SAS 4: Agents Used in Dyslipidemia PDF

SAS 4: AGENTS USED IN DYSLIPIDEMIA Peripheral Artery Disease occurs if plaque builds up in the major arteries DYSLIPIDEMIAS...

SAS 4: AGENTS USED IN DYSLIPIDEMIA Peripheral Artery Disease occurs if plaque builds up in the major arteries DYSLIPIDEMIAS that supply oxygen-rich blood to your legs, One or more abnormalities of blood lipids arms, and pelvis. Produce atherosclerosis, which in turn produces If blood flow to these parts of your body is reduced coronary heart disease (CHD)/ coronary artery or blocked, you may have numbness, pain, and, disease (CAD) sometimes, dangerous infections ATHEROSCLEROSIS Chronic Kidney Disease occur if plaque builds up in the renal arteries. These arteries supply oxygen-rich blood to your kidneys Over time, chronic kidney disease causes a slow loss of kidney function. The main function of the kidneys is to remove waste and extra water from the body. 3 IMPORTANT LIPIDS: CHOLESTEROL Cholesterol plays the central role in the pathogenesis of atherosclerosis Cholesterol is a naturally occurring sterol that is essential for life: a. Precursor molecule for the formation of bile acids (which are required for absorption of nutrients) b. Synthesis of steroid hormones (which provide important modulating effects in the body) c. Formation of cell membranes Atherosclerosis is a disease in which plaque builds up inside your arteries. Arteries are blood vessels TRIGLYCERIDES that carry oxygen-rich blood to your heart and other Triglycerides are an important source of stored parts of your body energy in adipose tissue. Plaque is made up of fat, cholesterol, calcium, and TG are synthesized from three molecules of fatty other substances found in the blood. Over time, acids esterified to glycerol. plaque hardens and narrows your arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death Atherosclerosis can affect any artery in the body, including arteries in the heart, brain, arms, legs, pelvis, and kidneys. As a result, different diseases may develop based on which arteries are affected. PHOSPHOLIPIDS Coronary Heart/Artery Disease The structure of phospholipid molecule consists of occurs when plaque builds up in the coronary two fatty acids and a phosphate group attached arteries. These arteries supply oxygen-rich blood to to a glycerol backbone. your heart Phospholipids are essential for cellular function and If blood flow to your heart muscle is reduced or the transport of lipids in the circulation by forming a blocked, you may have angina (chest pain or membrane bilayer of lipoproteins discomfort) or a heart attack. Plaque also can form in the heart's smallest arteries. This disease is called coronary microvascular disease (MVD) Carotid Artery Disease occurs if plaque builds up in the arteries on each side of your neck (the carotid arteries) These arteries supply oxygen-rich blood to your brain. If blood flow to your brain is reduced or blocked, you may have a stroke  CHOLESTEROL SYNTHESIS: make the cholesterol and triglycerides more soluble Cells derive cholesterol in two ways: by intracellular in blood. synthesis or by uptake from the systemic circulation. LIPID + PROTEIN = LIPOPROTEINS (can travel) ❖ Intracellular synthesis These particles contain an oily inner lipid core made up of cholesterol esters and TG and an outer hydrophilic coat made up of phospholipids and unesterified cholesterol HMG-CoA Synthase The outer coat also contains at least one protein, which provides the ligand for interaction with receptors on cell surfaces. The presence of a central lipid core and an outer protein gives rise to the name of these particles, lipoproteins 3 MAJOR LIPOPROTEINS VERY-LOW-DENSITY LIPOPROTEINS They normally contain 15% to 20% of the total blood cholesterol concentration and most of the total blood TG concentration. VLDL is made in the liver and is responsible for delivering triglycerides to cells in the body, which is needed for cellular processes. One important and early step in its synthesis is the triglycerides get delivered to cell = VLDL is left with conversion of hydroxymethylglutaryl-coenzyme A cholesterol and protein (HMG-CoA) to mevalonate. As this process occurs, VLDL will eventually The enzyme HMG-CoA reductase catalyzes this become an LDL molecule. step VLDL particles are large and appear to play only a One of the most effective therapies developed to small role in the pathogenesis of atherosclerosis date for managing dyslipidemias (i.e., HMG-CoA As VLDL particles flow through capillaries, some of reductase inhibitors or statins) interferes with this their TG content is removed through the action of the enzyme and thereby reduces the cellular synthesis enzyme lipoprotein lipase of cholesterol. Drugs that enhance the activity of lipoprotein lipase ❖ Uptake from the systemic circulation (i.e., fibrates) increase the delipidization process and (Lipoproteins) lower blood TG levels. The removed TG = converted to fatty acids and The source of this cholesterol is the liver, where it is stored as an energy source in adipose tissue synthesized and secreted into the systemic circulation. LOW-DENSITY LIPOPROTEINS LDL is responsible for carrying cholesterol to cells that need it. Approximately half of the LDL particles are removed from the systemic circulation by the liver; the other half may be taken up by peripheral cells or deposited in the intimal space of coronary, carotid, and other peripheral arteries, where atherosclerosis can develop. Low-density lipoprotein particles carry 60% to 70% of the total blood cholesterol and make the greatest contribution to the development of atherosclerosis. This is why LDL-C is the primary target of cholesterol lowering therapy The probability that atherosclerosis will develop is directly related to the concentration of LDL-C in the systemic circulation and the length of time this level of exposure persists (the cumulative risk of CHD in Cholesterol and triglycerides are fatty molecules. men and women increases with age) Because of their fat-like properties, they are not able to easily circulate in the bloodstream. In order for cholesterol and triglycerides to travel in the blood, they are often carried by proteins that  HIGH-DENSITY LIPOPROTEINS LIPID-LOWERING DRUGS High-density lipoprotein particles transport A. HMG- CoA reductase inihibitors (STATINS) cholesterol from peripheral cells back to the liver, a process called reverse cholesterol transport In contrast to LDL, high HDL-C concentrations are desirable because cholesterol is being removed from vascular tissue and is not available to contribute to atherogenesis CHYLOMICRONS Unlike the lipoproteins that transport cholesterol from the liver to peripheral cells and back (endogenous These compounds are structural analogs of HMG- system), chylomicrons transport fatty acids and CoA (3-hydroxy 3-methylglutaryl-coenzyme A) cholesterol derived from the diet or synthesized Lovastatin, atorvastatin, fluvastatin, pravastatin, in the intestines from the gut to the liver simvastatin, rosuvastatin, and pitavastatin (exogenous system) belong to this class. Chylomicrons are large, TG-rich lipoproteins. They are most effective in reducing LDL As they pass through capillary beds on the way to the liver, some of the TG content is removed through CHEMISTRY AND PHARMACOKINETICS the action of lipoprotein lipase in a manner similar to Lovastatin and simvastatin are inactive lactone that described for TG removal from VLDL particles prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives, whereas HYPERLIPOPROTEINEMIA pravastatin has an open, active lactone ring A. Pathogenesis Atorvastatin, fluvastatin, and rosuvastatin are ❖ Premature or accelerated development of fluorine-containing congeners that are active as atherosclerosis is strongly associated with elevated given. concentrations of certain plasma lipoproteins, especially the low-density lipoproteins (LDLs) that Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception participate in cholesterol transport of fluvastatin, which is almost completely absorbed ❖ A depressed level of high-density lipoproteins (HDLs) is also associated with increased risk of All have high first-pass extraction by the liver. Most atherosclerosis. of the absorbed dose is excreted in the bile; 5–20% is excreted in the urine. TREATMENT STRATEGIES Plasma half-lives of these drugs range from 1 to 3 1. DIET hours, except: o Cholesterol and saturated fats are the primary ❖ atorvastatin (14 hours) dietary factors that contribute to elevated levels of ❖ pitavastatin (12 hours) plasma lipoproteins ❖ rosuvastatin (19 hours) o Dietary measures designed to reduce the total intake of these substances constitute the first MECHANISM OF ACTION method of management and may be sufficient to Statins competitively inhibit the enzyme responsible for reduce lipoprotein levels to a safe range converting HMG-CoA to mevalonate in an early rate- o Because alcohol raises triglyceride and very-low- limiting step in the biosynthetic pathway of cholesterol density lipoprotein (VLDL) levels, it should be THERAPEUTIC USES avoided by patients with hypertriglyceridemia Reductase inhibitors are useful alone or with 2. DRUGS resins, niacin, or ezetimibe in reducing levels of o The drugs that are most effective at lowering LDL LDL. cholesterol include the HMG-CoA reductase Women with hyperlipidemia who are pregnant, inhibitors, resins, ezetimibe, and niacin. lactating, or likely to become pregnant should not be o The fibric acid derivatives (eg, gemfibrozil), given these agents. niacin, and marine omega-3 fatty acids are most Because cholesterol synthesis occurs predominantly effective at lowering triglyceride and VLDL at night, reductase inhibitors— except atorvastatin, concentrations and raising HDL cholesterol rosuvastatin, and pitavastatin —should be given concentrations in the evening Absorption generally (with the exception of pravastatin and pitavastatin) is enhanced by food TOXICITY Elevations of serum aminotransferase activity (up to three times the upper limit of normal) occur in some patients = stop statins Myositis (presence of muscle symptoms) including aches, soreness, or weakness (myalgia) and  increase in serum Creatine phosphokinase > 10 MECHANISM OF ACTION times the upper limit of normal Fibrates activate peroxisome proliferator- Myositis has also been reported more often when a activated receptors alpha (PPARα) which explains statin is combined with gemfibrozil or when a most of their effects on blood lipids drug is given concomitantly that can increase blood Stimulation of PPARa: lipolysis of TG from VLDL levels of the statin (ex. macrolide antibiotics) particles and the removal of these particles via ❖ Statin + enzyme inhibitors = toxicity hepatic LDL receptors is enhanced (increased Rhabdomyolysis-breakdown of damaged muscle synthesis by adipose tissue of lipoprotein lipase) releasing myoglobin in urine THERAPEUTIC USES AND DOSAGE Myoglobinuria-excretion of myoglobin in urine Gemfibrozil and other fibrates are used to treat Acute tubular necrosis-acute kidney injury hypertriglyceridemia ❖ Tubular cells die The usual dose of gemfibrozil is 600 mg orally once ❖ Most of these cases have occurred with high or twice daily doses, in patients with impaired renal or The dosage of fenofibrate (as Tricor) is one to three hepatic function, in older individuals, or 48 mg tablets (or a single 145 mg tablet) daily when statins are used in combination with interacting drugs Absorption of gemfibrozil is improved when the drug is taken with food The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, TOXICITY whereas that of fluvastatin and rosuvastatin, and to a Nausea is the most common adverse effect with all lesser extent pitavastatin, is mediated by CYP2C9 members of the fibric acid derivatives subgroup. Pravastatin is catabolized through other pathways Skin rashes are common with gemfibrozil (isomerization in the gut to a relatively inactive A few patients show decreases in white blood metabolite), including sulfation count or hematocrit, and these drugs can ❖ 3A4-dependent reductase inhibitors tend to potentiate the action of anticoagulants. accumulate in plasma in the presence of drugs There is an increased risk of cholesterol that inhibit or compete for the 3A4 cytochrome. gallstones; these drugs should be used with caution ❖ Some of the more commonly encountered drugs in patients with a history of cholelithiasis. that inhibit the 3A4 enzyme system are: When used in combination with reductase o Azole antifungals (itraconazole, ketoconazole, inhibitors, the fibrates significantly increase the risk and miconazole) of myopathy o CCBs (diltiazem, verapamil) o macrolide antibiotics (clarithromycin, and C. Niacin (Nicotinic acid) erythromycin) Niacin decreases triglycerides and LDL levels & o protease inhibitors (ritonavir) increases HDL levels significantly. Favorable o antidepressants (nefazodone) attributes: ❖ Inhibitors of 2C9 isoenzymes include a. Low cost alprenolol, diclofenac, hexobarbital, tolbutamide b. A long history of use and warfarin c. Clinical trial evidence that it can reduce CHD Creatine kinase activity should be measured in events patients receiving potentially interacting drug MECHANISM OF ACTION combinations Niacin inhibits the mobilization of free fatty acids In all patients, CK should be measured at baseline. If from peripheral adipose tissue to the liver, which, muscle pain, tenderness, or weakness appears, CK either alone or together with other hepatic effects, should be measured immediately and the drug results in reduced synthesis and secretion of discontinued if activity is elevated significantly over VLDL particles by the liver. (This explains its baseline. effectiveness in lowering TG levels.) The myopathy usually reverses promptly upon Because LDL is a VLDL degradation product, cessation of therapy reducing the secretion of VLDL particles secondarily lowers the LDL-C level. B. FIBRIC ACID DERIVATIVES (FIBRATES) Increased clearance of VLDL via the LPL pathway ▪ Gemfibrozil contributes to reduction of triglycerides. ▪ Fenofibrate Decrease The catabolic rate for HDL is decreased = longer ▪ Bezafibrate (N/a in the USA) ▪ Clofibrate (available in the USA) VLDL half-life of HDL, stays longer in the body Niacin inhibits the intracellular lipase of adipose *Gemfibrozil and fenofibrate are both indicated for the tissue via receptor-mediated signaling, possibly reduction of TG levels in patients with reducing VLDL production by decreasing the flux hypertriglyceridemia of free fatty acids to the liver  CLINICAL USE E. INHIBITORS OF INTESTINAL STEROL Because it lowers serum LDL cholesterol and triglyceride ABSORPTION concentrations and increases HDL cholesterol Ezetimibe inhibits intestinal absorption of concentrations, niacin has wide clinical usefulness in the phytosterols and cholesterol. treatment of hypercholesterolemia, hypertriglyceridemia, Its primary clinical effect is reduction of LDL levels and low levels of HDL cholesterol MECHANISM OF ACTION TOXICITY Ezetimibe is a prodrug that is converted in the liver Cutaneous flushing is a common adverse effect of to the active glucuronide form. niacin This active metabolite inhibits a transporter ❖ Pretreatment with aspirin or other nonsteroidal Niemann Pick G1 Like1 (PC1LI) that mediates anti-inflammatory drugs (NSAIDs) reduces the gastrointestinal uptake of cholesterol and intensity of this flushing, suggesting that it is phytosterols (plant sterols that normally enter mediated by prostaglandin release (NSAIDs gastrointestinal epithelial cell but then are inhibit prostaglandin) immediately transported back into the intestinal ❖ Tolerance to the flushing reaction usually lumen) develops within a few days. By preventing absorption of dietary cholesterol and Dose-dependent nausea and abdominal discomfort cholesterol that is excreted in bile, ezetimibe often occur reduces the cholesterol in the tightly regulated Pruritus and other skin conditions are reported hepatic pool Moderate elevations of liver enzymes and even Average reduction in LDL cholesterol with ezetimibe severe hepatotoxicity may occur. alone in patients with primary hypercholesterolemia Severe liver dysfunction has been associated with is about 18%, with minimal increases in HDL an extended-release preparation, which is not the cholesterol. It is also effective in patients with same as the sustained-release formulation. phytosterolemia Hyperuricemia occurs in about 20% of patients, and Ezetimibe is synergistic with reductase inhibitors, carbohydrate tolerance may be moderately impaired producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase D. BILE ACID BINDING RESINS inhibitor alone Normally, over 90% of bile acids, metabolites of cholesterol, are reabsorbed in the gastrointestinal CLINICAL USE tract and returned to the liver for reuse. Ezetimibe is used for treatment of hypercholesterolemia Bile acid-binding resins (cholestyramine, and phytosterolemia, a rare genetic disorder that results colestipol, and colesevelam) are large from impaired export of phytosterols. nonabsorbable polymers that bind bile acids and TOXICITY similar steroids in the intestine and prevent their Ezetimibe is well tolerated. When combined with absorption. HMG-CoA reductase inhibitors, it may increase the ▪ Resins bind to bile acids = not reasorbed, risk of hepatic toxicity excreted, since liver makes bile through Serum concentrations of the glucuronide form are cholesterol, more cholesterol is used up increased by fibrates and reduced by to compensate loss of bile acids cholestyramine. By preventing the recycling of bile acids, bile acid- TREATMENT WITH DRUG COMBINATIONS binding resins divert hepatic cholesterol to synthesis All patients with hyperlipidemia are treated first with of new bile acids, thereby reducing the amount of dietary modification, but this is often insufficient and cholesterol in a tightly regulated pool. drugs must be added. The resins cause a modest reduction in LDL Drug combinations are often required to achieve the cholesterol maximum lowering possible with minimum toxicity CLINICAL USE and to achieve the desired effect on the various The resins are used in patients with lipoproteins (LDL, VLDL, and HDL) hypercholesterolemia They have also been used to reduce pruritus in patients with cholestasis and bile salt accumulation TOXICITY Adverse effects from resins include bloating, constipation, and an unpleasant gritty taste. Absorption of fat-soluble vitamins (eg, vitamin A, D, E, K, dietary folates) and drugs (eg, thiazide diuretics, warfarin, pravastatin, fluvastatin) is impaired by the resins  SAS 5.1: DRUGS USED IN ASTHMA AND 1. Short- acting B2 adrenergic agonists (SABAs) CHRONIC OBSTRUCTIVE PULMONARY DISEASE Quick relief: Short-acting β2 agonists (SABAs) have ASTHMA a rapid onset of action (5 to 30 minutes) and provide is a chronic inflammatory disease of the airways relief for 4 to 6 hours characterized by episodes of acute They are used for symptomatic treatment of bronchoconstriction causing shortness of breath, bronchospasm, providing quick relief of acute cough, chest tightness, wheezing, and rapid bronchoconstriction. respiration. All patients with asthma should be prescribed a The immediate cause of asthmatic SABA inhaler. bronchoconstriction is the release of several β2 agonists have no anti-inflammatory effects, and mediators from IgE-sensitized mast cells and other they should never be used as the sole therapeutic cells involved in immunologic responses agents for patients with persistent asthma PATHOGENESIS OF ASTHMA However, monotherapy with SABAs may be appropriate for patients with intermittent asthma or exercise-induced bronchospasm SABAs: MALT o Metaproterenol o Albuterol/ Salbutamol o Levalbuterol o Terbutaline These agents provide significant bronchodilation with little of the undesired effect of α or β1 stimulation. Adverse effects of B2 agonists, 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- acting B2 agonists (LABAs) o Formoterol o Indacaterol o Vilanterol o Salmeterol Exposure to antigen causes synthesis of IgE, which indacaterol and vilanterol are currently approved binds to and sensitizes mast cells and other only for COPD inflammatory cells. Salmeterol and formoterol have a long duration of When such sensitized cells are challenged with action, providing bronchodilation for at least 12 antigen, a variety of mediators are released that can hours account for most of the signs of the early The long-acting agents (salmeterol, formoterol) bronchoconstrictor response in asthma. should be used for prophylaxis, in which their 12-h These mediators include the leukotrienes LTC4 duration of action is useful. They should not be used and LTD4. In addition, chemotactic mediators for acute episodes because their onset of action is such as LTB4 attract inflammatory cells to the too slow. airways. Use of LABA monotherapy is contraindicated, Finally, several cytokines and some enzymes are and LABAs should be used only in combination released, leading to chronic inflammation. with an asthma controller medication. Inhaled corticosteroids (ICS) A. Β2-ADRENERGIC AGONISTS remain the long-term controllers of choice in Inhaled β2-adrenergic agonists directly relax airway asthma, and LABAs are considered to be useful smooth muscle adjunctive therapy for attaining asthma control. They are used for the quick relief of asthma Some LABAs are available as a combination product symptoms, as well as adjunctive therapy for long- with an ICS: term control of the disease. o Formoterol/ Budesonide Beta agonists are given almost exclusively by o Formeterol/ Mometasone inhalation, usually from pressurized aerosol o Salmeterol/ Fluticasone canisters but occasionally by nebulizer o Vilanterol/ Fluticasone The inhalational route decreases the systemic dose Adverse effects of LABAs are similar to quick- relief β2 (and adverse effects) while delivering an effective dose locally to the airway smooth muscle  B. METHYLXANTHINES ❖ Beta blockers are useful in reversing severe The methylxanthines are purine derivatives cardiovascular toxicity from theophylline Three major methylxanthines are found in plants and provide the stimulant effects of 3 common A. MUSCARINIC ANTAGONISTS (CHOLINERGIC beverages: caffeine (in coffee), theophylline (tea), ANTAGONISTS) and theobromine (cocoa). The anticholinergic agents block vagally mediated Theophylline is the only member of this group that is contraction of airway smooth muscle and mucus important in the treatment of asthma. secretion Atropine and other naturally occurring THEOPHYLLINE belladonna alkaloids were used for many years in is a bronchodilator that relieves airflow obstruction in the treatment of asthma but have been replaced by chronic asthma and decreases its symptoms. ipratropium, a quaternary antimuscarinic agent may also possess anti-inflammatory activity, designed for aerosol use. This drug is delivered to although the mechanism of action is unclear. the airways by pressurized aerosol and has little Previously, the mainstay of asthma therapy, systemic action theophylline has been largely replaced with β2 Tiotropium and aclidinium are longer-acting agonists and corticosteroids due to its narrow analogs approved for use in COPD. therapeutic window, adverse effect profile, and potential for drug interactions. MECHANISM OF ACTION Theophylline is metabolized in the liver and is a When given by aerosol, these drugs competitively CYP1A2 and 3A4 substrate. It is subject to block muscarinic receptors in the airways and numerous drug interactions. effectively prevent bronchoconstriction mediated by Serum concentration monitoring should be vagal (parasympathetic) discharge performed when theophylline is used chronically Inhaled ipratropium, a quaternary derivative of atropine, is not recommended for the routine MECHANISM OF ACTION treatment of acute bronchospasm in asthma, as its inhibit phosphodiesterase (PDE), the enzyme that onset is much slower than inhaled SABAs. However, degrades cAMP (cyclic adenosine monophosphate) it may be useful in patients who are unable to to 5 ’- AMP (adenosine monophosphate) and thus tolerate a SABA or patients with concomitant COPD increase Camp (Bronchodilation occurs when Because these agents are delivered directly to the cAMP level rises) airway and are minimally absorbed, systemic effects is a competitve antagonist at adenosine are small. When given in excessive dosage, minor receptors (adenosine binds to its receptors causing atropine-like toxic effects may occur bronchoconstriction; theophylline inhibits the In contrast to the β2 agonists, muscarinic adenosine action thereby causing bronchodilation antagonists do not cause tremor or arrhythmias CLINICAL USE B. CORTICOSTEROIDS The major clinical use of methylxanthines is asthma All the corticosteroids are potentially beneficial in and COPD. severe asthma Slow-release theophylline (for control of nocturnal However, because of their toxicity, systemic (oral) asthma) is the most commonly used methylxanthine corticosteroids (usually prednisone) are used Aminophylline is a salt of theophylline that is chronically only when other therapies are sometimes prescribed. unsuccessful. Roflumilast, an oral, nonpurine, more selective In contrast, local aerosol administration of surface- PDE4 inhibitor, has been approved for use in active corticosteroids (Inhaled cotricosteroids: COPD beclomethasone, budesonide, ciclesonide, Another methylxanthine derivative, pentoxifylline, flunisolide, fluticasone, mometasone) is relatively is promoted as a remedy for intermittent safe, and inhaled corticosteroids have become claudication; this effect is said to result from common first-line therapy for individuals with decreased viscosity of the blood moderate to severe asthma. Important intravenous corticosteroids for status ADVERSE EFFECTS asthmaticus include prednisolone (the active The common adverse effects of methylxanthines metabolite of prednisone) and hydrocortisone include: (cortisol). ❖ gastrointestinal distress ❖ tremor and insomnia ❖ Severe nausea and vomiting, hypotension, cardiac arrhythmias, and seizures may result from overdosage. ❖ Very large overdoses (eg, in suicide attempts) are potentially lethal because of arrhythmias and seizures.  MECHANISM OF ACTION C. LEUKOTRIENE ANTAGONISTS These drugs interfere with the synthesis or the action of the leukotrienes Although their value has been established, they are not as effective as corticosteroids in severe asthma. Leukotrienes: LTB4 is a potent chemoattractant for neutrophils and eosinophils, whereas the cysteinyl leukotrienes (LTC4, LTD4, LTE4) constrict bronchiolar smooth muscle, increase endothelial permeability, and promote mucus secretion. ❖ LEUKOTRIENE RECEPTOR BLOCKERS Montelukast and zafirlukast are selective antagonists of the cysteinyl leukotriene-1 receptor, they block the effects of cysteinyl leukotrienes These drugs are orally active and have been shown to be effective in preventing exercise-, antigen-, and aspirin-induced bronchospasm They are not recommended for acute episodes of asthma Corticosteroids reduce the synthesis of arachidonic Toxicity is generally low. Rare reports of Churg- acid by inhibiting phospholipase A2 (PLA2) Strauss syndrome, allergic granulomatous concentrations →prostaglandins and leukotrienes angiitis, have appeared, but an association with are reduced. these drugs has not been established Leukotrienes: LTC4, LTD4 & LTE4 are potent bronchoconstrictors & LTB4 attract inflammatory ❖ LIPOXYGENASE BLOCKERS cells to the airways Zileuton is an orally active drug that selectively increase the responsiveness of β adrenoceptors in inhibits the airway 5-lipoxygenase, a key enzyme in the conversion of ICS (inhaled corticosteroids) are the drugs of arachidonic acid to leukotrienes (both LTB4 and the choice for long-term control in patients with any cysteinyl leukotrienes. degree of persistent asthma. effective in preventing exercise-, antigen-, and No other medications are as effective as ICS in the aspirin- induced bronchospasm long-term control of asthma in children and adults. The toxicity of zileuton includes occasional elevation ICS deposition on the oral and laryngeal mucosa of liver enzymes, and this drug is therefore less can popular than the receptor blockers cause adverse effects, such as oropharyngeal candidiasis (due to local immune suppression) and D. MAST CELL STABILIZERS hoarseness. Patients should be instructed to rinse Cromolyn (disodium cromoglycate) and the mouth in a “swish-and-spit” method with water nedocromil are unusually insoluble chemicals, so following use of the inhaler to decrease the chance even massive doses given orally or by aerosol result of these adverse events in minimal systemic blood levels If oral therapy is required, adrenal suppression can The drugs have no bronchodilator action but can be prevent bronchoconstriction caused by a challenge reduced by using alternate-day therapy (ie, giving with antigen to which the patient is allergic the Cromolyn and nedocromil may cause cough and drug in slightly higher dosage every other day rather irritation of the airway when given by aerosol than smaller doses every day) Patients with a severe exacerbation of asthma MECHANISM OF ACTION (status asthmaticus) may require intravenous inhibits mast cell degranulation & decrease the release methylprednisolone or oral prednisone to reduce of mediators (such as leukotrienes and histamine) from airway inflammation. mast cells. Due to the increased incidence of adverse effects Cromolyn is the prototype of this group not useful in with oral therapy, chronic maintenance with systemic managing an acute asthma attack, because it is not administration of corticosteroids should be reserved a bronchodilator for patients who are not controlled on an ICS. Cromolyn is available as a nebulized solution for use in asthma.  Due to its short duration of action, this agent A. BRONCHODILATORS requires dosing three or four times daily, which Inhaled bronchodilators, including the β2- adrenergic affects adherence and limits its use. agonists and anticholinergic agents (ipratropium and tiotropium) are the foundation of therapy for E. ANTI-IgE ANTIBODY COPD Omalizumab is a humanized murine monoclonal These drugs increase airflow, alleviate symptoms, antibody to human IgE. and decrease exacerbation rates MOA: binds to human immunoglobulin E (IgE).This The long-acting agents, LABAs and tiotropium, leads to decreased binding of IgE to its receptor on are preferred as first-line treatment of COPD for the surface of mast cells and basophils all patients except those who are at low risk with Reduction in surface-bound IgE limits the release of less symptoms mediators of the allergic response. Combination of both an anticholinergic and a β2 indicated for the treatment of moderate to severe agonist may be helpful in patients who have persistent asthma in patients who are poorly inadequate response to a single inhaled controlled with conventional therapy bronchodilator Its use is limited by the high cost, route of administration (subcutaneous), and adverse effect B. CORTICOSTEROIDS profile The addition of an ICS to a long-acting Adverse effects include serious anaphylactic bronchodilator may improve symptoms, lung function reaction (rare), arthralgias, fever, and rash. and quality of life in COPD patients with FEV1 of Secondary malignancies have been reported less than 60% predicted However, the use of an ICS is associated with an CHRONIC OBSTRUCTIVE PULMONARY DISEASE 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. ROFLUMILAST Is an oral phosphodiesterase-4 inhibitor used to reduce exacerbations in patients with severe chronic bronchitis 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. Unfortunately, with currently available care, many patients still experience declining lung function over time. SAS 5.2: DRUGS USED IN THYROID DISORDERS Within thyroglobulin, 2 molecules of DIT combine to form T4, while 1 molecule each of MIT and DIT THYROID HORMONES combine to form T3 Proteolysis of thyroglobulin liberates the T4 and T3, which are then released from the thyroid. After release from the gland, T4 and T3 are transported in the blood by thyroxine-binding globulin, a protein synthesized in the liver Thyroid function is controlled by the pituitary through the release of thyrotropin (thyroid- stimulating hormone [TSH]) and by the availability of iodide Thyrotropin stimulates the uptake of iodide as well as synthesis and release of thyroid hormone It also has a growth-promoting effect that causes thyroid cell hyperplasia and an enlarged gland (goiter) High levels of thyroid hormones inhibit the release of TSH, providing an effective negative feedback control mechanism In Graves’ disease, an autoimmune disorder, B The thyroid secretes 2 iodine-containing lymphocytes produce an antibody that activates the hormones: thyroxine (T4) and triiodothyronine (T3) TSH receptor and can cause a syndrome of Inadequate secretion of thyroid hormone hyperthyroidism called thyrotoxicosis (hypothyroidism) results in bradycardia, poor Because these lymphocytes are not susceptible to resistance to cold, and mental and physical slowing. negative feedback, patients with Graves’ disease In children, this can cause mental retardation and can have very high blood concentrations of thyroid dwarfism hormone at the same time that their blood In contrast, excess secretion of thyroid hormones concentrations of TSH are very low (hyperthyroidism) can cause tachycardia and cardiac arrhythmias, body wasting, nervousness, tremor, and heat intolerance A. Synthesis and Transport of Thyroid Hormones A. DRUGS FOR HYPOTHYROIDISM Hypothyroidism usually results from autoimmune destruction of the gland or the peroxidase and is diagnosed by elevated TSH. Thyroid hormone therapy can be accomplished with either T4 or T3 ❖ Synthetic levothyroxine (T4) is usually the form of choice ❖ T3 (liothyronine) is faster-acting but has a shorter half-life and is more expensive The iodine necessary for the synthesis of these ❖ T3 is about 10 times more potent than T4 molecules comes from food or iodide supplements ❖ Because T4 is converted to T3 in target cells, Iodide ion is actively taken up by and highly the liver, and the kidneys, most of the effect of concentrated in the thyroid gland, where it is circulating T4 is probably due to T3 converted to elemental iodine by thyroidal The organ-level actions of the thyroid hormones peroxidase include normal growth and development of the nervous, The protein thyroglobulin serves as a scaffold for skeletal, and reproductive systems and control of thyroid hormone synthesis metabolism of fats, carbohydrates, proteins, and Tyrosine residues in thyroglobulin are iodinated to vitamins. form monoiodotyrosine (MIT) or diiodotyrosine (DIT) in a process known as iodine organification  these salts also decrease the size and vascularity of the hyperplastic thyroid gland. Because iodide salts inhibit release as well as synthesis of the hormones, their onset of action occurs rapidly, within 2–7 d. Iodide salts are used in the management of thyroid storm and to prepare patients for surgical resection of a hyperactive thyroid The usual forms of this drug are Lugol’s solution (iodine and potassium iodide) and saturated solution of potassium iodide Adverse effects include rash, drug fever, metallic taste, bleeding disorders, and, rarely, anaphylactic reactions C. Radioactive Iodine Radioactive iodine (131I) is taken up and concentrated in the thyroid gland so avidly that a dose large enough to severely damage the gland can be given without endangering other tissues Unlike the thioamides and iodide salts, an effective dose of 131I can produce a permanent cure of thyrotoxicosis without surgery 131I should not be used in pregnant or nursing women o Levothyroxine (T4) D. Anion Inhibitors used for the o Liothyronine (T3) Anions such as thiocyanate (SCN–) and treatment of perchlorate (ClO4–) block the uptake of iodide by o Liotrix (T3/T4 combination products) hypothyroidism the thyroid gland through competitive inhibition of the ❖ Levothyroxine- is better tolerated than T3 iodide transporter preparations and has a longer half-life. Their effectiveness is unpredictable and ClO4– can – It is dosed once daily, and steady state is achieved cause aplastic anemia, so these drugs are rarely in 6 to 8 weeks. used clinically ❖ Toxicity is directly related to T4 levels and manifests as nervousness, palpitations and tachycardia, heat E. Other Drugs intolerance, and unexplained weight loss 1. An important class of drugs for the treatment of thyrotoxicosis is the β blockers. B. ANTITHYROID DRUGS ❖ These agents are particularly useful in controlling the A. Thioamides tachycardia and other cardiac abnormalities of Methimazole and propylthiouracil (PTU) are small severe thyrotoxicosis sulfur containing thioamides that inhibit thyroid ❖ Propranolol also inhibits the peripheral conversion of hormone synthesis by blocking peroxidase- T4 to T3 catalyzed reactions, iodination of the tyrosine 2. The iodine-containing antiarrhythmic drug amiodarone residues of thyroglobulin and coupling of DIT and can cause hypothyroidism through its ability to block the MIT peripheral conversion of T4 to T3 Propylthiouracil and, to a much lesser extent, ❖ It also can cause hyperthyroidism either through an methimazole inhibit peripheral conversion of T4 to iodine-induced mechanism in persons with an T3 underlying thyroid disease such as multinodular Methimazole is generally preferred because it can goiter or through an inflammatory mechanism that be administered once per day causes leakage of thyroid hormone into the However, PTU is preferred in pregnancy because circulation it is less likely than methimazole to cross the ❖ Amiodarone-associated hypothyroidism is treated placenta and enter breast milk with thyroid hormone Toxic effects include skin rash (common) and ❖ Iodine-associated hyperthyroidism caused by severe reactions (rare) such as vasculitis, amiodarone is treated with thioamides, whereas the agranulocytosis, hypoprothrombinemia, and liver inflammatory version is best treated with dysfunction. These effects are reversible corticosteroids. Iodinated radiocontrast media (eg, oral diatrizoate and B. Iodide Salts and Iodine intravenous iohexol) rapidly suppress the conversion of Iodide salts inhibit iodination of tyrosine and T4 to T3 in the liver, kidney, and other peripheral tissues. thyroid hormone release SAS 6: Pancreatic Hormones, Antidiabetic Agents, GLUCOSE TRANSPORTERS & Glucagon GLU km TISSUES FUNCTION (mmol/L ENDOCRINE PANCREAS GLUT ALL tissues, The endocrine pancreas in the adult human consists of 1 Basal uptake of especially approximately 1 million islets of Langerhans interspersed 1-2 glucose; transport throughout the pancreatic gland. red cells, across the BBB brain Within the islets, at least five hormone producing cells GLUT Beta cells of Regulation of insulin are present 2 pancreas; release, other 15-20 liver, kidney, aspects of glucose gut homeostasis GLUT Brain, Uptake into 3 placenta