Mark Corson

By G. Gonzales. Northern Arizona University. 2018.

Ligand-activated ion channel is an example of interaction of specific ligand with an ion channel buy 20mg cialis soft amex erectile dysfunction doctors in tulsa, which permits passage of ions through the channel discount cialis soft 20mg overnight delivery erectile dysfunction medication with high blood pressure. Receptor-activated tyrosine kinase is exemplified by insulin discount cialis soft 20mg on-line erectile dysfunction causes treatment, where binding of ligand acti- vates specific tyrosine kinase, leading to a cascade of reactions within the cell. The ability to target intracellular receptors depends on the ligand’s ability to cross lipid barriers, such as the nuclear envelope. Recruitment of intracellular kinases is charac- terized by some receptor-activated tyrosine kinases. Interaction with G-proteins and adenylyl cyclase are characteristics of mem- brane receptors. Lithium is an example of drug with a very low therapeutic index, which requires frequent monitoring of the plasma level to achieve the balance between the desired effect and untoward toxicity. Efficacy of the drug is the maximal drug effect that can be achieved in a patient under a given set of conditions. Bio- availability of the drug is the fraction of the drug that reaches the bloodstream unaltered. Adequate passage of drug through the small intestine is required to observe the effects of the drug, because most of the absorption takes place in the small intestine. After extensive abdominal surgery, especially that involving a resection of a portion of small bowel, the passage may be slowed, or even stopped, for a period of time. Abdominal surgery rarely results in reduced blood flow to the intestine, nor does such an operation influence protein binding, or the first-pass effect. Because of the patient’s edema and ascites, the apparent volume of distribu- tion will be increased, which may require small adjustments in his usual medication doses. In first-order elimination, the rate of elimination actually depends on the concentration of the drug, multiplied by proportionality constant. Biotransformation simply refers to the general mechanism of a partic- ular drug’s elimination. Redistribution is one of the possible fates of a drug, which usually termi- nates drug action. Since vancomycin is cleared by the kidneys, renal functional status needs to be considered when prescribing such a drug, because it may accumulate and produce undesirable toxic side effects. Switching from the vancomycin to an oral preparation will reduce its bioavaila- bility. There is no indication that the patient is in the state of increased volume of distribution (such as edema), and water restriction will not have a noticeable effect on apparent volume of 23 24 Pharmacology distribution. Changes to the current regimen are necessary because of the patient’s acute renal failure, and this has to be done regardless of the urgency of the situation. The fact that the patient is being ventilated may indicate that she needs extra hydration because of increased insensible losses, but this has nothing to do with her vancomycin dose directly. First-pass metabolism simply means passage through the portal circulation before reaching the systemic circulation. A hepatic function panel is generally not used to deduce a patient’s sus- ceptibility to the drug. Bioavailability of drugs is decreased, not increased by the fraction removed after the first pass through the liver. Drugs are usually less rapidly metabolized when hepatic enzymes are elevated (which indicates hepatic dysfunction). Alterations of urinary pH affect renal distal tubular reabsorption of drugs by changing the degree of ionization. Glomerular filtration depends mainly on the size of the drug as well as protein binding. Drug metabolism is not affected at the levels of the kidney, where most elimination takes place. Alkalinization of urine is unlikely to affect undesirable side effects of the drug. Dosing schedules of drugs are adjusted according to their half-lives to achieve steady-state plasma concentration. Attempting to avoid the toxicity of the drug because of its low therapeutic index represents an unlikely scenario, since to reduce toxicity of a drug with a low therapeutic index, one would reduce the dosing schedule, not increase it. Some fluctuation in plasma concentration occurs even at steady state; it is the aver- age concentration over time that is the goal of steady state. The rationale for the loading dose is to give a patient a sufficient dose of a med- ication to achieve the desired effect quickly, which is necessary in some situation (such as pre- vention of further seizures). When drug is administered at maintenance rate, steady state is achieved after about five half-lives. The loading dose depends on the volume of distribution, whereas the maintenance dose depends on the clearance of the drug. To calculate the volume of distribution, use the formula in which the dose of the drug is divided by the plasma concentration. For the plasma concentration of drug to decrease by 50%, half the drug present in the body initially must be eliminated. The amount of drug in the body initially is the volume of distribution 3 the plasma concentration (50 liters 3 4 mg/liter ¼ 200 mg). When the plasma concentration falls to 2 mg/liter, the body will contain 100 mg of drug (50 L 3 2 mg/L ¼ 100 mg). Since the body eliminates the drug at a rate of 2 mg/hour, it will require 50 hours for 100 mg of the drug to be eliminated.

Phenotypically order cialis soft 20mg mastercard erectile dysfunction vacuum, these individuals are male but have eunuchoid features order cialis soft 20 mg amex can erectile dysfunction cause low sperm count, small tes- tes order cialis soft 20 mg with amex erectile dysfunction 70 year olds, decreased virilization, and gynecomastia. The other disorders listed in the question may result in sexual ambiguity, more commonly in males. Testic- ular dysgenesis results from the absence of müllerian inhibiting substance during embryonic development and may be caused by multiple genetic mutations and may be associated with the absence of müllerian-inhibiting substance and reduced testosterone production. Feminization may also occur through androgen insensitivity and mutations in the androgen receptor. Most cases are diag- nosed perinatally on the basis of reduced fetal growth or lymphedema at birth with nu- chal folds, a low posterior hairline, or left-sided cardiac defects. Some girls may not be diagnosed in childhood and come to attention much later in life because of delayed growth and lack of sexual maturation. Limited pubertal development occurs in up to 30% of girls with Turner syndrome, with approximately 2% reaching menarche. Owing to the frequency of congenital heart and genitourinary defects, a thorough workup should be done after the diagnosis, including an echocardiogram and renal imaging. Long-term management includes growth hormone replacement during childhood and estrogen replacement to maintain bone mineralization and feminization. The presentation is not consistent with the bony deformities or blue sclera seen in patients with osteogenesis imperfecta, and he is tall with long extremities, which makes chondroplasia very unlikely. However, his hypermobility and lens disorders suggest Marfan syndrome or, less com- monly, Ehlers-Danlos syndrome. Given the high risk of aortic root disease in Marfan syn- drome, echocardiography is indicated in this patient. The other screening tests are not specific to Marfan syndrome and are not appropriate in a 30-year-old male. These patients often have skin cancers as a result of the mutagenic effects of ultraviolet light. Ataxia-telangiectasia is characterized by large telangi- ectatic lesions on the face, cerebellar ataxia, immunologic defects, and hypersensitivity to 38 I. Fanconi’s anemia is caused by mutations in multiple complementation groups that are characterized by various congenital anomalies and a marked predisposition to aplastic anemia and acute myeloid leukemia. It is characterized by X- linked inheritance and typical large ears, macroorchidism, and mental retardation. Areas of high dependence on oxidative phosphorylation include skeletal and cardiac muscle and the brain. During repli- cation, the number of mitochondria can drift among various cells and tissues, resulting in heterogeneity, or heteroplasmy. Acquired mutations in the mitochondrial genome are thought to play a significant role in age-related degenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Uniparental disomy is the inheritance of dual copies of either maternal or paternal chromosomes. The Prader-Willi and Angelman’s syndromes may result from uniparental disomy involving inheritance of defective maternal or paternal chromosomes, respectively. Similarly, hydatidiform moles may contain normal numbers of diplid chromosomes, all of which are of paternal origin. Lyonization is epigenetic inactivation of one of the two X chromosomes in every cell of the female. Somatic mosaicism is the presence of two or more genetically dis- tinct cell lines in the tissue of an individual. The term anticipation is often used to refer to diseases caused by trinucleotide repeats that are often characterized by worsening of clin- ical phenotypes in successive generations. These diseases, such as Huntington’s disease and fragile X syndrome, are characterized by expansion of these repeats in subsequent generations of individuals, resulting in earlier and often more severe clinical phenotypes. Disorders of any of these macromolecules may result in a disorder of connective tissue. Clinically, it is characterized by decreased bone mass, brittle bones, blue sclerae, dental abnormalities, joint laxity, and progressive hearing loss. The phenotype may range from severe disease with in utero death to milder forms with lesser severity and survival into adulthood. Ehlers-Danlos syndrome is a heterogenous set of disorders characterized by joint laxity, hyperelasticity of the skin, and other defects in collagen synthesis. A variety of defects have been identified in differ- ent types of collagen as well as enzymes that facilitate collagen cross-linking. Marfan syn- drome is characterized by a triad of features: long, thin extremities (with arachnodactyly and loose joints), reduced vision as a result of ectopia lentis, and aortic aneurysms. McArdle’s disease is a defect in glycogenolysis that results from myophosphorylase deficiency. Lysosomal storage diseases result from mutations in various genes for these hydrolyases. In the infantile form, these patients have macrocephaly, loss of motor skills, an increased startle reaction, and a macular cherry red spot. The juvenile-onset form presents with ataxia and progressive dementia that result in death by age 15. The adult-onset form is characterized by clumsiness in childhood, progressive motor weakness in adoles- cence, and neurocognitive decline. The disease is seen most commonly in Ashkenazi Jews, with a carrier frequency of about 1 in 30. Clinical features result from an accumulation of lipid-laden macrophages, termed Gaucher cells, throughout the body.

Carvedilol discount cialis soft 20mg fast delivery erectile dysfunction and smoking, a combined a- and nonselective b-adrenoreceptor antagonist discount 20 mg cialis soft free shipping erectile dysfunction drugs with the least side effects, has been shown in several clinical trials to reduce morbidity and mortality in mild-to-severe heart failure order 20mg cialis soft free shipping erectile dysfunction drugs wiki. Arrhythmias may be due to both improper impulse generation and impulse conduction. These manifest as abnormalities of rate or regularity or as disturbances in the normal sequence of activation of atria and ventricles. Increased vagal activity can impair nodal + pacemaker cells by elevating K conductance, leading to hyperpolarization. Ectopic foci are areas within the conduction system that may, in the diseased state, develop high rates of intrinsic activity and function as pacemakers. Triggered automaticity results from delayed after-polarizations that reach threshold and are capable of initiating an impulse. Therapy aims to restore normal pacemaker activity and modify impaired conduction that leads to arrhythmias. Therapeutic effects are achieved by sodium- or calcium-channel blockade, prolongation of effective refractory period, or blockade of sympathetic effects on the heart. Many antiarrhythmic drugs affect depolarized tissue to a greater extent than they affect normally polarized tissue. Class I drugs block fast Na+ channels, thereby reducing the rate of phase 0 depola- rization, prolonging the effective refractory period, increasing the threshold of excitability, and reducing phase 4 depolarization. Quinidine (Quinidex, Duraquin, Cardioquin) (1) Effects and pharmacologic properties (a) At therapeutic levels, direct electrophysiologic effects predominate, including depression of the pacemaker rate and depressed conduction and excitability, pro- longation of Q-T interval, and heart block. Quinidine syncope (dizziness and fainting) may occur as a result of ventricular tachycardia; this condition is associ- ated with a prolonged Q-T interval. Disopyramide (Norpace) (1) Disopyramide has action similar to that of quinidine, but has the longest T1=2 of its class. Lidocaine (Xylocaine) (1) Lidocaine acts exclusively on the sodium channel (both activated and inactivated), and it is highly selective for damaged tissues. Mexiletine (Mexitil) (1) Mexiletine is an agent similar in action to lidocaine, but can be administered orally. Flecainide (Tambocor) and encainide (Enkaid) (1) Flecainide is orally active; it is used for ventricular tachyarrhythmias and maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter. Propafenone (Rythmol) (1) Propafenone has a spectrum of action similar to that of quinidine. Propranolol (Inderal, generic), a nonselective b-adrenoceptor antagonist, and the more selective b1-adrenoceptor antagonists acebutolol (Sectral) and esmolol (Brevibloc) are used to treat ventricular arrhythmias. Esmolol is ultrashort acting, is administered by infusion, and is used to titrate block during surgery. They also are used for a variety of other arrhythmias, including atrial flutter and atrial fibrillation. These drugs act by interfering with outward K currents or + slow inward Na currents. It increases refractoriness, and it also depresses sinus node automaticity and slows conduction. Although electrophysiologic effects may be seen within hours after parenteral administration, effects on abnormal rhythms may not be seen for several days. The antiarrhythmic effects may last for weeks or months after the drug is discontinued. Amiodarone is used for treatment of refractory life-threatening ventricular arrhythmias in preference to lidocaine; additional uses include the treatment of atrial and/or ventricular arrhythmias including conversion of atrial fibrillation and the suppression of arrhythmias in patients with implanted defibrillators; it also possesses antianginal and vasodilatory effects. Serious noncardiac adverse effects include pulmonary fi- brosis and interstitial pneumonitis. Other adverse effects include photosensitivity, ‘‘gray man syndrome,’’ corneal microdeposits, and thyroid disorders (due to iodine in the drug preparation). Solatol prolongs the cardiac action potential, increases the duration of the refractory period, and has nonselective b-adrenoceptor antagonist activity. Uses include treatment of atrial arrhythmias or life-threatening ventricular arrhythmias, and treatment of sustained ventricular tachycardia. Its adverse effects include significant proarrhythmic actions, dyspnea, and dizziness. Dofetilide is approved for the conversion and maintenance of normal sinus rhythm in atrial fibrillation or atrial flutter. Dofetilide is a potent inhibitor of K+-channels and has no effect on conduction velocity. Bretylium inhibits the neuronal release of catecholamines, and it also has some direct anti- arrhythmic action. This drug is used intravenously for severe refractory ventricular tachyarrhythmias and also for prophylaxis and treatment of ventricular fibrillation. These drugs prolong nodal conduction and effective refractory period and have predomi- nate actions in nodal tissues. Verapamil is a phenylalkylamine that blocks both activated and inactivated slow calcium channels. Although verapamil is excreted primarily by the kidney, dose reduction is necessary in the presence of hepatic disease and in the elderly. Bioavailability following oral administration is about 20%; much lower doses are required when administered intravenously. Verapamil is useful in reentrant supraventricular tachycardia, and it can also reduce ven- tricular rate in atrial flutter and fibrillation. Verapamil can pre- cipitate sinus arrest in diseased patients, and it causes peripheral vasodilation. The adverse cardiac effects of verapamil, including sinus bradycardia, transient asystole, and other arrthythmias, may be exacerbated in individuals taking b-adrenoceptor antagonists; this can be reversed by atropine, b-adrenoceptor agonists, or calcium. Verapamil should not be used in patients with abnormal conduction circuits as in Wolff-Parkinson-White syndrome.

In computing these statistics from the Crosstabulation table buy 20mg cialis soft free shipping erectile dysfunction massage, the concordant cells are not used and only the information from the discordant cells is of interest as shown in Table 8 generic 20mg cialis soft with visa osbon erectile dysfunction pump. The two discordant cells (b and c) show the number of children who changed their knowledge status in either direction between the two occasions discount 20 mg cialis soft visa erectile dysfunction shakes menu. The table shows that the increase in knowledge converted back to a percentage is 26. The 95% confidence interval does not cross the zero line of no difference which reflects the finding that the change in proportions is statistically significant. Research question A second outcome that was measured in the study was whether children knew when to use their rescue medication appropriately. In the Crosstabulation table, the percentages in the discordant cells indicate a small increase in knowledge of 15. The Chi-Square Tests table shows that this difference is not significant with a P value of 0. Crosstabs Medication-Time 1 * Medication-Time 2 Crosstabulation Medication-Time 2 No Yes Total Medication-Time 1 No Count 17 13 30 % of total 19. The number of children who knew when to use their rescue medication slightly changed but not significantly on completion of the camp. By reporting the per cent of children with knowledge on both occasions, the per cent increase and the P value, all information that is relevant to interpreting the findings is included. The P values often depend on the sample size and can be biased by cells with only a small number of expected counts. When critically appraising an article that presents categorical data analyzed using univariate statistics or crosstabulations, it is important to ask the questions shown in Box 8. No one (with the possible exception of certain statisticians) intuitively understands a ratio of odds. However, apart from the P value, chi-square tests do not provide a statistic for describing the strength of the relationship. Two risk statistics that are useful for measuring the mag- nitude of the association between two binary variables measured in a 2 × 2 table are the odds ratio and the relative risk. Both of these statistics are estimates of risk and, as such, describe the probability that people who are exposed to a certain factor will have a disease compared to people who are not exposed to the same factor. The odds ratio is the odds of the outcome occurring in one group divided by the odds of the outcome occurring in another group. Relative risk is the ratio of the probability of the outcome occurring in one group (i. The choice of using an odds ratio or a relative risk depends on both the study design and whether bivariate or multivariate analyses are required. Odds ratios have the advantage that they can be used in any study design, including experimental and case–control studies in which the proportion of cases is unlikely to be representative of the proportion in the population. In addition, direct comparisons of effect can be made between different study designs and odds ratios from different studies can be compared and combined, and are often used to report the results of sys- tematic reviews and meta-analyses. Odds ratios can be adjusted for the effects of other related exposures in multivariate analyses in which case the summary estimates are called ‘adjusted’ odds ratios, which are discussed later in this chapter. The relative risk statistic relies on the probability of the outcome in the sample being the same as the probability of the outcome in the population. Therefore, relative risk can be calculated when the sample has been selected randomly or when a representative sample has been enrolled. Random samples are often enrolled in cross-sectional studies, some cohort studies and clinical trials. As such, relative risk is commonly calculated in these types of studies and when only bivariate analyses are required. In non-random samples, the probability of outcome will be altered by the selection criteria and therefore the relative risk will not represent the population risk. Thus, relative risk should only be calculated from a sample that has the same characteristics as the population from which it is drawn and in which the proportion of people with the outcome represents the population prevalence rate of the disease. The odds ratio will always overestimate the effect when interpreted as a relative risk and the degree of overesti- mation will increase as the effect becomes larger. Conversely, an odds ratio can be interpreted as the odds of a person having been exposed to a factor when having the disease compared to the odds of a person having been exposed to a fac- tor when not having the disease. This converse interpretation is useful for case–control studies in which participants are selected on the basis of their disease status and their exposures are measured. In this type of study, the odds ratio is interpreted as the odds that a case has been exposed to the risk factor of interest compared to the odds that a control has been exposed. The odds ratio is a ratio of the probability of an event occurring to the probability of an event not occurring. This calculation shows why an odds ratio is sometimes called a ratio of cross-products. In this chapter, the first option is used so that the layout of the tables is as shown in Table 8. A chi-square test indicates whether the difference in the proportion of participants with and without disease in the exposure present and exposure absent groups is statistically significant, but an odds ratio quantifies the relative size of the difference between the groups. Odds ratio is a less valuable statistic than relative risk because it represents the odds of disease, which is not as intuitive as the relative risk. Although the odds ratio is not the easiest of statistics to explain or understand, it is widely used for describing an association between an exposure and a disease because it can be calculated from studies of any design, including cross-sectional, cohort studies, case–control studies and experimental trials as shown in Table 9. Odds ratio has the advantage that it can be used to make direct comparisons of results from studies of different designs and, for this reason, odds ratios are often used in meta-analyses. The odds ratio and the relative risk are always in the same direction of risk or protection.

Note: Do not be confused by the fact that we use X to represent the scores when computing the means 20mg cialis soft with mastercard impotence clinic. The type of graph to select is determined by the characteristics of the independent variable generic 20mg cialis soft fast delivery erectile dysfunction treatment atlanta ga. Line Graphs Create a line graph when the independent variable is an interval or a ratio variable discount cialis soft 20mg on-line impotence quiz. We use straight lines to connect the data points here for the same reason we did when producing polygons: Anytime the variable on the X axis in- volves an interval or ratio scale, we assume that it is a continuous variable and there- fore we draw lines. The lines show that the relationship continues between the points shown on the X axis. For example, we assume that if there had been a 6-item list, the mean error score would fall on the line connecting the means for the 5- and 10-item lists. Each mean implies a sample of scores and their corresponding data points are around—above and below—the mean’s data point. Because the vertical positions of the means change as the conditions change, we know that the raw scores also change, so a relationship is present. Notice that you can easily spot such a relationship because the different means pro- duce a line graph that is not horizontal. On any graph, if the summary data points form a line that is not horizontal, it indicates that the individual Y scores are changing as the X scores change, so a relationship is present. This implies that (as in the figure on the right) the individual scores stay the same regardless of the condition, so no relationship is present. Thus, on any graph, if the summary data points form a horizontal line, it indicates that the indi- vidual Y scores do not change as the X scores change, and so a relationship is not present. Bar Graphs Create a bar graph when the independent variable is a nominal or an ordinal variable. Notice that the rule here is the same as it was in Chapter 3: Create a bar graph whenever the X scores are nominal or ordinal scores. With experiments, we place a bar above each condition on the X axis to the height on the Y axis that corre- sponds to the mean for that condition. As usual, adjacent bars do not touch: Recall that nominal or ordinal scales are discrete, meaning that you can have one score or the other, but nothing in-between. For example, say that we compared the recall errors made by psychology majors, English majors, and physics majors. The independent variable of college major is a nominal variable, so we have the bar graph shown in Figure 4. Because the tops of the bars do not form a horizontal line, we know that different means and thus different scores occur in each condition. We can again envision that we would see individual er- ror scores at around 8 for physics majors, around 4 for psychology majors, and around 12 for English majors. Thus, the scores change as a function of college major, so a rela- tionship is present. Then, again depending on the characteristics of the independent vari- able, we would create either a line or bar graph. The characteristics of the ____ variable determine We ask males and females to rate their satisfaction whether to plot a line or bar graph. To graph this, gender is a nominal inde- pendent variable, so plot a bar graph, with the labels 6. Instead, say we measure the satisfaction scores of Answers students tested with either a 10-, 40-, or 80-question 1. Recall that to make inferences about the population, we must first compute the appro- priate inferential statistics. Assuming that our data passed the inferential test, we can conclude that each sample mean represents the population mean that would be found for that condition. The mean for the 5-item condition was 3, so we infer that if everyone in the population recalled a 5-item list, the mean error score 1 2 would be 3. Similarly, if the population recalled a 10-item list, would equal the condition’s mean of 6, and if the population recalled a 15-item list, would be 9. Because we are describing how the scores change in the population, we are describing the relationship in the population. In research publications, we essentially assume that a graph for the population would be similar to our previous line graph of the sample data. However, so that you can understand some statistical concepts we will discuss later, you should envision the relationship in the population in the following way. Each sample mean provides a good estimate of the corresponding , indicating approximately where on the depend- ent variable each population would be located. Thus, we can envision the relationship in the population as the normal distributions shown in Figure 4. Essentially, the dis- tributions change from one centered around 3 errors, to one around 6 errors, to one around 9 errors. Then we would envision the one, same population of scores, located at the of 5, that we’d expect regardless of our conditions. If, as the independent variable changes, everyone’s behavior changes, then we have learned about a law of nature involving that behavior. Above, we believe that everyone’s recall behavior tends to change as list length changes, so we have evidence of how human memory generally works in this situation.