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The steepest descent method is superior if the starting geometry of the drug molecule under consideration is far from the global minimum on the energy surface order topiramate 200mg amex. The Newton–Raphson method topiramate 100 mg free shipping, on the other hand topiramate 100 mg fast delivery, is superior when fine-tuning the geometry of the drug molecule within the depths of the energy surface well. The two methods are frequently used in sequence, with the steepest descent method being used prior to final optimization by a Newton–Raphson method. For example, if the putative drug being studied is a hexapeptide, it will exist in a multiplicity of low energy shapes; the hexapeptide’s potential energy surface will have many, many low energy wells, and trying to identify the global energy minimum (the lowest energy well) is a challenging task. Such energy surfaces may have billions of low energy wells, and trying to identify the single lowest energy well is a computationally demanding problem. The multiple minima problem also explains our inability to predict protein folding when our only starting information is the primary amino acid sequence of a protein. There exist a number of techniques for addressing the multiple minima problem when trying to identify the lowest energy conformer for a flexible drug or for a recep- tor protein. These techniques are computational chemistry methods that enable one to “search the conformational space” of the floppy drug molecule or protein under study. The Monte Carlo method was one of the first methods used to search conformational space, having been adapted from classical statistical mechanics. Using this method, random moves are made to the rotatable bonds of an isolated molecule. Then, using a Metropolis sampling procedure, it is possible to generate a large number of suitable conformations. The spectrum of acceptable conformations is then energy minimized (using a quantum mechanics or molecular mechanics approach, as discussed above), and ranked by energy. Although it is necessary to generate a large number of confor- mations, in principle it is possible, within a user-defined timeframe, to achieve a repre- sentative sample from low-energy conformational space. A second, widely used method for searching conformational space is through mole- cular dynamics calculations. A simple definition of molecular dynamics is that it sim- ulates the motions of a system of atoms with respect to the forces that are present and acting on the molecule. This collection of forces causes the system to change, but by collective motion of atoms over time, in a way that is described by integrating Newton’s second law of motion (F = ma, where F is the force acting on an atom, m is its mass, and a is its acceleration). If one can calculate the next configuration of the collection of atoms, it is possible to follow the evolution of the atomic movements within the mole- cule over time. This is different from the Monte Carlo method, which requires outside intervention to produce change by a random move; in molecular dynamics, all changes result without external intervention and arise from within the system itself. In a molec- ular dynamics calculation, the molecule is “heated” by assigning velocities randomly to the atoms for a given temperature. Once the first velocities have been assigned, the mol- ecular dynamics simulation is self perpetuating. As the simulation of the atomic move- ments progresses, the new atomic positions are calculated. By “heating” the molecule and permitting it to cool, it is possible to explore the conformational space of the molecule, thereby identifying low energy shapes. The genetic algorithm method is a technique that has very recently gained attention for searching conformational space. Genetic algorithms may be applied to the multiple minima problem of molecular conformational analysis via a variety of methods. In one such method, the torsional angles within a given molecule are designated as “genes. If this offspring has a lower energy than its parents (as determined using either molecular mechanics or quantum mechanics calculations), the conformation is said to have “fitness” and is permitted to survive. The “most fit” conformations are permitted to propagate by exchanging their genes with their sibling conformers. A mathematical pro- cedure, termed a “mutation operator,” is used to incorporate greater diversity amongst the genes as successive generations are created. Genetic algorithm calculations permit families of low energy conformers to be identified. Monte Carlo methods, molecular dynamics calculations, and genetic algorithm meth- ods are all techniques for searching conformational space; each has strengths and weak- nesses. The techniques are complementary rather than competitive, and may be used together in a concerted attempt to identify low energy conformers of drug molecules. Since these methods are simply techniques for skipping across the conformational space of a molecule, they must be used in conjunction with a mechanics method (e. One final issue, which confounds the use of these methods for identifying the elusive global energy minimum, concerns the biological relevance of this lowest energy con- formation once it has been identified. Just because a detailed quantum mechanics cal- culation has identified a given conformation as the lowest energy shape for a drug molecule, this does not mean that this is the bioactive conformation. The interaction of a drug with its receptor is a dynamic process in which each molecule flexes to fit the other. It is entirely possible that the drug molecule may assume a higher energy con- formation (by several kcal/mol) in order to achieve this fit, thereby rendering the search for a global energy minimum somewhat irrelevant. For someone who has never taken a course in quantum mechanics, this discussion of quantum pharmacology may have been somewhat confusing. However, understanding these basic principles is important because of the important and ever-increasing role of molecular modeling in drug design and discovery. Since a mole- cule may have an almost infinite variety of shapes, the infinite number of single energy values corresponding to these shapes define a surface (termed the potential energy hypersurface). The lowest point on this surface (global minimum) is assumed to repre- sent the most probable shape of the molecule. Methods such as Monte Carlo, molecular dynamics, and genetic algorithms (section 1.
Tooker says quality 200 mg topiramate, “the remedy of all remedies and the one most often called for during the teething period is chamomile generic topiramate 100mg without prescription. This remedy is to children what pulsatilla is to women purchase topiramate 200 mg fast delivery, a veritable vade mecum, “ Chamomile, acts mildly on the nervous system to subdue irritability and on the gastro-intestinal tract to relieve irritation there. It is adapted to the restless, peevish, irritable, discontented, and impatient infant who insists on being carried in arms constantly. With these there is usually hepatic tenderness with watery or greenish, slimy discharges, yellowish and white lumps of undigested curds, the fecal excordiating the external parts. There is often difficulty and pain in urination, and bloating of the abdomen with flatulence. It prevents convulsions by relieving the irritation, but has not sufficient antispasmodic effect to control the convulsions. The many conditions with the adult woman it is beneficial, especially to those in the latter months of pregnancy where there are present false pains, nervous twitching, reflex cough, explosion of irascibility; where there is fretfulless, peevishness, impatience and discontent; where there is morbid sensitiveness to pain; where there are sudden fits of temper during menstruation with muscular twitchings. Therapy—This agent in hot infusion is emetic, a stimulating diaphoretic, and it promotes the menstrual flow when suppressed from cold. In suppression of the secretions from Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 35 acute cold it is a useful remedy. If drank during an alcohol sweat or Turkish bath, its influence is greatly increased. In acute rheumatism it will prove of service, It is a mild stomachic and general tonic in half-ounce doses of the cold infusion, and it seems to mildly stimulate digestion. In acute colic in infants, with nervous excitability and tendency to spasm, a few drops may be dropped into a half glass of water and a teaspoonful given every ten minutes with immediate relief. In flatulent colic and in colic accompanying diarrhea, the discharges of a greenish, feculent character with reflex nervous irritation or increased nervous susceptibility, it is a specific remedy. In constant worry and fretfulness of very young infants, without apparent cause, it is a soothing remedy of much value. It is excellent during the teething period to allay nervous irritation and soothe pain. It soothes general irritation and quiets imaginary pains, especially if occurring at the menstrual epoch. In amenorrhea with intermittent pains, and sensations of appearing menstrual flow, it is useful. It may be given for the erratic pains and reflex nerve irritations of the last months of pregnancy, the reflex cough and unbearable muscular cramps and twitchings. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 36 Administration—It may be necessary to vary the form of the remedy in its administration in certain cases before a marked result occurs. It may act promptly in doses of from one- half to one drop frequently repeated, and it may be necessary to give five drops or more at a dose, but close watch must be kept on its action upon the bowels that it be not too severe and prostrating. The agent has a general tonic influence which so sustains the body forces that considerable violence of cathartic action can be obtained in some cases, without marked depression, but usually this violent action should be avoided. Fluid extracts are usually unreliable and uncertain in their action, some acting promptly, others producing marked irritation and depression, and still others being inert. If the fresh root of the apocynum can be obtained, an infusion of one ounce to the pint of water may be made, and from a teaspoonful to a tablespoonful of this infusion given often and increased or diminished as indicated. A tincture carefully prepared from the fresh root sometimes is the superior preparation. While specific medicine apocynum and the normal tincture of apocynum are both excellent forms of this remedy for administration, there are some cases in which these produce considerable irritation of the stomach and intestinal canal. A distilled extract of apocynum is now supplied, which is nearly tasteless; can be administered in larger closes, and in many cases produces more satisfactory results than any other form, as it has less irritating properties. Physiological Action—Whether this agent acts most directly upon the heart or upon the kidneys has been an unsettled question except to those who have used it in cases where the heart was greatly enfeebled and relaxed, and when dropsy resulted from that condition. It is certainly an excellent heart tonic in such cases, improving the strength of the heart muscle, the character and force of the pulse, and increasing to a most marked extent the arterial tonus. It strengthens the nerve force, improves the respiration, and facilitates oxidation of the blood. Its influence is similar to convallaria or digitalis, and it acts in harmony with cactus, the influence of both being increased. Given in large doses, it stops the Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 37 heart in complete systole, and in small doses slows the beats and strengthens their force. It contains an active principle which acts as does digitalis, with, however, these differences, that it is not cumulative, and when administered in a medicinal dose it does not give rise to any inconvenience excepting some headache. Froment has reported ten instances of diverse cardiac disease in which the pulse was slowed, the rhythm was made regular, the arterial tension was raised, and edema disappeared; in certain cases it acted when strophanthus and tincture of convallaria had failed. It seems to be useful in certain febrile conditions where the frequency of the pulse gives rise to anxiety, notably so in pulmonary tuberculosis, although a large dose may increase the diarrhea if present. Wood conducted independent experiments to determine the physiological action of this remedy, under the auspices of the National Academy of Science. His observations have confirmed my early and later statements concerning the direct influence of apocynum upon the heart. He states that, notwithstanding all early observations were made with reference to the action of this drug upon the kidneys, his experiments prove that its influence is directly upon the circulation. Injected into the veins of a dog, there was a marked slowing of the pulse with a rise in the blood pressure, usually, but in some cases the slowing of the pulse was so great and so immediate as to prevent any rise of blood pressure.
When their function is disrupted 100 mg topiramate amex, heart rate is disturbed buy 200mg topiramate amex, thus resulting in various clinical symptomology cheap topiramate 200mg on-line. Arrhythmia may also be associated with ectopic centers, which generate impulses more frequently than normal pacemakers. The rhythm of heart contractions depends on many parameters: condition of pacemaker cells and the conduction system, myocardial blood flow, and other factors; consequently, arrhythmia can originate for different reasons that are caused by disruptions in electrical impulse generation or conduction. They can be caused by heart disease, myocardial ischemia, electrolytic and acid–base changes, heart innervation problems, intoxication of the organism, and so on. Drugs used for treating arrhythmia can have an effect on the electrical conduction sys- tem of the heart, its excitability, automatism, the size of the effective refractory period, and adrenergic and cholinergic heart innervation. Accordingly, compounds of various chemi- cal classes can restore heart rate disturbances. As already noted, arrhythmia originates from problems forming electric impulses and propagating them to the heart, or when both of these happen simultaneously, which can be accomplished by transferring Na ,K , and Ca2 ions through cell membranes. Therefore, the mechanism of action of many antiarrhythmic drugs consists of blocking Na and Ca ion channels of the myocardium, which prolongs the time necessary for restoration after being activated by these channels, and which in turn acts on the electrical conduction sys- tem of the heart, its excitability, automatism, and so on. Based on an understanding of the mechanism that causes tachycardia, which requires a good understanding of electrophysiology, and an understanding of the effects of various group of drugs on this mechanism, in most cases a specific drug for a specific patient can almost always be selected. Classifying antiarrhythmic drugs is based on different principles; for example, the loca- tion of the drug action. They can be substances that act directly on the myocardium and the conduction system of the heart itself, or substances that have an effect on the efferent 245 246 18. They can be viewed as groups of drugs effective for supraven- tricular arrhythmia, and those effective for ventricular arrhythmia. Currently, however, the more or less universally accepted classification of drugs used for treating tachyarrhythmia is based on the characteristics of their effect on electrophysio- logical or biochemical processes in the myocardium. The first group is made up of drugs that block Na channels of the myocardium (quinidine, procainamide, disopyramide, lidocaine, tocainide, phenytoin, mexiletine, flecainide, encainide). Drugs that block action of endogenous catecholamines on the heart that have certain significance in the pathogenesis of arrhythmia belong to the second group of antiarrhythmia drugs (β- blockers—propranolol etc. The third group is made up of drugs, which predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased (amiodarone, bretylium). Finally, the fourth group of antiarrhythmic drugs is represented by antianginal drugs— Ca2 channels blockers (verapamil). These groups, in particular the first group, are in turn subdivided based on specific char- acteristics of various substances within that group. Some researchers adhere to a system of dividing antiarrhythmic drugs into five groups without putting them in subgroups. This series of drugs prolongs action potentials and increases the effective refractory period of the myocardium. Automatism of ectopic centers is suppressed in the myocardium, primarily in the ventricles. The antiar- rhythmic drugs quinidine, procainamide, and disopyramide belong to this subgroup. Drugs of this subgroup are used for treating irregular sinus rhythm, paroxysmal, supraven- tricular, and ventricular arrythmia, preventing arterial fibrillation, and premature heart- beats. Quinidine only differs from quinine in the configuration of the carbon atom of the carbinol group, and it can be made by isomerization of quinine (37. Quinidine is used in various forms of arrhythmia for preventing tachycardia and atrial fibrillation, and particularly for preventing ciliary fib- rillation, paroxysmal supraventricular tachycardia, extrasystole, and ventricular tachycar- dia. As an antiar- rhythmic, procainamide is preferred over procaine because unlike procaine, it is better absorbed when taken orally and it is more difficult for the esterases of the plasma to hydrolyze it, which results in long-lasting action. Procainamide is intended for treating paroxysmal atrial tachycardia, atrial fibrillation, premature ventricular contraction, and ventricular tachycardia. For quickly reaching thera- peutic concentrations, parenternal introduction of procainamide is preferred over cynidine. Synonyms of this drug are amidoprocaine, cardiorythmine, novocainamide, pronestyl, and others. It causes a decrease in contractability and excitabil- ity of the myocardium, slowing of conductivity, and suppression of sinoatride automatism. Disopyramide is used for preventing and restoring atrial and ventricular extrasystole and tachycardia in order to prevent atrial flutter and arrhythmia. This drug is also prescribed under the name dicorantil, dimodan, napamid, norpace, rhythmilen, rhythmodan, and others. This means that they have little effect on healthy regions of the myocardium because they are quickly eliminated from nor- mal, open Na channels. In terms of myocardial ischemia, hypoxia causes cellular mem- branes to depolarize and arrhythmogenic centers to emerge. During this, many Na channels are inactivated and become sensitive to drugs of this class, which increase con- ductivity and reduce the repolarization time of heart cells. Drugs of this subgroup—lidocaine, tocainide, and mexiletine are local anesthetics; however, they are used for severe ventricular arrhythmia that can originate during myocardial infarction, surgical intervention, catheterization of the heart, and intoxication by cardiac glycosides. Penytoin, which does not belong to the class of local anesthetics and is an anticonvulsant drug, is used only as an oral agent, thus replac- ing lidocaine in paroxysmal tachycardia caused by intoxication. Lidocaine is usually administered intravenously for short-term therapy of ventricular extrasystole, tachycardia, especially in the severe phase of myocardial infarction, arrhythmia of natural cause, and for arrhythmia that can originate in the heart during surgical manipulations.