By M. Anog. Pennsylvania State University at Harrisburg. 2019.
It can be manifested in severe form buy lithium toronto, as a sharp decline in cardiac output with symptoms of disrupted blood flow cheap 150mg lithium free shipping, and in chronic form purchase lithium 300mg, which is manifest as heart pain. In addition to inotropic agents, also used for treating cardiac insufficiency are: diuret- ics (Chapter 21), which increase sodium ion and water secretion from the organism, lower the volume of circulated blood, increase the workload on the heart, and relieves edema; vasodilating agents (vasodilators), which facilitate reduction of venous and arterial blood pressure, thus reducing vessel tonicity and therefore workload on the heart, and reducing the need for oxygen. Adrenomimetics, epinephrine (adrenaline), norepinephrine (nora- drenaline), isoproterenol, terbutaline, and albuterol are sometimes also used because of their ability to enhance strength of cardiac contractions and stimulate an elevation in car- diac output. However, the simultaneous raise in heart rate, have arrythmogenic action, and also increase the myocardial need for oxygen, which is undesirable and can lead to increased ischemia. Cardiotonic Drugs into dopamine in the organism, thus being an oral form of dopamine in the form of a pro- drug. All of the mentioned sympathomimetics are limited to short-term use (24 h or less) for supporting the heart. Optimal therapy for cardiac insufficiency frequently requires simultaneous use of two or more of the aforementioned groups of drugs. The main property of cardiac glycosides is their selective action on the heart, the main effect of which is the strengthening of systole, which creates a more economic condition for heart work: strong systolic contractions change into periods of “rest” (diastole), which facilitate restoration of energetic resources of the myocardium. The general cardiodynamic effects of cardiac glycosides are quite complex because of the combination of their direct action on the heart and indirect action, which changes the electrophysiological properties of the heart (automatism, conductivity, and excitability). There is reason to believe that cardiac glycosides, like other inotropic substances, act on the contractibility of the heart by affecting the process of calcium ion transfer through the membrane of myocardiocytes. Cardiac glycosides are used for treating severe, chronic cardiac insufficiency, for cer- tain forms of cardiac arrhythmia, and for cardiac shock. They are examined as a single group since they have similar pharmacological characteristics. When choosing a drug of this series, not only its activity should be taken into consideration, but also the speed with which it takes effect, which depends a great deal on the physicochemical properties of this series of drugs, which can be subdivided into polar and nonpolar. Strophanthin, which is used in injectable form and whose effect is already observed within 5–10 min after introduc- tion, is usually grouped with polar (hydrophilic) glycosides. Digitoxin and digoxin, which are generally taken orally or rectally, and whose effects are seen within 2–4 h after introduction are grouped with nonpolar glycosides. Strophanthin or corglucon are intravenously administered for severe cardiovascular insufficiency and sudden decompensation. That which is usually extracted from both types of Digitalis is made up of already par- tially hydrolyzed glycosides. Purpureaglycoside A and B are natural glycosides contained in Digitalis purpurea that are broken down by enzymes into digitoxin and glucose, or 17. During alkaline hydrolysis, Lanthozide A liberates an acetyl group and turns into purpureaglycoside A, while lanthozide B turns into purpureaglycoside B. The structure of two of these lanthozides, lanthozide B and lanthozide C differs only in that lanthozide B has a hydroxyl group at C16 of its genin (ditox- igenin), while in the genin of lanthozide C (digoxigenin) there is an additional hydroxyl group at C12 of genin. The product usually extracted from both types of Digitalis is made up of already par- tially hydrolyzed glycosides, namely digitoxin and digoxin. A mixture of cardiac glycosides isolated from Strophantus kombe mainly contains K-strophanthin-β and K-strophanthozide. K-Strophanthin-β consists of the aglycon of strophanthidin and a sugar residue made up of cymarose-β-D-glucose. K-strophantozide has a sugar residue of three units: cymarose- β-D-glucoso-α-D-glucose. The carbohydrate part of various cardiac glycosides can be mono-, di-, tri-, and tetrasaccharide, and the aglycon (genin) is a steroid with certain unique structural char- acteristics. The main purpose of sugar residues is evidently to facilitate solubility of genins. The following unique structural features are characteristic of glycons of cardiac glyco- sides: a coupling of rings A and B—cis, rings B and C—trans, rings C and D—cis, and a butenolide region is located at position 17β. The main purpose of sugar residues, which esterify hydroxyl groups at C3, evidently lies in facilitating the solubility of genins. The most simple cardiac genins, digitoxigenin, gitoxigenin, and strophanthidin are aglycons of the most important glycosides Digitalis lanta, Digitalis purpurea, and Strophantus kombe. It differs from digitoxin in that it has an additional hydroxyl group at C16 of the steroid skeleton. It is extracted form the leaves of Digitalis lanta, Digitalis orientalis, or Scrophulariaceae [10–16]. It is used from chronic cardiac insufficiency in decompensated valvular disease of the heart, myocardium overload in arterial hypertension, tachycardia, ventricular fibrillation, and other analogous situations. Strophanthin: Strophanthin is made up of a mixture of glycosides, mainly K-strophan- thin-β,3β,5,14-trihydroxy-10-oxo-5β-card-20(22)-enolide-3-D-cymaro-β-D-glycoside (17. However, digitalis drugs can be counter productive in some patients for a number of reasons. Theophylline has been intensively studied as an inotropic agent; how- ever, it turned out to be unfit for long-term use. Derivatives of the bipiridine series, such as amrinone and minrinone, have recently been found useful as inotropic agents. They are used for short-term control of patients that inadequately react to cardiac glycosides, diuretics, and coronary vasodilating agents. Reacting this with cyanoacetamide gives 3-cyano-5-(4-piridyl)-2(1H)-pyidinone (17. Hydrolysis of the cyano group of this product gives 3-carbamyl-5-(4-piridyl)-2(1H)-pyidi- none (17. A Hofmann rearrangement of this product (using bromine in sodium hydroxide) gives amrinone (17. Reducing the nitro group of this product with hydrogen gives the desired amrinone (17. It is unique in that it causes dila- tion of vessels and does not cause arrhythmia or signs of myocardial arrhythmia. Amrinone is used for short-term treatment of cardiac insufficiency that does not respond to treatment of other drugs. Arrhythmia results from disruptions in the formation of electric impulses and their conduction to the heart, or when both of these happen simultaneously. Heart rate normally depends on the activity of pacemaker cells of the synoatrial ganglia. When their function is disrupted, heart rate is disturbed, thus resulting in various clinical symptomology. 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.
However purchase 150mg lithium mastercard, in a magnetic feld the magnets will be oriented “with” or “against” the magnetic feld purchase lithium 150 mg with mastercard. The two states have different energies – and the energy difference increases with the feld B as shown order lithium 150 mg otc. It is possible to induce transitions between the energy states by electromagnetic radiation. The condition for inducing transitions between the energy states is that the energy of the radiation (hn) is equal to the energy difference. The condition for an absorption can be written: hn = gbB for electrons and hn = g b B for protons N N The fgure indicates that we can have resonance at any given frequency as long as the magntic feld follows the resonance condition. However, it is a big difference since gb for electrons is much larger than g b for protons. The electromagntic radiation yields transitions in both directions with the same probability. Thus, if the populations of the two levels is equal, the net result would be nil – neither absorption, nor emis- sion. The population of the states follows a Boltzman distribution with the lowest level most popu- lated. In order to have a constant absorption, the difference in population must be kept. It appears that these relaxation times changes when going from normal to pathological tissue – and this can be used in diagnostics. It is therefore easy to understand that it is possible to fulfll the resonance condition for a small volume element. However, it is a long way from a volume element to a picture – and the question is: How is it possible to go from a point (a tiny volume element) to construct a whole picture? The frst solution of this came when Paul Lauturbur tried out his ideas in the early 1970s. He intro- duced magnetic feld gradients and by analysis of the characteristics of the emitted radio waves, he was able to determine their origin. In 1973 206 he demonstrated how it was possible to see the difference between tubes flled with water from an environment of heavy water. These very frst experiments showed that one could use a set of simple linear gradients, oriented in three dimensions and slowly build up a picture. Peter Mansfeld showed how the radio signals could be mathematically analyzed, which made it possible to develop a useful imaging technique. This snap-shot technique meant that in principle complete two-dimensional images could be achieved in extremely short times like 20 – 50 ms. They are rapidly turned on and off (which causes that banging noise), and the gradient magnets allow the scanner to image the body in slices. The transverse (or axial, or x-y) planes slice you from top to bottom; the coronal (x-z) plane slice you lengthwise from front to back; and the sagittal (y-z) planes slice you lengthwise from side to side. Y Coil Z Coil X Coil Transceiver Patient An illustration of the feld gradient coils. Mansfeld showed how the radio signals can be mathematically analyzed, and thus made the image possible. Echo-planar imaging allows T weighted im- 2 ages to be collected many times faster than previously possible. The electromagnets consist of a so- lenoid cooled down to about 4 K by liquid helium. At such temperatures superconduction is attained and it is possible to send large currents through the solenoid and thus get the large magnetic felds required. For parts of the body with bones it is dif- fcult to use x-rays to study the tissue around – because the bones absorb the x-rays much more than the tissue. This is a Lanthanide element (atomic number 64) that is paramagnetic and has the effect that it strongly decrease the T1 relaxation times of the tissues. These compounds are taken up by, and accumulate in, glycolytically active cells, such as rapidly dividing tumor cells. These compounds also bind to albumin in the blood, allowing for the assessment of blood volume at tumor sites prior to cellular uptake (similar to imaging with gadolinium), a valuable diagnostic indicator and tool for treatment response in its sur- roundings. Formation of ultrasound In 1880 Pierre Curie and his brother Jacques discovered that certain crystals (the socalled piezoelec- tric crystals) can produce a pulse of mechanical energy (sound pulse) by electrically exciting the crystal. Furthermore, the crystals can produce a pulse of electrical energy by mechanically exciting the crystal. This ultrasound physics principle is called the piezoelectric effect (pressure electricity). Crystalline materials with piezoelectric properties are quartz crystals, piezoelectric ceramics such as barium titanate or lead zirconate titanate. A device that converts one form of energy into another is called a “transducer” – and they can be used for production and detection of diagnostic ultrasound. We are not going into more details about the equipment here, but it is possible to use ultrasound tech- nique to produce pictures of the inside of the body. Since ultrasound images are captured in real-time, they can show the structure and movement of the body’s internal organs, as well as blood fowing through the blood vessels. Ultrasound imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. A short history The origin of the technology goes back to the Curies, who frst discovered the piezoelectric effect. Attempts to use ultrasound for medical purposes startet in the 1940s when they used a contineous ultrasonic emitter to obtain images from a patient`s brain. The use of Ultrasonics in the feld of medicine had nonetheless started initially with it’s applications in therapy rather than diagnosis, utilising it’s heating and disruptive effects on animal tissues. An excellent review of the history of ultrasound can be found in the following address: http://www. The transducer is coupeled to the body by a gel and the pulse of ultrasound goes into the soft tissuse (speed of about 1500 m per second). The transducer will then sense the refected, weaker pulses of ultrasound and transform them back into electrical signals. These echoes from different organs are amplifed and processed by the receiver and sent to the computer, which keeps track of the return times and amplitudes. You can see how arms and legs of a fetus move, or see the heart valve open and close. Computer Receiver A lot of technology is involved in the different parts Transducer of the ultrasound technique. Let us shortly mention that the transducer, that trans- mits and receives the ultrasound energy into and from the body is a key component. It is built up of hundreds of transducers in order to take a high reso- The main components of ultrasound lution real-time scan.
Materials needed: shoe box aluminum foil stiff paper 2 bolts and nuts nail 4 alligator clip test leads (3 very short buy 150mg lithium fast delivery, 1 about 24 inches) 2 ordinary light switches cheap lithium uk. Make a hole through each with a small nail buy lithium 150 mg without a prescription, and enlarge with a pencil point until you can fit a small bolt through. The bolt should be at least one inch long, to make it easy to clip leads to inside the box. Mount two ordinary light switches on the front side of the shoe box, one in front of each plate. Push a pin from the inside through the screw holes, enlarge them, and replace the screws from the out- side. Using a short alligator clip test lead, attach the tissue plate bolt to the tissue switch at one screw terminal. If there are three screw terminals, one will be green for ground—do not use it, use the other two. Finally at- tach a long alligator clip test lead to the other substance switch screw terminal. If you can not find all plastic boxes, remove the metal top and mount the test plates to the bottom. The places to attach the probe and handhold are described with the circuit instruc- tions. Acceptable For the probe use an empty ball point pen (no ink) with a metal collar by the point. For the hand- hold use a cheap metal can opener (the kind that fills your hand) Fig. Best The Archer Precision Mini-Hook Test Lead Set has a ba- nana plug for the probe on one end and a mini-hook on the other end for easy attachment to the circuit. The best hand- hold is simply a 4 inch piece of ¾ inch copper pipe (which a hardware store could just saw off for you) connected to the cir- cuit with a three foot alligator clip test lead. The leads (wires) you need to do this depend on the terminals your stereo has, but the end of the lead to the circuit should have either alli- gator clips or mini-hooks for easy attachment. Best The Archer Mini Amplifier Speaker is inexpensive and small (about the size of a transistor radio), making it easy to take with you. Remove the screw at the center back of the speaker using a Phillips screw driver to gain access to the battery compartment. If there are no holes use alliga- tor clip leads, but slip a piece of plastic tape between the posts to make sure the alligator clips do not touch each other. A dermatron is a device invented dec- ades ago to measure body resistance (as opposed to skin resistance which is what lie detectors measure). The Easy Way Circuit Build The Electrosonic Human (in the 200 in One Elec- tronic Project Lab by Science Fair, Cat. If your kit has a different catalog number you may have different connection numbers. Instead of connecting the probe to terminal T2, just clip it directly to terminal 137, and remove the 137-T2 wire. Simi- larly, clip the handhold to terminal 76 and remove the 76-26 and 25-T1 wires. Later, when you use the probe to press against your knuckle you may find it painful. Positive (the short post, if using the 1/8 inch phono jack) goes to 53, and negative (long post) goes to 54. If it does not, check that your alligator clips are not bending the spring terminals so much that other wires attached there are loose. Get a shoe box, save the lid, photocopy the picture in this book and tape it to the bottom (inside) of the box. Mount the light switch (a) just like you did for the test plates on the front of the shoe box. Pierce a hole with a large nail or pencil for the shaft of the potentiometer (b), and a smaller hole for the tab on the side of the potentiometer (the tab keeps the potentiometer from rotating when you turn the switch). Remove the nut and washer from the base of the potentiometer shaft, in- sert the shaft into the hole from the inside of the shoe box. When the ceramic part is almost touching the box, bend the wires inside to keep it in place. The ca- pacitors look very much alike, so be careful not to switch them (open one capacitor package at a time and put the part directly in place, double checking the diagram). Hold it in your left hand with the flat side on the left and wires pointing up at you. Bend the base wire away to the left slightly so you will be able to insert the transistor into the triangle of holes. A diagram on the transistor package tells you that the top wire is the “collector” and the bottom wire is the “emitter”. Insert the transistor from the outside of the box so each wire goes where it is supposed to, and bend the wires sideways to secure. If they are not, strip away ¼ inch of insulation and twist the strands together on each wire to keep them neat (practice using the wire stripper, first, on a different piece of wire). Push them through the box and bend them down with a knife or screwdriver on the inside to keep the trans- former firmly in place or tape the transformer to the out- side of the box. You will only use three batteries, so in one of the battery slots, fill the space with a paper clip. Hook the other end to the spring, and thread the straight part through the hole on the other side. In the picture there are both mini- hook and alligator clips depicted, but it is not important which kind you use, only that you make secure connec- tions. The speaker should produce a sound like popping corn (readjust speaker volume to a comfortable level). Now turn the knob almost fully counter-clockwise, mark the box, and listen to this pitch. After you have used the Syncrometer for a while you may wish to take your device to an electronics shop and ask some- one to mount the components in an all plastic box and solder the connections. This would let you travel with it in your suit- case without mashing it into a jumbled mess of wires. Using another alligator clip connect the other screw terminal to your other test surface (the “tissue plate”). You were probably trained to listen for a slight current in- crease when testing substances. The concept was if the sub- stance was anywhere in the body there would be higher conductance. Resonance will occur when a substance and a tissue specimen are placed on your test plates that precisely match a body tissue and substance. With the additional infor- mation of where the substance has accumulated in the body, you can make much more accurate determinations how prob- lems originate. You now have the following equipment: • Electronic circuit with speaker • Test surfaces • Probe and handhold You are ready to learn to use them.
Water has a very high dielectric constant (80 Debye units [D] versus 21 D for acetone) order discount lithium online, which counteracts the electrostatic attraction of ions generic 300 mg lithium free shipping, thus favoring further hydration order lithium uk. The dielectric constant of a medium can be defined as a dimensionless ratio of forces: the force acting between two charges in a vacuum and the force between the same two charges in the medium or solvent. Since D appears in the denominator, the higher the dielectric constant, the weaker the interaction between the two charges. Compounds containing such func- tional groups dissolve to a greater or lesser extent, depending on the proportion of polar to apolar moieties in the molecule. Solutes cause a change in water properties because the hydrate “envelopes” (which form around solute ions) are more organized and therefore more stable than the flickering clusters of free water. The properties of solutions, which depend on solute concentration, are different from those of pure water; the differences can be seen in such phenomena as freezing-point depression, boiling-point elevation, and the increased osmotic pressure of solutions. Water molecules cannot use all four possible hydrogen bonds when in contact with hydrophobic (literally, “water-hating”) molecules. This restriction results in a loss of entropy, a gain in density, and increased organization. So-called “icebergs”—water domains more stable than the flickering clusters in liquid water—are formed. Such ice- bergs can form around single apolar molecules, producing inclusion compounds called clathrates. The interaction between a solute and a solid phase—for example, a drug with its lipoprotein receptor—is also influ- enced by water. Hydrate envelopes or icebergs associated with one or the other phase will be destroyed or created in this interaction and may often contribute to conformational changes in macromolecular drug receptors and, ultimately, to physiological events. Hydrophilic (“water-loving”) molecules are also relevant to the process of drug design. Water is one of the most impor- tant players in determining the pharmacokinetic properties of a drug molecule. Water bathes every drug molecule, hydrogen bonding to important functional groups of the molecule (see figure 1. Despite these obvious facts, water has frequently been forgotten during the drug design process. In the past (and still to this day), many computer-aided studies on drugs calculated the drug properties in vacuo, completely neglecting the influence of water. In future, comprehensive studies of drug structure must include an equally comprehen- sive evaluation of the role of water. However, the equally important nonaqueous structures of cells, such as plasma membranes or the membranes of organelles, are of a lipid nature, and prefer to dissolve nonpolar hydropho- bic (lipophilic) molecules. Theoretically, there are no absolutely insoluble compounds; every molecule is soluble in both the aqueous and nonaqueous lipid “compartments” of a cell. The pro- portion of these concentrations at equilibrium—or the ratio of solubilities—is called the partition coefficient; partition coefficients are extremely important when understanding the properties of drug molecules. Most successful drugs exhibit solubility to some extent in both water and lipid environments. Ionization, molecular struc- ture and size, stereochemistry, and electronic structure all influence the basic interac- tions between a solvent and solute. The ion or molecule will thus acquire a hydrate envelope and separate from the bulk solid; that is, it dissolves. The interaction of nonpolar compounds with lipids is based on a different phenomenon, the hydrophobic interaction, but the end result is the same: formation of a molecular dispersion of the solute in the solvent. Although successful drugs tend to exhibit solubility in both aqueous and lipid envi- ronments, there are a few examples in which solubility in only one of these phases cor- relates with pharmacological activity. One such example is the local anesthetic activity of p-aminobenzoic acid esters, which is partly proportional to their lipid solubility. Another thoroughly investigated example is the bactericidal activity of aliphatic alco- hols. In the homologous series beginning with n-butanol and ending with n-octanol, the bactericidal activity changes with increasing molecular weight. Whereas n-butanol and n-pentanol are active against Staphylococcus aureus, higher members of the series fail to kill the bacteria because the necessary concentration cannot be reached, arising from solubility considerations. Since partition coefficients are difficult to measure in living systems, they are usually deter- mined in vitro, using n-octanol as a model of the lipid phase and an aqueous phosphate buffer at pH 7. P is also an additive property of a molecule, since each functional group helps determine the polarity and therefore the lipophilic or hydrophilic character of the molecule. These substituent con- tributions are widely utilized in quantitative structure-activity studies, as discussed in chapter 3, section 3. Partition coefficients thoroughly influence drug transport characteristics during the pharmacokinetic phase; that is, partition coefficients affect the way drugs reach the site of action from the site of administration (e. Drugs are usually distributed by the blood, but must also penetrate and traverse many barriers before reaching the site of action. Hence, the partition coefficient (which reflects a drug’s ability to be soluble in both aqueous and lipid phases) will determine what tissues a given compound can reach. On the one hand, extremely water-soluble drugs may be unable to cross lipid barriers (e. On the other hand, compounds that are very lipophilic will be trapped in the first lipid environment they encounter, like fat tissue, and will be unable to leave this site quickly to reach their target. Naturally, the partition coefficient is only one of several physicochemical para- meters that influence drug transport and diffusion, which itself is only one aspect of drug activity. The effect increases with increasing partition coefficient, regardless of the structure of the substance. Although the absolute drug concentration necessary to achieve anesthesia varies greatly, the drug concentration in the lipid phase—that is, in the cell membrane—is within one order of magnitude, or 20–50 mM, for all anesthetic agents. In 1954, Mullins, in a modification to the Overton hypothesis, proposed that besides the membrane concentration of the anesthetic, its volume, expressed as its volume frac- tion (mole fraction × partial molal volume), is important. This reasoning implied that the anesthetic, due to its solubility properties, expands the cell membrane, and that anesthesia occurs when a critical expansion value is reached, at about 0. The notion that general anesthesia was solely a property of molecule lipid solubility persisted into the 1990s. Until that time, it was felt that a high value of logP (logarithm of the octanol–water partition coefficient) would enable molecules somehow to affect neuronal membrane structure (“influencing membrane fluidity and function”), thereby inducing anesthesia. However, by the mid 1990s it was realized that this time-honored notion of how general anesthetics worked was probably incorrect. To be successful during the pharmacokinetic phase of drug action, the drug molecule should demonstrate the right combination of lipid solubility and water solubility. If the logP value is too low, the compound is too water soluble and thus will be unable to penetrate lipid barriers and will be excreted too rapidly; if the logP value is too high, the com- pound is too lipid soluble and will be undesirably sequestered in fat layers. Being able to predict these solubility properties is important to the process of drug design. Accordingly, being able to determine, calculate, or predict logP values is highly desirable to the drug designer. The central importance of logP values in drug design and in determining the phar- macokinetic properties of a drug was extensively studied by Hansch in the 1960s. Hansch pioneered the importance of logP values in structure–activity relationship stud- ies (see section 3.
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