Respiratory System Pharmacology PDF

Pharmacology College of Dentistry Dr Maha Mohsin Khalaf University of Baghdad Respiratory System Asthma, chronic obstructive pul...

Pharmacology College of Dentistry Dr Maha Mohsin Khalaf University of Baghdad Respiratory System Asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis are commonly encountered respiratory disorders. Each of these conditions may be associated with a troublesome cough, which may be the only presenting complaint. Asthma is a chronic disease characterized by hyperresponsive airways and episodes of acute bronchoconstriction causing shortness of breath, Allergic rhinitis characterized by itchy, watery eyes, runny nose, and a nonproductive cough that can significantly decrease quality of life. Whereas asthma is characterised by reversible airways obstruction and bronchial hyperreactivity, COPD is characterised by incompletely reversible airways obstruction and mucus hypersecretion; it is predominantly a disease of the smaller airways. Nevertheless, distinguishing the two can be difficult in some patients. Drugs used to treat respiratory conditions can be delivered topically to the nasal mucosa, inhaled into the lungs, or given orally or parenterally for systemic absorption. Local delivery methods, such as nasal sprays or inhalers, are preferred to target affected tissues while minimizing systemic side effects. ASTHMA The bronchi become hyperreactive (Figure 1) as a result of a persistent inflammatory process in response to a number of stimuli that include biological agents, e.g. allergens, viruses, and environmental chemicals such as ozone and glutaraldehyde. Inflammatory mediators are liberated from mast cells, eosinophils, neutrophils, monocytes and macrophages. Some mediators such as histamine are pre-formed and their release causes an immediate bronchial reaction. Others are formed after activation of cells and produce more sustained bronchoconstriction; Preferred drugs used to treat asthma: β2 -Adrenergic agonists Inhaled β2 -adrenergic agonists directly relax airway smooth muscle. They are used for the quick relief of asthma symptoms, as well as adjunctive therapy for long-term control of the disease. 1. Quick relief: Short-acting β2 agonists (SABAs) have a rapid onset of action (5 to 30 minutes) and provide relief for 4 to 6 hours. They are used for symptomatic treatment of bronchospasm, providing quick relief of acute bronchoconstriction. All patients with asthma should be prescribed a SABA inhaler. β2 agonists have no anti-inflammatory effects, and they should never be used as the sole therapeutic agents for patients with persistent asthma. However, monotherapy with SABAs may be appropriate for patients with intermittent asthma or exercise-induced bronchospasm. Direct acting β2 -selective agonists 1 Figure 1: difference between normal and asthmatic airways include albuterol and levalbuterol. These agents provide significant bronchodilation with little of the undesired effect of α or β1 stimulation. Adverse effects, such as tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia, are minimized with inhaled delivery versus systemic administration. These agents can cause β2 -mediated skeletal muscle tremors. 2. Long-term control: Salmeterol and formoterol are long-acting β2 agonists (LABAs) and chemical analogs of albuterol. Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours. Neither salmeterol nor formoterol should be used for quick relief of an acute asthma attack. Use of LABA monotherapy is contraindicated, and LABAs should be used only in combination with an asthma controller medication. Inhaled corticosteroids remain the long-term controllers of choice in asthma, and LABAs are considered to be useful adjunctive therapy for attaining asthma control. Some LABAs are available as a combination product with an ICS. Adverse effects of LABAs are similar to quick-relief β2 agonists. Corticosteroids ICS are the drugs of choice for long-term control in patients with any degree of persistent asthma. Corticosteroids inhibit the release of arachidonic acid through phospholipase A2 inhibition, thereby producing direct anti-inflammatory properties in the airways. No other medications are as effective as ICS in the long-term control of asthma in children and adults. To be effective in controlling inflammation, glucocorticoids must be used regularly. Severe persistent asthma may require the addition of a short course of oral glucocorticoid treatment. 1. Actions on lung: ICS do not directly affect the airway smooth muscle. Instead, ICS therapy directly targets underlying airway inflammation by decreasing the inflammatory cascade (eosinophils, macrophages, and T lymphocytes), reversing mucosal edema, decreasing the permeability of capillaries, and inhibiting the release of leukotrienes (Figure 2). After several months of regular use, ICS reduce the hyperresponsiveness of the airway smooth muscle to a variety of bronchoconstrictor stimuli, such as allergens, irritants, cold air, and exercise. 2. Routes of administration a. Inhalation: The development of ICS has markedly reduced the need for systemic corticosteroid treatment to achieve asthma control. However, as with all inhaled medications, appropriate inhalation technique is critical to the success of therapy. b. Oral/systemic: Patients with a severe exacerbation of asthma (status asthmaticus) may require intravenous methylprednisolone or oral prednisone to reduce airway inflammation. In most cases, suppression of the hypothalamic–pituitary–adrenal cortex axis will not occur Figure 2: Mechanism of action of Corticosteroids 2 during the short course of oral prednisone “burst” typically prescribed for an asthma exacerbation. Therefore, prednisone dose taper is unnecessary prior to discontinuation. Due to the increased incidence of adverse effects with oral therapy, chronic maintenance with systemic administration of corticosteroids should be reserved for patients who are not controlled on an ICS. 3. Adverse effects: Oral or parenteral glucocorticoids have a variety of potentially serious side effects (Figure 3), whereas ICS, particularly if used with a spacer, have few systemic effects. ICS deposition on the oral and laryngeal mucosa can cause adverse effects, such as oropharyngeal candidiasis (due to local immune suppression) and hoarseness. Patients should be instructed to rinse the mouth in a “swish-and-spit” method with water following use of the inhaler to decrease the chance of these adverse events. Figure 3: ICS side effects Alternative drugs used to treat asthma These drugs are useful for treatment of asthma in patients who are poorly controlled by conventional therapy or experience adverse effects secondary to corticosteroid treatment. These drugs should be used in conjunction with ICS therapy for most patients, not as monotherapy. A. Leukotriene modifiers Leukotrienes (LT) B4 and the cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are products of the 5-lipoxygenase pathway of arachidonic acid metabolism and part of the inflammatory cascade. 5-Lipoxygenase is found in cells of myeloid origin, such as mast cells, basophils, eosinophils, and 3 neutrophils. LTB4 is a potent chemoattractant for neutrophils and eosinophils, whereas the cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase endothelial permeability, and promote mucus secretion. Zileuton is a selective and specific inhibitor of 5-lipoxygenase, preventing the formation of both LTB4 and the cysteinyl leukotrienes. Because zafirlukast and montelukast are selective antagonists of the cysteinyl leukotriene-1 receptor, they block the effects of cysteinyl leukotrienes (Figure 2). All three drugs are approved for the prevention of asthma symptoms. They should not be used in situations where immediate bronchodilation is required. Leukotriene receptor antagonists have also shown efficacy for the prevention of exercise induced bronchospasm. Pharmacokinetics: All three drugs are orally active and highly protein bound. Food impairs the absorption of zafirlukast. The drugs are metabolized extensively by the liver. Zileuton and its metabolites are excreted in urine, whereas zafirlukast, montelukast, and their metabolites undergo biliary excretion. Adverse effects: Elevations in serum hepatic enzymes have occurred with all three agents, requiring periodic monitoring and discontinuation when enzymes exceed three to five times the upper limit of normal. Other effects include headache and dyspepsia. B. Cromolyn is a prophylactic anti-inflammatory agent that inhibits mast cell degranulation and release of histamine. It is an alternative therapy for mild persistent asthma. However, it is not useful in managing an acute asthma attack, because it is not a bronchodilator. Cromolyn is available as a nebulized solution for use in asthma. Due to its short duration of action, this agent requires dosing three or four times daily, which affects adherence and limits its use. Adverse effects are minor and include cough, irritation, and unpleasant taste. C. Cholinergic antagonists The anticholinergic agents block vagally mediated contraction of airway smooth muscle and mucus secretion. Inhaled ipratropium, a quaternary derivative of atropine, is not recommended for the routine treatment of acute bronchospasm in asthma, as its onset is much slower than inhaled SABAs. However, it may be useful in patients who are unable to tolerate a SABA or patients with concomitant COPD. Ipratropium also offers additional benefit when used with a SABA for the treatment of acute asthma exacerbations in the emergency department. Adverse effects such as xerostomia and bitter taste are related to local anticholinergic effects. D. Theophylline is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms. It may also possess anti-inflammatory activity, Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. Previously, the mainstay of asthma therapy, theophylline has been largely replaced with β2 agonists and corticosteroids due to its narrow therapeutic window, adverse effect profile, and potential for drug interactions. Overdose may cause seizures or potentially fatal arrhythmias. Theophylline is metabolized in the liver. It is subject to numerous drug interactions. Serum concentration monitoring should be performed when theophylline is used chronically. E. Omalizumab is a recombinant DNA-derived monoclonal antibody that selectively binds to human immunoglobulin E (IgE). This leads to decreased binding of IgE to its receptor on the surface of mast cells and basophils. Reduction in surface-bound IgE limits the release of mediators of the allergic response. Omalizumab is indicated for the treatment of moderate to severe persistent asthma in patients who are poorly controlled with conventional therapy. Its use is limited by the high cost, route of administration (subcutaneous), and adverse effect profile. Adverse effects include serious anaphylactic reaction (rare), arthralgias, fever, and rash. Secondary malignancies have been reported. 4 CHRONIC OBSTRUCTIVE PULMONARY DISEASE COPD is a chronic, irreversible obstruction of airflow that is usually progressive. Symptoms include cough, excess mucus production, chest tightness, breathlessness, difficulty sleeping, and fatigue. Although symptoms are similar to asthma, the characteristic irreversible airflow obstruction of COPD is one of the most significant differences between the diseases. Smoking is the greatest risk factor for COPD and is directly linked to the progressive decline of lung function as demonstrated by forced expiratory volume in one second (FEV1). Smoking cessation and/or continued avoidance should be recommended regardless of stage/ severity of COPD and age of patient. Drug therapy for COPD is aimed at relief of symptoms and prevention of disease progression. A. Bronchodilators Inhaled bronchodilators, including the β2 -adrenergic agonists and anticholinergic agents (ipratropium and tiotropium), are the foundation of therapy for COPD. These drugs increase airflow, alleviate symptoms, and decrease exacerbation rates. The long-acting agents, LABAs and tiotropium, are preferred as first-line treatment of COPD for all patients except those who are at low risk with less symptoms. Combination of both an anticholinergic and a β2 agonist may be helpful in patients who have inadequate response to a single inhaled bronchodilators. B. Corticosteroids The addition of an ICS to a long-acting bronchodilator may improve symptoms, lung function and quality of life in COPD patients. However, the use of an ICS is associated with an increased risk of pneumonia, and therefore, use should be restricted to these patients. Although often used for acute exacerbations, oral corticosteroids are not recommended for long-term treatment. C. Other agents: Roflumilast is an oral phosphodiesterase-4 inhibitor used to reduce exacerbations in patients with severe chronic bronchitis. Although its activity is not well defined in COPD, it is theorized to reduce inflammation by increasing levels of intracellular cAMP in lung cells. Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm. Its use is limited by common side effects including nausea, vomiting, diarrhea, and headache. As in asthma, the use of theophylline has largely been replaced by the more effective and tolerable long- acting bronchodilators. DRUGS USED TO TREAT ALLERGIC RHINITIS Rhinitis is an inflammation of the mucous membranes of the nose and is characterized by sneezing, itchy nose/eyes, watery rhinorrhea, nasal congestion, and sometimes, a nonproductive cough. An attack may be precipitated by inhalation of an allergen (such as dust, pollen, or animal dander). The foreign material interacts with mast cells coated with IgE generated in response to a previous allergen exposure. The mast cells release mediators, such as histamine, leukotrienes, and chemotactic factors that promote bronchiolar spasm and mucosal thickening from edema and cellular infiltration. Antihistamines and/or intranasal corticosteroids are preferred therapies for allergic rhinitis. A. Antihistamines (H1 -receptor blockers) Antihistamines are useful for the management of symptoms of allergic rhinitis caused by histamine release (sneezing, watery rhinorrhea, itchy eyes/nose). However, they are more effective for prevention of symptoms, rather than treatment once symptoms have begun. Ophthalmic and nasal antihistamine delivery devices are available for more targeted tissue delivery. First- generation antihistamines, such as diphenhydramine and chlorpheniramine, are usually not preferred due to adverse effects, such as sedation, performance impairment, and other anticholinergic effects. The second generation antihistamines (for example, fexofenadine, loratadine, desloratadine, cetirizine, and 5 intranasal azelastine) are generally better tolerated. Combinations of antihistamines with decongestants are effective when congestion is a feature of rhinitis. B. Corticosteroids Intranasal corticosteroids, such as beclomethasone, budesonide, fluticasone, ciclesonide, mometasone, and triamcinolone, are the most effective medications for treatment of allergic rhinitis. They improve sneezing, itching, rhinorrhea, and nasal congestion. Systemic absorption is minimal, and side effects of intranasal corticosteroid treatment are localized. These include nasal irritation, nosebleed, sore throat, and, rarely, candidiasis. To avoid systemic absorption, patients should be instructed not to inhale deeply while administering these drugs because the target tissue is the nose, not the lungs or the throat. For patients with chronic rhinitis, improvement may not be seen until 1 to 2 weeks after starting therapy. C. α-Adrenergic agonists Short-acting α-adrenergic agonists (“nasal decongestants”), such as phenylephrine, constrict dilated arterioles in the nasal mucosa and reduce airway resistance. Longer-acting oxymetazoline is also available. When administered as an aerosol, these drugs have a rapid onset of action and show few systemic effects. Unfortunately, the α-adrenergic agonist intranasal formulations should be used no longer than 3 days due to the risk of rebound nasal congestion (rhinitis medicamentosa). For this reason, the α-adrenergic agents have no place in the long-term treatment of allergic rhinitis. Administration of oral α-adrenergic agonist formulations results in a longer duration of action but also increased systemic effects. As with intranasal formulations, regular use of oral α-adrenergic agonists (phenylephrine and pseudoephedrine) alone or in combination with antihistamines is not recommended. D. Other agents Intranasal cromolyn may be useful in allergic rhinitis, particularly when administered before contact with an allergen. To optimize the therapeutic effect, dosing should begin at least 1 to 2 weeks prior to allergen exposure. A nonprescription (over-the-counter) nasal formulation of cromolyn is available. DRUGS USED TO TREAT COUGH Coughing is an important defense mechanism of the respiratory system to irritants and is a common reason for patients to seek medical care. A troublesome cough may represent several etiologies, such as the common cold, sinusitis, and/or an underlying chronic respiratory disease. In some cases, cough may be an effective defense reflex against an underlying bacterial infection and should not be suppressed. Before treating cough, identification of its cause is important to ensure that antitussive treatment is appropriate. The priority should always be to treat the underlying cause of cough when possible. A. Opioids: Codeine, an opioid, decreases the sensitivity of cough centers in the central nervous system to peripheral stimuli and decreases mucosal secretion. These therapeutic effects occur at doses lower than those required for analgesia. However, common side effects, such as constipation, dysphoria, and fatigue, still occur. In addition, it has addictive potential. Dextromethorphan is a synthetic derivative of morphine that has no analgesic effects in antitussive doses. In low doses, it has a low addictive profile. However, it is a potential drug of abuse, since it may cause dysphoria at high doses. Dextromethorphan has a significantly safer side effect profile than codeine and is equally effective for cough suppression. Guaifenesin, an expectorant, is available as a single-ingredient formulation and is also a common ingredient in combination products with codeine or dextromethorphan. 6 B. Benzonatate Unlike the opioids, benzonatate suppresses the cough reflex through peripheral action. It anesthetizes the stretch receptors located in the respiratory passages, lungs, and pleura. Side effects include dizziness, numbness of the tongue, mouth, and throat. These localized side effects may be particularly problematic if the capsules are broken or chewed and the medication comes in direct contact with the oral mucosa. Table 1 summarize all the drugs used in respiratory system diseases treatment Table 1 drugs for respiratory system diseases 7  Lecture 8 HISTAMINE AND ANTIHISTAMINE Histamine is a naturally occurring amine that is found in most tissues in an inactive bound form, and pharmacologically active free histamine, released in response to stimuli such as physical trauma or immunoglobulin (Ig) E-mediated activation, is an important component of the acute inflammatory response. The physiological functions of histamine are suggested by its distribution in the body, in:  Body epithelia (the gut, the respiratory tract and in the skin), where it is released in response to invasion by foreign substances  Glands (gastric, intestinal, lachrymal, salivary), where it mediates part of the normal secretory process  Mast cells near blood vessels, where it plays a role in regulating the microcirculation. \  Histamine functions as a neurotransmitter in the brain.  It also occurs as a component of venoms and in secretions from insect stings. Release of histamine: Most often, histamine is just one of several chemical mediators released in response to stimuli. The stimuli for release of histamine from tissues may include destruction of cells as a result of cold, toxins from organisms, venoms from insects and spiders, and trauma. Allergies and anaphylaxis can also trigger significant release of histamine. Actions Histamine acts as a local hormone (autacoid) similarly to serotonin or prostaglandins, i.e. it functions within the immediate vicinity of its site of release. With gastric secretion, for example, stimulation of receptors on the histamine containing cell causes release of histamine, which in turn acts on receptors on parietal cells which then secrete hydrogen ion. Histamine receptors Histamine binds to H1, H2 and H3 receptors, all of which are G-protein coupled. The H1 receptor is largely responsible for mediating its pro-inflammatory effects, including the vasomotor changes, increased vascular permeability and upregulation of adhesion molecules on vascular endothelium, i.e. it mediates the oedema and vascular effects of histamine. H2 receptors mediate release of gastric acid. Blockade of histamine H1 and H2 receptors has substantial therapeutic utility. H3 receptors are expressed in a wide range of tissues including brain and nerve endings, and function as feedback inhibitors for histamine and other neurotransmitters. More recently identified is the H4 receptor, which is involved in leucocyte chemotaxis. HISTAMINE ANTAGONISM AND H1- AND H2-RECEPTOR ANTAGONISTS The effects of histamine can be opposed in three ways:  By using a drug with opposing effects. Histamine constricts bronchi, causes vasodilatation and increases capillary permeability; adrenaline (epinephrine), by activating α and β2 adrenoceptors, produces opposite effects - referred to as physiological antagonism.  By blocking histamine binding to its site of action (receptors), i.e. using competitive H1- and H2-receptor antagonists. 8  By preventing the release of histamine from storage cells. Glucocorticoids and sodium cromoglicate can suppress IgE-induced release from mast cells; β2 agonists have a similar effect. Drugs that competitively block H1-histamine receptors were the first to be introduced and are conventionally called the 'antihistamines'. They effectively inhibit the components of the triple response and partially prevent the hypotensive effect of histamine, but they have no effect on histamine-induced gastric secretion which is suppressed by blockade of histamine H2 receptors. Thus, histamine antagonists are classified as:  histamine H1-receptor antagonists  histamine H2-receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine Histamine H1-receptor antagonists. The selectivity implied by the term 'antihistamine'is unsatisfactory because the older first-generation antagonists show considerable blocking activity against muscarinic receptors, and often serotonin and α-adrenergic receptors as well. These features are a disadvantage when H1 antihistamines are used specifically to antagonise the effects of histamine, e.g. for allergies. Hence the appearance of second-generation H1 antagonists that are more selective for H1 receptors and largely free of anti-muscarinic and sedative effects has been an important advance. Actions H1-receptor antihistamines oppose, to varying degrees, the effects of liberated histamine. They are generally competitive, surmountable inhibitors and strongly block all components of the triple response (a pure H1-receptor effect), but only partially counteract the hypotensive effect of high-dose histamine (a mixed H1- and H2-receptor effect). H1 antihistamines are of negligible use in asthma, in which non-histamine mediators, such as the cysteinyl leukotrienes, are the predominant constrictors. They are more effective if used before histamine has been liberated, and reversal of effects of free histamine is more readily achieved by physiological antagonism with adrenaline (epinephrine), which is used first in life-threatening allergic reactions. The older first- generation H1 antihistamines cause drowsiness and patients should be warned of this, e.g. about driving or operating machinery, and about additive effects with alcohol. Paradoxically, they can increase seizure activity in epileptics, especially children, and can cause seizures in non-epileptic subjects if taken in overdose. The newer second-generation H1 antihistamines penetrate the blood-brain barrier less readily and are largely devoid of such central effects. Antimuscarinic effects of first-generation H1 antihistamines are sometimes put to therapeutic advantage in parkinsonism and motion sickness. Uses The H1 antihistamines are used for symptomatic relief of allergies such as hay fever and urticaria. They are of broadly similar therapeutic efficacy. INDIVIDUAL H1-RECEPTOR ANTIHISTAMINES Non-sedative second-generation drugs These newer drugs are relatively selective for H1 receptors, enter the brain less readily than do the earlier antihistamines, and lack the unwanted antimuscarinic effects. Differences lie principally in their duration of action. Cetirizine (t½ 7 h), loratadine (t½ 15 h) and terfenadine (t½ 20 h) are effective taken once daily and are suitable for general use. Acrivastine (t½ 2 h) is so short acting that it is best reserved for intermittent therapy, e.g. when breakthrough symptoms occur in a patient using topical therapy for hay fever. Other non-sedating antihistamines are desloratadine, fexofenadine, levocetirizine and mizolastine. Adverse effects The second-generation antihistamines are well tolerated but a noteworthy effect occurs with terfenadine. This drug can cause ventricular tachycardia and probably explains the sudden deaths reported during early use of terfenadine. The event is prone to occur with high dose or when metabolism of 9 terfenadine is inhibited, and inhibiting drugs include erythromycin, ketoconazole and even grapefruit juice. Fexofenadine, the active metabolite of terfenadine, appears to be safer regarding the effect on the heart. Sedative first-generation agents Chlorphenamine (t½ 20 h) is effective when urticaria is prominent, and its sedative effect is then useful. Diphenhydramine (t½ 32 h) is strongly sedative and has antimuscarinic effects; it is also used in parkinsonism and motion sickness. Promethazine (t½ 12 h) is so strongly sedative that it is used as an hypnotic in adults and children. Alimemazine, azatadine, brompheniramine, clemastine, cyproheptadine, diphenylpyraline, doxylamine, hydroxyzine and triprolidine are similar. Adverse effects Apart from sedation, these include: dizziness, fatigue, insomnia, nervousness, tremors and antimuscarinic effects, e.g. dry mouth, blurred vision and gastrointestinal disturbance. Dermatitis and agranulocytosis can occur. Severe poisoning due to overdose results in coma and sometimes in convulsions. Corticosteroids The adrenal gland consists of the cortex and the medulla. The medulla secretes catecholamines, whereas the cortex, secretes two types of corticosteroids (glucocorticoids and mineralocorticoids) and the adrenal androgens. The adrenal cortex has three zones, and each zone synthesizes a different type of steroid hormone from cholesterol. The outer zona glomerulosa produces mineralocorticoids (for example, aldosterone) that are responsible for regulating salt and water metabolism. Production of aldosterone is regulated primarily by the renin–angiotensin system. The middle zona fasciculata synthesizes glucocorticoids (for example, cortisol) that are involved with metabolism and response to stress. The inner zona reticularis secretes adrenal androgens. A. Glucocorticoids Cortisol is the principal human glucocorticoid. Normally, its production is diurnal, with a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon. Factors such as stress and levels of the circulating steroid influence secretion. The effects of cortisol are many and diverse. In general, all glucocorticoids: 1. Promote normal intermediary metabolism: Glucocorticoids favor gluconeogenesis. They stimulate protein catabolism (except in the liver) and lipolysis, thereby providing the building blocks and energy that are needed for glucose synthesis. 2. Increase resistance to stress: By raising plasma glucose levels, glucocorticoids provide the body with energy to combat stress caused by trauma, fright, infection, bleeding, or debilitating disease. 3. Alter blood cell levels in plasma: Glucocorticoids cause a decrease in eosinophils, basophils, monocytes, and lymphocytes by redistributing them from the circulation to lymphoid tissue. Glucocorticoids also increase hemoglobin, erythrocytes, platelets, and polymorphonuclear leukocytes. 4. Anti-inflammatory effect They have powerful anti-inflammatory and immunosuppressant effects. They prevent or suppress the clinical features of inflammation such as redness, heat, pain and swelling. At tissue level, they suppress the early phenomena (capillary permeability, oedema, cellular infiltration and phagocytosis) and late responses like capillary proliferation, collagen deposition, fibroblast activity and scar formation (Figure 4). 10  Figure 4: anti-inflammatory effect of glucocorticoids a. Glucocorticoids induce a protein called lipocortin, which inhibits phospholipase A2, so prostaglandins (PGs), leukotrienes (LTs) and PAF are not formed. b. Tumour necrosis factor-alpha (TNF-α- is inhibited by glucocorticoids, which is necessary for initiating infl ammatory process. Figure 5: another mechanism of action of steroid hormones c. Glucocorticoids stabilize the lysosomal membrane and prevent the release of inflammatory mediators. B. Mineralocorticoids Mineralocorticoids help to control fluid status and concentration of electrolytes, especially sodium and potassium. Aldosterone acts on distal tubules and collecting ducts in the kidney, causing reabsorption of sodium, bicarbonate, and water. Conversely, aldosterone decreases reabsorption of potassium, which, with H+, is then lost in the urine. Enhancement of sodium reabsorption by aldosterone also occurs in gastrointestinal mucosa and in sweat and salivary glands. 11 Therapeutic uses of the corticosteroids (disturbance of corticosteroids production from adrenal cortex can cause two diseases. Reduction in corticosteroids is called Addison disease, while increase is called Cushing syndrome) Endocrinal uses: 1. Acute adrenal insufficiency: It is a medical emergency. It is treated with i.v. hydrocortisone and i.v. normal saline with 5% glucose to correct fluid and electrolyte imbalance. Precipitating causes such as trauma, infection or haemorrhage should be treated. 2. Chronic adrenal insufficiency: Treated with oral hydrocortisone (two-third of the daily dose is given in the morning and one-third in the evening) along with adequate salt and water. Non-endocrinal uses Corticosteroids are one of the most important groups of drugs used clinically in a variety of diseases. Because of their dramatic symptomatic relief, they are often misused. Non-endocrinal diseases require supra-physiological doses of steroid, which inevitably carries risk. The beneficial effects of glucocorticoids are mainly due to their anti-inflammatory and immunosuppressant effects. 1. In dentistry: Topical or systemic glucocorticoids are used in: a. Recurrent aphthous stomatitis b. Chronic ulcerative stomatitis c. Oral pemphigoid d. Erythema multiforme e. Temporomandibular joint pain: Intra-articular triamcinolone is used. 2- Relief of inflammatory symptoms: Corticosteroids significantly reduce the manifestations of inflammation associated with rheumatoid arthritis and inflammatory skin conditions, including redness, swelling, heat, and tenderness that may be present at the site of inflammation. These agents are also important for maintenance of symptom control in persistent asthma, as well as management of asthma exacerbations and active inflammatory bowel disease. In noninflammatory disorders such as osteoarthritis, intra-articular corticosteroids may be used for treatment of a disease flare. Corticosteroids are not curative in these disorders. 3- Treatment of allergies: Corticosteroids are beneficial in the treatment of allergic rhinitis, as well as drug, serum, and transfusion allergic reactions. [Note: In the treatment of allergic rhinitis and asthma, fluticasone and others are applied topically to the respiratory tract through inhalation from a metered dose dispenser. This minimizes systemic effects and allows the patient to reduce or eliminate the use of oral corticosteroids.] 4- Acceleration of lung maturation: Respiratory distress syndrome is a problem in premature infants. Fetal cortisol is a regulator of lung maturation. Consequently, a regimen of betamethasone or dexamethasone administered intramuscularly to the mother within the 48 hours proceeding premature delivery can accelerate lung maturation in the fetus. 12