Antianginal İlaçlar 1.

... konulu sunumlar: "Antianginal İlaçlar 1."— Sunum transkripti:

1 Antianginal İlaçlar 1

2 Ders Planı Angina Tipleri Antianginal Etki Mekanizmaları
Antianginal İlaçlar Organik Nitratlar (Nitrovazodilatörler) Beta-Adrenerjik Reseptör Blokörleri (Beta Blokörler) Kalsiyum Kanal Blokörleri 2

3 Angina Tipleri Stabil angina (klasik angina) (efor anginası)
Stabil-olmayan angina (unstable angina) Varyant angina (Prinzmetal angina) (vazospastik angina) Stabil olmayan angina aterom plağının yırtılması sonucu gelişen trombusun damar lümeninin tam olmayan tıkanıklığı sonucu ortaya çıkar; infarktus öncüsüdür. İskemi sırasında oluşan ağrının nedeni: Laktat ve benzeri asit metabolitlerin Potasyum iyonunun Tromboksan A2 Kinin peptidlerin Birikmesine bağlı olduğu sanılmaktadır. Nöbet sırasında tromboksan A2 düzeyindeki artmanın iskeminin nedeni değil, sonucu olduğu anlaşılmıştır. 3

4 Note: Plavix® (clopidogrel bisulfate) is not indicated for all the conditions listed on this slide.
Vascular disease is the common underlying disease process for MI, ischemia and vascular death. Acute coronary syndrome (ACS) is a classic example of the progression of vascular disease to an ischemic event. ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by rupture or erosion of an atherosclerotic plaque followed by formation of a platelet-rich thrombus. Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries, which can begin in childhood and progress throughout a person’s lifetime. Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms. 4

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7 O2 sunumu/O2 tüketimi ↑= antianginal etki ↓= anginal etki 7

8 Myokardın Oksijen Gereksinimini Etkileyen Parametreler
Kalp atış hızı ve arteriyel kan basıncı ikili çarpım Ventrikülün diyastol sonu gerilmesi Kontraktilite 8

9 Debi = Atım Hacmi x Nabız W= TPD x Nabız2
W = V x I W= TA x Debi TA = Debi x TPD W= TPD x Debi x Debi W= TPD x Debi2 Debi = Atım Hacmi x Nabız W= TPD x Nabız2 9

10 Antianginal Etki Mekanizmaları
Koroner dilatasyon Preşarjın azaltılması Postşarjın azaltılması Kalp üzerindeki sempatik etkinliğin azaltılması Kalbin hemodinamiğinin bozulması: Normal kimsede standart bir egzersizin SVDSB’de yaptığı yükselme 8-10 mmHg iken, aynı egzersiz anjinalı hastada 40 mmHg’ya kadar varan bir yükselme yapar. Bu anormal yükselme 2 nedene bağlıdır: Myokard iskemisi sonucu ventrikülün diyastol sırasında uyuncunun bozulması ve yeterince genişleyememesi İskemi sonucu ventrikülün sistolik fonksiyonunun bozulması, kalp debisinin azalması ve kalbin kendine gelen kanı dışarı pompalamakta güçlük çekmesi. 10

11 Organik Nitratlar (Nitrovazodilatörler)
Nitrates — Nitrates are a first-line therapy for the treatment of acute anginal symptoms. While they act as venodilators, coronary vasodilators, and modest arteriolar dilators [5,6], the primary antiischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation more than coronary vasodilation. This systemic vasodilation reduces LV systolic wall stress. (See "Nitrates in the management of stable angina pectoris"). In patients with exertional stable angina, nitrates improve exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta blockers or calcium channel blockers, nitrates produce greater antianginal and antiischemic effects. There are various preparations of nitrates available; there is no difference in efficacy among these preparations (show table 1).   Sublingual nitroglycerin — Sublingual nitroglycerin remains the therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina. The onset of action is within several minutes and the duration of action is 30 to 40 minutes. The initial dose is 0.3 mg (1/200 grains); one-half the dose (0.15 mg or 1/400 grains) can be used if the patient becomes hypotensive. The traditional recommendation is for patients to take one nitroglycerin dose sublingually every five minutes for up to three doses before calling for emergency medical services (EMS) evaluation. However, studies suggest that this approach may result in significant delays in obtaining EMS assistance [7,8]. As a result, the 2004 ACC/AHA guidelines recommend contacting EMS if chest pain or discomfort is unimproved or worsening five minutes after one nitroglycerin dose has been taken [9]. For patients known to their providers to have frequent angina, physicians may consider a selected, more tailored message that takes into account the frequency and character of the patient's angina and their typical time course of response to nitroglycerin.   Chronic nitrate therapy — Chronic nitrate therapy, in the form of an oral or transdermal preparation (isosorbide dinitrate, isosorbide mononitrate, or transdermal nitroglycerin) can prevent or reduce the frequency of recurrent anginal episodes and improve exercise tolerance [10,11]. However, tolerance to long-acting nitrates can develop and has limited their use as first-line therapy. A 12 to 14 hour nitrate-free interval must be observed in order to avoid tolerance [12,13], and some patients have a reduced anginal threshold during this period. As a result, many physicians prefer chronic nitrate therapy for second-line antianginal therapy. (See "Nitrates in the management of stable angina pectoris", section on Nitrate tolerance). When using isosorbide dinitrate, a recommended dosing schedule is beginning with a dose of 10 mg at 8 AM, 1 PM, and 6 PM, which results in a 14 hour nitrate dose-free interval. The dose is increased to 40 mg three times daily as needed. Alternatively, isosorbide dinitrate can be taken twice daily at 8 AM and 4 PM. The extended release preparation of isosorbide mononitrate, which is administered once per day, may be preferable to improve compliance. The starting dose is 30 mg once daily and can be titrated to 120 mg once daily as needed. This preparation is particularly useful in patients who have effort-induced angina. However, since the effect lasts only about 12 hours, some patients may develop nocturnal or rebound angina. Such patients require twice daily dosing or additional antianginal therapy.   Transdermal nitroglycerin — Use of a transdermal patch is a convenient way to administer nitroglycerin. The patient must remember to remove the patch for 12 to 14 hours. Since most patients have angina with activity, we suggest that the patch be applied at 8 AM and removed at 8 PM. The occasional patient with significant nocturnal angina can be treated with a patch-on period from 8 PM to 8 AM. We begin with a dose of 0.2 mg per hour; the dose can be increased to 0.8 mg per hour as needed. 11

12 Organik Nitratlar (Nitrovazodilatörler)
Gliserol ve benzeri polialkollerin nitrat esterleridirler. 100 yıldan fazla süredir kullanılmaktadırlar. nitrogliserin izosorbid mononitrat izosorbid dinitrat eritritil tetranitrat 12

13 Farmakodinamik Özellikler
Nitratlar vücutta nitrik oksid (NO) açığa çıkararak etkilerini oluştururlar. NO, solubl guanilat siklaz’ı aktive eder; hücre içinde sGMP düzeyini yükseltir. sGMP damar düz kaslarında gevşemeye neden olur. Tüm düz kaslı yapıları gevşetirler. Venler arterlerden daha duyarlıdır. Preşarjı ve postşarjı azaltırlar. Koroner dilatasyon yaparlar. Kan basıncını düşürürler ve refleks taşikardi yaparlar. The nitrates and nitrites are probably denitrated in smooth muscle and the resulting nitric oxide (NO) activates guanylate cyclase and increase the synthesis of cyclic GMP.  A cyclic GMP-dependent protein is stimulated and this leads to dephosphorylation of the light chain of myosin and resulting in smooth muscle relaxation (Note: (i) The cyclic GMP system is similar to that of the opposing cyclic-AMP system and consists of guanylate cyclase, cyclic GMP-dependent protein kinase and phosphodiesterase  (ii) phosphorylation of the light chain of myosin would result in smooth muscle contraction e.g. as mediated through the action of calcium-calmodulin.)    13

14 İnaktif Guanilil siklaz
Nitratlar NOS Arjinin NO Endotel İnaktif Guanilil siklaz M-LC M-LCK Nitratlar NO M-LC-PO4 Kasılma Aktif Guanilil siklaz Aktin Gevşeme M-LC GTP sGMP Düz kas 14

15 Membranda reseptöre bağlı ve sitoplazmada çözünmüş (soluble) olmak üzere 2 tip guanilil siklaz vardır. Guanylyl cyclase Doris Koesling, Ruhr-Universität Bochum, Germany, Synonyms: Guanylate cyclase, guanyl cyclase Definition: Guanylyl cyclases (GC) are a family of enzymes (EC ) that catalyse the formation of the second messenger cyclic GMP (cGMP)from GTP. GCs are subdivided in soluble GCs and GCs that membrane-bound and linked to a receptor. Activation occurs by nitric oxide (NO) and peptide hormones, respectively (1,2). Characteristics: Activation of GCs leads to an increase of the intracellular messenger molecule cGMP. cGMP-signalling is mediated by three different groups of cGMP effector molecules: the cGMP-activated protein kinases, the cGMP-regulated phosphodiesterases and the cGMP-gated ion channels, see Fig. 1. Levels of cGMP is reduced by cGMP-degrading phosphodiesterases. It has been established that cGMP plays a role in the relaxation of smooth muscle, the inhibition of platelet aggregation and in retinal phototransduction. It also participates in signal transduction within the nervous system. Moreover, cGMP is involved in the regulation of the water and electrolyte household  as well as in the metabolism of the bone. According to their structural features and their regulation, GCs can be divided into NO-stimulated and receptor-linked enzymes. cGMP-signalling. Shown are the two groups of cGMP-forming guanylyl cyclases (receptor-linked membrane-bound GC and NO-activated GC) and the three effector proteins, which mediate the cGMP effect (see text for further explanation). ANP: A-type natriuretic peptide; BNP: B-type natriuretic petide; CNP: C-type natriuretic peptide; Sta: heat-stable enterotoxin of E. coli. NO-stimulated GC: The soluble, NO-stimulated GC (sGC) represents the most important effector enzyme for the signalling molecule NO, which is synthesized by NO synthases in a Ca2+-dependent manner (3). The NO-stimulated GC contains a prosthetic heme group, which provides the acceptor site for NO. Formation of the NO-heme complex leads to a conformational change, resulting in an up to 200-fold increase in catalytic activity of the enzyme (1). The organic nitrates (see below) commonly used in the therapy of coronary heart disease exert their effects via the stimulation of this enzyme. So far two isoforms of the NO-sensitive heterodimeric enzyme have been identified, the ubiquitous a1b1 isoform and the less broadly distributed a2b1 isoform. Although both isoforms show the same regulatory properties, they appear to differ in their subcellular distribution. The N-termini of the subunits are responsible for heme binding and heme coordination, whereas the cyclase catalytic domains are located in the C-terminal regions. The cyclase catalytic domain is conserved in the membrane-bound guanylyl cyclases as well as in the adenylyl cyclases (see below). Soluble GCs occur in relatively high concentration in vascular smooth muscle cells and platelets as well as in lung, kidney and brain tissues. The NO-induced increase in cGMP causes smooth muscle relaxation and the inhibition of platelet aggregation. Aside from the cardiovascular system, the NO/cGMP cascade has an important function in the nervous system, where it is thought to participate in synaptic plasticity, i.e. the use-dependent change of the efficiency of synaptic transmission. Besides NO, only few other sGC-activating substances have been reported. Carbon monoxide (CO) is known to bind heme groups with high affinity but has been shown to induce enzyme activity only marginally (3 to 5-fold). An about 10-fold increase of activity has been reported for the NO-sensitive GC when using YC-1 ([3-(5’-hydroxymethyl-2’-furyl)-1-benzyl indazole]) as an activator. Moreover, YC-1 induces NO and CO sensitivity of the enzyme. Apart from an increase in the formation of cGMP via the stimulation of sGC, the substance also inhibits phosphodiesterases. In intact cells, YC-1 causes pronounced increases in cGMP levels by preventing cGMP degradation. Thus, YC-1 may represent a new class of drugs that are of potential use in the treatment of cardiovascular diseases. YC-1-related compounds have already been developed and their therapeutic benefits are currently under investigation. Receptor-linked GC: Membrane-bound GCs belong to the group of receptor-linked enzymes with one membrane-spanning region (2). Although all of these GCs share a conserved intracellular catalytic domain, they differ in their extracellular ligand-binding domains and are activated by different peptide hormones. The guanylyl cyclase A (GC-A) isoform acts as the receptor for the natriuretic peptides ANP and BNP two, primarily cardiac, hormones that are involved in the regulation of blood pressure as well as in the water and electrolyte household. ANP-induced and BNP-induced increases in cGMP levels mediate physiological effects such as smooth muscle relaxation, inhibition of aldosteron secretion in the adrenal cortex and salt and water excretion in the kidney. A second ANP receptor, containing only a very short intracellular C-terminal region and without any GC activity, has also been identified. As intracellular signalling of this ANP receptor has not been detected, this protein was suggested to function as a ‘clearance receptor’, removing excess ANP from the circulating blood. Another GC isoform, GC-B, displays the highest affinity for the natriuretic peptide of the C-type (CNP). GC-B is mainly found in the vascular endothelium and is thought to participate in smooth muscle relaxation. However, occurrence of the above GC isoforms and the natriuretic peptides is not limited to the cardiovascular system, they may also play a role in the central nervous system. Further GC isoforms are GC-C, GC-D, GC-E and GC-F. Of these, GC-C binds the peptide hormone guanylin that occurs mainly in the intestine. It is stimulated by the heat-stable enterotoxin of Escherichia coli, a fact that, pathophysiologically, can lead to severe diarrhoea. Therefore, GC-C and its ligand are probably involved in regulating the salt and water balance in the intestine. The other receptor-linked GC isoforms are restricted to sensory cells. GC-D is only expressed in olfactory neurons, GC-E and GC-F are exclusively found in the retina. Regulation of these GC isoforms by proteins that interact with the intracellular cGMP-forming domain has been demonstrated. Since no ligand to the N-terminal domain of such isoforms has been identified to date, it is not clear whether cGMP forming activity is controlled by the receptor domain at all. Drugs acting on soluble GC: Clinically, the organic nitrates glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate, are mainly used in the treatment of coronary heart disease. They exert their main therapeutic effect by activating sGC via NO (4). Neither of the nitrates release NO spontaneously, instead they undergo a complex enzymatic bioactivation that either yields NO or bioactive S-nitrosothiols. Enzyme(s) and cofactors required for this biotransformation have not been clearly identified, yet it appears that the activity of certain enzyme(s) and cofactors can vary within different regions of the vascular system. This may cause, or may contribute to the observed differences in NO sensitivity. Since nitrate-induced vasodilation is more pronounced in veins than in arteries, the organic nitrates cause marked venorelaxation and reduce central venous pressure. In turn, the preload and the cardiac work decrease, resulting in a relief of angina pectoris symptoms. Treatments with organic nitrates that reduce cardiac preload are also used in patients with heart failure. However, direct coronary dilatation or redistribution of the blood flow to ischemic regions of the myocardium remains controversial. In general, nitrates are either used to treat or to prevent acute episodes of angina, or they are employed to provide long-term prophylaxis against episodes of  angina in patients with frequent angina attacks. For the appropriate application of organic nitrates, pharmacokinetical and pharmaceutical aspects have to be taken into account. A hepatic high-capacity organic nitrate reductase, rapidly inactivates organic nitrates by effectively removing nitrate groups. The bioavailability of the traditional organic nitrate glyceryl trinitrate is therefore very low and for the immediate treatment of angina, the sublingual application of glyceryl trinitrate is preferred. This way, the first pass effect is circumvented and a therapeutic blood level of glyceryl trinitrate is rapidly achieved. The nitrate can be efficiently absorbed and exerts its antianginal effect within a few minutes. However, because the drug’s duration of effect is very short (15-30 minutes), sublingually applied glyceryl trinitrate is not suitable for maintenance therapy. In such case the sublingual application of isosorbide dinitrate, which is similar to glyceryl trinitrate is advised. In comparison, it has a slightly delayed onset of activity but its duration of effect (2 hours) is more sustained. For a drug effect that lasts even longer, nitrates such as sustained-release preparations of nitroglycerin, isosorbide dinitrat or isosorbide mononitrat are administered orally at sufficient dosage, to provide effective plasma levels after first-pass-degradation. Other options to administer nitroglycerin include transdermal and buccal absorption from slow release preparations. Isosorbide mononitrate as an active metabolite of isosorbide dinitrate is available for clinical use and has a bioavailability of 100%. A major problem of nitrate-based prophylaxis of angina is the loss of drug efficacy. The continuous application of nitrates for more than a few hours leads to the development of nitrate tolerance. Although the precise mechanisms of this tolerance phenomenon are unknown, it is conceivable that tolerance occurs at the level of the metabolising enzymes and/or the NO receptor GC. Moreover, an increase in the NO-scavenging superoxide ion and other counter-regulatory mechanisms may contribute to the development of tolerance. However, since the marked attenuation of the nitrate effect is rapidly reversible upon discontinuation of the drug, any tolerance development can be controlled and is achieved by allowing a ‘nitrate-free’ period of about 8 hours (usually at night) within 24 hours. An option for patients who develop nocturnal angina is molsidomine, another NO containing compound that is believed to not induce tolerance. Molsidomine features a similar pharmacological profile as the organic nitrates. As a prodrug it is bioactivated in the liver and yields SIN-1 that decomposes, enzyme-independently, in a two-step reaction, In the first step, SIN-1 undergoes a base-catalysed ring opening, forming SIN-1A. This in turn, in the second step, yields NO and the stable metabolite SIN-1C. As the onset of action of molsidomine is comparatively slow, it is not used to treat acute cases of angina. Furthermore, due to its putative carcinogenic effect, molsidomine should only be considered when the treatment with organic nitrates is not sufficient, for example in the ‘nitrate-free’ interval. The acute toxicity of the organic nitrates as well as molsidomine is directly related to their therapeutic vasodilatation of orthostatic hypotension, tachycardia and throbbing headache. Apart from the substances mentioned above, there is one other NO-containing compound, sodium nitroprusside (SNP), which effectively reduces ventricular preload and afterload, This powerful vasodilatator has to be administered parenterally and is used in intensive care units that deal with emergencies who exhibit hypertension. In the presence of reducing agents such as glutathione, SNP spontaneously releases NO concomitantly with cyanide. Its most serious adverse effects are therefore related to the accumulation of cyanide. In low doses, inhaled NO may have a beneficial therapeutic effect, since NO in the inspired air leads to pulmonary vasodilatation. In persistent pulmonary hypertension of the newborn, NO inhalation has already been used with some success. NO inhalation as the treatment for acute respiratory distress syndrome, however, has been disappointing. Only transient improvements of oxygenation were detected and the outcome of placebo-controlled trials did not show any improvement Drugs acting on receptor-linked GC: In theory, one could utilize GC-A ligands to lower blood pressure and to reduce blood volume because they increase the excretion of water and salt. The effectiveness of BNP in managing acute congestive heart failure is currently under investigation in clinical trials. Besides the attempt to substitute natriuretic hormones with the recombinant form of BNP, there is a pharmacological approach to elevate the concentration of natriuretic peptides by inhibiting degradation by the neutral endopeptidase. Of special interest are dual-function inhibitors that block not only the neutral natriuretic peptide-degrading endopeptidase but also the angiotensin-converting enzyme, thereby decreasing the level of angiotensin II. References 1. Koesling D, Friebe A (1999) Structure and regulation of soluble guanylyl cyclase. Rev Physiol. Biochem. Pharmacol. 135, 35-41 2. Wedel, BJ, Garbers DL (2001) The guanylyl cyclase family at Y2K. Annu. Rev. Physiol. 63, 3. Moncada S, Higgs EA (1995) Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J. 13: 4. Harrison DG, Bates JN (1993) The nitrovasodilators. New ideas about old drugs. Circulation 87: 15

16 Farmakokinetik Liposolübiliteleri yüksektir.
Ciltten, mukozalardan hızlı emilirler. Sublingual Transdermal Oral yoldan kullanılabilirler. Gastrointestinal kanaldan emilimleri tama yakındır; ancak ilk-geçiş etkisine uğrarlar. Biyoyararlanımları düşüktür. Karaciğerde denitrasyona uğrayarak metabolize edilirler. 16

17 TTS ve oral sprey formlarında kullanılabilir.
Nitrogliserinin transmukozal kontrollü salan preparatları da (Nitrogard) üretilmiştir (Türkiye’de yok). Bu tabletler üst dudakla dişeti arasına yerleştirilir. Oradan saatlerce absorbe edilir. Nitrogliserin, liposolubilitesinin fazlalığı nedeniyle ciltten, mukozalardan hızlı emilir. TTS ve oral sprey formlarında kullanılabilir. 17

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20 İlaç Etkinin başlaması Etki süresi Doz Nitrogliserin İntravenöz Hemen İnfüzyon süresince mg/dak Transdermal 30 dak 24 h SR tablet Yavaş 8-12 h Sublingual tablet Hızlı (1-4 dak) <30 dak mg* Sprey 0.4 mg Bukkal tablet 4-8 h İsosorbid dinitrat 2-10 mg/saat mg Hızlı 5-10 mg Oral tablet 30-40 dak İsosorbid mononitrat 6-12 h 20 mg x 2-3 12-24 h 50 mg x 1 Farmakokinetik Nitroglycerin tablets are stable but should be dispensed in glass containers and protected from moisture, light, and extremes of temperature. Active tablets usually produce a burning sensation under the tongue, but the absence of this sensation does not reliably predict loss of activity; elderly patients especially may be unable to detect the burning sensation. SR: sürekli salıveren (sustained release) *Ağrı geçmezse 3 dakika sonra ikinci tablet verilir. 20

21 Endikasyonlar Stabil angina pektoris kriz tedavisi profilaktik tedavi
Stabil-olmayan angina pektoris Akut myokard infarktüsü Vazospastik angina Konjestif kalp yetmezliği Hipertansif kriz veya vazokonstriktör ilaçlara bağlı akut hipertansiyon Kontrollü hipotansiyon istenen durumlar 21

22 Tolerans ve Bağımlılık
Nitratların vazodilatör etkilerine karşı tolerans gelişir. Tolerans tam değil kısmidir. Tolerans bütün hastalarda görülmez. Kişiler arasında toleransın derecesi farklılık gösterir. Sürekli ve yüksek dozda kullanma durumunda tolerans daha belirgindir. Aralıklı (intermitent) uygulama tolerans gelişme olasılığını ve şiddetini azaltır. TTS gece yatarken çıkarılıp kalsiyum antagonisti verilebilir. Oral verilişlerin asimetrik yapılması (örneğin saat 8 ve 14’te vermek gibi) Uzun süre nitrat kullanan hastalarda ilaç birden kesilmemeli, doz azaltılarak kesilmelidir. rebound vazokonstriksiyon ve angina riski Mechanisms of tolerance — How nitrate tolerance occurs is incompletely understood. It is due to attenuation of the vascular effect of nitrates, not to altered pharmacokinetics [2]. At least three, not mutually exclusive, mechanisms have been proposed to explain the development of nitrate tolerance [2]. These include: Impaired nitroglycerin bioconversion to 1,2-glyceryl dinitrate with decreased formation of nitric oxide. This effect is nitrate-specific and is not seen with non-nitrate sources of nitric oxide such as nitroprusside [17]. Consistent with this theory are the experimental observations that there is no tolerance to the effect of S-nitrosothiols and that the activity of mtALDH, the enzyme required for metabolism of nitrates to 1,2-glyceryl dinitrate in markedly reduced [5]. The same findings can be induced by inhibitors of mtALDH [5]. Reduced bioactivity of nitric oxide [18]. Consistent with this theory is the finding in an animal study that vascular and hemodynamic tolerance to nitrates occurred despite high levels of nitric oxide and rates of nitric oxide formation that were similar in those animals that were not tolerant [19]. Also in support of this hypothesis is that transgenic animals that overexpress endothelial nitric oxide synthase have chronically elevated nitric oxide release, which is associated with reduced vascular reactivity to nitric oxide-mediated vasodilators [20]. Activation of the vasoconstrictor renin-angiotensin-aldosterone and sympathetic nervous systems in response to nitrate-induced vasodilation [21,22]. There is also increased peripheral sensitivity to these vasoconstrictors, an effect that can be reversed by angiotensin converting enzyme inhibition [21]. Abnormal coronary vasoconstrictor responses have also been described with continuous nitrate exposure [23]. 22

23 Spesiyaliteler İsosorbid dinitrat
CARDİOKET %0.1, 10 ml’lik 10 ampul 5 mg, 40 dilaltı tablet 20 mg, 20 retard tablet 40 mg, 50 ve 100 retard tablet İSORDİL 5 mg, 50 dilaltı tablet 10 mg, 50 tablet NİTROFİX 5 ve 10 mg, 20 tablet (SR dilaltı tablet) Nitrogliserin NİTROGLYCERİN 25 mg, 1 flakon PERLİNGANİT 10 mg/10 ml, 10 ampul DEPONİT NT 5 Flaster, 10 ve 30 flaster (5 mg/24 saat serbestleşme hızı) 10 Flaster, 10 ve 30 flaster (10 mg/24 saat serbestleşme hızı) NİTRODERM TTS-5 flaster: 25 mg, 5 ve 30 flaster TTS-10 flaster: 50 mg, 5 ve 30 flaster NİTROLİNGUAL 400 mcg/sıkım, 250 sıkım oral sprey Spesiyaliteler İsosobid mononitrat İSORAT 20 ve 40 mg, 20 tablet MONODUR 60 mg, 30 tablet MONOKET 20 ve 40 mg, 20, 50 ve 100 tablet 50 mg, 20, 50 ve 100 long retard kapsül MONOLONG SR 40 ve 60 mg, 30 mikropellet kapsül Pentaeritritol tetranitrat DANİTRİN FORTE 20 mg, 50 tablet (200 mg meprobamat içerir) 23

24 Sorpsiyon Nitrogliserin’in intravenöz infüzyonu için cam şişe, infüzyon borusu olarak polietilen boru kullanılır. Polivinilklorürden (PVC) yapılmış olağan borular kullanılırsa, ilaç molekülleri infüzyon setinin çeperine yapışır ve damara ulaşan ilaç miktarı azalır. 24

25 Yan Etkileri Hipotansiyon (ortostatik) Refleks taşikardi Flushing
Başağrısı (intrakraniyal basınç artışı olanlarda kontrendike) Göz içi basıncı yükselmesi Methemoglobinemi Bütün nitratlar vücutta oluşturdukları nitrit iyonunun hemoglobini methemoglobine oksitlemesi nedeniyle yüksek dozda verildiklerinde methemoglobinemi yapabilirler ve buna bağlı olarak siyanoz oluşturabilirler. Toxicity and Untoward Responses Untoward responses to the therapeutic use of organic nitrates are almost all secondary to actions on the cardiovascular system. Headache is common and can be severe. It usually decreases over a few days if treatment is continued and often can be controlled by decreasing the dose. Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop, particularly if the patient is standing immobile, and may progress occasionally to loss of consciousness, a reaction that appears to be accentuated by alcohol. It also may be seen with very low doses of nitrates in patients with autonomic dysfunction. Even in severe nitrate syncope, positioning and other measures that facilitate venous return are the only therapeutic measures required. All the organic nitrates occasionally can produce drug rash. Interaction of Nitrates with Phosphodiesterase 5 Inhibitors. Erectile dysfunction is a frequently encountered problem whose risk factors parallel those of coronary artery disease. Thus many men desiring therapy for erectile dysfunction already may be receiving (or may require, especially if they increase physical activity) antianginal therapy. The combination of sildenafil and other phosphodiesterase 5 (PDE5) inhibitors with organic nitrate vasodilators can cause extreme hypotension. 25

26 Kontrendikasyonlar Hipertrofik obstrüktif kardiyomiyopati
Kor pulmonale ve diğer nedenlere bağlı hipoksemisi olan hastalar İntrakraniyal basınç artışına neden olan durumlar Hipertrofik obstrüktif kardiyomiyopati: kalbe venöz dönüşü azaltarak kanın aortaya çıkışındaki tıkanıklığı artırabilirler. Kor pulmonale ve diğer nedenlere bağlı hipoksemisi olan hastalarda hipoksemiyi artırdıklarından kullanılmamalıdırlar. 26

27 Beta Blokörler Relative effectiveness of medical therapies — Beta blockers and calcium channel blockers generally have equal efficacy in the management of stable angina [1,16]. A meta-analysis was performed of 90 randomized or crossover studies comparing at least two of the classes of beta blockers, calcium channel blockers, and long-acting nitrates for efficacy and tolerability in the treatment of patients with stable angina [16]. The following observations were noted: There were no observed differences in outcome (eg, cardiac death and MI) between beta blockers and calcium channel blockers. Too few patients received long-acting nitrates for efficacy analysis of these drugs against either of the other classes. For the variables where differences existed between beta blockers and calcium blockers (eg, episodes of angina per week and side effects), the major effect was observed with beta blockers compared to nifedipine. As an example, there were 0.31 fewer episodes of angina per week with beta blockers than with calcium channel blockers as a group and 0.63 fewer episodes per week than with nifedipine. However, as noted above, nifedipine is typically avoided now in the treatment of patients with CHD. Short-acting calcium channel blockers were also associated with a 0.44 increase in weekly angina episodes compared to beta blockers, while long-acting calcium channel blockers decreased angina frequency by 0.08 episodes per week. Beta blockers were discontinued because of adverse reaction less often than calcium channel blockers (odds ratio 0.72). Again, this difference was most striking with nifedipine. Despite the differences in angina frequency, there were no differences in nitroglycerin use or exercise time between beta blockers and calcium channel blockers. 27

28 Beta Blokörler Kalpteki beta-1 reseptörleri bloke ederek kalbin oksijen tüketimini azaltırlar. Kardiyoselektif olanlarla olmayanlar arasında antianginal etkinlik yönünden bir fark yoktur. Stabil ve stabil-olmayan anginalı hastalarda kullanılırlar. Vazospastik anginada kontrendikedirler. Normal bir kişide egzersiz kapasitesini azalttıkları halde, anginalı hastada egzersize dayancı artırırlar. 28

29 Kalsiyum Kanal Blokörleri
When to use — All of the calcium channel blockers reduce anginal symptoms and increase exercise tolerance and exercise time before the onset of angina or ischemia, especially when used in conjunction with other antianginal agents. (See "Calcium channel blockers in the management of stable angina pectoris"). They should be used in combination with beta blockers when initial treatment with beta blockers is not successful. They may be a substitute for a beta blocker when beta blockers are contraindicated or cause side effects. Calcium channel blockers (eg, diltiazem at a dose of 240 to 360 mg per day) are effective in patients with vasospastic or variant (Prinzmetal) angina; they are the preferred agents in this setting. (See "Variant angina"). 29

30 Kalsiyum Kanalları Reseptörle çalıştırılan kalsiyum kanalları
Voltaja-bağımlı kalsiyum kanalları Düşük voltajla aktive edilenler (düşük eşikli) -80 mV, -70 mV değerlerinde aktive olurlar T-tipi kanallar blokör: amilorid, mibefradil Yüksek voltajla aktive edilenler (yüksek eşikli) 0 mV’da aktive, -10 mV’da inaktive olurlar L-tipi kanallar: damar düz kaslarında ve kalpte bulunurlar. N-tipi kanallar: presinaptik yerleşimli, mediyatör salıverilmesini düzenleyen kanallardır. Q-tipi kanallar: SSS’deki nöronlarda bulunurlar R-tipi kanallar: SSS’deki nöronlarda bulunurlar P-tipi kanallar: SSS ve periferde bazı presinaptik uçlardan mediyatör salıverilmesini düzenleyen kanallardır. 30

31 L-Tipi Kalsiyum Kanalları
5 alt birimden oluşur: a1, a2, b, g, d Kanal fonksiyonu yapan ve ilaçları bağlayan alt a1 alt birimdir. a1 Alt birim üzerinde bulunan bağlanma yerleri: Dihidropiridin bağlanma yeri Fenilakilamin bağlanma yeri Benzotiazepin bağlanma yeri 31

32 32

33 Ca2+ -kalmodulin kompleksi
Endotel M-LC M-LC-PO4 Kasılma Kalmodulin Aktin Ca2+ M-LCK* Gevşeme M-LC Ca2+ -kalmodulin kompleksi Düz kas M-LCK 33

34 Kalsiyum Kanal Blokörleri
Dihidropiridinler Amlodipin Barnidipin Benidipin Felodipin İsradipin Lasidipin Lerkanidipin Nifedipin Nikardipin Nilvadipin Nimodipin Nitrendipin Nizoldipin Fenilalkilaminler Verapamil Gallopamil Benzotiazepinler Diltiazem 34

35 Etkiler Vazodilatasyon (arteriyoller venüllerden daha duyarlı)
Arteriyoler dilatasyon (postşarj ↓↓) Venöz dilatasyon (preşarj ↓) Koroner vazodilatasyon Negatif inotrop etki (oksijen tüketiminin azalması) Bradikardi (dihidropiridinlerde taşikardi) A-V iletimin yavaşlaması (- dromotrop etki) (verapamil ve diltiazem için) 35

36 Klinik Kullanılış Etki Dihidropiridinler Fenilalkilaminler
Benzotiazepinler Antianjinal +++ Vazodilatör + ++ Antiaritmik  36

37 Farmakokinetik İlaç VS Oral F (%) t1/2 (h) PPB (%) Oral Doz (antianginal olarak) Amlodipin ++ 65-90 30-50 >90 5-10 mg x 1 Felodipin 5.4 15-20 11-16 İsradipin 7.4 15-25 8 >95 2.5-5 mg x 1 Nikardipin 17.0 35 2-4 20-40 mg x 3 Nifedipin 3.1 45-70 4 ~90 20 mg x 1 veya 10 mg x 2 Nimodipin 13 1-3 98 Nisoldipin <10 6-12 99 10-40 mg x 1 Nitrendipin 14.4 10-30 5-12 Lasidipin 10 13-19 2-6 mg x 1 Diltiazem 0.3 40-65 3-4 70-80 mg x 2 Verapamil 1.3 20-35 6 mg x 3 VS: vazoselektiflik (IC50damar/IC50kardiyak kalsiyum kanal blokajı); ++ belirgin vazoselektiflik; PPB: Plazma Proteinlerine Bağlanma Genellikle karaciğerde yüksek oranda metabolize edilirler. Biyotransformasyon kalıbı üyeler arasında değişkenlik gösterir. 37

38 Spesiyaliteler Amlodipin AMLODİS AMLOKARD AMLOVAS BİOCARD CADUET
DİLOPİN MONOVAS NİPİDOL NORLOPİN NORMOPRES NORVADİN NORVASC VASOCARD VAZKOR 5 ve 10 mg, 20 tablet Spesiyaliteler Felodipin PLENDİL 2.5, 5 ve 10 mg, 20 tablet Lerkanidipin LERCADİP 10 mg, 20 tablet Nilvadipin NİLVADİS 8 ve 16 mg, 28 tablet Nitrendipin BAYPRESS 10 mg, 30 tablet 20 mg, 20 tablet Nifedipin ADALAT CRONO 30 ve 60 mg, 20 tablet (kontrollü salıveren) KARDİLAT 10 mg, 30 tablet 20 mg, 10 ve 30 kapsül (mikropelet kapsül) NİDİCARD 10 mg, 30 kapsül NİDİLAT 10 mg, 30 kapsül Nimodipin NİMOTOP 30 mg, 30 tablet 10 mg/50 ml, 50 ml solüsyon İsradipin DYNACİRC SRO 5 mg, 30 kapsül Lasidipin LACİPİL 4 mg, 28 tablet 38

39 Spesiyaliteler Diltiazem
ALTİZEM-SR 60 mg, 30 kapsül 120 mg, 120 kapsül DİLTİCARD 30 ve 60 mg, 50, 90, 500 ve 1000 tablet DİLTİZEM 25 mg, 1 ampul 30 ve 60 mg, 48 tablet 90 ve 120 mg, 48 SR tablet 240 mg, 16 SR tablet Verapamil İSOPTİN 5 mg, 5 ampul 40 mg, 30 tablet 80 mg, 50 tablet ORMİL 40 mg, 30 tablet 80 mg, 50 tablet VEROPTİN mg, 50 tablet FİBROKARD L.P. 240 mg, 30 mikropellet kapsül İSOPTİN 240 mg, 50 SR tablet 120 mg, 50 KKH tablet TARKA 180 mg, 28 tablet (tabletler 2 mg trandolapril içerir) Barnidipin LİBRADİN 10 ve mg, 30 kapsül Benidipin CONİEL 4 mg, 20 tablet Nikardipin LOXEN 20 mg, 30 tablet 39

40 Endikasyonlar Hipertansiyon Stabil angina
Stabil-olmayan angina (nitratlar ve beta blokörler daha önce düşünülmeli) (verapamil ve diltiazem) Vazospastik angina Migren Hipertrofik kardiyomiyopati Difuz özofagus spazmı Dismenore Üriner inkontinens Pulmoner hipertansiyon 40

41 Yan Etkiler Başağrısı Yüzde ve boyunda kızarma Ayak bileklerinde ödem
Refleks taşikardi (dihidropiridinler) bradikardi ve A-V blok (verapamil ve diltiazem) Ortostatik hipotansiyon 41

42 İncelenen Yeni Medikal Antianginal Tedaviler
Ranolazin Trimetazidin Perheksilin Nikorandil Endotelin reseptör antagonistleri (bosentan) İvabradin Fasudil Testosteron 42

43 Nitrogliserinin kontrendike olduğu durum hangisidir? (Nisan 1990)
Kalp yetmezliği Unstabil angina Raynaud hastalığı Myokard infarktüsü Stabil angina (Cevap ?) Nitratların vazodilatör etkisi aşağıdaki enzim sistemlerinden hangisinin aktivasyonuna bağlıdır? (Nisan 1994) Adenilil siklaz Guanilil siklaz Na+, K+-ATPaz Fosfodiesteraz Diaminoksidaz (Cevap B) Guanilil siklaz aktivasyonu ile etkisini gösteren hangisidir? (Eylül 1994) Forskolin Dopamin Nitrik oksid Asetilkolin Adrenalin (Cevap C) Nitrik oksid hücrede temel etkisini nereye bağlanarak gösterir? (Eylül 2002) L-arginindeki guanidino grubu L-sitrülindeki karboksil terminali Nitrik oksid sentaz – G proteini bağlantı bölgesi cAMP molekülleri Çözünür guanilil siklaz hem demiri (Cevap E) Antianginal etkisi en uzun süren ilaç hangisidir? (Eylül 1999) Nitrogliserin Amil nitrit Sublingual isosorbid dinitrat Oral isosorbid dinitrat Oral isosorbid mononitrat TUS Soruları 43