1. a. Explain etiopathogenesis and pharmacotherapy of osteoporosis

Osteoporosis is a progressive disease characterised by low bone mass and micro-architectural deterioration of bone tissue resulting in increased bone fragility and susceptibility to fracture. It is an important cause of morbidity in postmenopausal women. The most important complication of osteoporosis is fracture of the hip.

PHARMACOTHERAPY OF OSTEOPOROSIS:

Vitamin D and calcium: Vitamin D deficiency is common in elderly people. Treatment for 12–18 months with 800 IU of vitamin D plus 1.2 g of calcium given daily has been shown to reduce hip and non-vertebral fractures in elderly womenCalcitriol and alfacalcidol: Calcitriol (1,25-dihydroxyvitamin D), the active metabolite of vitamin D, and alfacalcidol, a synthetic analogue of calcitriol, reduce bone loss and have been shown to reduce vertebral fractures, but not consistently. Serum calcium should be monitored regularly in patients receiving these drugs. Bisphosphonates: Bisphosphonates, synthetic analogues of pyrophosphate, bind strongly to the bone surface and inhibit bone resorption. Currently, three oral bisphosphonates are available for the treatment of osteoporosis: alendronate, etidronate and risedronate. Alendronate can be given either daily (10 mg) or weekly (70 mg) with equal efficacy. It is effective in reducing vertebral, wrist and hip fractures. Etidronate is given cyclically with calcium supplements to reduce the risk of bone mineralisation defects. It reduces the risk of vertebral fractures. Alendronate and risedronate are currently used as first-line drugs in older women with osteoporosis.Strontium ranelate: It increases both bone formation and reduces bone resorption, reduces vertebral and non-Vertebral (including hip) fractures in postmenopausal women with osteoporosis.Hormone replacement therapy (HRT): Oestrogens increase bone formation and reduce bone resorption. They also increase calcium absorption and decrease renal calcium loss. HRT, if started soon after the menopause, is effective in preventing vertebral fractures but has to be continued lifelong if protection against fractures is to be maintained.Raloxifene: Raloxifene, an oral selective oestrogen receptor modulator (SERM) that has oestrogenic actions on bone and anti-oestrogenic actions on the uterus and breast. It reduces the risk of vertebral fractures, but not those at other sites. Adverse effects include hot flushes, leg cramps, and risk of venous thromboembolism. It also protects against breast cancer.Parathyroid hormone peptides: Teriparatide is the recombinant portion of human parathyroid hormone, amino acid sequence 1–34, of the complete molecule (which has 84 amino acids). It reduces vertebral and non-vertebral fractures in postmenopausal women. It does not reduce hip fractures. It is given subcutaneously at a dose of 20 μcg daily.

Calcitonin: Calcitonin inhibits osteoclasts and decreases the rate of bone resorption, reduces bone blood flow and may have central analgesic actions. It is effective in all age groups in preventing vertebral bone loss. It is costly and has to be given parenterally or intranasally. Antibodies do develop against calcitonin, but they do not affect its efficacy. Calcitonin is useful in treating acute pain associated with osteoporotic vertebral fractures.

2. Write short notes on Diagnosis test of COPD

Breathing, Exercise, and Oxygen Tests

Pulmonary function testing measures how well you are breathing. There are different types of breathing tests that can be done during pulmonary function testing.

Spirometry: A spirometry test measures airflow into and out of the lungs. This indicates whether or not there is airway obstruction. Spirometry test results are useful in making the diagnosis of a specific lung disorder. Even more important, yearly spirometry measurements help to detect lung disease at an early stage when lifestyle changes and treatment may help forestall future problems.

Arterial Blood Gas Testing: Arterial blood gas is a blood sample test ordered by your physician to evaluate measurements of oxygen level, carbon dioxide (effectiveness of respiration), and several other parameters..

Bronchial Provocation Test: The bronchial provocation test evaluates how sensitive the airways in your lungs are. A spirometry breathing test is done before and after you inhale a spray such as methacholine. The spirometry results are compared before and after you inhale the spray to see what changes there are in your breathing.

Exercise Tolerance Testing: The exercise tolerance test evaluates the ability of your heart and lungs to provide oxygen and remove carbon dioxide from the bloodstream before, during and after you exercise.

Exercise for Desaturation Testing: The exercise for de-saturation test evaluates your oxygen needs at rest and during exercise.

X-Rays and CT (CAT) Scans

• X-rays: X-rays can show irregularities or damage in the lungs caused by COPD and other chronic lung diseases.

•CT Scan of the Chest : A CT or CAT scan is a shortened name for computerized tomography. During a CT scan of the chest pictures are taken of cross sections or slices of the thoracic structures in your body. Thoracic structures include your lungs, heart and the bones around these areas.

CT Scan of the Sinuses : During a CT scan of the sinuses pictures are taken of cross sections or slices of the sinuses. The sinuses are air-filled cavities in your head. CT scans can identify problems with sinuses.

Other Tests

Bronchoscopy: A bronchoscopy allows the doctor to look inside the airways in the lungs. The bronchoscopy can be videotaped to look at later. Your doctor may also do a lavage, which involves putting a small amount of fluid into the airways, and the fluid is then pulled out with cells from the airways of your lungs. A biopsy of the airway may also be done, where a small amount of the tissue is taken from the lining of the lung.

Mucus Culture: Some kinds of bacteria like to live in the mucus produced in the sinuses and airways of the lungs. A culture of this mucus can help identify an infection. Lung and/or sinus infections can complicate and/or mimic some symptoms of COPD.

Bone Scan: A bone scan is a test that can identify bone that is diseased or injured. Normally, bone absorbs nutrients that are the building blocks of bone formation. If bone is diseased or injured nutrients are absorbed differently. The bone scan takes pictures of this process. A bone scan can pick up on bone disease or injury that may not be seen with a traditional x-ray.

pH Probe Study: A pH probe study measures the amount of gastroesophageal reflux you child has. Gastroesophageal reflux is the backward flow or reflux of food and acid from the stomach into the esophagus. The esophagus is the tube that takes food from your mouth into your stomach. A pH probe will help identify if you have increased amounts of reflux and if it is causing you to have trouble breathing or other symptoms.

3. Explain the etiology and Pharmacotherapy of chronic obstructive airways diseaseAetiology :Tobacco smoking is the most important and dominant risk factor in the development of COPD but other noxious particles also contribute, such as occupational exposure to chemical fumes, irritants, dust and gases. A person's exposure can be thought of in terms of the total burden of inhaled particles.These cause a (normal) inflammatory response in the lungs. Smokers, however, seem to have an exaggerated responsewhich eventually causes tissue destruction and impaired repair mechanisms. In addition to inflammation, the othermain processes involved in the pathogenesis of COPD arean imbalance of proteinases and antiproteinases in the lungs,and oxidative stress.Not all smokers go on to develop clinically significant COPD; genetic factors seem to modify each individual's risk.The age at which an individual begins smoking, total pack-years smoked and current smoking status are predictive of COPD mortality. Passive exposure to cigarette smoke may also contribute to respiratory symptoms and COPD by increasing the lungs' total burden of inhaled particles and gases (GOLD, 2009).Tobacco exposure is quantified in ‘pack-years’: Additional risk factors include the natural ageing process of the lungs. Males are currently more at risk of developing chronic bronchitis, but as the number of women who smoke increases, the incidence of chronic bronchitis in females will also rise. The major risk factors are summarized

RISK FACTOR EFFECTSSmoking Risk increases with increasing consumption but

there is also large interindividual variation in susceptibility

Age Increasing age results in ventilatory impairment; most frequently related to cumulative smoking

Gender Male gender was previously thought to be a risk factor but this may be due to a higher incidence of

Occupation The development of COPD has been implicated with occupations such as coal and gold mining, farming,grain handling and the cement and cotton industries

Genetic factors 1-Antitrypsin deficiency is the strongest single genetic risk factor, accounting for 1–2% of COPD. Other genetic disorders involving tissue necrosis factor and epoxide hydrolase may also be risk factors

Air pollution Death rates are higher in urban areas than in rural areas. Indoor air pollution from burning biomass fuel is also implicated as a risk factor, particularly in underdeveloped areas of the world

Socio economic status More common in individuals of low socioAirway hyper-responsiveness and allergy Smokers show increased levels of IgE, eosinophils

and airway hyper-responsiveness but how theseinfluence the development of COPD is unknown

InflammationCOPD is characterised by chronic inflammation throughout the airways, parenchyma and pulmonary vasculature. This is a different pattern of inflammation from that of asthma, with an increase in neutrophils, macrophages and T-lymphocytes (particularly CD8+); increased eosinophils occur in some patients during exacerbations. These inflammatory cells cause the release of inflammatory mediators and cytokines such as leukotriene B4, interleukin-8 and tumour necrosis factor- (TNF-). Over time the actions of these mediators damages the lungs and leads to the characteristic pathological changesobserved.Proteinase and antiproteinase imbalanceThe observation that 1-antitrypsin-deficient individuals are at increased risk of developing emphysema has led to the theory that an imbalance between proteinases and antiproteinases leads to lung destruction. In COPD, there is either an increased production/activity of proteinases or a decreased production/activity of antiproteinases. The main proteinases, proteolytic enzymes such as neutrophil elastin are released by macrophages or neutrophils. The antiproteinases inhibit the damage caused by the proteolytic enzymes. The main antiproteinase is 1-antitrypsin, also known as 1-proteinaseinhibitor. Cigarette smoke has been shown to inactivate this protein. Oxidative stress also decreases the activity of antiproteinases.Oxidative stressAn imbalance of oxidants and antioxidants exists in COPD with the balance in favour of the oxidants. This state of oxidative stress contributes to the development of the disease by damaging the intracellular matrix, oxidising biological molecules which cause cell destruction and promoting histone acetylation. There also seems to be a link between oxidative stress and the poor response to corticosteroids seen in COPD. To work, corticosteroids must recruit histone deacetylase to switch off the transcription of inflammatory genes. In COPD,the activity of histone deacetylase is impaired by the oxidative stress, thereby reducing the responsiveness to corticosteroids. Cigarette smoke also impairs the function of histone deacetylase.PHARMACOTHERAPY: The primary goals of pharmacotherapy are to control symptoms (including dyspnea), reduce exacerbations, and improve exercise tolerance and health status.According to the guidelines, patients with intermittent symptoms should be treated with short-acting bronchodilators. When symptoms become more persistent, long-acting bronchodilators should be initiated. For patients with an FEV1 less than 50% and who experience frequent exacerbations, inhaled corticosteroids should be considered. Short-acting bronchodilators relieve symptoms and increase exercise tolerance. Long-acting bronchodilators relieve symptoms,reduce exacerbation frequency, and improve quality of life and health status. Patients have a variety of choices in using inhalationaltherapies, including metered dose inhalers (MDIs), dry powder inhalers (DPIs), or nebulizers.Bronchodilators: Bronchodilator classes available for the treatment of COPD include β2-agonists, anticholinergics, and methylxanthines. Bronchodilators generally work by reducing the tone of airway

smooth muscle (relaxation), thus minimizing airflow limitation. In patients with COPD, the clinical benefits of bronchodilators include increased exercise capacity, decreased air trapping in the lungs, andrelief of symptoms such as dyspnea.

Short-Acting Bronchodilators: The initial therapy for COPD patients who experience symptoms intermittently are short-acting bronchodilators. Among these agents, the choices are a shortactingβ2-agonist or an anticholinergic. Either class of agents has a relatively rapid onset on action, relieves symptoms, and improves exercise tolerance and lung function.Short-Acting Sympathomimetics (β2-Agonists) : β2-Agonists cause bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate. Cyclic adenosine monophosphate is responsible for mediating relaxation of bronchial smooth muscle, leading to bronchodilation. In addition, it may improve mucociliary clearance. Although shorter-acting andless-selective β-agonists are still used widely (e.g., metaproterenol,isoetharine, isoproterenol, and epinephrine), they should not be used owing to their shorter duration of action and increased cardiostimulatory effects. Short-acting, selective β2-agonists such as albuterol, levalbuterol, and pirbuterol, are preferred for therapy. The preferred route of administration is by inhalation.The use of oral and parenteral β-agonists in COPD is discouraged because they are no more effective than a properly used MDI or DPI, and the incidence of systemic adverse effects such as tachycardia and hand tremor is greater.Albuterol is the most frequently used β2-agonist. It is available as an oral and inhaled preparation. Albuterol is a racemic mixture of (R)-albuterol that is responsible for the bronchodilator effect and(S)-albuterol that has no therapeutic effect. Levalbuterol is a single-isomer formulation of (R)-albuterol. The duration of action of short-acting β2-agonists is 4 to 6 hours.Short-Acting Anticholinergics: When given by inhalation, anticholinergics such as ipratropium or atropine produce bronchodilation by competitively inhibiting cholinergic receptors in bronchial smooth muscle. This activity blocks acetylcholine, with the neteffect being a reduction in cyclic guanosine monophosphate, which normally acts to constrict bronchial smooth muscle. Muscarinic receptors on airway smooth muscle include M1, M2, and M3 subtypes. Activation of M1 and M3 receptors by acetylcholine resultsin bronchoconstriction; however, activation of M2 receptors inhibits further acetylcholine release.Ipratropium is the primary short-acting anticholinergic agent used for COPD .It provides a peak effect in 1.5 to 2 hours and has a duration of effect of 4 to 6 hours. Ipratropium has a slower onset of action and a more prolonged bronchodilator effect compared with standard β2-agonists.Long-Acting Bronchodilators: For patients with moderate to severe COPD who experience symptoms on a regular and consistent basis, or in whom short-acting therapies do not provide adequate relief, long-acting bronchodilator therapies are the recommended treatment. Long-acting, inhaled bronchodilator therapy can be administered as a β2-agonist or an anticholinergic. Long-acting bronchodilators provide similar benefits to short-acting agents. In addition, they reduce exacerbation frequency and improve quality of life.Long-Acting, Inhaled β2-Agonists: Long-acting, inhaled β2-agonists offer the convenience and benefit of a long duration of action for patients with persistent symptoms. Both salmeterol and formoterol are dosed every 12 hours and provide sustained bronchodilation. Formoterol has an onset of action similar to albuterol (less than 5 minutes), whereas salmeterol has a slower onset (15 to 20 minutes)Long-acting β-agonists are also useful to reduce nocturnal symptoms and improve quality of life. When compared to short-acting bronchodilators or theophylline, both salmeterol and formoterol improve lung function, symptoms, exacerbation frequency and quality of lifeLong-Acting Anticholinergics : Tiotropium bromide, a long acting quaternary anticholinergic agent This agent blocks the effects of acetylcholine by binding to muscarinic receptors in airway smooth muscle

and mucus glands, blocking the cholinergic effects of bronchoconstriction and mucus secretion. When inhaled, tiotropium is minimally absorbed into the systemic circulation and results in bronchodilation within 30 minutes, with a peak effect in 3 hours.Corticosteroids : The antiinflammatory mechanisms whereby corticosteroids exert their beneficial effect in COPD include (a) reduction in capillary permeability to decrease mucus, (b) inhibition of release of proteolytic enzymes from leukocytes, and (c) inhibition of prostaglandins.

α1-Antitrypsin Replacement Therapy : In patients with inherited AAT deficiency-associated emphysema,treatment focuses on reduction of risk factors such as smoking, symptomatic treatment with bronchodilators, and augmentation therapy with replacement AAT. Augmentation therapy consists of weekly infusions of pooled human AAT to maintain AAT plasma levels greater than 10 micromolars.

4. Write about the rational use of drugs in following disordersa) Osteoporosis b) Diabetes mellitus