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Cialis Sublingual

By D. Pakwan. Heritage University.

The metabolism is similar to adrenaline cheap cialis sublingual 20mg fast delivery; only a little is excreted unchanged in urine order cialis sublingual 20mg fast delivery. Pharmacodynamics Nor adrenaline is a predominantly α receptor agonist with relatively less β agonist action when compared to adrenaline purchase 20mg cialis sublingual free shipping. Adverse effects include: - Anxiety, headache, bradycardia are common side effects - Severe Hypertension in sensitive individuals - Extravasation of the drug causes necrosis and sloughing. These are the other catecholamines which have similar properties to adrenaline and noradrenaline. These drugs have advantage over the others because they are 45 more selective in their action so that they have fewer side effects than adrenaline and nor adrenaline. It has a good distribution through out the body and is resistant to hydrolysis by the liver enzymes. Because of its stability to metabolism it has long duration of action than the catecholamines. This effect is partly by a direct action on the receptors and partly indirectly by releasing noradrenaline from its tissue stores the effect of the drug to various organs and systems is similar to that of adrenaline. Nocturnal enuresis Side effects The side effects are similar to those of adrenaline; but in addition it may produce insomnia and retention of urine. Based on their selectivity to specific receptors the rest of the catecholamines, are classified but it is very difficult to exhaust all the drugs. More over their effect and pharmacology is discussed where they are clinically indicated. Drugs blocking theβ Adrenergic receptor These drugs prevent the response of effectors organs to adrenaline, noradrenaline and other sympathomimetic amines whether released in the body or injected. Circulating catecholamines are antagonized more readily than are the effects of sympathetic nerve stimulation. The drugs act by competing with the catechoamines for α or β receptors on the effectors organs. Irreversible antagonists tightly bind to the receptor so that their effects may persist long after the drug has been cleared from the plasma e. Hence, postural hypotension and reflex tachycardia are common during the use of these drugs. It has high affinity for alpha1 receptor and relatively low affinity for the alpha2 receptor. Prazosin leads to relaxation of both arterial and venous smooth muscles due to the blockage of alpha1 receptors. Drugs blocking all the β receptor effects of adrenaline (non-selective beta blockers) e. Drugs blocking mainly the β1 effects (those on the heart) with less effect on the bronchi and blood vessels (beta1-selective blockers), e. Pharmacokinetics Propranolol is almost completely absorbed following oral administration. How ever, the liver, leaving only 1/3 rd of the dose to reach the systemic circulations, metabolizes most of the administered dose. Cardiovascular system • Bradycardia • Reduces force of contraction • Reduces blood pressure 2. However, the problem of cardiovascular disorders is also increasing in developing countries including Ethiopia. The most commonly encountered cardiovascular disorders include hypertension, congestive heart failure, angina pectoris and cardiac arrhythmias. Most drugs available currently are able to reduce the morbidity and mortality due to these disorders, and therefore, this chapter discusses the pharmacology of these drugs. General consideration:- Hypertension is defined as an elevation of arterial blood pressure above an arbitrarily defined normal value. The American Heart Association defines hypertension as arterial blood pressure higher than 140/90mmHg (based on three measurements at different times). Hypertension may be classified in to three categories, according to the level of diastolic blood pressure: • Mild hypertension with a diastolic blood pressure between 95-105 mmHg • Moderate hypertension with a diastolic blood pressure between 105 – 115mmHg • Severe hypertension with a diastolic blood pressure above 115mmHg. Effective pharmacologic lowering of blood pressure prevents the damage to blood vessels and reduces the morbidity and mortality rate. In order to understand the pathophysiology of hypertensive states and, in turn, the underlying rationale of drug therapy, an appreciation of the systems normally involved in monitoring and regulating blood pressure is required. Two factors which determine blood pressure are cardiac out put (stroke volume x heart rate) and total peripheral resistance of the vasculature. Blood pressure is regulated by an interaction between nervous, endocrine and renal systems Elevated blood pressure is usually caused by a combination of several abnormalities such as psychological stress, genetic inheritance, environmental and dietary factors and others. Patients in whom no specific cause of hypertension can be found are said to have essential hypertension or primary hypertension (accounts for 80-90 % of cases). Secondary hypertension arises as a consequence of some other conditions such as, atherosclerosis, renal disease, endocrine diseases and others. The central issue of antihypertensive therapy is to lower arterial blood pressure, irrespective of the cause. The choice of therapy of a patient with hypertension depends on a variety of factors: age, sex, race, body build, life-style of the patient, cause of the disease, other co-existing disease, rapidity of onset and severity of hypertension, and the presence or absence of other risk factors for cardiovascular disease (e. Non pharmacological therapy of hypertension Several non-pharmacological approaches to therapy of hypertension are available. These include: • Low sodium chloride diet • Weight reduction • Exercise • Cessation of smoking • Decrease in excessive consumption of alcohol 52 • Psychological methods (relaxation, meditation …etc) • Dietary decrease in saturated fats. The sensitivity of patients differs to these non-pharmacological approaches, but, on the average, only modest reductions (5 to 10 mmHg) in blood pressure can be achieved. The major advantage of non-pharmacological approaches is the relative safety and freedom from side effects, compared with drug therapy. Most patients with hypertension require drug treatment to achieve sustained reduction of blood pressure. However, physiological mechanisms tend to oppose a drug – induced reduction of blood pressure. Anti - hypertensive drugs are classified according to the principal regulatory site or mechanism on which they act. They include: A) Diuretics, which lower blood pressure by depleting the body sodium and reducing blood volume.

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This flexibility is useful for survival in the changing environments within the human host that range from high oxygen tension in the lung alveolus to microaerophilic/anaerobic condi- tions within the tuberculous granuloma buy 20mg cialis sublingual. In total cheap cialis sublingual 20 mg mastercard, there are genes encoding for 250 distinct enzymes involved in fatty acid metabolism buy discount cialis sublingual 20mg on-line, compared to only 50 in the genome of E. These proteins are believed to play an important role in survival and multiplication of mycobacteria in different environments (Marri 2006). Pro- teins in this class contain multiple tandem repetitions of the motif Gly-Gly-Ala, hence, their glycine concentration is superior to 50 %. This gene encodes the enzyme in charge of removing oxidized guanines whose incorporation during repli- cation causes base-pair mismatching (Mizrahi 1998, Cole 1999). With the aim of making the information publicly available and the search and analysis of information easier, the Pasteur Institute (http://www. This database is freely available for use on the Internet and is known as the Tuberculist Web Server http://genolist. As more information was generated, databases grew bigger, more experimental information became available, and better and more accurate algorithms for gene identification and prediction were released. The letter C was not included since it usually stands for “comple- mentary”, which means that the gene is located in the complementary strand. As expected, the classes that exhibited the greatest numbers of changes were the un- known category and the conserved hypothetical category (Table 4-1). The re- annotation of the genome sequence allowed the identification of four sequencing errors making the current sequence size change from 4,411,529 to 4,411,532 bp (Camus 2002). Comparative genomics In recent times, new technologies have been developed at an overwhelming pace, in particular those related to sequencing and tools for genome sequence data man- agement, storage and analysis. As of April 2007, 484 microbial genomes have been finished and projects are underway aimed at the sequencing of other 1,155 micro- organisms (http://www. Mycobacteria are not an exception in this titanic genome-sequencing race; since 1998, when the first myco- bacterial genome sequence was published (Cole 1998a); many genome projects have been initiated. Until April 2007, 34 projects on the genome sequencing of different mycobacterial species are finished or in-process. For this reason, these are the strains that have been used as reference strains for comparative genomics both in vitro and in silico. The next step in comparative genomics was the use of genomic subtractive hybridi- zation or bacteria artificial chromosome hybridization for the identification of re- gions of difference among the strains under analysis (Mahairas 1996, Gordon 1999). As a result, they identified 10 regions of difference, including the three previously described (Mahairas 1996). Until 2002, most studies concerning comparative genomics were based on differ- ences among the strain type M. Some excellent reviews are available on comparative genomics, made before the publication of the second M. This strain was considered to be highly transmissible and virulent for human beings (Fleischmann 2002). With the sequence of this second strain, a first approach to the bioinformatic analysis of intraspecies variability became possible. Dark gray filled cells indicate the presence in all strains tested, light gray indicate the presence in some strains, white is absence from all strains tested. These studies have been complemented with data obtained from the genome sequence of a third organism of the M. Sequencing con- firmed the absence of 11 regions of difference, and the presence of only one inser- tion in comparison to the sequenced M. The comparison of the three genomes reflects the high degree of conservation among the members of the M. However, it is important to mention that the greatest degree of variation among these bacilli is found in genes encoding cell wall components and secreted proteins. Some other changes are registered in genes coding for lipid synthesis and secretion as the mmpL and mmpS family of genes. The sequencing of whole genomes of Mycobacterium leprae (Cole 2001), Mycobacterium avium subspecies paratuberculosis (Li 2005) and of other mem- bers of the genus, such as Mycobacterium smegmatis and M. Recently, a report compared the metabolic pathways shared among five of the mycobacterial genomes that have been sequenced (the genome sequence of M. The characteristics of the sequenced ge- 124 Genomics and Proteomics nomes of organisms in the genus Mycobacterium are presented in Table 4-2. The microarray approach allows the comparison of a large number of genomes, providing information on the diversity, frequency, and phenotypic effects of poly- morphisms in the population (Tsolaki 2004). Unfortunately, the microarray technique cannot detect genes present in a clinical isolate that are absent in the reference strain. These changes can originate from small deletions, deletions in homologous repetitive elements, point mutations, genome rearrangements, frame-shift mutations, and multi-copy genes (Ochman 2001, Schoolnik 2002). Although associations be- tween host and pathogen populations seems to be highly stable, the evolutionary, epidemiological, and clinical relevance of genomic deletions and genetic variation regions remain ill-defined, as do the molecular bases of virulence and transmissi- bility (Hirsh 2004). Evidently, these differences cannot include sequences present in clinical isolates that are absent from M. That number accounts for near half of all 126 Genomics and Proteomics the mycobacterial strains that are currently undergoing complete genome sequenc- ing. The rate of deletion in genes involved in intermediary metabolism and respiration, and in cell wall synthe- sis is surprisingly high. The use of microarray-based comparative genomics for the study of the genetic variability of pathogens provides interesting information. Not only the identifica- tion of the deleted or absent genes is important, but also the differential hybridiza- tion signal between samples is of interest. These differential signals can indicate sequence divergence or a difference in the copy number, which may provide an insight into strain evolution and pathogenesis (Taboada 2005). Functional genomics Functional genomics is the analysis of the biological function of the genes and their products within a cell or organism. Unlike genomics and proteomics, functional genomics focus on gene transcription, translation, and protein-protein interactions. Genes operate as long as they are expressed and their expression is regulated at the transcriptional or post-transcriptional level. Microarrays have additional applications in functional genomics apart from gene expression studies, and other uses have also been reported. A number of mutants carrying an insert in each gene were obtained, which were later isolated and identified (Sassetti 2001). In fact, gene knock-out followed by transcript analysis and proteome definition seems to be the way to identify essential genes.

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The percentage of isolates sent for checking is determined before the beginning of the survey cialis sublingual 20 mg amex. Additionally cheap cialis sublingual 20mg, there are now efforts to standardize the panels circulated to countries for easier interpretation of results between countries and over time buy 20mg cialis sublingual with mastercard. It was recommended that special groups likely to have higher levels of resistance, e. In almost all settings, with the exception of Australia, Kinshasa, Democratic Republic of Congo, and Scotland, data were divided by treatment status. In some European countries, “unknown” was a category of treatment status; though this category is not displayed individually the cases are captured in the combined column. In geographical areas where people may be reluctant to reveal treatment status, verification of treatment status plays a particularly important role. All data files and epidemiological profiles have been returned to countries for verification before publication. The Global Project requests that survey protocols include a description of methods used for the quality assurance of data collection, entry, and analysis. However, to date there has been no systematic procedure to ensure that the methods described are actually employed at the country level. The data checking was not restricted to the third report, but included also the first and second reports. Inconsistencies and errors have been corrected if the available evidence allowed it. Where the analysis of the trends showed irregularities, verification was requested from the reporting parties. Arithmetic means, medians and ranges were determined as summary statistics for new, previously treated, and combined cases, for individual drugs and pertinent combinations. For geographical settings reporting more than a single data point since the second report, only the latest data point was used for the estimation of point prevalence. Chi-squared and Fisher exact tests were used to test the null hypothesis of equality of prevalences. Ninety-five percent confidence intervals were calculated around the prevalences and the medians. Reported notifications were used for each country that conducted a representative nationwide survey. For surveys carried out on a subnational level (states, provinces, oblasts), information representing only the population surveyed is included where appropriate. In order to be comprehensive, all countries and settings with more than one data point were included in this exercise; thus some information from the second phase of the global project is repeated. In geographical settings where only two data points were available since the start of monitoring, the prevalences were compared through the prevalence ratio (the first data point being used as the base for comparison), and through error bar charts, representing the 95% confidence interval around the prevalence ratio. For settings that reported at least three data points, the trend was determined visually as ascending, descending, flat or “saw pattern”. Where the trend was linear, the slope was tested using a chi-squared test of trend. The variables included were selected in function of their presumed impact on resistance and their potential for retrieval. A conceptual framework was developed that structured the retained variables along three axes: patient-related, health-system-related, and contextual factors. Several countries did not report on specific ecological variables, thus reducing the impact of the analysis. Ecological analysis was performed at the country level, thus the indicators reflect national information. The significant variables were retained for the multivariate analysis and a multiple regression technique was used. The arcsin transformation of the square root of the outcome variables was carried out as a normalization procedure to safeguard the requirements of the multiple linear regression modelling. This procedure stabilizes the variances when the outcome variable is a rate, and is especially useful when the value is smaller than 30% or higher than 70%, which is the case for both outcome variables. The impact of weighting on the regression results was explored, taking sample sizes at country level as weights. However, the differences between the weighted and unweighted regressions were trivial and the results given are those of the unweighted multiple linear regression. The most parsimonious models were retained as final models, for which the normal plot for standardized residuals complied best with the linearity requirements. This approach is highly dependent on case-finding in the country and the quality of recording and reporting of the national programme. Ninety-five percent confidence limits around proportions were determined using the Fleiss quadratic method in Epi Info (version 6. Almost 90 000 isolates, representative of the most recent data point for every country surveyed between 1994 and 2002, were included in the analysis. Patterns were determined for prevalence (in relation to total number of isolates tested) and for proportion (in relation to the total number of isolates showing any resistance). Those errors, or biases, may be related to the selection of subjects, the data-gathering or the data analysis. As a result, in the first report, these data were excluded from the analysis; we have also excluded the Italian data from the trend analysis. For various reasons, patients may be unaware of their treatment antecedents, or prefer to conceal this information. Consequently, in some survey settings, a certain number of previously treated cases were probably misclassified as new cases. Test bias Another bias, which is often not addressed in field studies, is the difference between the true prevalence and the observed or “test” prevalence. That difference depends on the magnitude of the true prevalence in the population, and the performance of the test under study conditions (i. Therefore reported prevalence will either over- or underestimate the true prevalence in the population. Representativeness of rates Some settings reported a small number of resistant cases, and a few settings reported a small number of total cases examined. There were a number of possible reasons for these small denominators in various participating geographical settings, ranging from small absolute populations in some surveillance settings to feasibility problems in survey settings. The resulting reported prevalences thus lack stability and important variations are seen over time, though most of the variations are not statistically significant. Analysis of trends Although serious efforts have been made to obtain data that are as reliable as possible, some residual irregularities were detected in a number of settings.

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B) Environmental toxicology Environmental toxicology deals with the potentially deleterious impact of chemicals order cialis sublingual 20 mg on-line, present as pollutants of the environment order 20mg cialis sublingual with visa, to living organisms buy cialis sublingual 20 mg with amex. It is concerned with the toxic effects of chemical and physical agents on living organisms, especially in populations and communities with defined ecosystems. C) Clinical toxicology Clinical toxicology deals with diagnosis and treatment of the normal diseases or effects caused by toxic substances of exogenous origin i. D) Forensic toxicology Forensic toxicology closely related to clinical toxicology. It deals with the medical and legal aspects of the harmful effects of chemicals on man, often in post mortem material, for instance, where there is a suspicion of murder, attempted murder or suicide by poisoning. Toxicokinetics and Toxicodynamics - Toxicokinetics deals with absorption, distribution, biotransformation (biotransformation) and excretion of chemicals. Toxicokinetics i) Absorption Absorption is the process by which the chemical enters the body. It depends on the route of administration, dissociation (to become ionized), dissolution (ability of solid dosage form to become soluble), concentration, blood flow to the site, and the area of the absorptive site. Bioavailability is the fraction of unchanged drug reaching the systemic circulation following of non-vascular administration. Volume of distribution (Vd) is calculated from the dose taken and the resulting plasma concentration: Vd = dose /plasma concentration The importance of volume of distribution in toxicology is - Predicting peak blood concentration of the chemical taken - Calculating the amount of substance in the body to verify the quantity ingested - Deciding whether to apply systemic toxin elimination techniques Factors determining the rate of distribution of chemicals in the body are - Protein binding – chemicals highly bound to protein have small volume of distribution - Plasma concentration – when the volume of distribution of chemicals is small, most of the chemical remains in the plasma - Physiological barriers – chemicals will not uniformly distributed to the body due to specialized barriers e. It is a process by which the body transforms a chemical and makes it more water soluble so the chemical can be eliminated more rapidly via the kidney into the urine. Biotransformation can produce metabolites that are pharmacologically active and toxic E. Liver is the major site of biotransformation for many chemicals & other organs that are involved are lungs, kidneys, skin &so on. Interactions during biotransformation includes There are two phases of biotransformation Phase I – the drug is converted into more polar compound e. Half life (t ½) –is the time required to reduce the blood concentration of the chemical to half. Excretion through the lungs is the major route for gaseous substances; and in the case of non-volatile water – soluble drugs, the kidneys are the most important routes of excretion. Additional routes include sweat, saliva, tears, nasal secretions, milk, bile and feces. It is a quantitative measure of the volume of blood cleared of drug per unit time, usually expressed in milliliter pe4r minute. B - Certain points regarding the toxicokinetics of toxic agents;  Drug absorption after a toxic ingestion may be delayed and prolonged;  The half-life and total body clearance are often lengthened;  Liver-metabolizing enzymes may become saturated, slowing hepatic elimination; 12 Toxicology  Chemicals with large volumes of distribution are often highly tissue-bound and measures to enhance their elimination are not effective;  Poor perfusion of the liver and kidneys secondary to the toxic effects of the substance may slow clearance. Toxicodynamics Toxicodynamics is the mechanism of action of a toxic chemical to the body (what chemicals do to the body). We have two types of responses so called Quantal dose response (all- or – none response) & graded dose response (when dose increases, the response increases in graded fashion). Comparison of dose –response curves for efficacy (A), toxicity (B), & lethality (C). The effective,toxic, &lethal dosage for 50% of the population in the groupcan be estimated as shown. Common effects of chemicals to cause symptoms Chemicals can cause symptoms through the following mechanisms a. Interfere with the transport or tissue utilization of oxygen (carbon monoxide, cyanide), resulting in hypoxia or a decrease in an essential substrate such as glucose b. Affect the autonomic nervous system, producing cholinergic action (organophosphate insecticide) d. Affect the heart and vasculature producing myocardial dysfunction, dysrrhythmias (antiarrhythmic agents) and hypertension or hypotension f. Potential sources of toxicities The potential causes of toxicities include • Therapeutic agents –drug toxicity can be due to over doses, unusual adverse effects, frequent administrations of therapeutic doses & drug interactions 15 Toxicology • Industrial chemicals- these chemicals may contribute to environmental pollution & they may be a direct hazard in the work place they are used. Environmental pollutants may be released into the air, water, or dumped onto land. Natural toxins may feature in poisoning via containing in food, by accidental ingestions of poisonous plants or animals & by stinging & biting • Food additives – have usually low biological activity. Many different additives are added to food to alter the flavor or colour, prevent spoilage or in some other way change the nature of the food stuff. There are also many potentially toxic substances which are regarded as contaminants. Unfortunately, misconceptions regarding safety &efficacy of the agents are common. Furthermore, the doses for 16 Toxicology active botanical substances may be higher. There are a lot of drugs of abuse with high potential of dependence & tolerance (e. Environmental considerations Certain chemical and physical characteristics are known to be important for estimating the potential hazard involved for environmental toxicants. In addition to information regarding effects on different organisms, knowledge about the following properties is essential to predict the environmental impact: The degradability of the substance; its mobility through air, water and soil; whether or not bioaccumulation occurs; and its transport and biomagnification through food chains. If the intake of a long-lasting contaminant by an organism exceeds the latter’s ability to metabolize or excrete the substance, the chemical accumulates within the tissues of the organism (e. Although the concentration of a contaminant may be virtually undetectable in water, it may be magnified hundred or thousand time as the contaminant passes up the food chain. Chemicals that are poorly degraded (by abiotic or biotic pathways) exhibits environmental persistence and thus can 17 Toxicology accumulate. Lipophilic substances tend to accumulate in body fat, resulting in tissue residues. When the toxicant is incorporated in to the food chain, biomagnification occurs as one species feed upon others and concentrates the chemical. The pollutants that have the widest environmental impact are poorly degradable & relatively mobile in air, water and soil, exhibits bioaccumulation; and also exhibits biomagnification. In ecotoxicology there are three interacting components; the toxicant, the environment and the organisms (community, population or ecosystem). Poison prevention &control strategies a) Keep all household poisons separate from food. Understand diagnosis of poisoning by history, physical examination and different investigations 2.