, ATP , CP , “osmotic load”)
CHEST PAIN
Exercise, emotional stress,exertion, increased sympathetic tone
Blood demand (oxygen demand)
Electrophysiological changes
K+ ST-deviations, peaked T- Arrhythmias
Clinical manifestations
I. Conventional ischaemic syndromes - Angina pectoris - effort angina (classical) - angina at rest (vasospastic) - unstable angina - An myocardial infarction - Ischaemic cardiomyopathyII. New ischaemic syndromes - Silent ischaemia (1974) - Myocardial stunning (1975) (acute, chronic, maimed) - Hibernating myocardium (1984) - Ischaemic peconditioning (1986)
PATHOPHYSIOLOGY OF ISCHAEMIC HEART DISEASE
I. Conventional ischaemic syndromes
1.) Angina of effort (classic angina)•Coronary stenosis is the sine qua non of classical angina pectoris• Usually fixed coronary stenosis due to atherosclerosis (atherosclerotic plaques in the arterial trunks - morphologically, excentric or concentric). •Myocardium distal from a fix occlusion is potentially ischaemic (fall in CPP). Factors increase O2 demand (exercise, emotional stress, etc.), result coronary insufficiency (the fixed stenosis prevents coronary dilatation) and manifest clinically as myocardial ischaemia or anginal attack.
2.) Variant angina (angina at rest or vasospastic angina)• Vasospasm of coronary arteries (conductance vessels) may be responsible, which reduce CBF. Blood supply is inadequate even in resting heart.
• Morphologic picture - normal or stenosed • Cyclic recurrent chest pain (ST-elevation), prolonged anginal attacks occur at the same time each day (eg. morning - "warm up" phenomenon), may culminate in myocardial infarction and sudden cardiac death.
3.) Unstable angina • Vasospasm superimposed upon more or less pronounced coronary stenosis. • Functional link between fixed stenosis (usually excentric) which restrict any increase in flow and the pure spasm (dynamic stenosis).
• Mixed pathophysiological picture with changing intensity of the attacks (ST- elevation and depression), terminate usually in myocardial
infarction.
4. Acute myocardial infarctionSudden and complete occlusion of a coronary artery. "No flow ischaemia".
5. Ischaemic cardiomyopathy
II. New ischaemic syndromes 1. Silent ischaemia (1974; Stern and Tzivoni)
• Episodes of silent ischaemia can cause temporary heart failure (reduced perfusion LV dysfunction). • The mechanism of silent ischaemia is poorly understood. Possible explanations may include an increased threshold for pain, and increased release of pain modifiers such as beta-endorphins.
2. Myocardial stunning 1975 Heyndrickx and colleagues (experimental), 1982 Braunwald and Kloner (clinical)A stunned myocardium is defined as viable myocardium salvaged by coronary reperfusion that exhibit prolonged postischaemic dysfunction after reperfusion. • Stunning can be characterised by delayed mechanical recovery despite full reperfusion after ischaemia „perfusion-contraction mismatch” • Acute stunning: mechanical function recovers minutes and hours • Chronic stunning: recovery is measured in weeks or months. • Maimed myocardium: incomplete recovery • Myocardial stunning may occur: in MI patients follwing thrombolysis or angioplasty, unstable angina patients, exercise-induced angina, coronary artery spasm, platelet aggregation or transient thrombosis of a coronary artery, angioplasty for chronic myocardial ischaemia, and immediately following coronary bypass surgery. • The concept is that ischaemia does something that impairs mechanical function or activity even after the actual ischaemic event is over.
3. Hibernating myocardium (1984 Rahimtoola)• Clinical observation: to describe a state of persistently impaired myocardial and
left ventricular function at rest due to reduced coronary blood flow that can be partially or completely restored to normal if the myocardial oxygen supply-demand
relationship is favourably altered either by improving blood flow and\or by reducing demand.
•Hibernating myocardium is defined as ischaemic myocardium supplied by a narrowed coronary artery in which ischaemic cells remain viable but contraction is chronically depressed. •The current sine qua non concept for hibernating myocardium would be threefold:
(1) impaired contractile activity (2) the presence of severe coronary artery disease (3) recovery of myocardial function after revascularisation
•Hibernating myocardium is found in patients with severe coronary artery stenosis, even in asymptomatic patients at rest.
4. Mixed postinfarct ischaemic syndrome
•This includes LV dysfunction and LV remodelling, postischaemic diastolic and systolic failure
5. Ischaemic preconditioning (1986; Murry, Jennnings, Reimer) • "Multiple brief ischaemic episodes might actually protect the myocardium during
a subsequent sustained ischaemic insult, so that, in effect, we could exploit ischaemia to protect the heart from ischaemic injury"
Major determinants of myocardial oxygen supply and demand
1.) Factors influencing myocardial oxygen demand• Heart rate • Wall tension - preload and afterload • Myocardial contractility • Heart size
2.) Factors influencing myocardial oxygen supply • Hematologic factors - haemoglobin, free oxygen (pO2) • Myocardial extraction of oxygen from blood • Coronary blood flow (CBF) • coronary vascular resistance • autoregulation
• compression of the deep arteries during diastole• fixed resistance (eg. atherosclerotic plaque)• coronary perfusion pressure (CPP)• distribution of the blood (endo/epi)
OBJECTIVE OF THE THERAPY
1.) Reduction of the frequency and severity of attacks of chest pain2.) Remove of any underlying cause if possible3.) Promotion of growth of collateral vessels4.) Prevention of sudden cardiac death
There are two ways to achieve these:
1. To improve coronary blood flow (?)
2. To reduce myocardial oxygen requirements - decrease preload- decrease afterload- decrease contractility- decrease heart rate- decrease sympathetic tone
CLASSIC ANGINA VASOSPASTIC ANGINA UNSTABLE ANGINA
NITRATES Ca++ ANTAGONISTS BLOCKERS
-Blockers
propranolol
Heart rateContractility
Oxygen demand
Ischaemicarea
REDUCEDPRELOAD
Actin
Contraction
StoredCa2+
+
Reducedafterload
Dilate
Drugs used in the treatment of angina pectoris
Systemiccirculation
Venouscapacitance vessels
Reduced venousreturn
Dilate
Ca2+
Ca2+-
Calmodulin
Ca2+ calmodulin complex
Ca
2+ -ch
ann
elsT
issu
e thio
ls
RSH
NO3-
Miosinlight chain
(MLC)MLC- P MLC
cGMP GTP
Guanilate-cyclase
RSNO
NO
NO2-
RSH
+
MLCKa
+
MLCK
RELAXATION
Calcium-antagonistsnifedipinediltiazemverapamil
Dilate
Dilate
Arterialresistance vessels
Dilate
Nitrates
gliceril-trinitrátizosorbide-dinitrateizosorbide-5-mononitrate
R - O - NO2
R - O - NO2
R - OH+
NO2
NO3
NO’
guanylate cyclase
GTP cGMP
PROTEIN KINASE PROTEIN P KINASE
PMLC MLC
CONTRACTION RELAXATION
Ca++
NON - ENZYMATIC
NO2
NO3
SMOOTH MUSCLE CELL
cystein
glutatione
S transfe
rase
ENZYMATIC
BASIC PHARMACOLOGY OF VASODILATORSA: ORGANIC NITRITES AND NITRATES1.) Chemistry
Nitric and nitrous acid esters of polyalcohols(nitroglycerin = griceryl trinitrate)
CH2 - O - NO2
CH - O - NO2
CH2 - O - NO2All therapeutically active agents are capable of release nitric oxide (NO) in vascular smooth muscle cells.2.) Pharmacological actions 2.1. Mechanism of action
2.2. Organ system effectsNitroglycerin relaxes all types of smooth muscle resulting in general vasodilatationa.) Effects on coronary blood vessels
• Dilates large coronary vessels (conductance vessels) but the total coronary blood flow is unchanged
• Improves collateral circulation to the ischaemic area• Favoured perfusion to the subendocardium (explained by simple
haemodynamic changes)b.) Effects on myocardial oxygen demand
(1) Effects which reduce O2 demand • decreased preload (due to increased venous capacitance) • decreased afterload (due to reduced peripheral resistance) • decreased wall tension (decreased heart size and LVEDP/V)
(2) Effects which increase O2 demand • increased heart rate (due to fall in blood pressure) • increased contractility (due to compensation)
c.) Direct effect on the myocardium • niric oxide by stimulating guanylate cyclase increases cGMP • cGMP modulates L-type Ca2+ channels reduced Ca2+ influx • cGMP activates cGMP-dependent cAMP-phosphodiesterase, and results in a reduced Ca2+ influxBoth effects reduce myocardial contractility and O2 consumption
NITROGLYCERIN 1. VENOUS DILATIION
(pooling)
extracardial PRELOADfactors {LVEDP, LVEDP, PCWP}
O2 demand
WALL TENSION endocardial perfusion
2. ARTERIAL DILATATION afterload CO
3. DILATATION OF LARGEintracardial CORONARY ARTERIES 02 supply factors
4. COLLATERAL CIRCULATION
3. Toxicity and tachyphylaxisExtension of therapeutic vasodilatation • orthostatic hypotension
• tachycardia • throbbing headache
Tolerance develops with continuous exposure (eg. chemical industry, explosives, Monday disease - headache, dizziness)Dependence: withdrawal symptoms - exacerbated myocardial ischaemia
4. Mechanism of clinical effectPotential beneficial effects RESULTSDecreased ventricular volume Decreased arterial pressure Decreased myocardial Decreased ejection time oxygen requirementsVasodilation of epicardial Relief of coronarycoronary arteries artery spasmIncreased collateral flow Improved perfusion to
the ischaemic areaDecreased LVEDP Increased endocardial
perfusionPotential deleterious effectsReflex tachycardia Increased myocardialReflex increase in contractility oxygen requirementsDecreased diastolic perfusion time Decreased myocardialdue to tachycardia perfusiona.) Nitrate effects in angina of effort Reduced venous return reduces intracardiac volume reduces wall tension reduces O2 demand Decreased O2 demand during exercise is the primary effect (increased exercise tolerance)b.) Nitrate effects in angina at rest Vasodilatation of large epicardial coronary arteries relief of spasmc.) Nitrate effects in unstable angina
Reduction of O2 demand + dilation of epicardial coronary arteriesRelieve anginal attack and decrease the incidence of ischaemic episodes
5. Route of administration(1) To achieve an acute effect (to relief anginal pain) For this purpose: Sublingual or buccal tablets or spray - (rapid absorption) NITROGLYCERIN (Tabl. 0.5 mg) onset: 10-20 sec, duration 20 min ISOSORBIDE DINITRATE (ISORDIL) (Tabl. 2.5, 5 and 10 mg) AMYL NITRITE for inhalation, onset: 10 sec, duration 5-10 min Side effects: warmth, flushing, throbbing headache, dizziness, syncope, postural
hypotension(2) For long term treatment (to prevent anginal attacks) For this purpose: oral tablets, transdermal patches, oinments - high degree of "first pass" hepatic biotransformation NITROGLYCERIN (NITRONG, SUSTAC) (Tabl: 0.5 mg), onset: 15 min, duration: several hours PENTAERYTHRYL TETRANITRATE, ERYTRYL TETRANITRATE, ISOSORBID MONONITRATE (ISMN), ISOSORBID DINITRATE (ISDN) NITRO-BID (NTG) for iv. infusion Topical administration - longer duration (6-24 h) NITRO-BID (2 % ointment) Transdermal patches: DEPONIT (NTG 5 mg/24h),
NITRODUR (NTG 2.5 and 5 mg/24h) NITRODISC (NTG 5 mg/24h)
MOLSIDOMINENew vasodilator with novel structure for oral administration. Improves exercise tolerance. No tachycardiac effect (less pronounced reduction in afterload)
6. Therapeutic usesAcute and chronic angina pectoris (stenotic, vasospastic), acute myocardial infarction, postinfarction angina, acute left ventricular failure (adjuvant therapy)
B: CALCIUM ANTAGONISTS (CALCIUM CHANNEL BLOCKERS, SLOW CHANNEL BLOCKERS)
1.) ChemistryDifferent structures with similar actionsa.) Monophenylalkilamines: VERAPAMIL, BENCYCLAN,
PERHEXILINb.) Diphenylalkilamines: FENDILINE, PRENYLAMINE,
BEPRIDILc.) Dihydropyridines: NIFEDIPINE, NISOLDIPINE,
AMLODIPINE, FELODIPINE,NICARDIPINE, NITRENDIPINE
d.) Benzothiazepine: DILTIAZEMe.) Diphenylpiperazines: FLUNARIZINE, CINARIZINE,
LIDOFLAZIME
2.) Pharmacological actionsAll inhibit or block the influx of calcium through the voltage activated calcium channels.Voltage dependent calcium channels: • L-type (cardiac and vascular)
• N-type (mostly neuronal) • T-type (neuronal and gland)
Receptorial binding sites for nifedipine, diltiazem and verapamil are different.Voltage operated calcium channels open at -45 to -25 mV membrane potential inward calcium current (trigger calcium) promotes release of calcium from the sarcoplasmic reticulum (SR). (Na channels open at -90 to -50 mV, the Na+ inward current releases Ca2+ from the mithocondrium).
Ca-pump
Ca2+ Ca2+
ATP-ase
Ca2+
Ca2+ - CALMODULIN COMPLEX
CALMODULIN
cAMPMLCK(a) MLCK(a) MLCK(PO4)2 (i)
MLCK = MYOSIN LIGHT CHAIN KINASE
MYOSIN+
ACTIN
MYOSIN PO4+
ACTIN }CONTRACTION
Ca - ANTAGONISTVOLTAGE OPERATED RECEPTOR OPERATED
+
+
+
cAMP regulates:
Na+-K+-ATP-aseCa2+ channel phosphorylation (PKC) Ca2+ influx SR Ca-ATPase Ca2+ sequestration into the SRInactivation of MLCKCalcium-calmodulin complex formation
3. Organ-system effects
a.) SMOOTH MUSCLE - their contraction-relaxation is dependent upon Ca2+ influx. Calcium antagonists cause relaxation. Arterioles > veins reduction in
peripheral vascular resistance. Arterial blood pressure reducesb.) CARDIAC MUSCLE - is highly dependent upon Ca2+ influx for normal function. • Impulse generation in SA node and impulse conduction through the AV node is
based on slow inward current. Ca-blockers bradycardia and negative domotropic effect
• Contractility of the myocardium is also depending on Ca2+ influx. Ca-blockers result in negative inotropic effect reduction in myocardial O2 demand (ATP preservation increases) reduction in ischaemic damage (infarct size)
c.) SKELETAL MUSCLE - is not depressed by calcium antagonists (contraction not requires Ca influx, utilizes intracellular pools of calcium)
COMPARISON OF CARDIOVASCULAR EFFECTS OF CALCIUM ANTAGONISTS
1. Reduction in coronary vascular resistanceNIFEDIPINE >> DILTIAZEM > VERAPAMIL
2. Reduction in peripheral vascular resistanceNIFEDIPINE >> VERAPAMIL > DILTIAZEM
3. Negative inotropic effectVERAPAMIL > DILTIAZEM >>>>> NIFEDIPINE
4. Depression of sinus node pacemakerDILTIAZEM > VERAPAMIL (NIFEDIPINE, reflex tachycardia)
5. Slowing of AV conductionVERAPAMIL > DILTIAZEM (NIFEDIPINE has no effect)
4. Side and toxic effects of calcium antagonistsDirect extension of their therapeutic actionBradycardia, AV-block (especially verapamil), cardiac arrest, heart failure. Palpitation, reflex tachycardia, headache (especially after nifedipine) Flushing, edema, dizziness, nausea, constipation.
5. Mechanism of clinical effectsNegative inotropic effect O2 requirements ANTIANGINAL EFFECTVascular relaxation
CORONARY ARTERIES • improved collateral flow infarct size • relief and prevention of coronary spasm
Both result in ANTIANGINAL EFFECTPERIPHERAL ARTERIES • reduced vascular resistance (afterload and
preload) ANTIANGINAL AND ANTIHYPERTENSIVE EFFECT
Negative chronotropic (bradycardiac) effectSlowing HR O2 consumption improved myocardial perfusion during diastole)
ANTIANGINAL AND ANTIARRHYTHMIC EFFECTNegative dromotropic effectSlowing conduction through the AV node ANTIARRHYTHMIC EFFECT
6. Clinical use of calcium antagonists
(1) ANGINA PECTORIS (chronic stable angina, variant angina, unstable angina) VERAPAMIL, DILTIAZEM, NIFEDIPINE etc. Combinations with other antianginal drugs
VERAPAMIL + BLOCKER (AV block and strong negative inotropy)NIFEDIPINE + BLOCKER (in HF patients, BUT in low pressure states
NIFEDIPINE is contraindicated(2) HYPERTENSION - NIFEDIPINE, VERAPAMIL, DILTIAZEM(3) ATRIAL TACHYARRHYTHMIAS - WPW SYNDROME VERAPAMIL,
DILTIAZEM7. Drugs
VERAPAMIL (ISOPTIN, CALAN) - antianginal, antiarrhythmic (Tabl.: 40, 80, 120 mg), ISOPTIN retard (better kinetic)
NIFEDIPINE (ADALAT, PROCARDIA, CORINFAR) - vasospastic (Prinzmetal) and stable chronic angina, hypertension (Tabl. 10 mg)
NITRENDIPINE and FELODIPINE hypertensionNIMODIPINE profilactically after subaracnoid hemorrhage to prevent vasospasmDILTIAZEM (CARDIZEM, DILZEM) vasospastic and chronic stable angina (Tabl.:
30, 60, 90, 120 mg)FENDILINE (SENSIT) - calmodulin antagonist - antianginal, antihypertensive
C: BETA RECEPTOR BLOCKING DRUGS• They are not vasodilators. Their beneficial effects are related to the reduction in
HR, blood pressure and contractility. These are all reduce myocardial oxygen requirements.
• They result in redistribution of blood flow from the non-ischaemic to the ischaemic myocardial areas.
• They decrease the episodes of anginal pain but not normalize ischaemic ST-depression.
1. Pharmacological actionsa.) Effect on myocardial oxygen demand
(1) Reduction in O2 demand (due to ß-rceptor antagonism) • decreased contractility • decreased heart rate
(2) Increase in O2 demand (secondary to reduced contractility) • increased LVEDP (preload) • increased wall tension (due to increased heart size) These are undesirable effects.
b.) Combination of ß-blockers with nitratesAimed to offset each-other's deleterious effects on myocardial oxygen requirements
NITRATES ß-BLOCKERS COMBINATIONHeart rate reflex Blood pressure LVEDP 0/ TPR 0Myocardial contractility reflex 0LV ejection fraction variable Ejection time 0Diastolic perfusion time
Individual titration: against both rest and exercise (HR monitoring with BP and cardiac function measurements). • HR at rest: 50-60 beats/min and during exercise: 100-120 beats/min • ß-blockers, however can precipitate heart failure (?) and bronchoconstriction may
aggravate angina.
2. DrugsPOPRANOLOL (INDERAL, ß1, ß2)METOPROLOL (LOPRESSOR, ß1)
NADOLOL (ß1, ß2)ATENOLOL (TENORMIN, ß1)
PINDOLOL (ß1, ß2, partial agonist) ACEBUTOLOL (ß1 partial agonist) ALPRENOLOL (ß1, ß2, partial agonist) TIMOLOL (ß1, ß2).
GENERAL MANAGEMENT OF PATIENTS WITH ANGINA PECTORIS1. Pharmacological
2. Surgical interventions
AIM: Producing symptomatic relief and prolonging life
PROGNOSTIC DETERMINANTS: • degree of LV dysfunction • event of coronary atherosclerosis • severity of myocardial ischaemia
High risk of AMI coronary arteriography severe multiple vessel disease bypass surgery
Absence of high risk of AMI
pharmacological treatment
Immediate relief: NITRATES (sublingual, spray)Long term treatment:a.) Chronic stable angina: NITRATES + ß BLOCKERS (Ca ANTAGONISTS)b.) Unstable angina: immediate therapy - agressive NITRATE, ß-BLOCKER
and Ca ANTAGONIST continuous manifestation revascularisation
angioplastyc.) Variant angina: Ca ANTAGONISTS and NITRATES Patients with obstructive CAD ß-blockers may also be used
In the presence of severe fixed obstructive coronary artery lesions, angioplasty and revascularisation.
-Blockers
propranolol
Heart rateContractility
Oxygen demand
Ischaemicarea
REDUCEDPRELOAD
Actin
Contraction
StoredCa2+
+
Reducedafterload
Dilate
Drugs used in the treatment of angina pectoris
Systemiccirculation
Venouscapacitance vessels
Reduced venousreturn
Dilate
Ca2+
Ca2+-
Calmodulin
Ca2+ calmodulin complex
Ca
2+ -ch
ann
elsT
issu
e thio
ls
RSH
NO3-
Miosinlight chain
(MLC)MLC- P MLC
cGMP GTP
Guanilate-cyclase
RSNO
NO
NO2-
RSH
+
MLCKa
+
MLCK
RELAXATION
Calcium-antagonistsnifedipinediltiazemverapamil
Dilate
Dilate
Arterialresistance vessels
Dilate
Nitrates
gliceril-trinitrátizosorbide-dinitrateizosorbide-5-mononitrate
-Blockers
propranolol
Heart rateContractility
Oxygen demand
Ischaemicarea
REDUCEDPRELOAD
Actin
Contraction
StoredCa2+
+
Reducedafterload
Dilate
Drugs used in the treatment of angina pectoris
Systemiccirculation
Venouscapacitance vessels
Reduced venousreturn
Dilate
Ca2+
Ca2+-
Calmodulin
Ca2+ calmodulin complex
Ca
2+ -ch
ann
elsT
issu
e thio
ls
RSH
NO3-
Miosinlight chain
(MLC)MLC- P MLC
cGMP GTP
Guanilate-cyclase
RSNO
NO
NO2-
RSH
+
MLCKa
+
MLCK
RELAXATION
Calcium-antagonistsnifedipinediltiazemverapamil
Dilate
Dilate
Arterialresistance vessels
Dilate
Nitrates
gliceril-trinitrátizosorbide-dinitrateizosorbide-5-mononitrate
ORGANIC NITRITES AND NITRATESRoute of administration
(1) To achieve an acute effect (to relief anginal pain)For this purpose: Sublingual or buccal tablets or spray - (rapid absorption)
NITROGLYCERIN (Tabl. 0.5 mg) onset: 10-20 sec, duration 20 minISOSORBIDE DINITRATE (ISORDIL) (Tabl. 2.5, 5 and 10 mg)Side effects: warmth, flushing, throbbing headache, dizziness, syncope,
postural hypotension(2) For long term treatment (to prevent anginal attacks)
For this purpose: oral tablets, transdermal patches, oinments- high degree of "first pass" hepatic biotransformation
NITROGLYCERIN (NITRONG, SUSTAC) (Tabl: 0.5 mg),onset: 15 min, duration: several hoursPENTAERYTHRYL TETRANITRATE, ERYTRYL
TETRANITRATE, ISOSORBID MONONITRATE (ISMN), ISOSORBID DINITRATE (ISDN)
NITRO-BID (NTG) for iv. infusionTopical administration - longer duration (6-24 h)NITRO-BID (2 % ointment)Transdermal patches: DEPONIT (NTG 5 mg/24h),
NITRODUR (NTG 2.5 and 5 mg/24h)
NITRODISC (NTG 5 mg/24h)