By K. Karmok. Troy State University - Dothan.

Note that overall coronary resistance is 3-4 fold greater in systole than in diastole and results from increased compressive resistance (R3) during systole when intramyocardial forces are large buy on line cytotec. As a result generic 200 mcg cytotec overnight delivery, there is a marked difference in systolic and diastolic flow cytotec 200mcg low cost, and, in fact, only 15-20% of the total flow to the left ventricle occurs during systole. This is not the case for the less muscular right ventricle which receives a large proportion of its blood flow during systole as well as diastole (see Figure 4. Tracings of recordings of aortic pressure, coronary flow, and calculated coronary vascular resistance from a conscious animal. Resistance is appreciably greater during systole than diastole because of the compressive component of resistance. An additional important factor which is not illustrated in Figure 3 is the variation in the magnitude of R3 across the myocardial wall. This variation is a consequence of the normal transmural distribution of intramyocardial pressure during systole (Figure 2). While its detailed pattern remains unsettled, R3 is definitely greater in the subendocardium than it is in the subepicardium. The normal transmural gradient in R3 implies that a disproportionately low fraction of coronary flow reaches the subendocardium during systole, and, in tact, it may cease entirely in the inner-most layer of Endothelium & Coronary Circulation - James Topper, M. This situation has important consequences for the autoregulatory component of resistance. To counteract this diminished subendocardial perfusion during systole, a correspondingly greater amount of flow needs to be delivered to the inner layers of the left ventricle during diastole. This is accomplished by a selective reduction of autoregulatory tone (R2) in the subendocardium, allowing it to be perfused at a higher rate then the subepicardium during diastole. Therefore, the subendocardial arterioles are relatively vasodilated in the basal state, permitting the subendocardium and subepicardium to receive the same overall flow rates. This figure illustrates that, while systolic compressive resistance is greater in the subendocardium than in the subepicardium, autoregulatory resistance is normally less, thereby allowing the subendocardium to make up its relative systolic flow deficit during diastole. As mentioned previously, the autoregulatory component of resistance (R2) exhibits a substantial degree of tonic constriction under basal conditions. During periods of increased myocardial oxygen demand, this arteriolar tone can decrease sufficiently to allow flow for the entire cardiac cycle to increase 3-6 fold. The normal circulation, therefore, possesses a reserve capacity for vasodilation which is of pivotal importance during stress, exercise and in pathological states. Figure 5 illustrates that coronary reserve is not uniform across the myocardial wall, but is less in the subendocardium than in the subepicardium. A portion of this potential reserve is required to overcome the effects of Endothelium & Coronary Circulation - James Topper, M. The ability of the autoregulatory component of resistance (R2) to regulate local myocardial blood flow according to its oxygen requirements allows two additional points to be discussed. When myocardial oxygen demand is constant, flow is constant over a wide range of perfusion pressures. Within this range of pressures, changes in arteriolar tone (R2) can maintain flow constant in the face of a reduction in driving pressure. At an arterial pressure of about 60 mmHg, the arterioles are maximally vasodilated, and further decrements in arterial pressure are associated with a decrease in coronary flow. Autoregulatory resistance also explains the occurrence of myocardial reactive hyperemia, i. Figure 7 is a record of aortic pressure and coronary flow in a conscious animal and illustrates the hyperemic response following a brief period of coronary artery occlusion. The volume of flow of which the heart is deprived by the interval of coronary occlusion is known as flow debt; it is calculated as the product of control flow rate and the duration of the occlusion. Reactive hyperemic flow is the volume of flow in excess of the control rate and is equal to the difference between the total reactive hyperemic flow and control flow. Experimental studies indicate that flow debt is usually greatly overpaid, and the repayment of flow debt, i. The myocardial reactive hyperemic response is predictable in that the volume of hyperemic flow is determined by both the duration of coronary occlusion and the control flow rate. The peak flow rate during reactive hyperemia increases with increasing length of occlusion up to occlusions lasting 15-30 seconds, longer occlusions do not increase the magnitude of peak flow, indicating that this degree of ischemia causes maximum vasodilation of the coronary bed (i. R2 is at a minimum) in order to further discuss autoregulatory resistance, it is necessary to consider those factors which regulate coronary blood flow. Coronary vascular smooth muscle is subject to neural, humoral, metabolic, and myogenic and endothelial influences, all of which may modulate autoregulatory resistance (R2). Studies of neural mechanisms for adjusting coronary resistance have suggested the presence of direct adrenergic innervation involving both constrictor and dilator mechanisms (see Table 1). Both beta-adrenergic (Beta-2) vasodilatory influences as well as cholinergic vasodilatory influences have been demonstrated in animals, but their role in regulating the tone of the resistance vessels in man is unclear. The interactions of cholinergic stimulation and the endothelium will be discussed later. Autonomic Receptors that Influence Various Classes of Coronary Vessels Receptors Large Conduit Small Coronary Endo-Epicardial Activated Vessels Resistance Collateral Ratio Vessels Vessels B1 Dilate? B2 No effect Dilate Small dilator No change effect alpha1 Constrict > 50 µm No effect No change constrict < 50µm dilate* alpha2 Dilate > 50 µm No effect No change constrict < 50 µm dilate* muscarinic1 Dilate ** Uniform dilate? The myogenic hypothesis for control of coronary perfusion was originally proposed by Bayliss in 1902. According to this theory, blood vessels are intrinsically able to respond to changes in intraluminal arterial pressure. Increases in blood pressure increase the distention of the blood vessel which in turn stimulates contraction of the vascular smooth muscle. In this way, decreases in perfusion pressure are met with a decrease in resistance, allowing flow to remain constant (c. Recent studies suggest that in certain vascular beds, possibly including human coronary arteries, the vasoconstriction observed in conductance arteries in response to increasing intraluminal pressure may be due to the release of endothelially-derived Endothelium & Coronary Circulation - James Topper, M. Of all factors considered to be involved in the control of autoregulatory resistance, metabolic factors appear to play the largest role. For a substance to be proved an important mediator of the coronary dilatation associated with increased myocardial 02 consumption, it must fulfill several criteria: 1) have potent vasoactive properties, produced endogenously in the vicinity of coronary resistance vessels, 2) must be able to be released in s 1 cardiac cycle and have maximal effect in < 20 seconds, 3) infusion should mimic metabolically induced dilatation and blockade must prevent metabolically induced vasodilatation, 4) changes in concentration in the vicinity of resistance vessels should precede and parallel changes in metabolically induced dilatation. Numerous agents, including adenosine, prostaglandins, oxygen tension, carbon dioxide tension, lactic acid, hydrogen, potassium, phosphate, and pH have, at one time or another, been proposed as "the" metabolic regulator of resistance. All of these agents are endogenously produced potent vasodilators that fulfill at least some of the above criteria. However, none of these substances satisfies all of the criteria and none has been established as the primary biochemical coupling agent between increased myocardial 02 demand and coronary vasodilation. After the release of a 20- second coronary occlusion, a prolonged hyperemic response occurs. During the dilator phase the myocardial concentration of C02, hydrogen, potassium and oxygen are nearly opposite of what might be expected if they were the mediator of the vasodilator response. Blockade of adenosine or prostaglandins does not dramatically attenuate this hyperemic response. Although adenosine was at one time considered the primary biochemical mediator of metabolic autoregulation, adenosine blockers do not alter the close coupling between myocardial perfusion and myocardial 02 consumption during exercise.

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Blackwell Publishing makes no representation 100 mcg cytotec overnight delivery, express or implied cheap 100mcg cytotec amex, that the drug dosages in this book are correct buy 100 mcg cytotec. Readers must therefore always check that any product mentioned in this publication is used in accordance with the prescribing information prepared by the manufacturers. The author and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this book. During the past several decades, however, pioneering work has revealed many of the complexities of cardiac arrhythmias and of the drugs used to treat them. To the dismay of most reasonable people, the old, convenient viewpoint finally proved utterly false. Indeed, in the decade since the first edition of this book appeared, the widespread notion that antiarrhythmic drugs are a salve for the irritated heart has been, appropriately, completely reversed. Every clinician worth his or her salt now realizes that antiarrhythmic drugs are among the most toxic substances used in medicine, they are as likely as not to provoke even more dangerous arrhythmias, and, indeed, the use of most of these drugs in most clinical situations has been associated with an increase (and not a decrease) in mortality. This newfound respect for (if not fear of) antiarrhythmic drugs has been accompanied by the comforting murmurs of an elite army of electrophysiologists, assuring less adept clinicians that, really, there is no reason to worry about these nasty substances anymore. After all (they say), what with implantable defibrillators, radiofrequency ablation, and other emerging technologies (that, by the way, only we are qualified to administer), the antiarrhythmic drug as a serious clinical tool has become nearly obsolete. It is certainly true that the use of antiarrhythmic drugs has been considerably curtailed over the past decade or so and that other emerging treatments have led to significantly improved outcomes for many patients with cardiac arrhythmias. But neither the widely acknowledged shortcomings of these drugs nor the dissemination of new technologies has eliminated the usefulness of antiarrhythmic drugs or obviated the need to apply them, when appropriate, in the treatment of patients with cardiac arrhythmias. Consider that implantable defibrillators, while in clinical use for over 25 years, are still indicated for only a tiny proportion of pa- tients who are at increased risk of arrhythmic death and are actually v vi Preface implanted in only a small proportion of these. Until these devices are made far cheaper, easier to implant, and more reliable than they are today (changes that would require dramatic—and thus unlikely— alterations in the business models of both the companies that make them and the doctors who implant them), they will never be used in the vast majority of patients who are at risk of arrhythmic death. And consider that ablation techniques to cure atrial fibrillation—the ar- rhythmia that produces the greatest cumulative morbidity across the population—have failed, despite prolonged and dedicated efforts, to become sufficiently effective or safe for widespread use. And finally, consider that with a deeper understanding of cellular electrophysiol- ogy, drug companies are now beginning to “tailor” new compounds that might be more effective and less toxic than those in current use, and that some future generation of antiarrhythmic drugs— possibly even some of the investigational drugs discussed herein— may offer a very attractive alternative to certain expensive or risky technologies. It remains important, therefore, for any health-care professional caring for patients who are at risk of developing cardiac arrhyth- mias (and not just the electrophysiologists) to understand some- thing about antiarrhythmic drugs. Accordingly, this book is intended for nonexperts—the practitioners, trainees, and students—who are most often called upon to make decisions regarding actual patients with cardiac arrhythmias. The book attempts to set out a framework for understanding antiarrhythmic drugs: how they work, what they actually do to improve (or worsen) the cardiac rhythm, and the fac- tors one must consider in deciding when and how to use them. Such a framework, it is hoped, will not only serve as a guidepost in making clinical decisions, but will also provide a basis for interpreting new information that comes to light on antiarrhythmic drugs and their place in the treatment of cardiac arrhythmias. Part 1 is an introduction to basic principles—the mechanism of cardiac arrhythmias and how antiarrhythmic drugs work. Part 2 discusses the clinically relevant features of the drugs themselves, including emerging investigational drugs that appear to show promise. Part 3 draws on this basic infor- mation to explore the treatment of specific cardiac arrhythmias and emphasizes the current roll of antiarrhythmic drugs in managing these arrhythmias. Accord- ingly, when a choice had to be made between simplicity and Preface vii complexity, simplicity prevailed in almost every case. The author recognizes that some colleagues may not agree with an approach that risks oversimplification of an inherently complex topic. It is an ap- proach, however, that reflects a deep-seated belief—by keeping the basics simple, the specifics (clinical cases and scientific reports) can be more readily weighed, categorized, absorbed, and implemented. Acknowledgments The author thanks Gina Almond, Publisher at Blackwell Publishing, for asking me to consider writing a second edition to this book, and Fiona Pattison, Senior Development Editor at Blackwell, for helping to shepherd me through the process of actually doing so. The author also thanks Anne, Emily, and Joe Fogoros for once again overlooking the temporary inattentiveness that always seems to accompany such endeavors. Indeed, it is nearly im- possible withoutafirm understanding of the basic mechanismsof cardiac tachyarrhythmias and the basic concepts of how antiarrhyth- mic drugs work. Chapter 1 reviews the normal electrical system of the heart and the mecha- nismsand clinical features of the major cardiac tachyarrhythmias. Chapter 2 examines the principles of how antiarrhythmic drugs af- fect arrhythmias. The electrical system of the heart On a very fundamental level, the heart isan electrical organ. The electrical signals generated by the heart not only cause muscle con- traction (by controlling the fluxofcalcium ionsacross the cardiac cell membrane) but also organize the sequenceofmuscle contrac- tionwith each heartbeat, thusoptimizing the pumping action of the heart. In addition,and especially pertinent to the subjectofthis book, the pattern and timing of the cardiac electrical signals deter- mine the heart rhythm. Thus, a well-functioning electrical systemis vital for adequate cardiacperformance. The fibrous skeletonis electrically inert, and therefore stops the electrical impulse. Onceon the ventricular side, the electrical impulse follows the His-Purkinje system as it divides first into the right and left bun- dle branches and theninto the Purkinje fibers. The Purkinje fibers speed the impulse to the furthermost reaches of the ventricular my- ocardium. In this way, the electrical impulse israpidly distributed throughout the ventricles. Mechanismsofcardiac tachyarrhythmias 5 The heart’s electrical system thusorganizes the sequenceofmy- ocardial contractionwith each heartbeat. Cardiac action potential The electrical impulse of the heart isactually the summation of thou- sandsoftiny electrical currents generated by thousandsofindivid- ual cardiaccells. The electrical activity of an individual cardiaccell is described by the cardiac actionpotential (Figure 1. Fortu- nately, for our purposes there are onlyafew thingsone needsto know about the actionpotential, and these are reasonably simple to understand. The voltage differenceacross the cell membrane(normally –80 to –90 mV) is called the transmembrane potential and is the result of an accumulation of negatively chargedmolecules within the cell. The magnitude of the transmembrane potential remains fixed through- out the lives of most living cells. When excitable cells are stimulatedinjust the right way, a variety of tiny channels in the cell membrane are induced to open and close in a complex sequence, which allows various electrically charged particles—ions—to pass backand forth across the membrane in an equally complex sequence. The movementofelectrical current across the cell membraneoccurs in a very stereotypic pattern and leadstoapatterned sequenceofchanges in the transmembrane po- tential. When the stereotypic changes in voltage are graphed against time, the result is the cardiac actionpotential. Although the cardiac actionpotential is classically dividedinto five phases (named,somewhat perversely, phases 0 through 4), it is most helpfultoconsider the actionpotential in terms of three general phases:depolarization,repolarization,and the resting phase. Depolarization The depolarizationphase of the actionpotential, phase 0, occurs when the so-called rapid sodium channels in the cell membrane are stimulated to open, which allows positively charged sodium ions to rush into the cell. The suddeninfluxofpositive ions causes a voltagespike—a rapid, positively directedchange in the transmem- brane potential.

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Each neurotransmitter acts on its own family of receptors and these receptors show a high degree of specificity for their transmitter discount 200mcg cytotec with amex. Diversity of neurotransmitter action is provided by the presence of multiple receptor subtypes for each neurotransmitter discount cytotec 100mcg with amex, all of which still remain specific to that neurotransmitter safe 100mcg cytotec. This principle is illustrated by the simple observations outlined in Neurotransmitters, Drugs and Brain Function. These simple qualitative observations by Langley and others at the beginning of the twentieth century led to the development of more quantitative pharmacological methods that were subsequently used to identify and classify receptors. These methods were based on the use of both (1) agonist and (2) antagonist drugs: (1) If a series of related chemicals, say noradrenaline, adrenaline, methyladrenaline and isoprenaline, are studied on a range of test responses (e. On the other hand, if, as Ahlquist first found in the 1940s, these compounds give a distinct order of potency in some of the tests, but the reverse (or just a different) order in others, then there must be more than one type of receptor for these agonists. In fact, careful quantitative analysis of the order of activity of the agonists in each test, and of the precise potency of antagonists (see Chapter 5 for quantitative detail) has often successfully indicated, although rarely proved, the presence of subclasses of a receptor type (e. The affinity of receptors for selective antagonists determined using the Schild method was a mainstay of receptor classifica- tion throughout the second half of the twentieth century. Thus, a muscarinic receptor can be defined as a receptor with an affinity for atropine of around 1 nM and the M1 subtype of muscarinic receptor can be identified as having an affinity of around 10 nM for the selective antagonist, pirenzepine while muscarinic receptors in the heart (M2 subtype) are much less sensitive to pirenzepine block (K $ 10À7 M). B Classification of receptors according to agonist potency can be problematic because agonist potency depends partly on the density of receptors in the tissue and therefore use of selective antagonists has become a mainstay of receptor identification and classification. The development of radioligand binding techniques (see Chapter 5 for principles) provided for the first time a means to measure the density of receptors in a tissue in addition to providing a measure of the affinity of drugs for a receptor and allowed the relative proportion of different receptors in a tissue to be estimated. These approaches to receptor identification and classification were, of course, pioneered by studies with peripheral systems and isolated tissues. Today we know not only that there is more than one type of receptor for each neuro- transmitter, but we also know a great deal about the structural basis for the differences between receptor subtypes which are due to differences in the amino-acid sequence of the proteins which make up the receptor. Finding the amino-acid sequence of a receptor protein has been approached in three main ways. The library is then screened by, for example, functional expression in Xenopus oocytes or mammalian cell lines, for the proteins coded by the library. The clones are then isolated and sequenced and used in expression studies to confirm the identity of the receptor. The first tentative steps towards determining the structure of individual receptors were taken by protein chemists. A high-affinity ligand that binds specifically to the receptor (generally an antagonist) was identified by traditional pharmacological methods and attached to the matrix of an appropriate chromatography column. A tissue source, rich in receptors, is homogenised and the cell membranes disrupted with detergents to bring the membrane bound proteins into solution. This solution is then passed through the affinity column and the receptor of interest will stick to the column hence separating it from all the other proteins in the tissue. The receptor is then eluted from the column using a solution of ligand specific for the receptor. This strategy allowed isolation of the nicotinic acetylcholine receptor from the electric organ of the Californian ray (Torpedo). The isolation method used a snake toxin from the venom of the Taiwan banded krait (a-bungarotoxin) as the ligand of the affinity column and the purified receptor was eluted from the column using a high concentration of the competitive antagonist, tubocurarine. In contrast, the G-protein-coupled receptors require both G- proteins and those elements such as phospholipase-C illustrated in Fig. Thus, at any glutamatergic synapse in the brain there is the potential for a single neurotransmitter to generate fast and slow signals with parti- cular characteristics which depend on the properties of the neurotransmitter receptors expressed in the target cell membrane. Since all properties of the receptor are determined by the amino-acid sequence of the protein this method has the final say. The explosion in use of molecular genetic techniques in the final decade of the twentieth century has led to the cloning and sequencing of the genes of all the known neurotransmitter receptors in the brain. From the gene sequence, the amino-acid sequence of the receptor protein can be inferred and hence a final classi- fication of all receptors can be made. Ultimately, the human genome sequencing programme will mean that the amino-acid sequence of all human receptors will be known. Does this mean pharmacologists can now retire happy in the knowledge that all is now known that there is to know? The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. The properties and subtle functional differences between receptor subtypes can be studied in increasing detail utilising receptor expression systems such as Xenopus oocytes and clonal mammalian cell lines where single receptor populations at high density can be studied without the complications arising from the diversity of receptors present in brain tissue, or the difficulty of recording responses from receptors in the brain. The hope is that if this diversity of receptor subtypes is matched by diversity of function in the brain, then subtype-selective drugs may provide the means to selective therapeutic agents with a minimum of side-effects for use in treating diseases of the brain. More detailed material on these topics may be found in the relevant chapters on individual neurotransmitters. Six different neurotransmitters are known to activate ligand-gated ion channel receptors (Table 3. A general principle in the nervous system is that only a few transmitters are used and diversity of effect is achieved by utilising a diversity of receptors. Except for glycine, all fast neurotransmitters have also been found to act at a diversity of G- protein-coupled receptors (Table 3. Subunit transmembrane topology The ligand-gated ion channel receptors form three distinct super-families based on the number of times the receptor subunits are predicted to cross the cell membrane (Fig. In (b), the transmembrane topology of the ionotropic glutamate receptors is shown. As illustrated below, the likely stoichiometry of the glutamate receptors is a tetramer. These subunits cross the cell membrane only twice and the ion channel is probably formed by a short polypeptide loop entering the membrane from the outside. The ionotropic glutamate receptor subunits have a large extracellular amino terminal domain and a long intracellular carboxy terminal domain (Fig. The P2X receptor subunits are unusual in having only two transmembrane domains with both the amino terminal and carboxy terminal located intracellularly. The ion channel is proposed by analogy with the structure of some potassium channels to be formed by a short loop which enters the membrane from the extracellular side (North and Surprenant 2000). Subunit stoichiometry The ion channel receptors are multi-subunit proteins which may be either homomeric (made up of multiple copies of a single type of subunit) or heteromeric (composed of more than one subunit type). These subunits come together after synthesis in the endoplasmic reticulum to form the mature receptor. A receptor composed of two a and three b subunits is therefore denoted as having a stoichiometry of a2b3. This can cause confusion when related subunits are given sequential numbers: b1, b2, b3, etc. The convention is there- fore that subunits are numbered normally while stoichiometry is indicated by subscripts so that a pentamer of a4 and b3 subunits might have a stoichiometry of a42b33. Their structure has been most extensively studied in the case of the nicotinic acetylcholine receptor (analogous to the muscle endplate receptor) from Torpedo electroplaque (Unwin 2000) where there is now a detailed knowledge of the receptor in both resting and active conformations.