Michele Manahan, M.D.

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0015818/michele-manahan

If the drug dissolves very slowly gastritis healing symptoms purchase clarithromycin 500 mg, then very little drug will be able to pass into solution while the formulation is in the body gastritis kiwi order clarithromycin 250 mg with visa. This is likely to result in drug concentrations too low to have a therapeutic effect treating gastritis with diet 500 mg clarithromycin buy with mastercard. If the solubility is very low gastritis extreme pain purchase clarithromycin toronto, it is less likely that a therapeutic concentration will be reached treating gastritis naturally purchase clarithromycin with a mastercard. Most often, drugs that are highly soluble also dissolve quickly, but this is not always true. The concepts of kinetics are equally useful in the consideration of chemical processes, in which there is a change in the molecular structure of the species being considered. Because molecular mobility is high in the liquid and gas phases, the processes are uniform throughout the whole reacting mass. Heterogeneous processes involve more than one phase: for instance, a solid dissolving into a liquid. These processes frequently can only occur at the phase boundary and their rates depend on the supply of fresh material to this boundary. In a bimolecular process, two molecules must collide with sufficient energy (and in an appropriate orientation) to react, and the likelihood of collision depends on the concentration of each species. Rate laws and order of reaction Much of the material in this chapter will be discussed in the context of chemical reactions, but the same principles apply equally to physical processes. This is because for them to react, molecules must collide, and the probability of collisions occurring increases with the concentration. The rate of formation of the product C is given by d[C]/dt (the change in the concentration of C per unit time). A negative sign is used for the latter, because the rate is a positive quantity, and the change in the amount of B with time is negative. Given the stoichiometry of this reaction, expressions for the change in concentration of all the species involved can be written: - 1 d[A] d[B] d[C] 1 d[D] =- = = 2 dt dt dt 2 dt (7. The higher the value of x (or y), the greater the influence of the concentration of A (or B) on the rate of reaction. Molecularity the molecularity of a reaction describes the number of reactant molecules involved in forming the product. Some reactions, particularly decomposition processes, are unimolecular, in that only a single molecule is involved in the reaction. In a unimolecular process, a molecule will react if it has sufficient energy to overcome the activation energy barrier. It is also possible to have zero-order processes, in which the rate is independent of the concentration: rate = k (7. A quantitative treatment of rate laws and kinetics is usually needed, which requires the use of some simple concepts of calculus. Background information on these concepts can be found in the texts listed in the bibliography. For an example process A products, the rate law can be written as follows: d[A] = -k dt (7. Zero-order processes In a zero-order reaction, the rate is constant, regardless of the concentration(s) of species present. Zero-order drug release from a formulation can be highly desirable, because it allows the drug concentration in the blood plasma to be maintained at a constant level for prolonged periods. Many processes occurring at phase boundaries appear to be zero order; for instance, decomposition reactions in a suspension. Here it often seems that the rate of decay is constant, but on closer examination the rate may be correlated to the level of light in the container, or the presence of a catalyst (a nonreacting species that accelerates the rate of reaction). Zero-order can be seen where the concentration of reacting material at a surface remains constant either because reaction sites are saturated (enzyme kinetics, drug­receptor interactions) or because it is replenished constantly by diffusion of fresh material from within the bulk. The latter applies to the hydrolysis of drugs in suspensions and drug delivery from dosage forms such as transdermal patches. Conveniently, because k for a first-order process involves no concentration term, it is not necessary to convert experimental data to concentration in order to determine its value. For the zero-order processes discussed previously, concentration data are needed to determine k, but here any experimental measure which is directly proportional to concentration can be used. These values can be used directly to analyse first-order processes, whereas for zero-order (or indeed second or any other order) reactions it is necessary first to use these measurements to calculate the concentrations. For example, the absorbance of light (Abs) by a drug solution is directly proportional to its concentration in accordance with the Beer­Lambert law. This states that Abs = cl, where c is the concentration (in mol dm-3 or mol L-1) and and l are the molar absorptivity and the length of solution the light must pass through respectively. First-order processes are by a significant margin the most common processes in pharmaceutics. For instance, drug decomposition during storage is commonly a first-order reaction, and the passage of drugs from one body compartment to another. For the generic reaction A products, if the process is first order, then the rate law is written d[A] = - k[A] dt (7. In such situations, it is reasonable to make the assumption that the concentration of water is constant throughout the reaction, and thus the reaction will appear to be first order, with a rate constant k (where k = k[H2O]). For two species A and B, their initial concentrations are probably not the same (although they could be). Considering this process, the rate law can be written as d[A] d[B] = = - k[A][B] dt dt (7. Determination of order and rate constant the order of a process and its rate constant are most easily determined by making three plots. For our exemplar process A products, the following would be plotted: Half-life, t1/2 the half-life (t1/2) is the time taken for the concentration of a substance of interest to decline to half its initial value. For instance, for the process A products, t1/2 is the time taken for [A]0 to decline to [A]0/2. Half-life is a particularly useful concept when we are considering drug concentration in the blood, as it gives us an idea of the length of time for which the drug persists in the body. Equations for the half-life can easily be determined from the integrated rate equations. On occasion, the product can itself affect the reaction process, and there may be multiple reactions occurring concurrently. Such processes are termed complex reactions, and there are three main types of these. Reversible reactions Reversible reactions arise where there is an equilibrium between the product(s) and the starting material(s), and the product(s) can reform into the reactant(s): A B+C (7. The forward reaction can be described by the rate constant k1 and the reverse process with k-1. In reversible reactions, the amount of products (B and C) present contributes to the rate of change in the concentration of A. Conversely, if k1 > k2, then A is converted to B more quickly than B is turned into C. The slower step of a consecutive process is described as the rate-determining step. This is because it is this stage of the reaction which governs the overall rate at which the process can go to completion. The overall order of the reaction is also determined by this step: if the rate-limiting step is first order, the overall reaction will be first order. Parallel (side) reactions In this case, the reactant A can form a mixture of products. If a drug decomposition process is considered, then both products are undesirable as they diminish the amount of active ingredient present. Such processes are widely observed in the life sciences, for instance in enzyme­ substrate binding. Its role is to bind the substrate and facilitate the conversion of the latter to the product. The overall rate of reaction is hence the rate at which P is formed ­ this is often referred to as the velocity of reaction, V. This states that after an initial induction period where the concentration of the intermediate increases from zero, its concentration remains constant. Under such concentrations, there are many more substrate molecules than there are enzymes present, and thus the enzyme sites are saturated by substrate. The intercept on the y-axis is given by 1/Vmax, meaning the maximum rate of reaction can easily be determined. At the point at which the line crosses the x-axis, the y value is zero, hence 1/V0 = 0. The values of these parameters give further information on the nature of the enzyme-catalysed process. More quantitative parameters can be extracted from a simple equation known as the Arrhenius equation. This builds on the ideas established at the start of the chapter, where it was noted that for them to react, two molecules must collide with sufficient energy to overcome the activation energy barrier. The exact physical meaning of A is complex, but it can be thought of as the maximum possible rate constant if the reaction were infinitely hot. A is representative of the number of collisions occurring, and the orientation of these collisions (to react, it is not enough for two molecules to simply collide; they must collide in the correct orientation and with sufficient energy). For successful reaction, the incoming nucleophile must not only hit its target molecule, but must also collide with it at the + electrophilic centre where the reaction can occur. As previously discussed, the activation energy, Ea, is the energy barrier which must be overcome for the reaction to proceed. The intercept at 1/T = 0 will be ln A, but because this occurs at infinite temperature. Typically to find ln A, a point on the line is chosen, and the calculated gradient is used to evaluate ln A (and thus give A). The Arrhenius equation is very widely used in pharmaceutics, most commonly in determining the shelf life of medicines. In the early stages of development, it is necessary to obtain approximate data on this quickly so that the development process is not held up. To do this, formulations are commonly aged at elevated temperatures (much greater than the intended storage temperature) and the rate of reaction determined at these temperatures. As discussed in Chapter 49, there are some problems with this approach, but it is very useful for initial approximate studies. Summary this article has considered the fundamental points of reaction kinetics, illustrating these with examples. The detailed mathematics are helpful to understand where equations come from, but the details of the derivations are not so important for our purposes ­ the applications are the real focus of this chapter. In a sealed container, vapours will diffuse to occupy the total space, liquids will flow to fill part of the container completely, whereas solids will retain their original shape unless a compressive force is applied to them. Importantly, their physical form (the packing of the molecules and the size and shape of the particles) can have an influence on the way the material will behave. At normal room temperature and pressure, most drugs and excipients exist as solids; thus the study of solid-state properties is of enormous pharmaceutical importance. Solid particles are made up of molecules that are held in close proximity to each other by intermolecular forces. The strength of interaction between two molecules is due to the individual atoms within the molecular structure. For example, hydrogen bonds occur because of an electrostatic attraction involving one hydrogen atom and one electronegative atom, such as oxygen. The term van der Waals forces is generally taken to include dipole­dipole (Keesom), dipole­induced dipole (Debye) and induced dipole­induced dipole (London) forces. In this context a dipole is where the molecule has a small imbalance of charge from one end to the other, making it behave like a small bar magnet. When the molecules pack together to form a solid, these dipoles align and give attraction between the positive pole of one and the negative pole on the next. Induced dipoles are where the free molecule does not have an imbalance of charge, but an imbalance is caused by a second molecule being brought into close proximity with the first. Crystallization Materials in the solid state can be crystalline or amorphous (or a combination of both). Crystalline materials are those in which the molecules are packed in a defined order, and this same order repeats over and over again throughout the particle. This is not a real molecule ­ it has been drawn to provide an easy representation of a possible crystal packing arrangement. The melting point is the temperature at which the crystal lattice breaks down, due to the molecules having gained sufficient energy from the heating process to overcome the attractive forces that hold the crystal together. It follows that crystals with weak forces holding the molecules together (such as paraffins, which have a only London van der Waals interactions) have low melting points, whereas crystals with strong lattices. Crystals are produced by inducement of a change from the liquid to the solid state. Pharmaceutical examples of crystallizing through cooling include the formation of suppositories, creams and semisolid matrix oral dosage forms (although these will not always yield crystalline material). The other method of crystallization is to have a solution of the material and to change the system so that the solid is formed. At a given temperature and pressure, any solute (where the solute is the material that has been dissolved and the liquid is the solvent) has a certain maximum amount that can be dissolved in any liquid (called a saturated solution). If crystals are to be formed from a solution, it is necessary to have more solute present than can be dissolved, which is known as a supersaturated solution. As crystals form from a supersaturated solution, the systems will progress until there are solid particles in equilibrium with a saturated solution. To make a solid precipitate out of solution one can: · remove the liquid by evaporation, thus making the concentration of solute rise in the remaining solvent (this is the way sea salt is prepared); · cool the solution, as most materials become less soluble as the temperature is decreased; or · add another liquid which will mix with the solution, but in which the solute has a low solubility. Many drugs are crystallized by addition of water as an antisolvent to a solution of the drug in an organic liquid. For example, if a drug is almost insoluble in water but freely soluble in ethanol, the drug could be crystallized by addition of water to a near-saturated solution of the drug in ethanol. To achieve nucleation and growth, it is necessary to have a supersaturated solution.

However gastritis diet management quality clarithromycin 250 mg, in vitro tests have significance only when they are related to in vivo results gastritis for dogs 500 mg clarithromycin with mastercard. Once such a relationship has been established gastritis chronic nausea generic clarithromycin 500 mg amex, in vitro dissolution tests can be used as a predictor of in vivo behaviour gastritis diet emedicine clarithromycin 250 mg order with visa. The importance of dissolution testing gastritis diet quiz discount 250 mg clarithromycin, for quality control purposes, has been widely recognized by official compendia, as well as drug regulatory authorities, with the inclusion of dissolution specifications using standardized testing procedures for a range of preparations. This system has proved extremely useful in aiding the design of oral medicines and has recently been extended with the Biopharmaceutics Drug Disposition 13 Dissolution As mentioned already, for a drug to be absorbed it must first be dissolved in the fluid at the site of absorption. For example, an orally administered drug in tablet form is not absorbed until drug particles are dissolved or solubilized by the fluids at some point along the gastrointestinal tract, depending on the pH­solubility profile of the drug substance. During dissolution, the drug molecules in the surface layer dissolve, leading to a saturated solution around the particles to form the diffusion layer. Dissolved drug molecules then pass throughout the dissolving fluid to contact absorbing mucosa and are absorbed. Replenishment of diffusing drug molecules in the diffusion layer is achieved by further drug dissolution, and the absorption process continues. If dissolution is fast or the drug remains in solution form, the rate of absorption is primarily dependent on the ability of the drug to traverse the absorbing membrane. If, however, drug dissolution is slow because of its physicochemical properties or formulation factors, then dissolution may be the rate-limiting step in absorption and impacts drug bioavailability. Partition coefficient and pKa As pointed out earlier, for relatively insoluble compounds the dissolution rate is often the ratedetermining step in the overall absorption process. Alternatively, for soluble compounds the rate of permeation across biological membranes is the ratedetermining step. Whilst the dissolution rate can be changed by modification of the physicochemical properties of the drug and/or alteration of the formulation composition, the permeation rate is dependent on the size, relative aqueous and lipid solubilities and ionic charge of drug molecules, factors which can be altered through molecular modifications. The absorbing membrane acts as a lipophilic barrier to the passage of drugs, which is related to the lipophilic nature of the drug molecule. The partition coefficient, for example between oil and water, is a measure of lipophilic character. Most low molecular weight drugs are weak acids or bases and, depending on the pH, exist in an ionized or un-ionized form. Membranes of absorbing mucosa are more permeable to un-ionized forms of drugs than to ionized species because of the greater lipid solubility of the un-ionized forms and the highly charged nature of the cell membrane, which results in the binding or repelling of the ionized drug, thereby decreasing penetration. The dominating factors that therefore influence the absorption of weak acids and bases are the pH at the site of absorption and the lipid solubility of the un-ionized species. These factors, together with the Henderson­Hasselbalch equations for calculating the proportions of ionized and un-ionized species at a particular pH, constitute the pH-partition theory for drug absorption. However, these factors do not describe completely the process of absorption as certain compounds with low partition coefficients and/or which are highly ionized over the entire physiological pH range show good bioavailability, and therefore other factors are clearly involved. Crystal properties: polymorphism Practically all drug substances are handled in powder form at some stage during their manufacture into 14 dosage forms. However, for those substances composed of or containing powders or compacted powders in the finished product, the crystal properties and solid-state form of the drug must be carefully considered. In addition, many drug substances can exist in more than one form with different molecular packing arrangements in the crystal lattice. This property is termed polymorphism, and different polymorphs may be prepared by manipulation of the conditions of particle formation during crystallization, such as solvent, temperature and rate of cooling. It is known that only one form of a pure drug substance is stable at a given temperature and pressure, with the other forms, termed metastable, converting at different rates to the stable crystalline form. The different polymorphs differ in their physical properties such as dissolution ability and solid-state stability, as well as processing behaviour in terms of powder flow and compaction during tableting in some cases. These different crystalline forms can be of considerable importance in relation to the ease or difficulty of formulation and as regards stability and biological activity. As might be expected, higher dissolution rates are obtained for metastable polymorphic forms; for example, the alternative polymorphic forms of rifaximin exhibit different in vitro dissolution rates and bioavailability. The polypeptide hormone insulin, widely used in the regulation of carbohydrate, fat and protein metabolism, also demonstrates how differing degrees of activity can result from the use of different crystalline forms of the same agent. In the presence of acetate buffer, zinc combines with insulin to form an extremely insoluble complex of the proteinaceous hormone. This complex is an amorphous precipitate or crystalline product depending on the environmental pH. The amorphous form, containing particles of no uniform shape and smaller than 2 µm, is absorbed following intramuscular or subcutaneous injection and has a short duration of action, whilst the crystalline product, consisting of rhombohedral crystals of size 10 µm to 40 µm, is more slowly absorbed and has a longer duration of action. Polymorphic transitions can also occur during milling, granulating, drying and compacting operations. Granulation can result in solvate formation, and during drying, a solvent or water molecule(s) may be lost to form an anhydrous material. Consequently, the formulator must be aware of these potential transformations which can result in undesirable modified product performance, even though routine chemical analyses may not reveal any changes. Reversion from metastable forms, if used, to the stable form may also occur during the lifetime of the product. In suspensions, this may be accompanied by changes in the consistency of the preparation, which affects its shelf life and stability. Such changes can often be prevented by additives, such as hydrocolloids and surface-active agents. Stability the chemical aspects of formulation generally centre on the chemical stability of the drug and its compatibility with the other formulation ingredients. In addition, the packaging of the dosage form is an important factor contributing to product stability and must be an integral part of stability testing programmes. It has been mentioned previously that one of the principles of dosage form design is to ensure that the chemical integrity of drug substances is maintained during the usable life of the product. At the same time, chemical changes involving additives and any physical modifications to the product must be carefully monitored to optimize formulation stability. In general, drug substances decompose as a result of the effects of heat, oxygen, light and moisture. For example, esters such as aspirin and procaine are susceptible to solvolytic breakdown, whilst oxidative decomposition occurs for substances such as ascorbic acid. Whilst the mechanisms of solid-state degradation are complex and often difficult to analyse, a full understanding is not a prerequisite in the design of a suitable formulation containing solids. For example, in cases where drug substances are sensitive to hydrolysis, steps such as minimization of exposure to moisture during preparation, low moisture content specifications for the final product and moisture-resistant packaging can be used. For oxygen-sensitive drugs, antioxidants can be included in the formulation and, as with light-sensitive materials, suitable packaging can reduce or eliminate the problem. For drugs administered in liquid form, the stability in solution, as well as the effects of pH over the physiological range of pH 1­8, should be understood. Buffers may be required to control the pH of the preparation to increase stability; where liquid dosage forms are sensitive to microbial attack, preservatives are required. In these formulations, and indeed in all dosage forms incorporating additives, it is also important to ensure that the components, which may include additional drug substances as in multivitamin preparations, do not produce chemical interactions themselves. Interactions between the drug(s) and added excipients such as antioxidants, preservatives, suspending agents, colourants, tablet lubricants and packaging materials do occur and must be checked for during the design of formulations. Organoleptic properties Modern medicines require that pharmaceutical dosage forms are acceptable to the patient. Unfortunately, many drug substances in use today are unpalatable and unattractive in their natural state, and dosage forms containing such drugs, particularly oral preparations, may require the addition of approved flavours and/or colours. The use of flavours applies primarily to liquid dosage forms intended for oral administration. The taste buds of the tongue respond quickly to bitter, sweet, salt or acid elements of a flavour. Unpleasant taste can be overcome by use of water-insoluble derivatives of drugs which have little or no taste. An example is the use of amitriptyline pamoate, although other factors, such as bioavailability, must remain unchanged. If an insoluble derivative is unavailable or cannot be used, a flavour or perfume can be used. However, unpleasant drugs in capsules or prepared as coated particles or tablets may be easily swallowed, avoiding the taste buds. Selection of flavour depends on several factors but particularly on the taste of the drug substance. Certain flavours are more effective at masking various taste elements; for example, citrus flavours are frequently used to combat sour or acid-tasting drugs. In addition, the age of the intended patient should also be considered, since children, for example, prefer sweet tastes, as well as the psychological links between colours and flavours. Sucrose continues to be used, but alternatives, such as sodium saccharin, which is 200­700 times sweeter depending on the concentration, are available. Colours are used to standardize or improve an existing drug colour, to mask a colour change or complement a flavour. Lakes, which are generally calcium or aluminium complexes of water-soluble dyes, are particularly useful in tablets and tablet coatings because of their greater stability to light than corresponding dyes, which also differ in their stability to pH and reducing agents. However, in recent years, the inclusion of colours in formulations has become extremely complex because of the banning of many traditionally used colours in many countries. In addition to those properties previously discussed such as particle size and crystal form, other characteristics such as hygroscopicity, flowability and compactability are particularly important when solid dosage forms are being prepared where the drugs constitute a large percentage of the formulation. Hygroscopic drugs can require low moisture manufacturing environments and need to avoid water during preparation. Studies of the compactability of drug substances are frequently undertaken with use of instrumented tablet machines in formulation laboratories to examine the tableting potential of the material so as to foresee any potential problems during compaction, such as lamination or sticking, which may require modification of the formulation or processing conditions. Therapeutic considerations in dosage form design the nature of the clinical indication, disease or illness for which the drug is intended is an important factor when one is selecting the range of dosage forms to be prepared. Factors such as the need for systemic or local therapy, duration of action required, and whether the drug will be used in emergency situations need to be considered. In the vast majority of cases, a single drug substance is prepared in a number of dosage forms to satisfy both the particular preferences of the patient or physician and the specific needs of a certain clinical situation. For example, many asthmatic patients use inhalation aerosols, from which the drug is rapidly available to the constricted airways following deep inhalation for rapid emergency relief, and oral products for chronic therapy. Patients requiring urgent relief from angina pectoris, a coronary circulatory problem, place tablets of glyceryl trinitrate under their tongue (sublingual administration). This results in rapid drug absorption directly into the blood capillaries under the tongue. Thus, whilst systemic effects are generally obtained following oral and parenteral drug administration, other routes can be used as the drug and situation demand. Local effects are generally restricted to dosage forms applied directly, such as those applied to the skin, ear, eye, throat and lungs. Some drugs may be well absorbed by one route but not by another and must therefore be considered individually. Infants generally prefer liquid dosage forms, usually solutions and mixtures, given orally. Children can have difficulty in swallowing solid dosage forms, and for this reason many oral preparations are prepared as pleasantly flavoured syrups or mixtures. Adults generally prefer solid dosage forms, primarily because of their convenience. However, alternative liquid preparations are usually available for those unable to take tablets and capsules. Alternative technologies for preparing particles with the required properties ­ crystal engineering ­ provide new opportunities. Supercritical fluid processing using carbon dioxide as a solvent or antisolvent is one such method, allowing fine-tuning of crystal properties and particle design and fabrication. Undoubtedly, these new technologies and others, as well as sophisticated formulations, will be required to deal with the advent of gene therapy and the need to deliver such labile macromolecules to specific targets and cells in the body. Interest is also likely to be directed to individual patient requirements such as age, weight and physiological and metabolic factors, features which can influence drug absorption and bioavailability, and the increasing application of diagnostic agents will play a key role in this area. This topic incorporates (1) the use of in silico procedures to predict drug substance properties and (2) decision making and optimization tools, such as experimental design, artificial intelligence and neural computing. All these can facilitate faster and rational design of formulations and manufacturing processes. Summary this article has demonstrated that the formulation of drugs into dosage forms requires the interpretation and application of a wide range of information and knowledge from several study areas. Whilst the physical and chemical properties of drugs and additives need to be understood, the factors influencing drug absorption and the requirements of the disease to be treated also have to be taken into account when potential delivery routes are being identified. The formulation and associated preparation of dosage forms demand the highest standards, with careful examination, analysis and evaluation of wide-ranging information by pharmaceutical scientists to achieve the objective of creating high-quality, safe and efficacious dosage forms. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rate. Crystallisation processes in computing and formulation pharmaceutical technology and drug optimization. Aulton Introduction Definition of terms Solution, solubility and dissolution 18 19 19 · · Process of dissolution Dissolution mechanisms Energy/work changes during dissolution 19 19 20 Dissolution rates of solids in liquids Factors affecting the rate of dissolution of diffusion-controlled systems Intrinsic dissolution rate Measurement of dissolution rates of drugs from dosage forms 21 22 25 25 · · · Solubility Methods of expressing solubility and concentration Expressions of concentration Solubility of solids in liquids Solubility of gases in liquids Solubility of liquids in liquids Blending Distribution of solutes between immiscible liquids Solubility of solids in solids 26 26 26 28 32 33 34 34 35 this is not always the case the differences are explained in this chapter the process of dissolution involves a molecule, ion or atom of a solid entering a liquid phase in which the solid is immersed the rate of dissolution is controlled either by the speed of removal of the molecule, ion or atom from the solid surface or by the rate of diffusion of that moiety through a boundary layer that surrounds the solid Various factors influence the rate of diffusion of a solute through a boundary layer Some of these may be manipulated by the formulator It is important for the formulator to be aware of the parameters which affect the solubility of a solid in a liquid phase the dissolution rate and solubility of solids in liquids, gases in liquids and liquids in liquids are each important in pharmaceutical science, and these are discussed Introduction Solutions are encountered frequently in pharmaceutical development, either as a dosage form in their own right or as a clinical trials material. This article discusses the principles underlying the formation of solutions from a solute and a solvent and the factors that affect the rate and extent of the dissolution process. This process will be discussed particularly in the context of a solid dissolving in a liquid as this is the situation most likely to be encountered in the formation of a drug solution, either during manufacturing or during drug delivery. Because of the number of principles and properties that need to be considered, the contents of each of these chapters should only be regarded as introductions to the various topics. The student is encouraged, therefore, to refer to the bibliography at the end of each chapter to augment the present contents. The authors use a large number of pharmaceutical examples to aid the understanding of physicochemical principles.

The cerebellum finally receives second neurons fibres gastritis wiki purchase clarithromycin 250 mg online, whereas from the thalamus relayed third neuron fibres are projected to the sensory areas in the cerebral cortex (Table 3 gastritis diet mayo order clarithromycin 250 mg with visa. The peripheral process of these cells form the sensory fibres of peripheral nerves gastritis and constipation diet discount 500 mg clarithromycin fast delivery. These lie in continuity with each other in the anterolateral white column of spinal cord showing somatotopic lamination gastritis diet home remedy discount clarithromycin 500 mg buy on line. The sensations of pressure gastritis how long generic clarithromycin 250 mg overnight delivery, touch, temperature and pain are lying medial to lateral. Proprioceptive Sensations the sensations like deep touch, pressure, tactile localisation (the ability to locate exactly the proprioceptive part touched), tactile discrimination (the ability to localise two separate points on the skin that is touched), stereognosis (ability to recognise shape of object held in hand) and sense of vibration are carried by fasciculus gracilis and fasciculus cuneatus. These run directly upwards (without relaying in the spinal grey matter) in the posterior column of white matter of spinal cord. The fibres which enter in the coccygeal and lower sacral region are thrust medially by fibres which enter at higher levels. These ascend in the lateral white column of spinal cord anterior to the the reflex proprioceptive sensations are carried by dorsal and ventral spinocerebellar tracts. They convey to the cerebellum both exteroceptive (touch) and unconscious proprioceptive impulses arising in Golgi tendon organ and muscle spindle and are essential for the control of posture (Table 3. Brain­Neuroanatomy 1 Dorsal or posterior spinocerebellar tract: It begins at the level of 3rd lumbar segment of spinal cord. This relay gives rise to second neuron fibres which form dorsal spinocerebellar tract. This uncrossed tract ascends in the lateral column of white matter of spinal cord. Here it is situated as a flattened band at the posterior region of lateral column, medially in contact with lateral corticospinal tract. Functionally, both spinocerebellar tracts control the coordination and movements of muscles controlling posture of the body. The ventral tract conveys muscle and joint information from the entire lower limb, while the dorsal tract receives information from individual muscles of lower limb (Table 3. These are present in anterior, posterior and lateral columns of white matter adjacent to the grey matter of spinal cord. The clinical features involve weakness, atrophy of muscles of hands and arms and later extending to the lower limb. Subacute combined degeneration: the posterior and lateral funiculi are degenerated bilaterally and it is caused due to deficiency of intrinsic factor which helps in absorption of vitamin B12. The symptoms include upper motor neuron lesion with loss of position and vibratory sensation of lower limbs. If all motor neurons reaching a muscle get affected, muscle will be fully paralysed. Anterior spinothalamic Touch (crude) and (axons of 2nd order pressure from opposite neurons) half of body 3. Spinotectal (axons of 2nd order neurons) Afferent limb of reflex movements of eyes and head Dorsal and medial accessory olivary nuclei Tectum or superior colliculus of midbrain a. If upper motor neurons to a muscle get affected, initiation of movement may get lost. Since lower motor neurons are intact, basal ganglia may cause increase in muscle tone, leading to spasticity. Mostly upper motor neuron lesions are in internal capsule and since these fibres have not yet decussated, the functional loss will be on the contralateral side. Contralateral loss of pain and temperature and touch caused due to damage to lateral spinothalamic and anterior spinothalamic tracts. Ipsilateral lower motor neuron paralysis caused due to damage to ventral nerve roots. Ipsilateral anaesthesia over the skin of the segment due to injury to the ventral nerve roots. Above the level: Ipsilateral hyperaesthesia above the level of lesion due to irritation of dorsal nerve roots. As the decussation of lateral and anterior spinothalamic tracts occurs at different levels, there is dissociated sensory loss. As this disease occurs in lower cervical and upper thoracic regions, there is problem in both the upper limbs and front of chest. Partial cord lesion (unilateral): In high cervical lesions, there is weakness of finger movements accompanied by dragging of the leg. The result is loss of sensation and paralysis of muscles on both the sides at the level of section and below the level of section of spinal cord. There is flaccid paralysis of all the muscles including loss of all superficial and deep reflexes below the level of injury. If injury occurs between T1 and L1 segments, then there is paralysis of both lower limbs (paraplegia). Treatment of nerve cell injury is at experimental level only by stem cell transplantation. These get stimulated by burn, chemicals, physical injury, prostaglandins, histamine, etc. Pain can be treated by giving salicylates, which decreases the prostaglandin formation. Spina bifida: In spina bifida, the vertebral arches and spines of a few vertebrae do not develop. Underneath the bony defect, the spinal cord and meninges may also be affected due to failure of mesenchyme forming the verbetral arches. Muscles feel flaccid, tendon reflexes get absent, reaction of degeneration is seen. Case 2 A young person is involved in an automobile accident with injury at cervical 5 and cervical 6 vertebrae. He develops paralysis of all four limbs · What is the type of paralysis person suffering from The vertebral level of termination of the spinal cord during normal and abnormal development. The part of the nervous system affected is the anterior horn cells of the spinal cord from lumbar 2 to sacral 5 segments of spinal cord. The type of paralysis is the lower motor neuron 1­6 From Medical Council of India, Competency based Undergraduate Curriculum for the Indian Medical Graduate, 2018;1:44­80. Differences between upper motor neuron and lower motor neuron paralyses Brain­Neuroanatomy 1. Besides these, they are afferent to special senses like smell, sight, hearing, taste and touch. Some nerves form the afferent loop and others form the efferent loop of the reflex arc. Olfactory takes the sense of smell and stimulates dorsal nucleus of vagus for enhanced secretion, if the smell is good. Statoacoustic nerve is afferent for hearing and balance while spinal root accessory acts as its efferent component for turning the neck to the side from where sound is heard. The mantle layer represents grey matter and the marginal layer represents the white matter. Soon the mantle layer differentiates into a dorsal alar lamina (sensory) and a ventral basal lamina (motor), the two are partially separated internally by the sulcus limitans. The somatic columns are the general somatic efferent (motor or anterior horn) and the general somatic afferent (sensory or posterior horn). The visceral columns are the general visceral efferent (motor) and the general visceral afferent (sensory). In the brainstem, particularly hindbrain, the alar and basal laminae come to lie in the same ventral plane because of stretching of the roof plate (dorsal wall) of neural tube by pontine flexure. Further, the grey matter forms separate longitudinal functional columns, where the motor columns (from basal lamina) are medial and the sensory columns (from alar lamina) are lateral in position. In addition to the four functional columns differentiated in the spinal cord, there appear two more columns (a motor and a sensory) for the branchial apparatus of the head region, namely the special visceral (branchial) efferent and the special visceral afferent; and one column more for the special sense, namely the special somatic afferent. Its fibres enter the oculomotor nerve and supply 4½ extrinsic muscles of the eyeball except the lateral rectus and the superior oblique. It supplies seven out of eight muscles of the tongue through the hypoglossal nerve. Special Visceral Efferent/Branchial Efferent Nuclei the details of the nuclei of cranial nerves are summarized in Table 4. It forms an elongated column lying in both the open and closed parts of the medulla. General Visceral Efferent Nuclei these nuclei give origin to preganglionic neurons that relay in a peripheral autonomic ganglion. Its fibres pass through the oculomotor nerve to the ciliary ganglion to supply the sphincter pupillae and the ciliaris muscles. It gives off fibres that pass through the facial nerve and its branch, the greater petrosal nerve to relay in the pterygopalatine ganglion and supply the lacrimal, nasal, palatal and pharyngeal glands. It sends fibres through the facial nerve and its chorda tympani branch to the submandibular ganglion for supply of the submandibular, sublingual salivary glands and glands in the oral cavity. It gives off fibres that pass through the vagus nerve to be distributed to thoracic and abdominal viscera (the ganglia concerned are present in the walls of the viscera supplied). Through the glossopharyngeal nerve from the tonsil, pharynx, posterior part of the tongue, carotid body and carotid sinus. Through the vagus nerve from the pharynx, larynx, trachea, oesophagus and other thoracic and abdominal viscera. Its upper part also receives sensations of taste (special visceral afferent) as follows: a. From the posteriormost part of the tongue and from the epiglottis through the vagus (X) nerve in its inferior part. Exteroceptive sensations (touch, pain, temperature) from the skin of the face, through the trigeminal nerve; and from a part of the skin of the auricle through the vagus (auricular branch) and through the facial nerve. Proprioceptive sensations from muscles of mastication reach the mesencephalic nucleus through the trigeminal nerve. The nucleus is also believed to receive proprioceptive fibres from the ocular, facial and lingual muscles, teeth and temporomandibular joint. Special Features Muscles of facial expression of lower quarter of the face are supplied only from contralateral motor cortex. The genioglossus muscle of the tongue receives fibres from contralateral motor cortex only. Receptors and the First Neuron 1 the olfactory cells (16­20 million in man) are bipolar neurons. They lie in the olfactory part of the nasal mucosa, and serve both as receptors as well as the first neurons in the olfactory pathway. They pass through the cribriform plate of ethmoid and make synaptic glomeruli with cells of olfactory bulb. Second Neuron the uncus and anterior part of the parahippocampal gyrus, tertiary olfactory cortex in posterior part of orbitofrontal cortex. The fibres reach the cerebral cortex without synapsing in any of the thalamic nuclei. These are located in the primary olfactory cortex which includes the anterior perforated substance, periamygdaloid and prepiriform areas. Third Neuron Third neuron located in the primary olfactory cortex which includes the anterior perforated substance, and several small masses of grey matter around it like periamygdaloid and prepiriform areas. Fourth Neuron Fibres arising in the primary olfactory cortex go to the secondary olfactory cortex (entorhinal area) located in · Anosmia: Loss of olfactory fibres with ageing. These fits are of imaginary disagreeable odours with involvement of tongue and lips. Right eye sees a little additional of right side whereas left eye sees a little additional of left side of the object. Larger right temporal and smaller right nasal fields of vision fuse to form right Brain­Neuroanatomy part of binocular field. Most importantly there is a macular vision which is the most acute or sharp and coloured vision. Retina is also divided into temporal and nasal parts and each is further subdivided into upper and lower parts. Fibres from the nasal parts of the two retinae decussate to form the optic chiasma and travel to the contralateral side in the optic tract. Right optic tract carries the fibres of the right temporal hemiretina and the left nasal hemiretina and vice versa. Macular fibres lie in the central part of optic tract, upper retinal fibres project downwards and lower retinal fibres project upwards. Optic Nerve Optic nerve is made up of axons of ganglion cells of the retina which form the second order neurons. In a strict sense, the optic nerve is not a peripheral nerve because its fibres have no neurilemmal sheaths. A few of its fibres pass to the superior colliculus, the pretectal nucleus and the hypothalamus. Each optic tract contains temporal fibres of retina of the same side and nasal fibres of the opposite side. Lateral Geniculate Body Lateral geniculate body receives the lateral root of the optic tract. Medially, it is connected to the superior colliculus, and laterally, it gives rise to the optic radiation. The cells in this body are arranged in six layers which form the third order neurons. Layers 2, 3, 5 receive ipsilateral fibres, and layers 1, 4, 6 receive contralateral fibres. Objects are identified by integration of these perceptions with past experience stored in the parastriate and peristriate areas 18 and 19.

The short and long branches together thus provide the mesocolic region of the wall with abundant blood supply gastritis xanax generic clarithromycin 250 mg buy. Subserous coat of long branches is intimately related to appendices epiploicae gastritis diet cheese proven 250 mg clarithromycin, to which they contribute branches stomach ulcer gastritis symptoms buy clarithromycin 500 mg visa. During removal of these appendages gastritis vomiting blood discount clarithromycin uk, care must be taken not to pull on them in order to avoid traction on the subjacent vessel gastritis diet menus buy clarithromycin pills in toronto. Bowel wall is weakened where it is pierced by the vessels and at the sites of attachment of appendices epiploicae. Mucosa may herniate in these situations causing diverticulosis, with associated dangers of diverticulitis, fibrosis and stricture. Paracolic nodes, on the medial side of the ascending and descending colon and near the mesocolic border of the transverse and sigmoid colon. In carcinoma of the colon, the related paracolic and intermediate lymph nodes have to be removed. Their removal is possible only after the ligature of the main branch of the superior or inferior mesenteric artery along which the involved lymph nodes lie. It is necessary, therefore, to remove a large segment of the bowel than is actually required by the extent of the disease, in order to avoid gangrene as a result of interference with the blood supply. It is always wise to remove the whole portion of the bowel supplied by the ligated vessel. The midgut territory receives its sympathetic supply from the coeliac and superior mesenteric ganglia (T11 to L1), and its parasympathetic supply from the vagus. Both types of nerves are distributed to the gut through the superior mesenteric plexus. The hindgut territory receives its sympathetic supply from the lumbar sympathetic chain (L1, 2), and its parasympathetic supply from the pelvic splanchnic nerve (nervi erigentes), both via the superior hypogastric and inferior mesenteric plexuses. The ultimate distribution of nerves in the gut is similar to that in the wall of the small intestine. The parasympathetic nerves are motor to the large intestine and inhibitory to the internal anal sphincter. Pain impulses from the gut up to the descending colon travel through the sympathetic nerves, and from the sigmoid colon and rectum through the pelvic splanchnic nerves. It is situated in the right iliac fossa, above the lateral half of inguinal ligament. Vessels and Nerves · Large intestine can be directly viewed by a procedure called colonoscopy. The arterial supply of the caecum is derived from the caecal branches of the ileocolic artery. The nerve supply is same as that of the midgut (T11 to L1; parasympathetic, vagus). Control and Mechanism the lower end of the ileum opens on the posteromedial aspect of the caecocolic junction. Section 1 the valve is actively closed by sympathetic nerves, which cause tonic contraction of the ileocaecal sphincter. Incise the lateral wall of the caecum and locate the ileocaecal orifice and its associated valve. The appendix may lie in front of the ileum (preileal) or behind the ileum (postileal). Although the base of the appendix is fixed, the tip can point in any direction, as described below. The positions are often 1 the appendicular orifice is situated on the posteromedial aspect of the caecum 2 cm below the ileocaecal orifice. It runs behind the terminal part of the ileum and enters the mesoappendix at a short distance from its base. Here it gives a recurrent branch which anastomoses with a branch of the posterior caecal artery. The main artery runs towards the tip of the appendix lying at first near to and then in the free border of the mesoappendix. Blood from the appendix is drained by the appendicular, ileocolic and superior mesenteric veins, to the portal vein. Lumen of Appendix Sympathetic nerves are derived from T9 and T10 segments through the coeliac plexus. Referred pain of appendix is felt at umbilicus, similar to that of small intestine and testis. Lymphatic Drainage It is quite small and may be partially or completely obliterated after mid-adult life. Peritoneal Relations Most of the lymphatics pass directly to the ileocolic nodes, but a few of them pass indirectly through the appendicular nodes situated in the mesoappendix. Abdomen and Pelvis the operation for removal of the appendix is called appendicectomy. Some anatomical facts relevant to the diagnosis and treatment of appendicitis are as follows: · Pain caused by appendicitis is first felt in the region of the umbilicus. Note the fact that both the appendix and the umbilicus are innervated by segment T10 of the spinal cord; appendix by sympathetic fibres and umbilicus by somatic fibres. This is caused by involvement of the parietal peritoneum of the region (remember that parietal peritoneum is sensitive to pain, but visceral peritoneum is not): Appendicitis is common because: i. The point lies at the junction of the lateral one-third and the medial two-thirds of the line joining the umbilicus to the right anterior superior iliac spine. It is due to passage of infected lymph to the subpyloric nodes which cause irritation of pylorus. Anteriorly, it is related to the coils of small intestine, the right edge of the greater omentum, and the anterior abdominal wall. Posteriorly, it is related to the iliacus, the quadratus lumborum, the transversus abdominis, the lateral cutaneous, ilioinguinal, and iliohypogastric nerves and the right kidney. The flexure lies on the lower part of the left kidney and diaphragm, behind the stomach, and below the anterior end of the spleen. The flexure is attached to the eleventh rib (in the midaxillary line) by a horizontal fold of peritoneum, called the phrenicocolic ligament. This ligament supports the spleen and forms a partial upper limit of the left paracolic gutter. Section 2 Abdomen and Pelvis Transverse colon is about 50 cm long and extend across the abdomen from the right colic flexure to the left colic flexure. Anteriorly, it is related to the greater omentum and to the anterior abdominal wall. Posteriorly, it is related to the second part of the duodenum, the head of the pancreas, and to coils of small intestine. The differences between right two-thirds and left one-third of transverse colon are tabulated in Table 20. Descending colon is about 25 cm long and extends from the left colic flexure to the sigmoid colon. It runs vertically up to the iliac crest, and then inclines medially on the iliacus and psoas major to reach the pelvic brim, where it is continuous with the sigmoid colon. Posteriorly, it is related to the transversus abdominis, the quadratus lumborum, the iliacus and psoas muscles; the iliohypogastric, ilioinguinal, lateral cutaneous, femoral and genitofemoral nerves; the gonadal and external iliac vessels. It is suspended by the sigmoid mesocolon and is covered by coils of small intestine. Duodenum is supplied both by branches of coeliac axis (artery of foregut) and by branches of superior mesenteric artery (artery of midgut). Muscularis Externa Outer longitudinal coat is thickened at three places to form taenia coli. At the apex of the loop, it is connected to the yolk sac and grows very rapidly during 6th week, so much so that it protrudes into the umbilical cord. During this herniation and return, the midgut loop rotates by 270° in a counter-clockwise direction. At the same time, it lies against posterior abdominal wall and gets retroperitoneal. Duodenum develops partly from foregut and partly Its cranial part gives rise to left one-third of transverse colon, descending colon, pelvic colon, and proximal part of rectum. The distal part of hindgut is dilated to form the cloaca, which gets separated by urorectal septum into a posterior part-the anorectal canal and an anterior part- the primitive urogenital sinus. Distal or terminal part of anal canal is formed from an invagination of surface ectoderm called the proctodeum. The visceral peritoneum of appendix receives supply from lesser splanchnic nerve, arising from T10 sympathetic ganglion and T10 segment of spinal cord. Ans: Initially, the pain of acute appendicitis is referred to the skin in the region of umbilicus. Afferent nerve fibres from appendix are carried in lesser splanchnic nerve to T10 segment of spinal cord. The afferent impulses from the skin of umbilicus also reach T10 segment through 10th intercostal nerve. Since both the somatic and visceral impulses reach the same segment, and somatic impulses being appreciated better by brain, the pain is referred to the skin of the umbilicus. Investigations and analysis of the positions, fixation, length and embryology of the vermiform appendix, Acta Chir Scand 1973; 139:293­98. This article is the first in a volume dedicated to the development of structure and function of the gut, liver and pancreas. It includes the development of the immunological surveillance mechanisms and gastrointestinal flora. Intraoperative small bowel length measurements and analysis of demographic predictors of increased length. Information on small bowel length in living adults, which varies with sex, height and age. In this article, the coeliac trunk, the superior and inferior mesenteric vessels, and the portal vein will be studied. It supplies all derivatives of the foregut that lie in the abdomen, namely: 1 the lower end of the oesophagus, the stomach and upper part of the duodenum up to the opening of the bile duct. It runs upwards to the left behind the lesser sac to reach the cardiac end of the stomach where it turns forwards and enters the lesser omentum to run downwards along the lesser curvature of the stomach. The common hepatic artery runs downwards, forwards and to the right, behind the lesser sac to reach the upper border of the first part of duodenum. Reaching the porta hepatis, it terminates by dividing into right and left hepatic branches. Branches 1 the gastroduodenal artery is a large branch which arises at the upper border of the first part of the duodenum. The gastroduodenal artery runs downwards behind the first part of the duodenum and divides at its lower border into the right gastroepiploic and superior pancreaticoduodenal arteries. The right gastroepiploic artery enters the greater omentum, follows the greater curvature of the stomach, and anastomoses with the left gastroepiploic artery. The superior pancreaticoduodenal artery (often represented by two arteries-anterior and posterior) runs downwards in the pancreaticoduodenal groove, and ends by anastomosing with the inferior pancreaticoduodenal artery, a branch of the superior mesenteric. It runs to the left along the lesser curvature and ends by anastomosing with the left gastric artery. It passes behind the common hepatic and cystic ducts to reach the upper surface of the neck of the gallbladder where it divides into superficial and deep branches for the inferior and superior surfaces of the gallbladder, respectively. Branches It gives off the following branches: 1 Numerous pancreatic branches which supply the body and tail of the pancreas. One of the branches to the body of the pancreas is large and is known as the arteria pancreatica magna. These large arteries anastomose (on the back of the pancreas) with the left branch of a dorsal artery which may arise from one of the following arteries- superior mesenteric, middle colic, hepatic, or coeliac. As the name suggests, the gastroepiploic arteries supply both the stomach and greater omentum. It runs horizontally to the left along the upper border of the pancreas behind the lesser sac. It crosses the left suprarenal gland and the upper part of the left the superior mesenteric artery is the artery of the midgut. Relations Above the Root of the Mesentery 1 Anteriorly, it is related to the body of the pancreas and to the splenic vein. It runs downwards and to the right, forming a curve with its convexity towards the left. At its origin, it lies first behind the body of the pancreas and then in front of the uncinate process. Next it crosses the third part of the duodenum, enters the root of mesentery, and runs between its two layers. It terminates in the right iliac fossa by anastomosing with a branch of the ileocolic artery. Throughout its course, it is accompanied by the superior mesenteric vein which lies on its right side. The branches form an arch, from the convexity of which smaller branches are distributed to the upper two-thirds of the ascending colon and the right flexure of the colon. Ileocolic Artery Ileocolic artery arises from the right side of the superior mesenteric artery. It runs downwards and to the right, and divides into superior and inferior branches. The superior branch anastomoses with the right colic artery, and the inferior branch anastomoses with the termination of the superior mesenteric artery.

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