The maximum effect can take place within five to fifteen minutes. The other routes are orally (via tablets) and intravenously. Salomon has a number of medical uses, but It is mainly used to treat asthma and exercise Induced bronchus’s. Treatment of chronic obstructive pulmonary disease Is another key use of this drug (diseases In this category Include chronic bronchitis and emphysema). Other less widely applied uses is in treatment of premature labor in obstetrics since the drug can also relax uterine smooth muscles intravenous administration) and in the treatment of cystic fibrosis in combination with other drugs (3).
Despite ten Tact Tanat tens Aragua NAS Eden Invaluable In ten treatment AT serious medical conditions like asthma, there is still a serious pitfall in the long-term use of the drug since most people who have been on it for a long duration tend to the develop some form of drug resistance/tolerance to the drug. This results in a slower and less dynamic effect of the drug on patients who have been using it chronically. Therefore, directly translating to the need to adjust dose and frequency of the drug administration, this can become quite a burden to everyone involved.
Down regulation of the ;2-receptors and a reduction of their sensitivity (desensitizing) causes this resistance (4). The drug has an intricate mode of action that involves a number of pathways at microscopic cell level. Initially, it acts by binding on beta adrenaline receptors (4). The receptor is coupled to a stimulatory guanine nucleotide-binding protein (as – protein) and usually fluctuates between different conformations in the inactive state (5). Once the agonies (Salomon) binds to the receptor, it stabilizes one of the information leading to the activation of the G-protein.
The G-protein is a transmigrate signal transducer that has alpha and beta-gamma subunits (6). After activation of the protein the alpha subunit dissociates, resulting in a form that stimulates activity of the enzyme densely cycles (7). This enzyme now increases the production of cyclic adenosine Mephistopheles (CAMP) in the cell. It does this by transforming adenosine troposphere (TAP) into CAMP through depopulation’s and structure shifting (8). Increased levels of CAMP results in activation of CAMP- dependent protein kinas A.
Protein kingies are enzymes that modify proteins by adding to them a phosphate group(usually derived from TAP). This phosphorescently leads to a functional change in the targeted protein either by altering the enzyme activity, its intracellular location or its interaction with other proteins (9). Protein kinas A is a CAMP dependent kinas and in the activated form, it works in two ways (all of which leads to relaxation of a smooth muscle); first, it decreases the acting- myosin interactions by phosphorescently the myosin light chain (10). Secondly, it lowers intracellular calcium concentration in the smooth muscle cells.
This reduction comes about via two well researched and understood mechanisms. The first mechanism involves the regulation of influx and efflux of calcium through the calcium channels in the sarcoma (which is the cell wall). Protein kinas A causes the channels to increase the efflux of calcium from the cell and decreases influx (11). The second mechanism involves the ceroplastic reticulum which is the chief store of calcium in the cell. The kinas stimulates uptake of calcium into the store, therefore, reducing its overall concentration in the cytoplasm (12).
The effect of these woo mechanisms (low calcium) leads to smooth muscle relaxation. Lastly, research shows that raised levels of CAMP causes a cessation of the release of mediators of inflammation from mast cells in the respiratory tract (13). All of these elaborate actions give Salomon its potency in dilating constricted airways and reducing obstruction secondary to inflammatory processes. But prolonged use and exposure to this drug leads to development of a resistance to it. Many schools of thought have come up with possible explanations as to now tens napes rater years AT Intense research.
However, ten most accepted explanation is down regulation of the ;2-receptors and desensitizing of the same (14). It is now universally accepted that a cell’s surface expression of this receptor and its coupling to signaling pathways inside the cell shows a negative feedback loop that works to reduce the cell responsiveness to prolonged occupation of the receptor by agonies lagan’s. When an agonies attaches to the receptor, the stabilization involves phosphorescently (15). This usually interferes with how the receptor couples with the Gas-protein; therefore, limiting its function in what is commonly referred to as desensitizing.
Desensitizing thus leads to reduction in the activation of intracellular signaling pathways secondary to prolonged receptor stimulation (16). This mechanism of uncoupling is rapid and reversible in nature, usually seen after short-term exposure. Phosphorescently of the receptor usually happens due to protein kinas A dependent pathways or by activation of G-protein receptor kingies named beta -ARKS (17). Tissues of different types show different degrees of this uncoupling when exposed to stimulatory lagan’s, and this can be due to the differences in activity of the above mentioned phosphorescently mechanism.
Apart from desensitizing another key process leading to Salomon resistance is the receptor down regulation. When ;2-receptors stimulation occurs for prolonged duration, they show a negative feedback mechanism that reduces their quantity of expression on the cell surface (18). The mechanism behind this is not particularly clear, but it is strongly believed to be due to receptor trafficking to lissome for destruction. Research has shown that chronic exposure to Salomon does not only lead to uncoupling but also receptor initialization from the cell surface.
Initialization occurs through the process indications, which happens via Claritin coated pit endoscope pathway that works by forming buds from the cell membrane (19). When this process begins, Claritin (which is a small intracellular protein) begins to arrange on the inner surface of the cell’s plasma membrane below the soon to be internalized receptor. The linear ends then start coming together to form a circular Claritin coated pit that has now engulfed a part of the plasma membrane, the receptor and some extracurricular fluid (20).
The pit buds off into the cell and the ends of the plasma membrane come together to correct the deficit left on the surface. This pit is now referred to as a vesicle, and it traffics contents to a cell organelle known as a lissome (21). This organelle has an acidic environment and a number of enzymes that breakdown fats, proteins and carbohydrates. The vesicle fusses with the organelle’s membrane and regurgitates its contents leaving the Claritin molecules on the surface (22). The receptor and other contents are consequently degraded. This is not the only aspect of down regulation that plays a part in reducing receptor expression.
Research has shown that ;2-receptor Mrs. levels significantly reduce in the nucleus when levels of protein kinas A become elevated for long durations (days to months). Clinical features Clinical features of Salomon resistance occur when patients are intolerant to the drug therapy. Recovery, after therapy, is prolonged or absent even after maximum amelioration AT receive dose. I en most gallants clinical Torture appears in the deterioration of asthma and the subsequent exacerbation of the symptoms. Drug resistant asthma presents with (23); Worsening dyspepsia. Continuous wheezing and breathlessness. Chest tightness.
These patients have developed tolerance to Salomon, therefore, are resistant to the therapy. With subsequent increase in the dose therapy which is not effective, patients with theoretically hyper-responsiveness with or without exposure to allergens and with the resulting inflammatory changes and bronchi-constriction, asthma worsens. The most severe clinical feature can present like status asthmatics or acute severe asthma. This present as episodes of severe asthma, failing to respond to usual effective doses of Salomon (24). There is progressive respiratory failure even within the course of therapy.
This episode can progress to fatal asthma. Patients present with; Significant wheezing and dyspepsia. Severe respiratory distress. Hyperventilation and subsequent respiratory leukemia. Features of metabolic acidosis due to anaerobic respiration and elevated levels of lactate from the respiratory muscles (25). Severe asthma will occur with increasing degree of hyper-reactivity due to intolerance to drug therapy: ineffective relief and loss of bronchitis tone. Clinical feature can also occur as a result of high drug dosage. Resistance causes a patient who is in respiratory distress to use increasing and more frequent doses of albums.
High doses produce toxicities which can present with systemic features (26). In the respiratory system; there can be hyperemia. Salomon is a psychosomatic agent (beta 2 agonies) the vacillators effect of beta 2 Zionists increases perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (27). Significance of this effect depends on initial partial pressure of oxygen of the patient. Hyperemia will present clinically as occasions, respiratory distress, and tachyons. There can be paradoxical bronchus’s due to the Atonally antagonism to Transcendentalist erect AT Salomon
I en spasms, AT the smooth muscles lining the bronchi, are due to psychosomatic action of Salomon and adrenaline stimulation. In the cardiovascular system, the psychosomatic action of Salomon can cause toxicity which might result in cardiac arrhythmias, arterial fibrillation, supercritical tachycardia and extra systole (29). There can be an occurrence of coronary insufficiency due to hyperemia, atheistically and resulting tachycardia, peripheral bastardization with a compensatory small increase in heart rate, hypertension and palpitation. In the endocrine and metabolic system, there can be hypoglycemia.
Salomon may stimulate sodium and potassium Tapes which causes redistribution of electrolytes (30). Hyperglycemia in a diabetic patient; Salomon stimulates the beta 2 transporters which stimulate hepatic glycogen breakdown for pancreatic release of clangor which increase plasma glucose. In the central nervous system, overdose of Salomon therapy intolerance can produce CONS symptoms such as insomnia, weakness, dizziness, nervousness, tremors, transient muscle cramps and headache. Rarely reported effects include drowsiness, irritability, chest discomfort and difficulty in instruction (31).
Diagnosis Diagnosis of Salomon resistance follows the clinical guidelines of a full comprehensive history of the patient, physical exam, and investigation to confirm the patient’s tolerance to drugs. In taking the history certain question might lead to the discovery that a patient previously on Salomon therapy is unresponsive to the drug. When doing a physical exam, clinician should check out for general observation such as respiratory distress and occasions. In doing a systemic exam, focusing on the respiratory system may bring out worsening respiratory function.
Clinician may find wheezing with other signs indicative of exacerbated asthma. Investigation Investigative studies are confirmatory and supportive to the diagnosis. The base lines include; Full blood count. Urea electrolyte count. Liver function tests. Random blood sugar if suspecting diabetes. I en consoler long toner tests In prospector s o mol toxicity al u TA Pulmonary function tests Serum blood gas analysis with pH profile Cardiograms to check arrhythmias Gene typing; the cornerstone of Salomon resistance detection is gene typing. Experimental studies have shown that tolerance in asthma is in the polymorphism of he DRAB gene.
Analysis show that tolerance is in the glycogen allele at position 16 and 21 at the beta receptor gene. Gene typing for polymorphism can aid in identifying patients with drug resistant asthma (32). Management Management can be categorized as supportive, specific, preventive and rehabilitative. Supportive management include; Outpatient monitoring if not severe Admission to a hospital if severe. Severe asthma necessitates immediate admission as it can be fatal. Oxygen therapy. Intubations and mechanical ventilation if severe. Use of parental corticosteroids which are anti-inflammatory.
Fluid and electrolyte resuscitation in the case of hypoglycemia. Frequent monitoring of patients to the drug. Specific management is both surgical and medical. Surgical management, research is still underway and ongoing. Medical management includes the use of a second-line therapy like monopolies, astatine and antihistamines. There is also use of cardiac-selective beta adrenaline blocking agents and corticosteroids in Salomon toxicity. Other drugs can be used depending on symptom’s of resistance, for example; interventions, insulin and any other depending on the symptoms of the patient.
Surgical intervention for example attempting bronchial thermoplastic. This is a bronchitis procedure in which delivered thermal energy to airways; it reduces airway smooth muscle hyper responsiveness. It has been also shown to be beneficial in treatment of severe asthma where continuous therapy has failed. Preventive management Includes gene typing early enough to Isolate patients wilt Salomon resistance by checking the beta AR gene. The other way is to prevent high-drug toxicity. Rehabilitative management of any complication that might occur is essential.
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