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Bradykinesia erectile dysfunction kya hai buy sildenafil 100mg amex, an ial forms of parkinsonism with an autosomal dominant extreme slowness of movement erectile dysfunction 31 years old buy 25mg sildenafil, is the most disabling pattern of inheritance treatment of erectile dysfunction in unani medicine purchase 50 mg sildenafil otc. These genes encode kinesia results in a typical stooped posture when the for -synuclein, a protein found in abundance in vesi- person is standing or walking and a characteristic cles and synaptic regions, and for parkin and ubiquitin shuffling gait marked by the absence of normal arm- carboxy-terminal hydroxylase, both of which are in- swinging movements. Inability to swallow leads to drooling, while bradyki- specific entities, such as viral inflammation (e. Orthostatic hypotension may also be ob- trauma, stroke, and poisoning by manganese, carbon served and may complicate therapy. However, the informa- Parkinson’s disease is one of the few neurological dis- tion from research with this toxin has provided impor- orders in which knowledge of the pathology led directly tant insight into mitochondrial function and has led to to the rational development of drugs to treat the dis- the theory that impairment of mitochondrial function ease. The most prominent pathological findings in (whether of genetic or toxin derivation) may be a rele- Parkinson’s disease are degeneration of the darkly pig- vant risk factor in Parkinson’s disease. The causes are neuronal populations are also affected in Parkinson’s likely multifactorial, with genetic predisposition, envi- disease to a much lesser extent, but they may contribute ronmental toxins, and aging contributing to the initiation to some of the other pathology seen in parkinsonism and progression of the disease. Relatively smooth In postmortem examination of tissue, the substantia functioning of motor control is maintained until neu- nigra is readily identifiable because of the dark pigmen- ronal loss is such that it causes an 80% reduction of tation in the neurons that is the result of the accumula- dopamine in the striatum. At this time, clinical symptoms tion of neuromelanin, a substance whose neurochemical appear and then worsen with increasing neuronal loss. Lewy bodies are com- is, iatrogenic parkinsonism, which often is a complica- posed of many cytoskeleton and other proteins, includ- tion of antipsychotic therapy, especially following the ing -synuclein, ubiquitin, and synaptophysin. It is not use of the butyrophenone and phenothiazine drug clear whether the formation of these inclusions con- classes (see Chapter 34). Unlike idiopathic parkinson- tributes to neuronal degeneration or they are merely a ism, striatal content of dopamine is not reduced by ad- byproduct of degenerating neurons. In contrast, they produce a functional decrease in dopamine activity by blocking Basal Ganglia Anatomy the action of dopamine on postsynaptic dopamine re- ceptors. They are composed of several brain re- gions, including the neostriatum and the substantia ni- Clinical Findings gra (Fig. The neostriatum receives massive The onset of symptoms of Parkinson’s disease is usually excitatory input from the cortex that is mediated by gradual. The are tremor, rigidity, and bradykinesia, although the time dopamine neurons originate in the substantia nigra pars of onset and the relative severity of each symptom may compacta and project to the neostriatum, where they differ in individual patients. Tremors are often unilat- synapse on the input glutamatergic terminals and on eral in onset, present at rest, and cease during voluntary striatal projection neurons that use the neurotransmit- movement. Several brain regions and numerous neurotransmitters are involved with the function and regulation of neuronal activity within the basal ganglia. Dopamine is a catecholamine (see Chapter 10 and The inability of the neurons to eliminate the oxidative Fig. Dopamine actions on D3 4 1 receptors ex- source of oxidative stress may be dopamine metabolism ert an excitatory effect, whereas the actions of (Fig. The stantia nigra created by the loss of dopamine actions loss of striatal dopamine produces an imbalance in in- within the striatum could lead to excitotoxicity that is formation processing in the neostriatum that modifies mediated by glutamate. Also impor- tant in neural transmission are the striatal interneurons Therapy of Parkinsonism that are found within the confines of the striatum, that use the excitatory neurotransmitter acetylcholine, and Since there is no cure for parkinsonism, the aim of phar- that modulate the activity of striatal output neurons. This is obtained through the use of drugs that either in- crease dopaminergic actions or diminish neuronal out- Possible Mechanisms flow from the striatum. If levodopa is administered alone, it is extensively Other disturbing behaviors that can be produced by metabolized by L-aromatic amino acid decarboxylase in levodopa therapy are the dyskinesias. To prevent sive and abnormal choreiform movements of the limbs, this peripheral metabolism, levodopa is coadministered hands, trunk, and tongue. These dyskinesias eventually with carbidopa (Sinemet), a peripheral decarboxylase occur in 40 to 90% of patients receiving long-term high- inhibitor. The mechanism underlying lowers the necessary dose of levodopa and reduces pe- these abnormal movements is unclear, but it may be re- ripheral side effects associated with its administration. The parkinsonism except those associated with antipsy- dyskinesias can be reduced by lowering the dosage; chotic drug therapy. However, as parkinsonism pro- however, the symptoms of parkinsonism may then reap- gresses, the duration of benefit from each dose of levo- pear. Patients can also dyskinesia if their mobility can be improved by levo- develop sudden, unpredictable fluctuations between dopa therapy.

Measurement of the relative potencies of a series of agonists on different tissues has been one of the main ways used to classify recep- Other types of antagonism tors erectile dysfunction commercial bob sildenafil 75 mg without a prescription, e erectile dysfunction and testosterone injections buy sildenafil 100 mg with visa. Non-competitive antagonists do not bind to the receptor site but act downstream to prevent the response to an agonist erectile dysfunction red 7 purchase sildenafil 75mg without prescription, e. Membrane fragments Chemical antagonists simply bind to the active drug and inacti- from homogenized tissues are incubated with radiolabelled drug (usually 3H) and then recovered by fltration. Partial agonists If the decrease in effect occurs quickly (minutes), it is called tach- These are agonists that cannot elicit the same maximum response as a yphylaxis or desensitization. Drug resistance is a term reserved for the agonism depends on the affnity of the drug–receptor complex for a loss of effect of chemotherapeutic agents, e. Changes in receptors may cause desensitization, When acting alone at receptors, partial agonists stimulate a physi- e. A decrease in receptor number ological response, but they can antagonize the effects of a full agonist. Often is affected by many factors (left), but is usually proportional to the the concentration falls rapidly at frst, but then the rate of decline lipid solubility of the drug. Drugs are absorbed mainly from the small intestine because fall in plasma concentration because the rates at which the drug of the latter’s large surface area. The following processes are Drugs absorbed from the gastrointestinal tract enter the portal circula- involved. Drugs that are suffciently lipid soluble to be readily absorbed orally 3 Uptake by the liver and subsequent elimination in the bile ( are rapidly distributed throughout the body water compartments ( ). Routes of administration the extracellular fuid, whereas large volumes of distribution Drugs can be administered orally or parenterally. Oral Most drugs are absorbed by this route and, because of its convenience, it is the most widely used. It is the benzylpenicillin, insulin) are destroyed by the acid or enzymes in the volume of blood or plasma cleared of drug in unit time. Clearance, but not t1/2, provides an indication of the ability • for continuous administration (infusion); of the liver and kidney to dispose of drugs. Ideally, in drug treatment, a steady-state plasma concentration (Cpss) is required within a known therapeutic range. A steady state will be Intramuscular and subcutaneous injections Drugs in aqueous solu- achieved when the rate of drug entering the systemic circulation tion are usually absorbed fairly rapidly, but absorption can be slowed (dosage rate) equals the rate of elimination. Sublingual F × dose and rectal administration avoids the portal circulation, and sublingual = Clp × Cp, average dosing interval preparations in particular are valuable in administering drugs subject to a high degree of frst-pass metabolism. The t1/2 value of a drug is useful in choosing a dosing interval that does not produce excessively high Distribution and excretion peaks (toxic levels) and low troughs (ineffective levels) in drug Distribution around the body occurs when the drug reaches the circula- concentration. The t1/2 (half-life) is the time taken for the concentration of drug in Bioavailability This is a term used to describe the proportion the blood to fall by half its original value (right, top graph). Bioavailability Measurement of t1/2 allows the calculation of the elimination rate is 100% following an intravenous injection (F = 1), but drugs constant (Kel) from the formula: are usually given orally, and the proportion of the dose reaching the systemic circulation varies with different drugs and also from 0 69. Excretion The exponential curve of plasma concentration (C ) against time (t) Renal excretion This is ultimately responsible for the elimination of p is described by: most drugs. Drugs appear in the glomerular fltrate, but if they are lipid soluble they are readily reabsorbed in the renal tubules by passive C = C e−Kelt diffusion. Metabolism of a drug often results in a less lipid-soluble p 0 compound, aiding renal excretion (see Chapter 4). By taking loga- The ionization of weak acids and bases depends on the pH of the rithms, the exponential curve can be transformed into a more conven- tubular fuid. Manipulation of the urine pH is sometimes useful in ient straight line (right, bottom graph) from which C0 and t1/2 can increasing renal excretion. Drug absorption, distribution and excretion 13 4 Drug metabolism Cytochrome Enzyme induction Some drugs increase enzyme Increase metabolism P-450-dependent synthesis (e. Oxidations are the most common reactions and these are catalysed 1 The drug is made more hydrophilic – this hastens its excretion by by an important class of enzymes called the mixed function oxidases the kidneys (right, ) because the less lipid-soluble metabolite is not (cytochrome P-450s). Other phase I reactions are reductions (middle left) and However, this is not always so, and sometimes the metabolites are as hydrolysis (bottom left). Prodrugs are inactive until ciently polar to be excreted rapidly by the kidneys are made more they are metabolized in the body to the active drug.

Inhalation damages the lung infrastructure that produces the surfactant necessary to allow smooth and low effort lung alveolar expansion erectile dysfunction garlic discount sildenafil american express. The type I cells of the alveoli appear to be the cells chiefly affected by acute low to moderate inhalation exposure impotence under hindu marriage act buy sildenafil 25mg visa. If only type I cells are damaged erectile dysfunction other names generic sildenafil 100 mg otc, after an acute period of severe distress, it is likely that treatment with modern ventilation equipment and medications will result in recovery. Some patients develop nonallergic asthma, or “twitchy airway” disease, after such a respiratory insult. In addition to the direct deep lung effect, long-term exposure to lower concentrations of nitrogen dioxide has been linked to cardiovascular disease, increased incidence of stroke, and other chronic disease. Exposure for 1 hour to 50 ppm can cause pulmonary edema and perhaps subacute or chronic pulmonary lesions; 100 ppm can cause pulmonary edema and death. In some individuals, the clinical signs may subside in about 2 weeks; the patient may then pass into a second stage of abruptly increasing severity, including recurring pulmonary edema and fibrotic destruction of terminal bronchioles (bronchiolitis obliterans). These measures include maintenance of gas exchange with adequate oxygenation and alveolar ventilation. Ozone & Other Oxides Ozone (O ) is a bluish irritant gas found in the earth’s atmosphere, where it is an important absorbent of ultraviolet light at3 high altitude. These compounds are produced primarily when fossil fuels such as gasoline, oil, or coal are burned or when some chemicals (eg, solvents) evaporate. Nitrogen oxides are emitted from power plants, motor vehicles, and other sources of high-heat combustion. Volatile organic compounds are emitted from motor vehicles, chemical plants, refineries, factories, gas stations, paint, and other sources. Ozone can be generated in the workplace by high-voltage electrical equipment, and around ozone-producing devices used for air and water purification. There is a near-linear gradient between exposure to ozone (1-hour level, 20–100 ppb) and bronchial smooth muscle response. Severe exposure can cause deep lung irritation, with pulmonary edema when inhaled at sufficient concentrations. Ozone penetration in the lung depends on tidal volume; consequently, exercise can increase the amount of ozone reaching the distal lung. Some of the effects of O resemble those seen with radiation, suggesting that O3 3 toxicity may result from the formation of reactive free radicals. The morphologic and biochemical changes are the result of both direct injury and secondary responses to the initial damage. Chronic bronchitis, bronchiolitis, fibrosis, and emphysematous changes have been reported in a variety of species, including humans, exposed to concentrations above 1 ppm. Increased visits to hospital emergency departments for cardiopulmonary disease during ozone alerts have been reported. A study of the basic physiologic responses of humans to ozone exposure and the biomarkers evoked provides useful insight into the fundamental toxicologic impacts of ozone. The substances include carbon tetrachloride, chloroform, trichloroethylene, tetrachloroethylene (perchloroethylene), and 1,1,1- trichloroethane (methyl chloroform). Perchloroethylene and trichloroethane are still in use for dry cleaning and solvent degreasing, but it is likely that their use will be very limited in the future. The Canadian Center for Occupational Health and Safety lists occupations and exposures to occupational carcinogens at http://www. Fluorinated aliphatics such as the freons and closely related compounds have also been used in the workplace, in consumer goods, and in stationary and mobile air conditioning systems. Because of the severe damage they cause to the ozone layer in the troposphere, their use has been limited or eliminated by international treaty agreements. The common halogenated aliphatic solvents also create serious problems as persistent water pollutants. Trichloroethylene and tetrachloroethylene are listed as “reasonably anticipated to be a human carcinogen” by the U. Chronic workplace exposure to halogenated hydrocarbon solvents can cause significant neurotoxicity with impaired memory and peripheral neuropathy. All halohydrocarbon solvents can cause cardiac arrhythmias in humans, particularly in situations involving sympathetic excitation and norepinephrine release. Hepatotoxicity is also a common toxic effect that can occur in humans after acute or chronic halohydrocarbon exposures.

As a result enlarged prostate erectile dysfunction treatment order sildenafil from india, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased new erectile dysfunction drugs 2011 buy 25 mg sildenafil otc, and parasympathetic outflow is decreased top erectile dysfunction pills cheap sildenafil master card. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Neurohumoral antagonists and vasodilators reduce heart failure mortality by interrupting the cycle and slowing the downward spiral. Circled points 1, 2, and B represent points on the ventricular function curves depicted in Figure 13–4. After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac β1-adrenoceptor–G protein-effector system take place that result in diminished stimulatory effects. It has also been suggested that cardiac β receptors (which do not appear to be down-regulated in failure) may3 mediate negative inotropic effects. Other hormones are released, including natriuretic peptide, endothelin, and vasopressin (see Chapter 17). However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes. Ultimately, myocytes in the failing heart die at an accelerated rate through apoptosis, leaving the remaining myocytes subject to even greater stress. Preload: When some measure of left ventricular performance such as stroke volume or stroke work is plotted as a function of left ventricular filling pressure or end-diastolic fiber length, the resulting curve is termed the left ventricular function curve (Figure 13–4). The ascending limb (< 15 mm Hg filling pressure) represents the classic Frank-Starling relation described in physiology texts. As noted above, preload is usually increased in heart failure because of increased blood volume and venous tone. Because the function curve of the failing heart is lower, the plateau is reached at much lower values of stroke work or output. Increased fiber length or filling pressure increases oxygen demand in the myocardium, as described in Chapter 12. Reduction of high filling pressure is the goal of salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins. Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and systemic vascular resistance. As noted in Figure 13–2, as cardiac output falls in chronic failure, a reflex increase in systemic vascular resistance occurs, mediated in part by increased sympathetic outflow and circulating catecholamines and in part by activation of the renin-angiotensin system. Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in intrinsic contractility. As contractility decreases in the heart, there is a reduction in the velocity of muscle shortening, the rate of intraventricular pressure development (dP/dt), and the stroke output achieved (Figure 13–4). However, the heart is usually still capable of some increase in all of these measures of contractility in response to inotropic drugs. As the intrinsic function of the heart decreases in failure and stroke volume diminishes, an increase in heart rate—through sympathetic activation of β adrenoceptors—is the first compensatory mechanism that comes into play to maintain cardiac output. In heart failure, function is shifted down and to the right, through points 1 and 2, finally reaching point B. A “pure” positive inotropic drug (+ Ino) would move the operating point upward by increasing cardiac stroke work. Such plants have been known for thousands of years but were used erratically and with variable success until 1785, when William Withering, an English physician and botanist, published a monograph describing the clinical effects of an extract of the purple foxglove plant (Digitalis purpurea, a major source of these agents). Chemistry All of the cardiac glycosides, or cardenolides—of which digoxin is the prototype—combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus.

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