Drugs for Bronchial Asthma PDF

**DRUGS FOR BRONCHIAL ASTHMA** **[RESPIRATION]** Refers to the movement of air in and out of the lungs through a series of air passages. 1. Nose 2. Mouth 3. Trachea 4. Bronchial tree The branches of the bronchial tree are lined with **smooth muscle,** which adjusts the **constriction and...

**DRUGS FOR BRONCHIAL ASTHMA** **[RESPIRATION]** Refers to the movement of air in and out of the lungs through a series of air passages. 1. Nose 2. Mouth 3. Trachea 4. Bronchial tree The branches of the bronchial tree are lined with **smooth muscle,** which adjusts the **constriction and dilation** of the airways in response to the **needs of the body.** **[BODY SYSTEM AFFECTING RESPIRATION]** 1. **[Autonomic nervous system]** - regulate smooth muscle tone in the respiratory system and thereby maintain the balance between bronchoconstriction and bronchodilation - Bronchoconstriction - Pulmonary vasoconstriction - Bronchodilation - Pulmonary vasodilation 2. **[cAMP]** - Promotes bronchodilation - Pulmonary Vasodilation **[BRONCHIAL ASTHMA]** - Physiologically characterized by increased responsiveness of the trachea and bronchi to various stimuli - A recurrent, episodic shortness of breath - Caused by **bronchoconstriction** from airway **inflammation and hyperreactivity.** - Genetic - Environmental factors **Bronchial reactivity** - is assessed by measuring the fall in forced expiratory volume in 1 second **(FEV1)** - provoked by inhaling serially increasing concentrations of aerosolized **methacholine.** **BRONCHIAL ASTHMA** **[PATHOPHYSIOLOGY OF ASTHMA]** - First thing that happens during asthma is that there is **bronchospasm** which narrows the airways and 2nd there is increase **mucus secretion.** - Which when combined can make the individual difficult to breath that's why asthma is a type obstructive pulmonary disease. **5 main events that occur in asthma** 1. Triggering 2. Signalling 3. Migration 4. cell activation 5. tissue stimulation and damage 1. **[TRIGGERING]** - Allergens Non-allergic factors aspirin, viral infections - These antigen binds to IgE, which is attached to **activate mast cells** - Activation of mast cells will result to release of histamine & leukotriene. 2. **[SIGNALLING]** - After triggering, mast cells and other signaling cells are activated (lymphocytes, eosinophils, epithelial cells, macrophages) - **These inflammatory cells release chemical signals** (cytokines, chemokines, eicosanoids, leukotrienes) - These chemical signals attract additional inflammatory cells to the airways 3. **[MIGRATION]** - An influx of inflammatory cells (eosinophils, lymphocytes, monocytes, granulocytes) - **Upregulation of adhesion** molecules begins - These adhesion molecules affix themselves to cells in the circulation and attract these cells to the airways. 4. **[CELL ACTIVATION]** - Required before cells can release inflammatory mediators. Once present in the airways, eosinophils are activated. **Leukotrienes & Cytokines appear to be important in this cell activation.** - Once activated, they will **release inflammatory mediators.** These inflammatory mediators cause smooth-muscle constriction and set the stage for the late phase of the inflammatory process by initiating chemotaxis. 1. Histamine 2. Leukotrienes 3. Prostaglandins 4. Bradykinin 5. Adenosine 6. other chemotactic agents that attract eosinophils and nuetrophils 7. prostaglandin generating factor of anaphylaxis 5. **[TISSUE STIMULATION & DAMAGE]** - occurs as a result of these inflammatory mediators released from activated cells. - The epithelial damage is believed to contribute to airway hyperresponsiveness. - Rather than resolving, airway inflammation may persist and result in a structural change to the lung known as **airway remodeling.** **[TYPES OF ASTHMA]** **[TYPES OF ASTHMA]** **Determined by cause** **1. EXTRINSIC ASTHMA** - Common in children - Associated with a genetic predisposition - Precipitated by known allergens **2. INTRINSIC ASTHMA (non-IgE mediated)** - unknown origin - tends to develop in adulthood - symptoms are triggered by non-allergenic factors. **[TREATMENT GOALS]** 1. REDUCE IMPAIRMENT 2. REDUCE RISK **[DRUGS FOR ASTHMA]** - Bronchodilators - These are agents that treat asthma attacks right away. - agents that increase airway caliber by relaxing airway smooth muscle - β2 agonist - Methylxanthines - Anticholinergics/Antimuscarinics - Treat asthma over a long term (maintenance management) - Anti-inflammatory agent such as - inhaled corticosteroid - Leukotriene antagonist - Mast cell stabilizer *[BETA-2-AGONISTS]* Mechanism of Action: - Stimulate ß2-receptors - activating adenyl cyclase - increases intracellular production of CAMP - bronchodilation, improved mucociliary clearance, and reduced inflammatory cell mediator release **OTHER EFFECTS:** - **Uterus:** Uterine muscle relaxation - **Blood vessels:** Vasodilation - **Skeletal muscle:** Tremor, Stimulates Na/K ATPase Pump **A. [SHORT ACTING W/ RAPID ONSET]** 1. Salbutamol (Ventolin®) 2. Terbutaline (Bricanyl®) 3. Pirbuterol (Maxair®) 4. Fenoterol - First line in the treatment of acute exacerbation of bronchial asthma - Primary reliever medication - Available as inhalers (Salbutamol and Terbutaline are also given as oral tablet) - Terbutaline= tocolytic agents **B. [LONG ACTING W/ SLOW ONSET]** 1. Bambuterol (Bambec®) - It is the only beta-2-agonist administered orally (without inhalational route) - Prophylactic agent to reduce the frequency and severity of acute attacks. - For controlling nocturnal attacks - Controller medication **C. [LONG ACTING W/ RAPID ONSET]** 1. Formoterol 2. Salmeterol (Serevent®) - controller medication - usually given through inhalation - combined with corticosteroids - Salmeterol + Fluticasone (Seretide) - Formoterol + Budesonide (Symbicort) - Corticosteroids enhances the expression of beta 2 receptors. **Adverse Effects:** - skeletal muscle tremor - nervousness - occasional weakness **Toxicities:** - Tachyphylaxis or tolerance (occur with regular use of inhaled of oral ß-agonists) - Cardiac arrhythmias - Hypoxemia *[SYMPATHOMIMETICS]* Bronchodilator reserved for special situations (if cardiac stimulation is also needed) 1. **[EPINEPHRINE]** - Stimulates catecholamine receptor including beta 2 - is an effective, rapidly acting bronchodilator - **SQ:** subcutaneously (0.4 mL of 1:1000 solution) - **INH:** inhaled as a micro-aerosol from a pressurized canister (320 g per puff). - Can cause tachycardia, arrhythmias, and worsening of angina pectoris due to stimulation of beta 1 receptor. - Use: Anaphylactic shock 1. **[EPHEDRINE]** - An alkaloid from Ephedra sinica - Increase catecholamine release - Inhibition of reuptake - Compared to epinephrine, ephedrine has: - longer duration - Administered orally - more pronounced central effects - lower potency 2. **[ISOPROTERENOL]** - Isoprenaline® - A potent bronchodilator - It is a no---selective beta agonist - when inhaled as a microaerosol from a pressurized canister, 80--120 g causes maximal bronchodilation within 5 minutes. - It has a 60- to 90-minute duration of action. *[METHYLXANTHINES]* - Alternative controller medication because it possesses narrow therapeutic index **Mechanisms of Action:** - At high concentrations, it inhibit several members of the phosphodiesterase (PDE) enzyme family - At low doses, they inhibit the late phase of allergic reaction and may they may actually have anti inflammatory activity. - Inhibition of cell surface receptors for adenosine. **Examples:** 1. Theophylline 2. Aminophylline (80% theophylline)- a theophylline-ethylenediamine complex 3. Doxofylline 4. Dyphylline - a synthetic analog of theophylline less potent and shorter-acting than theophylline 5. Phentoxyfylline (not for asthma-for PAD/intermittent claudication) **Clinical uses:** - Alternative controller medication for asthma - Prevent nocturnal attacks - Sustained release formulation are given at bedtime - For the treatment of COPD (usually given at bedtime) - Alternative reliever for asthma A major adverse effect of the PDE4-selective drugs is **nausea and vomiting.** Higher levels (\> 40 mg/L) may **cause seizures or arrhythmias** - CNS -- stimulation, anxiety, irritability states, seizures - Cardiovascular -- tachycardia, palpitations, arrhythmia - GIT- stimulate secretion of both gastric acid and digestive enzymes. - Diuretic effec t- involve both increased glomerular filtration and reduced tubular sodium reabsorption *[ANTICHOLINERGICS]* 1. Ipratropium 2. Tiotropium- With 24-hour duration of action (Long acting) 3. Oxytropium 2. **[IPRATROPIUM (Atrovent®)]** - Datura stramonium/ - Datura metel **MOA:** - competitively inhibit the effect of acetylcholine at muscarinic receptors thus blocking the contraction of the airway smooth muscle. **Clinical Characteristics:** - more useful in COPD than in asthma - has minimal systemic toxicity-no atropine like effects - has a better safety profile compared to β2 agonist - slightly less effective than beta-agonist agents in reversing asthmatic bronchospasm - the addition of ipratropium enhances the bronchodilation produced by nebulized albuterol in acute severe asthma. 1. **Ipratropium (Atrovent)** - more peripheral effects (LUNGS) than CNS 2. **Ipratropium + Fenoterol** (Berodual) 3. **Ipratropium + Salbutero**l (Combivent) *[MAST CELL STABILIZERS]* - **Prophylactic agents for asthma** - It is stable but extremely insoluble salts - When used as aerosols (metered-dose inhalers), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. **Mechanism of action:** - stabilizes the membrane of the mast cells by increasing inward conduction of membrane to chloride ions thus inhibiting cellular activation. 1. **[CROMOLYN (Intal®)]** - poorly absorbed from the gastrointestinal tract and must be inhaled as a microfine powder or aerosolized solution. 3. **[NEDOCROMIL (Tilade®)]** - has a very low bioavailability and is available only in metered-dose aerosol form. **Clinical uses:** 1. Given for asthma as inhalation 2. May also be useful in allergic rhinitis 3. Cromolyn solution is also useful in reducing symptoms of allergic rhinoconjunctivitis. 4. used as prophylaxis of EIB **SIDE EFFECTS:** - Bronchospasm (acute administration) Because the drugs are so poorly absorbed, adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. **These include:** - throat irritation - Cough - mouth dryness - chest tightness & wheezing - Reversible dermatitis, myositis, or gastroenteritis *[ANTI-INFLAMMATORY]* **[Controller medication for asthma]** A. LEUKOTRIENE MODIFIERS, LIPOXYGENASE INHIBITOR, LTD4 ANTAGONISTS B. CORTICOSTEROIDS *[LIPOXYGENASE INHIBITOR]* 1. **[Zileuton (Zyflo®)]** - is the least prescribed because of the requirement of four times daily dosing and because of occasional liver toxicity. **Mechanism of action:** - inhibits 5-lipoxygenase thereby preventing leukotriene synthesis **Administration:** - In adults and children 12 years of age and older, the dosage of zilueton is 600 mg four times daily. - It may be taken without regard to meals. **Contraindication:** - Zileuton is contraindicated in patients with hepatic function impairment and should be monitored closely in patients who drink large quantities of alcohol. **Adverse Effects:** - Adverse effects include headache, abdominal pain, asthenia, nausea, dyspepsia and myalgia. *[LEUKOTRIENE ANTAGONISTS]* 1. Montelukast (Singulair®) 2. Zafirlukast (Accolate®) **MOA:** - prevents the binding of LTD4 to its specific receptor thus inhibiting its effects on airways. - It is a selective cysteinyl leukotriene 1 (CysLT1) receptor antagonists; therefore, they prevent leukotrienes from interacting with their receptors. **Clinical uses:** - NSAID induced asthma - alternative controller for persistent bronchial asthma - **Montelukast** - once a day dosing (beneficial, promote patient compliance) - **Zafirlukast** - twice a day dosing - **[MONTELUKAST]** - approved for children as young as 6 years of age. **PRECAUTION:** - The chewable forms of montelukast (4- and 5-mg tablets) contain aspartame and should be avoided in patients with **phenylketonuria.** **SIDE EFFECT:** - **Mask the symptom of Churg-Strauss syndrome** - a systemic vasculitis characterized by worsening asthma, pulmonary infiltrates, and eosinophilia *[CORTICOSTEROIDS]* **MECHANISM OF ACTION:** - Corticosteroids bind to glucocorticoid receptors on the cytoplasm of cells. - The activated receptor regulates transcription of target genes. **Corticosteroids reduce inflammation via:** - Inhibition of transcription and release of inflammatory genes. - Increased transcription of anti-inflammatory genes that produce proteins that participate in or suppress the inflammatory process. **[GLUCOCORTICOIDS]** **A. LONG ACTING (inhaled)** Budesonide Beclomethasone Fluticasone Flunisolide - **first line controller medication** - with minimal systemic side effect - oral trush (candidiasis) vocal cord irritation (Gargle 3-4x after use) **B. SYSTEMIC ORAL MEDICATIONS** Prednisone/Prednisolone - Short acting agents - used in the management of severe asthma attacks/exacerbations **C. SYSTEMIC PARENTERAL** Hydrocortisone Methylprednisolone - preferred agent for status asthmaticus - is a life-threatening condition that occurs when a severe asthma exacerbation fails to respond to usual treatment. Administration: **For control of asthma** - administer corticosteroids early in the morning, after endogenous ACTH secretion has peaked. - because secretion of corticosteroids has a diurnal variation **For prevention of nocturnal asthma** - oral or inhaled corticosteroids are most effective when given in the late afternoon **AEROSOL TREATMENT** - is the most effective way to decrease the systemic adverse effects of corticosteroid therapy. **SIDE EFFECTS: inhaled corticosteroids can cause:** 2. Oropharyngeal candidiasis & Hoarseness can also result from a direct local effect of inhaled corticosteroids on the vocal cords. 3. short-term complications in adults but may increase the risks of osteoporosis 4. cataracts over the long term. 5. In children, inhaled corticosteroid therapy (slow the rate of growth) **SIDE EFFECTS: ORAL/ SYSTEMIC** *[ANTI-IGE ANTIBODIES]* - Anti-IgE Monoclonal Antibodies Ex: **Omalizumab (anti-IgE Mab)** - inhibits the binding of IgE to mast cells - but does not activate IgE already bound to these cells and thus does not provoke mast cell degranulation. **DRUG DELIVERY** **Metered Dose Inhalers (MDIs)** - AZMACORT (triamcinolone) inhaler - Breath-actuated MDIs - require the patient to use a closed-mouth technique. **SPACERS AND HOLDING CHAMBERS** - Additions of a spacer in a patient with poor MDI technique improves pulmonary delivery of the agent. - (e.g., Aerochamber, Aerosol Cloud Enhancer, AeroVent, Brethancer, Ellipse, E-Z Spacer, Inhal-Aid, InspirEAse, OptiChamber, OptiHaler) **[NEBULIZERS]** - require less patient coordination during administration of multiple inhalations. **Disadvantages:** 1. Cost 2. preparation and administration time 3. size of the device 4. drug delivery inconsistencies between devices. **[DRY-POWDER INHALERS]** - to avoid the use of Freon propellants. - They are also being used more frequently because many patients find them easier to use than an MDI. **NON-PHARMACOLOGIC** 1. **[HUMIDIFIED OXYGEN]** - Although the fraction of inspire oxygen (FIO2) administered is based on the patient's arterial blood gas status, **1-3 L/min is generally given via facemask or nasal cannula.** - The goal is to keep the SaO2 greater than 90% (greater than 95% if the patient is pregnant or has heart disease). 2. **[HELIOX]** - A mixture of helium and oxygen that has a lower density than air. - Because of its decreased airflow resistance, heliox may increase ventilation during acute asthma exacerbations. 3. **[INTRAVENOUS FLUIDS]** - and electrolytes may be required if the patient is volume depleted.  4. **[ENVIRONMENTAL CONTROL]** - Some measures include use of allergen-resistant mattress and pillow encasements, use of high-filtration vacuum cleaners, removal of carpets and draperies, and avoidance of furry pets. 5. **[VACCINES]** - (e.g., influenze virus, polyvalent pneumococcals) are recommended to prevent infection, which may precipitate an exacerbation. **COMPLICATIONS** 1. **[STATUS ASTHMATICUS]** - is a life-threatening condition that occurs when a severe asthma exacerbation fails to respond to usual treatment. **Standard therapy for status asthmaticus involves:** - oxygen administration, intravenous rehydration, inhaled β-agonists and anticholinergics, and intravenous corticosteroids. - Aggressive therapy is indicated for any patient with acute severe exacerbation and for patients who fail to respond to conventional therapy for acute exacerbation 2. **[PNEUMOTHORAX ]** - is a condition characterized by accumulation of air in the pleural space, as sometimes occurs during an acute asthma exacerbation. - Therapy includes oxygen, aspiration of pleural air via a chest tube, and analgesics 3. **[Atelectasis]** - inhibits gas exchange during respiration - may occur as a result of airway obstruction. - In asthmatics, atelectasis usually involves the right middle lobe, but sometimes affects the entire lung. Physical findings include hyperventilation, diminished breath sounds, decreased chest excursion, mediastinal shift toward the affected side and cyanosis. **Therapy includes:** 1. Incentive spirometry 2. Postural drainage 3. Chest percussion 4. Coughing and deep breathing exercises, and bronchodilators. 5. Bronchoscopy **DRUGS FOR RESPIRATORY DISEASES** **[Chronic Obstructive Pulmonary Disease (COPD)]** - Chronic obstructive pulmonary disease is a chronic, irreversible obstruction of airflow. - The airways and air sacs lose their elastic quality. - The walls between many of the air sacs are destroyed. - The walls of the airways become thick and inflamed. - The airways make more mucus than usual, which tends to clog them.   **DIAGNOSIS:** **[SPIROMETRY]** ◉ measures how much air a person can inhale and exhale, and how fast air can move into and out of the lungs - Patient takes a deep breath and blows as hard as possible into tube - Clip on nose - Technician monitors and encourages patient during test - Machine records the results of the spirometry test **[Three of the major diseases that are grouped together as COPD:]** 1. Asthmatic bronchitis 2. Chronic bronchitis 3. Emphysema - Chronic Obstructive Lung Disease (COLD) - Chronic Lower Respiratory **CHRONIC BRONCHITIS** characterized by: - Chronic inflammation and excess mucus production - Presence of chronic productive cough **EMPHYSEMA** characterized by: - Damage to the small, sac-like units of the lung that deliver oxygen into the lung and remove the **[MANAGEMENT COPD]** **[ALLERGIC RHINITIS]** - Rhinitis is an inflammation of the mucous membranes of the nose and is characterized by sneezing, itchy nose/eyes, watery rhinorrhea, and nasal congestion. - An attack may be precipitated by inhalation of an allergen. - The foreign material interacts with mast cells coated with IgE generated in response to a previous allergen exposure **[Symptoms of Allergic Rhinitis ]** 1. Itchy ears, buzzing sound 2. Red, incy watery eyes 3. Sneezing, congestion, runny nose 4. Inchy or sore throat, post-nasal drip, cough **[TREATMENT]** *[Antihistamines]* - H1 receptor antagonists *[a1-selective agonists]* - Nasal decongestants **MOA:** - Constrict dilated arterioles in the nasal mucosa and reduce airway resistance by binding at α1 receptors. **DRUGS:** 1. Phenylephrine 2. Propylhexedrine 3. Tetrahydrazoline 4. Methoxamine 5. Oxymetazoline **S/E:** - Oral -- not be given \>5 days - Spray -- not be given \>3 days *[Inhaled corticosteroids]* **S/E:** 1. nasal irritation 2. dryness 3. epistaxis **[COUGH & COLDS]** **Common colds** - Virus invade the mucosa of the upper respiratory tract, nose, pharynx and larynx which leads to the upper respiratory system **Signs and symptoms:** excessive mucous production leads to sore throat, coughing, upset stomach. **[Symptoms of COLDS]** 1. Runny Nose 2. Nasal Congestion 3. Sore Throat 4. Headache **[TREATMENTS]** **1. [Decongestants]** - vasoconstriction resulting in mucosal drying **2. [Antihistamines]** - combat increased histamine = nasal congestion and mucosal irritation **3. [Mucous removal]** - Mucolytic and expectorant **4. [Antitussives]** - work to suppress coughing *[MUCOUS REMOVAL]* - Aid in the coughing up and spitting out of the excess mucous that has accumulated in the respiratory tract by breaking down and thinning the secretions **ACTIONS:** 1. **MUCOLYTIC** - Loosening and thinning the respiratory tract secretions 2. **EXPECTORANT** - Direct stimulation of the secretoryglands in the respiratory tract. **[MUCOLYTIC ]** **[EXPECTORANT ]** ------------------------------ --------------------------------  *[ANTITUSSIVE]* - suppress the cough. Use a central or a local mechanism. - Used to inhibit a cough via a central mechanism. - Cough center located in the medulla is targeted. **[Opioid drugs all have antitussive effects:]** - Codeine is the only opioid used as a cough medicine - gold-standard treatment for cough suppression - S/E: CNS and respiratory depression and addictive **[Non opioid]** - Dextromethorphan - synthetic derivative of morphine - Safe, non-addicting and does not cause CNS or respiratory depression. *[COLD PREPARATIONS]* 1. **[ROBITUSSIN DM®:]** Dextromethorphanhydrobromide + guaifenesin 2. **[TUSERAN FORTE® (REFORMULATED): ]** Dextromethorphan hydrobromide + phenylephrine hydrochloride + paracetamol **DRUGS FOR DYSLIPIDEMIA** **[CHOLESTEROL]** - A soft waxy substance found among lipids (fats) in the bloodstream and all cells - Needed for digesting fats, making hormones, building cell walls - Carried in particles called lipoproteins that act as transport vehicles delivering cholesterol to various body tissues to be used, stored or excreted - Excess circulating cholesterol can lead to plaque formation -- **[ATHEROSCLEROSIS]** **[LIPOPROTEINS]** Cholesterol, triglycerides, and phospholipids are transported in the bloodstream as complexes of lipid and proteins known as **lipoproteins.** 1. **LDL** - ("bad" cholesterol) The major cholesterol carrier in the blood. Excess most likely to lead to plaque formation. 2. **HDL** - ("good" cholesterol) Transports cholesterol away from arteries and back to the liver to be eliminated. Removes excess cholesterol from plaques, slowing growth. 3. **VLDL** - secreted by the liver and export triglycerides & cholesterol to peripheral tissues (Precursor of LDL) **[TRIGLYCERIDES]** - **It is the chemical form** in which most fat exists in foods as well as in the body. - develop when **calories** are not burned right away and are stored in fat cells. - store unused calories and provide your body with energy - formed in the intestine and carry triglycerides from dietary origin **[HYPERLIPIDEMIA]** Also known as **Hyperlipoproteinemia/ Dyslipidemia** It describes an increased concentration of the lipoprotein macromolecules that transport lipids in the plasma. - **Hypercholesterolemia,** also called high cholesterol, is a medical term for abnormally high levels of cholesterol in the blood. **Elevated Total Cholesterol (TC)** - **Hypertriglyceridemia,** a condition in which triglyceride levels are elevated. **Elevated triglycerides (TG)** - **Chylomicronemia,** a disorder in which the body does not break down fats (lipids) correctly. **Deficiency of Chylomicrons** - **Hypoalphalipoproteinemia**, A rare lipoprotein metabolism disorder characterized by **deficiency of HDL.** **[LIPID PROFILE : IDEAL FASTING BLOOD LEVEL]** **[PRIMARY DYSLIPIDEMIA]** - **Single or multiple gene mutation** resulting in disturbance of LDL, HDL and trigylceride, production or clearance. Presence of Risk Factors Should be suspected in patients with: 1. premature heart disease 2. family hx of atherosclerotic dx. 3. Serum cholesterol level \>240mg/dl. 4. Physical signs of hyperlipidemia. **Genetic factors cause primary dyslipidemia, and it is inherited. Common causes of primary dyslipidemia include:** 1. **Familial combined hyperlipidemia,** which develops in teenagers and young adults and can lead to high cholesterol. 2. **Familial hyperapobetalipoproteinemia,** a mutation in a group of LDL lipoproteins called apolipoproteins. 3. **Familial hypertriglyceridemia,** which leads to high triglyceride levels. 4. **Homozygous familial or polygenic hypercholesterolemia,** a mutation in LDL receptors. **[SECONDARY DYSLIPIDEMIA]** Causes: - OBESITY - Sedentary lifestyle - Excessive consumption of cholesterol --saturated fats and trans-fatty acids. - Diabetes (Type 2 DM) - Hypothyroidism - Cholestatic liver disease - Nephrotic syndrome - Cigarette smoking - Alcoholism - Cushing's syndrome **DRUGS CAUSING MILD TO MODERATE DEGREES OF DYSLIPIDEMIA:** 1. Beta-blockers- due to inhibition of lipolysis (Beta 3) 2. Thiazide diuretics- 5--15% increase in total serum cholesterol and low-density lipoproteins (LDLs) 3. Antiretroviral drugs 4. Hormonal agents **[COMPLICATIONS OF UNTREATED SEVERE DYSLIPIDEMIA]** - Severe or untreated dyslipidemia can lead to other conditions, including **coronary artery disease (CAD)** and **peripheral artery disease (PAD).** - Both CAD and PAD can cause serious health complications, including **heart attacks and strokes.** 1. **[ATHEROSCLEROSIS]** - One of the major sequelae of hyperlipidemia. - The process of forming atheromas, plaques in the inner lining (the intima) of arteries is **atherogenesis** 2. **[CORONARY ARTERY DISEASE]** - A condition correlated with high plasma lipid levels of cholesterol-and/or triacylglycerol-containing lipoprotein particles. **[SYMPTOMS ASSOCIATED WITH THESE CONDITIONS:]** - leg pain, especially when walking or standing - chest pain - tightness or pressure in the chest and shortness of breath - pain, tightness, and pressure in the neck, jaw, shoulders, and back - indigestion and heartburn - sleep problems and daytime exhaustion - dizziness - heart palpitations - cold sweats - vomiting and nausea - swelling in the legs, ankles, feet, stomach, and veins of the neck **[NON-PHARMACOLOGIC INTERVENTION]** 1. Weight reduction specially in overweight patients 2. Increase physical activity 3. Smoking cessation & avoid alcohol consumption 4. Diet modification (ex: reducing the consumption of unhealthy fats, such as those found in red meats, full-fat dairy products, refined carbohydrates, chocolate, chips, and fried foods 5. Eat plenty of Dietary Fibers (Fruits, Vegetables, Whole Grains) & drink plenty of water 6. Take OMEGA-3 **[PHARMACOLOGIC INTERVENTION]** 1. HMG-CoA reductase inhibitors 2. Bile acid sequestrants 3. Nicotinic acid 4. Fibric acid derivatives 5. Others - Cholesterol absorption inhibitor - Lipid-regulating agent  **[STATINS:]** **(HMG-COA REDUCTASE INHIBITORS)** **EXAMPLES:** 1. Rosuvastatin 2. Atorvastatin 3. Simvastatin 4. Lovastatin 5. Pravastatin 6. Fluvastatin **ADVERSE EFFECTS:** 1. Hepatotoxicity 2. Myositis 3. Rhabdomyolysis 4. GI symptoms: dyspepsia, constipations & abdominal pain **DRUG INTERACTIONS:** 1. Gemfibrozil - increase risk of rhabdomyolysis 2. Lovastatin & rosuvastatin may prolong bleeding time with warfarin 3. Increase muscular toxicity with drugs that inhibit CYP450 3A4 system (cyclosporine, erythromycin, calcium blockers, niacin, ketoconazole) **[RESINS:]** **(BILE ACID SEQUESTERANTS)** 1. Cholestyramine 2. Colestipol 3. Colesevelam large nonabsorbable polymers that bind bile acids and similar steroids in the intestine and prevent their absorption. MOA: - They bind bile acids in the intestine through anion exchange; this **reduces the enterohepatic recirculation** of bile acids, which releases feedback regulation on conversion of cholesterol to bile acids in the liver **Advantage:** a strong safety record (not absorbed from GI so lack of systemic toxicity) **Disadvantages:** unpleasant granulated texture of powder old resins **ADVERSE EFFECTS:** - GI: constipation, bloating, epigastric fullness, nausea & flatulence (specially with old ones) **DRUG INTERACTION:** - GI binding can reduce absorption of anionic drugs (warfarin, thyroxin, digitoxin, beta-blockers & thiazide diuretics) **[NIACIN:]** **(NICOTINIC ACID/ VITAMIN B3)** Niacin functions after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. Through multiple actions, niacin (but not nicotinamide) reduces LDL cholesterol, triglycerides, and VLDL and also often increases HDL cholesterol. **MOA:** - Inhibit the mobilization of free fatty acids from peripheral adipose tissue to the liver which reduces synthesis & secretion of VLDL particles by the liver **Three preparations:** 1. **Immediate release** crystalline form: Causes flushing 2. **Sustained release:** less flushing but maximum dose 2 gm to prevent liver toxicity 3. **Extended release:** New drug, Niaspan is extended release formula better than other forms due to less side effects **ADVERSE EFFECTS:** - Flushing & headache - Increase blood glucose by 10-20% - Hepatotoxicity - Niaspan: is the best, less flushing but more GI effects that can be reduce if given with food. Less hepatic toxicity in doses ≤ 2gm/day **[FIBRIC ACID:]** **\[DERIVATIVES (FIBRATES)\]** - Gemfibrozil (600mg once or twice daily) taken with food - Fenofibrate (Tricor)48mg one to three tablets daily **MOA:** Increases activity of Peroxisome proliferator-activated receptor-alpha **(PPARα),** this increases synthesis of **lipoprotein lipase** therefore increasing clearance of triglycerides. **ADVERSE EFFECTS:** - GI symptoms like nausea, dyspepsia & abdominal pain - Myositis & rhabdomyolysis: more common with gemfibrozil specially combination with statins - Cholelithiasis (Gallstones) **[EZETIMIBE:]** **(CHOLESTEROL ABSORPTION INHIBITOR)** - A prodrug that is converted in the liver to the active glucuronide form - Monotherapy or in combination with statin - Not recommended with fibrates - Reduces LDL number - Also used in **phytosterolemia,** a rare genetic disorder that results from impaired export of **phytosterols.** **Adverse effects:** - diarhea - cough & fatigue **[OMEGA 3:]** **(LIPID REGULATING AGENT)** - **Omega 3 Fish oil** (salmon, herring, mackerel, swordfish, albacore tuna, sardines, lake trout) - Only FDA approved supplement for tx of dyslipidemias - Decreases hepatic production of TG and VLDL **omega-3 fatty acids are:** 1. alpha-linolenic acid (ALA) 2. eicosapentaenoic acid (EPA) 3. docosahexaenoic acid (DHA) **[NEWER AGENTS:]** **[DRUGS UNDER INVESTIGATION]** 1. **CETP inhibitors(cholesteryl ester transferring protein)** - Torcetrapib,Anacetrapib,Evacetrapib 2. **ANTISENSE inhibition of APO B-100 synthesis** - Mipomersen 3. **PCSK9 inhibitor** - Proprotein convertase subtilisin/kexin type 9 - Evolocumab, alirocumab 4. **AMP kinase activation** - Increases fatty acid oxidation and insulin sensitivity, inhibits cholesterol and TG synthesis **DRUGS FOR BLOOD CELL DEFICIENCY** **[HEMATOPOIESIS]** - It is the production of erythrocytes, platelets, and leukocytes from **undifferentiated stem cells.** - The hematopoietic machinery reside in the **bone marrow in adults.** - It requires a constant supply of essential nutrients -- **iron, cyanocobalamin, folic acid** and presence of hematopoietic growth factors  **[ANEMIA]** - Anemia is a common clinical condition that is caused by an acquired or hereditary **abnormality of RBC or its precursor,** or it may be a manifestation of an underlying non **hematologic disorder.** - Anemia is defined as a **decrease in the circulating RBC mass;** the usual criteria are a Hb of less than **11.5 g/dl in women** and less than **14 g/dl in men.** **Signs & Symptoms:** - tissue hypoxia - Fatigue - Headache - Dyspnea - Pallor - Angina - Tachycardia - visual impairment - syncope - lymphadenopathy - hepatic and or splenic enlargement - bone tenderness, blood loss in feces, neurologic symptoms. **[TYPES OF ANEMIA]** **A. *Anemia associated with decrease RBC production:*** 1. **[Iron deficiency anemia]** - deficiency of iron 2. **[Megaloblastic anemia]** - a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts). Results from deficiency either of Vit B12 or Vit B9. 3. **[Pernicious anemia]** - a deficiency in red blood cells caused by lack of vitamin B12 in the blood. Caused by a defect in the synthesis of intrinsic factor or by surgical removal of that part of the stomach that secretes intrinsic factor 4. **[Thalassemia]** - a blood disorder passed down through families (inherited) in which the body makes an abnormal form or inadequate amount of hemoglobin **B. *Anemia due to increased RBC destruction:*** 1. **[Hemolytic anemia]** - a disorder in which red blood cells are destroyed faster than they can be made. 2. **[Sickle cell anemia]** - an inherited red blood cell disorder in which there aren\'t enough healthy red blood cells to carry oxygen throughout your body. The hemoglobin molecule is defective, after they give up their oxygen, some may cluster together and form long, rod like structures which become stiff and assume sickle shape. **C. *Anemia associated to destruction of BONE MARROW:*** 1. **[Aplastic anemia]** - a condition that occurs when your body stops producing enough new blood cells. The condition leaves you fatigued and more prone to infections and uncontrolled bleeding. **Treatment:** 1. Immunosupressant 2. Blood transfusion 3. Bone marrow transplant **Causes of aplastic anemia:** 1. Radiation 2. Drugs or chemicals/ Drug induced (Chemotherapy, Benzene, Chloramphenicol, antiepileptics such as Phenytoin) 3. Viruses (CMV, EBV, Hep B, C & D) 4. Immune disease 5. Pregnancy 6. Marrow replacement **D. *Anemia due to chronic disease and renal failure:*** - When you have kidney disease, your kidneys cannot make enough EPO. - Low EPO levels cause your red blood cell count to drop and anemia to develop. Most people with kidney disease will develop anemia **[Erythropoietin (EPO)]** promotes production of mature red blood cells in the bone marrow. More red blood cells in the circulation leads to increased oxygenation and lower levels of hypoxia-inducible factor, suppressing EPO production. **[Hypoxia-inducible factor]** is degraded under conditions of normal oxygen tension. But in anemia or hypoxia, it promotes gene transcription of erythropoietin (EPO), necessary for maturation of red blood cells. **[Iron]** is necessary as well for red blood cell production. Its absorption and transport are also promoted by hypoxia-inducible factor. *[DRUGS FOR IDA]* **[IRON]** - Iron is required for Hb production. - For oxygen transport in the blood - Total quantity of iron in the body is 4-5g In the body it is present in: 1. **[Hemoglobin]** - transporter of oxygen in the blood. 2. **[Transferrin]** - transporter of Iron 3. **[Ferritin]** - An iron storage protein 4. **[Myoglobin]** - Iron- and oxygen-binding protein found in the skeletal muscle tissue 5. **[Cytochrome oxidase]** - a metallo-protein (contains copper and iron) final, enzyme of the electron transport system found in the mitochondria. **CAUSES OF IDA** - inadequate dietary intake as in **malnourished patients.** - due to blood loss in women in **heavy menstruation** - when iron requirement is increased as in **pregnancy and in growing children.** - acute or chronic **blood loss.** ***Route Of Administration of IRON*** **1. [ORAL]** - **FeSO4** (325mg - 65mg elemental iron) - **Ferrous gluconate** - less irritating Fe salt (325mg - 37mg elemental iron) - **Ferrous fumarate** - high elemental Fe content (325mg - 106mg elemental iron) **2. [PARENTERAL]** - Iron Dextran (IM or IV) - Iron sorbitol (IM) - Sodium ferric gluconate - Iron sucrose - It should be reserved for patients with documented iron deficiency **unable to tolerate or absorb iron** ( patients With post gastrectomy, previous small bowel resection, malabsorption syndrome, inflammatory bowel, noncompliance of patient, advanced chronic renal disease. - With extensive **chronic blood loss** who cannot be maintained with oral iron alone. ***ADVERSE EFFECTS:*** **[Oral]** - GIT discomfort: Nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, **black stool.** - They may be minimized by lowering the daily dose or by taking iron tablets immediately after or with meals. **[Parenteral]** - Local pain in the injection site, brown discoloration of tissues (Hemosiderin) **[Hemachromatosis]** - excess iron is deposited in heart, liver, pancreas and other organs cause organ failure and death. **[TREATMENT OF IRON TOXICITY:]** 1. **Acute iron intoxication:** parenteral administration of **[deferoxamine]** 2. **Chronic iron intoxication:** For chronic iron intoxication and hematochromatosis are treated with parenteral **[deferoxamine]** or with the newer oral iron chelator **[deferasirox.]** *[DRUGS FOR ]* *[MEGALOBLASTIC & PERNICIOUS ANEMIA]* 1. **Vitamin B9** - Folic acid 2. **Vitamin B12** - Cyanocobalamin - Are required for normal DNA synthesis. - Impairment of DNA synthesis affects all cells, but because RBC must be produced continuously, deficiency of either of this vitamins usually manifests first as **megaloblastic anemia.** - Deficiency of either of these vitamins results in impaired production and abnormal maturation of RBCS giving rise the characteristic blood and bone marrow suppression known as megaloblastic anemia. **1. [FOLIC ACID (Vit B9)]** **Brand:** Folvite, Folart, Folicard, Hemarate FA, Fortifer FA **Source:** yeast, liver, kidney, & green vegetables. - Folic acid is converted to **tetrahydrofolate** by the action of dihydrofolate reductase - Like cobalamin, folic acid is required for normal DNA synthesis, and its deficiency usually presents as megaloblastic anemia. - In addition **deficiency of folic acid during pregnancy** increase the risk of **neural tube defects** in the fetus. **Route of administration:** - Anemia resulting from folic acid deficiency is readily treated by oral folic acid. **2. [COBALAMIN (Vit B12)]** **Brand:** Polynerv, Neurobion **Source:** Meat (liver), eggs, & dairy products. cobalamin is absorbed from the GIT in the presence of **intrinsic factor of castle,** a product of the parietal cells of the stomach. 1. cyanocobalamin 2. hydroxocobalamin has a longer circulating half-life. **Uses:** 1. Pernicious & Megaloblastic anemia 2. Neurologic abnormalities 3. Gastrectomy 4. Cyanide poisoning (convert cyanide into cyanocobalamin) **Route of administration:** - Because cobalamin deficiency anemia is almost always caused by inadequate absorption, therapy should be by replacement of cobalamin, using **parenteral therapy (Intramuscular)** **[HEMATOPOIETIC GROWTH FACTORS]** A. Erythropoiesis-Stimulating Agents (ESAs) **[ERYTHROPOIETIN]** - Produced by the kidneys - stimulates the production of red cells and increases their release from the bone marrow, through activation of receptors on erythroid progenitors in the bone marrow *[DRUGS FOR ANEMIA ASSOCIATED WITH RENAL FAILURE]* ERYTHROPOIETIN 1. **[EPOETIN Alfa (Epogen, Procrit)]** - Erythropoietin is used for anemia associated with renal failure and sometime effective for patients with other forms of anemia - e.g. primary bone marrow disorder or anemia secondary to cancer chemotherapy or HIV treatment, bone marrow transplantation, AIDS or cancer 2. **[DARBEPOETIN (Aranesp)]** - is a long-acting version of erythropoietin - a glycosylated form of erythropoietin, has a much longer half-life. - Therefore, darbepoetin has decreased clearance and has a half-life about three times that of erythropoietin. - Supplementation with iron may be required to assure an adequate response. - The protein is usually administered intravenously in renal dialysis patients, but the subcutaneous route is preferred. 3. **[Methoxy polyethylene]** - Glycol-epoetin beta is a long-lasting form of erythropoietin that can be administered once or twice a month. *[DRUG FOR SICKLE CELL ANEMIA]* **Sickle cell anemia** - an inherited red blood cell disorder in which there aren\'t enough healthy red blood cells to carry oxygen throughout your body. 1. **[HYDROXYUREA]** - Clinical trials have shown that **hydroxyurea** can relieve the painful clinical course of sickle-cell disease. - In sickle-cell disease, the drug apparently increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S (HbS).This process takes several months. - Polymerization of HbS is delayed in the treated patients so that painful crises are not caused by sickled cells blocking capillaries and causing tissue anoxia. ***Side effects:*** - include bone marrow suppression - cutaneous vasculitis. - It is important that hydroxyurea is administered under the supervision of a physician experienced in the treatment of sickle-cell disease. *[DRUG FOR THROMBOCYTOPENIA]* MEGAKARYOCYTE GROWTH FACTOR Aka: thrombopoietin (TPO). **Thrombocytopenia** - is when you don\'t have enough platelets, cells in your blood that stick together to help it clot. - Decrease in platelet count. **CAUSES:** 1. Aplastic anemia 2. Cancer - Leukemia and Lymphoma 3. Platelet-lowering disease like **Wiskott-Aldrich** or **May-Hegglin syndromes** 4. Viral infection- HIV, chickenpox, rubella 5. Heparin (HIT) 6. Chemotherapy 1. **[OPRELVEKIN]** - (interleukin-11 \[IL-11 - stimulates platelet production of peripheral platelets and decreases the number of platelet transfusions required by patients undergoing bone marrow suppression therapy for cancer. - Used to stimulate the bone marrow to produce platelets in order to prevent low platelets that may be caused by chemotherapy 2. **[ROMIPLOSTIM]** - A **thrombopoietin receptor agonist** with a novel peptide structure. - Used **subcutaneously** in patients with chronic idiopathic thrombocytopenia who have failed to respond to conventional treatment 3. **[ELTROMBOPAG]** - An oral **agonist of the thrombopoietin receptor** that is also used for patients with chronic idiopathic thrombocytopenia that is refractory to other agents. *[DRUG FOR NEUTROPENIA]* MYELOID GROWTH FACTOR **[NEUTROPENIA]** - Neutropenia occurs when you have **too few neutrophils,** a type of white blood cells. - Neutrophils are important for fighting certain infections, especially those caused by bacteria. **CAUSES:** 1. Infections, including hepatitis, tuberculosis, sepsis, or Lyme disease 2. Medications, including chemotherapy. Chemotherapy is one of the most common causes of neutropenia. 3. Cancer and other blood and/or bone marrow disorders 4. Deficiencies in vitamins or minerals, such as vitamin B12, folate, or copper 5. Autoimmune diseases, including Crohn's disease, lupus, and rheumatoid arthritis 1. **[FILGRASTIM]** (granulocyte colony-stimulating factor; **G-CSF**) and 2. **[SARGRAMOSTIM]** (granulocyte-macrophage colony-stimulating factor; **GM-CSF**) ***USE:*** - Both growth factors are used to accelerate the recovery of neutrophils after cancer chemotherapy and to treat other forms of secondary and primary neutropenia (eg, aplastic anemia, congenital neutropenia). - G-CSF may be combined with the novel hematopoietic stem cell mobilizer **plerixafor,** an inhibitor of the CXC chemokine receptor 4 (CXCR4). G-CSF is also used to mobilize peripheral blood stem cells in preparation for autologous and allogeneic stem cell transplantation ***MOA:*** - stimulate the production and function of neutrophils. GM-CSF also stimulates the production of other myeloid and megakaryocyte progenitors. 3. **[Pegfilgrastim]** - a covalent conjugation product of filgrastim and a form of polyethylene glycol, has a much longer serum half-life than recombinant G-CSF. 4. **[Lenograstim]** - used widely in Europe, is a glycosylated form of recombinant G-CSF. ***USE:*** - Both growth factors are used to accelerate the recovery of neu- trophils after cancer chemotherapy and to treat other forms of secondary and primary neutropenia (eg, aplastic anemia, congenital neutropenia). **HORMONAL AGENTS** **[ENDOCRINE SYSTEM]** System of ductless glands that secrete hormones - Hormones are "messenger molecules" - Circulate in the blood - Act on distant target cells - Target cells respond to the hormones for which they have receptors - The effects are dependent on the programmed response of the target cells - **Hormones** are just **molecular triggers** **[ENDOCRINE ORGANS]** ***Purely endocrine organs*** 1. Pituitary gland 2. Pineal gland 3. Thyroid gland 4. Parathyroid glands 5. Adrenal: 2 glands 6. Cortex 7. Medulla ***Endocrine cells in other organs*** 1. Pancreas 2. Thymus 3. Gonads 4. Hypothalamus **[HORMONES]** - The control of metabolism, growth, and reproduction is mediated by a combination of **neural and endocrine systems** located in the hypothalamus and pituitary gland. **[Mechanisms of hormone release]** 1. **Humoral:** in response to changing levels of ions or nutrients in the blood 2. **Neural:** stimulation by nerves 3. **Hormonal:** stimulation received from other hormones **[HYPOTHALAMUS]** - It is the **master endocrine organ** - It secretes releasing/inhibiting hormones **[PITUITARY GLAND]** - Consists of an **anterior lobe** and a **posterior lobe.** - Connected to hypothalamus by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. - The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from which they are released into the circulation. - Sits in hypophyseal fossa: depression in sella turcica of sphenoid bone **Pituitary secretes 9 hormones** **[HORMONAL AGENTS]** Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: 1. as replacement therapy for hormone deficiency states 2. as antagonists for diseases caused by excess production of pituitary hormones 3. as diagnostic tools for identifying several endocrine abnormalities. **[ANTERIOR PITUITARY HORMONES]**  **[GROWTH HORMONES]** Required during **childhood** and **adolescence** for: 1. Attainment of normal adult size. 2. Important effects throughout postnatal life. 3. Lipid and carbohydrate metabolism. 4. Lean body mass and bone density. Medicinal GH was isolated from the pituitaries of human cadavers. It is contaminated with prions that could cause **Creutzfeldt-Jakob disease** 1. **[Somatropin]** (the recombinant form of GH) 2. **[Somatrem]** (equivalent drug of GH) ***DEFICIENCY*** - can have a genetic basis - can be acquired as a result of damage to the pituitary or hypothalamus. - Breech or traumatic delivery - Intracranial tumors & infection **USES OF GROWTH HORMONES** 1. **Prader-Willi syndrome** - an autosomal dominant genetic disease associated with growth failure, obesity, and carbohydrate intolerance. 2. **Turner syndrome** (45 X karyotype and variants) 3. **Idiopathic short stature (ISS)** 4. **Anti-aging remedy** 5. Use by **athletes** for a purported increase in muscle mass and athletic performance. **TOXICITY OF GROWTH HORMONES** 1. Progression of scoliosis 2. Edema 3. Hyperglycemia 4. Increased risk of otitis media **[IGF-1 ANALOG]** **[EXCESSIVE GROWTH HORMONES]** 1. **[Acromegaly]** - Excess of GH while the epiphyseal plates are close - Unproportional features like hands and feet 2. **[Gigantism]** - Excess of GH while the epiphysealplates are open - Proportional features like hands and feet **[TREATMENT FOR EXCESSIVE GH:]** 1. Somatostatin analogs 2. Dopamine receptor agonists, which reduce the production of GH 3. **Pegvisomant** - GH receptor antagonist **[GONADOTROPINS]** These hormones serve complementary functions in the **reproductive process.** 1. Follicle stimulating hormone (FSH) 2. Luteinizing hormone (LH) **[GONADOTROPIN ANALOG]** 1. **[MENOTROPINS]** - Human menopausal gonadotropins (hMG) - extracted from the urine of postmenopausal women - **purified extract of FSH and LH** 2. **[FSH ANALOG]** - Available forms of purified FSH: - **Urofollitropin** - purified preparation of human FSH extracted from the urine of postmenopausal women - Recombinant forms of FSH - Follitropin alfa & Follitropin beta 3. **[LH ANALOG]** - **Lutropin alfa** - recombinant form of human LH - Lutropin has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency 4. **[HUMAN CHORIONIC GONADOTROPIN]** - produced by the human placenta and excreted into the urine - **Choriogonadotropin alfa** - recombinant form of hCG approved for the treatment of prepubertal cryptorchidism ***CLINAL USES:*** used in states of infertility: - Men - stimulate spermatogenesis - Women - induce ovulation **TOXICITY:** Ovarian hyperstimulation syndrome - ovarian enlargement - Multiple pregnancies **[Gonadotropin Releasing Hormone (GnRH) ANALOG]** - secreted by neurons in the hypothalamus. - **Gonadorelin** - acetate salt of synthetic human GnRH **Synthetic analogs/GnRH agonists long acting:** 1. goserelin 2. histrelin 3. leuprolide 4. nafarelin 5. triptorelin **CLINICAL USES:** 1. Female infertility 2. Male infertility 3. Prostate cancer 4. Controlled ovarian hyperstimulation 5. **Endometriosis** - syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of estrogen-sensitive endometrium-like tissue outside the uterus. ***TOXICITY:*** 1. **[Women]** - Symptoms of menopause - hot flushes, sweats, headaches. - Ovarian cysts - Reduced bone density and osteoporosis 2. **[Men]** - hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density **[GnRH ANTAGONISTS]** Examples: 1. Ganirelix 2. Cetrorelix 3. Degarelix inhibit the secretion of FSH and LH ***CLINICAL USES:*** 1. Suppression of Gonadotropin Production 2. Advanced prostate cancer **[ESTROGEN]** **Ovaries:** Estradiol, estrone, estriol **Synthetic:** Ethinyl estradiol, diethylstilbestrol **Uses:** 1. Oral contraceptive 2. Post menopausal syndrome 3. Acne 4. Prostate cancer **[ANTI-ESTROGEN]** 1. **[ESTROGEN RECEPTOR BLOCKERS:]** - Tamoxifen (Nolvadex), Clomiphene (Clomid) adjuvant therapy for Breast CA. 2. **[(SERM) Selective Estrogen Receptor Modulator:]** - Raloxifene (Evista) reduce bone resorption in osteoporosis. 3. **[AROMATASE INHIBITORS]** - Anastrazole (Arimidex) - Letrozole (Femara) **[PROGESTINS]** 1. Progesterone 2. Levonorgestrel 3. Norethindrone 4. Medroxyprogesterone **Uses:** Contraceptive, Dysmenorrhea, Endometriosis **[PROGESTIN ANTAGONISTS: ]** 1. mifepristone (abortifacient) **[CONTRACEPTIVES]** ***Types of Contraceptives:*** 1. **[POST COITAL CONTRACEPTIVES]** - "Morning after pills" - Ethinyl estradiol + Norgestrel - Conjugated Estrogen, Estrone 2. **[CHEMICAL CONTRACEPTIVES]** - **Gossypol** - destroys seminiferous tubule 3. **[COMBINATION CONTRACEPTIVES]** - Monophasic - Biphasic - Triphasic 4. **[PROGESTIN ONLY CONTRACEPTIVES:]** a. **Minipill** - Norethindrone + Norgestrel b. **Implant**- Norgestrel 216mg (Norplant) c. **IM** - M edroxyprogesterone (Depo-Provera) d. **Intrauterine** - Progestasert ***[TEMPERATURE METHOD]*** - Falling to rising temperature - Abstinence 5 days after onset of menses until 3 days after transition of temperature ***[CERVICAL MUCUS METHOD/ Billing's method]*** - Normal: Thick, creamy white - Ovulation: clear and tenacious (egg white) - Abstinence 3-4 days after peak change  ***[CALENDAR METHOD]*** - Women tabulate menstrual period for at least 1 year. **[ANDROGENS:]** Male Hormones - Testosterone (testis), Dihydrotestosterone, Androstenedione - Inc. muscle mass (Abused by athletes), secondary characteristic in males ***Uses:*** 1. Hypogonadism 2. Infertility 3. Impotence 4. Osteoporosis **[ANTI-ANDROGENS]** 1. **[ALPHA REDUCTASE INHIBITOR]** - Finasteride (Propecia, Proscar) for BPH and alopecia 2. **[ANDROGEN RECEPTOR BLOCKER]** - Flutamide, Bicalutamide, Nilutamide For prostate cancer **[ADRENAL GLAND]** 1. **[Adrenal cortex]** - Secretes lipid-based steroid hormones, called "corticosteroids" -- "cortico" as in "cortex" **MINERALOCORTICOIDS** - Aldosterone is the main one **GLUCOCORTICOIDS** - Cortisol (hydrocortisone) is the main one 2. **[Adrenal medulla]** - Secretes epinephrine and norepinephrine **[ALDOSTERONE:]** the main mineralocorticoid - Secreted by adrenal cortex in response to a decline in either **blood volume** or **blood pressure** (e.g. severe hemorrhage) - Is terminal hormone in renin-angiotensin mechanism (RAAS) - Prompts distal and collecting tubules in kidney to reabsorb more sodium - Water passively follows - Blood volume thus increases **[CORTISOL:]** the most important glucocorticoid - Glucocorticoid receptors are found in the cells of most vertebrate tissues) - It is essential for life - Helps the body deal with stressful situations within minutes **Physical:** trauma, surgery, exercise **Psychological:** anxiety, depression, crowding **Physiological:** fasting, hypoglycemia, fever, infection - Regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions including water balance [People with adrenal insufficiency:] these stresses can cause hypotension, shock and death: must give glucocorticoids, eg for surgery or if have infection, etc. - Keeps **blood glucose levels high enough** to support brain's activity - Forces other body cells to switch to fats and amino acids as energy sources - **Catabolic:** break down protein - Redirects circulating lymphocytes to lymphoid and peripheral tissues where pathogens usually are - In large quantities, **depresses immune** and **inflammatory response** - Used therapeutically - Responsible for some of its side effects **PROLACTIN** - The principal hormone responsible **for lactation** - Dopamine (prolactin-inhibiting hormone) - **[Hyperprolactinemia]** - a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men. **[POSTERIOR PITUITARY HORMONES]** **[OXYTOCIN]** - During the **second half of pregnancy,** uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. ***CLINICAL USES:*** 1. induce labor 2. control of uterine hemorrhage after vaginal or cesarean delivery. ***ANTAGONISTS:*** - **[Atosiban]** - treatment for preterm labor (tocolysis) **[VASOPRESSIN]** - Deficiency results in diabetes insipidus - ***[Desmopressin acetate]*** - synthetic analog of vasopressin. ***CLINICAL USES:*** - treatments of choice for pituitary diabetes insipidus ***TOXICITY:*** 1. Headache, nausea, abdominal cramps, agitation, and allergic reactions 2. hyponatremia and seizures 3. Vasopressin (but not desmopressin) can cause vasoconstriction ***ANTAGONISTS:*** - **[Conivaptan and Tolvaptan]** - approved by the FDA for intravenous administration in hyponatremia **THYROID & ANTI-THYROID DRUGS** **[THYROID GLAND]** - Anterior neck on trachea just inferior to larynx - Two lateral lobes and an isthmus 1. Thyroid hormone: tyrosine based with 3 or 4 iodine molecules - T4 (thyroxine) and T3 2. Calcitonin involved with calcium and phosphorus metabolism ***Thyroid is composed of spherical follicles*** - **Follicle cells:** produce thyroglobulin, the precursor of thryoid hormone (thyroxin) - **Colloid lumen** is of thyroglobulin - **Parafollicular "C" cells:** produce calcitonin **[THYROID PHYSIOLOGY]** ***Thyroid hormones:*** 1. **[Triiodothyronine & Tetraiodothyronine]** - normalize growth and development, bodytemperature, and energy levels. 2. **[Calcitonin]** - important in the regulation of calcium metabolism - they seem to activate the mRNA transcription process and can promote **protein synthesis** or (in excessive amounts) **protein catabolism.** Thyroxine and triiodothyronine, naturally occurring molecules are levo isomers. **Dextrothyroxine** - the synthetic dextro isomer of thyroxine **Thyroxine** is absorbed best in the duodenum and ileum 1. Growth and development 2. Calorigenics by increasing the rate of basal metabolism 3. CVS = by increasing the metabolic rate, which increases blood flow, cardiac output, and heart rate 4. The CNS by increasing or diminishing cerebration \- Musculature by causing a fine tremor \- Sleep by inducing fatigued wakefulness with hyperthyroidism or somnolence with hypothyrodism \- Lipid metabolism by stimulating lipid mobilization and degradation ***Iodine content*** - T3 = 59% - T4 = 65% **[BIOSYNTHESIS OF THYROID HORMONES]** - Synthesis & release is regulated by negative feedback mechanism  **[Wolff-Chaikoff block]** - Administration of large doses of iodine inhibit iodide organification **[PROTEIN BINDING OF THYROID HORMONES]** When in the circulation, thyroid hormone transported is bound to several plasma proteins, a process that: 1. Helps to protect the hormone from premature metabolism and excretion 2. Prolongs its half-life in the circulation 3. Allows the thyroid hormone to reach its site of action. - Most thyroid hormone is transported by **THYROXINE-BINDING** **GLOBULIN (TBG).** - Prealbumin and albumin also serves as carriers. **[METABOLISM OF THYROID HORMONES]** SITEs of Peripheral conversion of T3 and T4 - pituitary gland - Liver - kidneys ***DEIODINATION*** - it is the primary pathway for the peripheral metabolism of thyroxine. - Deiodination of T4 may occur by monodeiodination of the outer ring, producing **3,5,3\'-triiodothyronine** (T3), which is **three to four times more potent than T4.** - Alternatively, deiodination may occur in the inner ring, producing 3,3\',5\'-triiodothyronine (reverse T3, or rT3), which is metabolically inactive **[CLASSIFICATION OF HYPOTHYROIDISM]** 1. **PRIMARY:** - due to gland destruction or dysfunction caused by disease or medical therapies (e.g., radiation, surgical procedures) due to failure of the gland to develop or congenital incompetence (i.e., cretinism) 2. **SECONDARY** - due to a pituitary disorder that inhibits TSH secretion. - The thyroid gland is normal but lacks appropriate stimulation by TSH 3. **TERTIARY**: - a condition in which the pituitary-thyroid axis is intact, but the hypothalamus lacks the ability to secrete TRH to stimulate the pituitary. **[CONDITIONS OF HYPOTHYROIDISM]** - Cretinism & Myxedema - Hashimoto's disorder - Endemic and Sporadic goiter 1. **[CRETINISM]** - CONGENITAL HYPOTHYROIDISM - Physical and mental retardation - DIAGNOSIS: Newborn screening 2. **[MYXEDEMA]** - Hypothyroidism in adults - **Myxedema coma** is an end state of untreated - hypothyroidism. - It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death. 3. **[HASHIMOTO'S THYROIDITIS]** - autoimmune thyroid diseases (AITDs) and is characterized by the destruction of thyroid - cells - a chronic lymphocytic thyroiditis that is considered to be an autoimmune disorder. 4. **[ENDEMIC GOITER]** - results from inadequate intake of dietary - iodine. - This is common in regions with iodine-depleted soil and in areas of endemic malnutrition. 5. **[SPORADIC GOITER]** - can follow ingestion of certain drugs or foods containing **progoitrin,** which is inactive and converted by hydrolysis to **goitrin.** - isolated in cabbage, peanuts,mustard, spinach, cauliflower, and horseradish. - propylthiouracyl (PTU), iodides, phenylbutazone, cobalt and lithium. *[DRUGS FOR HYPOTHYROIDISM]* 1. **[LEVOTHYROXINE]** - synthetic T4 ***BRAND NAMES:*** - Eltroxin , Euthyrox, Levoxyl, Levothroid, Synthroid ***PHARMACOKINETICS:*** - Should be taken 30min before or 1 hour after meals - Once a day dosing (Long half-life) ***ADVANTAGES OF LEVOTHYROXINE:*** 1. stability 2. content uniformity 3. low cost 4. lack of allergenic foreign protein 5. easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration. 2. **[LIOTHYRONINE]** - synthetic T3 - BRAND NAMES: Cytomel, Triostat ***PHARMACOKINETICS:*** - Short half-life - Not used alone for long term treatment - Increase risk for cardiac side effects 3. **[LIOTRIX]** - FIXED RATIO PREPARATION - 4:1 ratio (T4:T3) - the T3 component proved unnecessary (because T4 is metabolized to T3) and even disadvantageous because of T3-induced adverse effects. **[DESSICATED THYROID PREPARATIONS]** - From animal source - ratio of T3 and T4varies with the animal source. - Porcine gland preparations have a higher T3 to T4 ratio than those from bovine sources.  HYPERTHYROIDISM: ANTI-THYROID DRUGS **[HYPERTHYROIDISM]** - is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone ***Conditions:*** - Exopthalmic goiter - Grave's disease - Thyroid storm 1. **[THYROID STORM]** - An acute, life-threatening state induced by excessive release of thyroid hormones - a syndrome of thyroid enlargement without excessive thyroid hormone production 2. **[Jod-Basedow effect]** - iodine-induced hyperthyroidism - Also seen as a side effect of administration of the iodine-containing contrast agents, or amiodarone, an antiarrhythmic drug 3. **[Toxic multinodular goiter]** - there is excess production of thyroid hormones from functionally autonomous thyroid nodules, which do not require stimulation from thyroid stimulating hormone (TSH) 4. **[Factitious hyperthyroidism]** - higher-than-normal thyroid hormone levels in the blood that occur from taking too much thyroid hormone medication - iatrogenic 5. **[GRAVE'S DISEASE]** - autoimmune disorder that leads to overactivity of the thyroid gland (hyperthyroidism) **[Management of Graves\' Disease]** The three primary methods for controlling hyperthyroidism are: 1. Antithyroid drug therapy 2. surgical thyroidectomy 3. destruction of the gland with radioactive iodine. *[DRUGS FOR HYPERTHYROIDISM]* 1. Thioamides 2. Inorganic anions 3. Iodides 4. Radiocontrast dye 5. β-blockers and glucocorticoids 6. Radioactive iodine 1. **[THIOAMIDES]** - Propylthiouracil - Methimazole - Carbimazole MOA: - Inhibit the enzyme thyroid peroxidase (Inhibit organification and coupling) - Blocks peripheral conversion of T4 to T3 (PTU) PHARMACOKINETICS: - Almost completely absorbed in the GIT - Can cross placental barrier (lesser with PTU) - Methimazole 10x more potent than PTU - PTU more protein-bound USES: 1. Used for treatment of mild thyrotoxicosis and in preparation of surgery. 2. Propylthiouracil is relatively safe and preferred in pregnancy. ADVERSE EFFECTS: - maculopapular rash - agranulocytosis - hepatitis (PTU) ; cholestatic jaundice (Methimazole) - vasculitis 2. **[INORGANIC ANIONS]** - K perchlorate - K thiocyanate MOA: - block uptake of iodide by the gland by competitive inhibition - can be overcome by large doses of iodides useful for iodide-induced hyperthyroidism (**amiodarone-induced hyperthyroidism**) rarely used due to its association with **aplastic anemia** 3. **[IODIDES]** - Iodone - KISS MOA: - acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis (\> 6 mg daily), - inhibit iodide organification - USES: - useful in thyroid storms: 2-7 days - Preoperatively - iodides decrease vascularity, size and fragility of hyperplastic gland CAUTION: - The gland will escape from inhibition after 2-8 weeks - Chronic use in pregnancy should be avoided -- fetal goiter ADVERSE EFFECTS: - They include **acneiform rash** (similar to that - of brominism) - swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely, anaphylactoid reactions. 4. **[IODINATED CONTRAST DYE]** - Ipodate (oral) (Oragrafin) - Iopanoic acid (oral) (Telepaque) - Diatrizoate (intravenous) (Hypaque) MOA: - inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary - inhibition of hormone release 5. **[BETA BLOCKERS & GLUCOCORTICOIDS]** DRUGS: - β-blockers - Propranolol, Metoprolol, Atenolol - Glucocorticoids - Prednisone MOA: - MSA: inhibits T4 to T3 - Ameliorate many disturbing s/sxs of hyperthyroidism 6. **[RADIOACTIVE IODINE]** - (I 131) sodium iodide 131 - the only isotope used in treatment of thyrotoxicosis MOA: - Trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells **NOTES:** Penetration range: 400-2000µm **Clinical uses:** Grave's, primary inoperable thyroid CA **Contraindication:** pregnancy Easy, effective, low cost and absence of pain are the advantages. - Six to 12 weeks following the administration of radioiodine, the gland will shrink in size and the patient will usually become euthyroid or hypothyroid. - Hypothyroidism occurs in about 80% of patients following radioiodine therapy. **[THYROIDECTOMY]** - A near-total thyroidectomy is the treatment of choice for patients with **very large glands or multinodular goiters.** - Patients are treated with antithyroid drugs until euthyroid (about 6 weeks). **[ADJUNCT THERAPY]** 1. **Diltiazem,** 90--120 mg three or four times daily, can be used to control tachycardia in patients in whom -blockers are contraindicated, eg, those with asthma. 2. **Adequate nutrition and vitamin** supplements are essential. 3. **Barbiturates** accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4 levels. **DRUGS FOR DIABETES MELLITUS** **[The Endocrine Pancreas]** - consists of approximately 1 million **islets of Langerhans** - four hormone-producing cells arepresent. **[DIABETES MELITUS]** - Metabolic disorder associated with **chronic hyperglycemia.** - A syndrome characterized by hyper glycemia resulting from absolute or relative impairment in insulin secretion and/or insulin action. **[TYPES OF DIABETES]** - Type I DM - Type II DM - Type III DM - Gestational DM 1. **[Type 1 DM]** - IDDM - **Absolute lack of insulin** - It results from the destruction of the β cells of the pancreas. - **Type IA:** auto-immune - **Type IB:** idiopathic (unknown cause) Tx: Insulin (important for survival) 2. [Type 2 DM] - NIDDM - **Relative lack of insulin** 1. Decrease insulin secretion and 2. Development of insulin resistance    3. **[Type 3 DM]** - Originate from diseases/drugs which can cause diabetes 3. Chronic pancreatitis 4. Endocrine diseases 4. **[Gestational DM]** - Seen during pregnancy (one of the risk factors for DM) - It is defined as any abnormality in glucose levels noted for the first time during pregnancy. - Tx: Insulin 5. **[MODY]** - ***Maturity-Onset Diabetes of the Young*** - occur in young, non-obese adolescents - have a mutation in the glucokinase gene. - Impairments in insulin secretion and in hepatic glucose regulation have been demonstrated in these patients. **[Diabetes associated with Acanthosis nigricans]** - **Type A** results from genetic alterations in the insulin receptor. - **Type B** results from circulating antibodies to the insulin receptor and may be associated with other evidence of autoimmune disease. **[Diabetes induced by Beta Cell Toxins]** - Vacor, a rodenticide commonly used in Korea in suicide attempts, is cytotoxic for human islet and can cause type I DM in survivors. - Streptozotocin can induce experimental diabetes in rats but rarely causes diabetes in humans. **Signs & Symptoms** - 3P's polyuria, polydipsia, polyphagia - blurred vision, fatigue, and nausea and lead to various fungal and bacterial infections. - very dry skin, sores that are slow to heal - Weight loss - ***Ketoacidosis*** - inc. free fatty acids - Hyperosmolar coma-dehydration ***Complications:*** ***1. [RETINOPATHY]*** - Type 2 diabetic patients can develop both proliferative and non-proliferative diabetic retinopathy, although it is the latter type complicated by macular edema that is leading cause of vision loss. ***2. [NEPHROPATHY]*** - Diabetic nephropathy is best detected by the presence of 2+ proteinuria on dipstick urinalysis. - Nephropathy is the single most critical determinant of overall prognosis. ***3. [DIABETIC FOOT PROBLEM]*** - Result from complex interactions between peripheral neuropathy, microangiopathy and macrovascular disease, and poor foot hygiene. **4. Coronary Heart Disease** **5. Cerebrovascular Disease** **6.** **Peripheral Vascular Disease** ***Diagnosis:*** 1. **Fasting blood sugar/Plasma Glucose** - No oral intake for at least 8 hours. - (FPG \> 126mg/dl= (+) DM ***[Fasting Blood Sugar Levels]*** - Normal: 100mg/dl (5.6 mmol/L) - Prediabetes: 100-125 mg/dl - Diabetes: GREATER THAN 126 mg/dl in two separate test 2. **Glycosilated Hemoglobin** - Glycosilated Hgb (\>6.5%) - Perform at least 2 determinations - Monitoring: glucose control for the past 3 months 3. **Oral glucose tolerance (OGGT)** - Give 75g anhydrous glucose - 2 hour postprandial glucose (\>200mg/dl=+ DM)  4. ***Treatment for DM*** - Insulin - Balanced Diet **[INSULIN]** - One of the hormone produce in the pancreas (consists of approximately 1 million islets of Langerhans) **PRECURSOR: PRO INSULIN** 5. Stimulates GLUCOKINASE-→ glycolysis 6. Causes translocation of glucose transporters (facilitates the entry of glucose into the cell) **[Insulin receptors]** - consists of two covalently linked heterodimers - The subunit contains a tyrosine kinase. **[Glucose Transporters]** **[Effects of Insulin]** 1. **Effect on liver:** - Reversal of catabolic features of insulin deficiency - Inhibits glycogenolysis - Inhibits conversion of fatty acids and amino acids to keto acids - Inhibits conversion of amino acids to glucose - Anabolic action - Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase) Increases triglyceride synthesis and very low density lipoprotein formation 2. **Effect on muscle:** - Increased protein synthesis - Increases amino acid transport - Increases ribosomal protein synthesis - Increased glycogen synthesis - Increases glucose transport - Induces glycogen synthase and inhibits phosphorylase 3. **Effect on adipose tissue:** - Increased triglyceride storage - Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins - Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoporotein transport - Intracellular lipase is inhibited by insulin **[Insulin]** - Used in patients who present initially with very high blood glucose levels, especially with weight loss. - Used in patients who have failed to respond oral therapy. ***Types:*** - Based on source - Based on the use - Based on duration of action 1. **[Based on source:]** ANIMAL SOURCE - Bovine and Porcine Insulin - More immunogenic (it can cause hypersensitivity reactions) = it is already obsolete RECOMBINANT INSULIN - It is less immunogenic 1. Native insulin (Human Insulin, NPH/Isophane insulin, Insulin Zn suspension) 2. Modified insulin - **Insulin** - Lispro, Aspart, Glulisine - **Protamine** - Lispro, Aspart - **Insulin** - Glargine, Detemir 2. **[Based on the use:]** 1. **Basal insulin** - given to provide glucose control over 24 hours (Intermediate-long acting) 2. **Demand insulin** - given to prevent postprandial hyperglycemia (short acting) 3. **[Based on duration of action:]** **SHORT ACTING W/ RAPID ONSET** - Regular insulin - short-acting soluble crystalline zinc insulin - Only insulin administered IV - Used in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections. **RAPID ACTING W/ RAPID ONSET & SHORT DURATION** - decreases the risk of late postmeal hypoglycemia. **INTERMEDIATE ACTING** 1. Lente (Monotard)- 70% ultralente & 30% semilente 2. NPH (Humulin N, Insulatard)- contains insulin and protamine (no excess of Protamine) 3. Protamine Lispro 4. Protamine Aspart **LONG ACTING WITH SHORT ONSET** 1. Ultralente = extended insulin zn suspension 2. PZI (Protamine Zinc Insulin) 3. Insulin Glargine (Lantus) - "peakless insulin" 4. Insulin Determir - with peak **[Initiation of Insulin Therapy]** - **Type I DM** patients received an average total dose of about 40 units insulin a day. - Because **type II DM** patients are insulin resistant, they require more insulin. - Those who are **severely hyperglycemic** and obese may be started on about 40 units insulin a day. **[Undesirable effects of INSULIN]** 1. **[Hypoglycemia "TIRED"]** - Tremors, Tachycardia - Irritability - Restless - Excessive hunger - Diaphoresis, Depression - **Redness** - Swelling at the - injection site - **Lipodystrophy** - Flushing, urticaria - **Weight gain** 2. **[Somogyi effect]** - Insulin-induced post-hypoglycaemic hyperglycaemia occurs when hypoglycaemia (e.g. in the early hours of the morning) induces an overshoot of hormones (adrenaline, growth hormone, glucocorticosteroids, glucagon) that elevate blood glucose (raised blood glucose on awakening) 3. **[Dawn phenomenon]** - Rise in blood sugar between 4 am and 8am - Reduce tissue sensitivity - Not associated with hypoglycemia **[The OHAs Oral Hypoglycemic Agents]** - Drug treatment should be added only when diet, physical activity and education have not achieved individual treatment targets. A. **Insulin releasers/Secretagogues** - SULFONYLUREAS and MEGLITINIDES B. **Insulin sensitizers** - decrease insulin resistance (BIGUANIDES, THIAZOLIDINEDIONES) *[**SULFONYLUREAS**]* (INSULIN RELEASERS) - Stimulates insulin release from the pancreatic beta cells ***Two additional mechanisms:*** 1. a reduction of serum glucagon levels 2. closure of potassium channels in extrapancreatic tissues. **[1st generation:]** **Chlorpropamide (Diabenese)** = the longest duration of action (60 HRS) half life: 32 hrs **Acetohexamide** = with diuretic and uricosuric activity **Tolbutamide** = shortest duration of action, safe among elderly **Tolazamide** 1. Glibenclamide (Euglucon) 2. Gliclazide (Diamicron) 3. Glimepiride (Solosa)= has the longest T ½ Once a day dosing is applicable. 4. Glipizide (Glucotrol)= has the shortest T ½ 5. Glyburide CONTRAINDICATIONS: 1. Pregnant, lactating and children (it can be secreted in the milk) 2. Not for px with allergy to sulfa drugs 3. Not for stressful conditions such as infection, injury or surgery (use insulin) SIDE EFFECTS: 1. Hypoglycaemia 2. Disulfiram like reaction 3. Nausea and vomiting 4. GI discomfort 5. Agranulocytosis and anemia 6. Dilutional Hyponatremia (Chlorpropamide) 7. Cardiotoxicity *[**MEGLITINIDES**]* (INSULIN RELEASERS) - Short duration of action - Used to prevent post prandial hyperglycemia 1. Repaglinide (Prandin, Novonorm) 2. Nateglinide (Starlix) - D-Phenylalanine Derivative ***[BIGUANIDES]*** (INSULIN SENSITIZERS) **[AKA: Euglycemic agents]** - Enhances insulin sensitivity and glucose uptake in the liver and muscles - Reduces TG and LDL and increases HDL - Proven to reduce mortality - Taken before meals to reduce GI effects Examples: 1. Metformin (Glucophage), Buformin, 2. Phenformin -associated with **lactic acidosis** Mechanisms of Action: - direct stimulation of glycolysis in tissues, with increased glucose removal from blood; - reduced hepatic and renal gluconeogenesis; - slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes; - reduction of plasma glucagon levels. 1. 1st line in the management of Type 2 DM (only drug approved for the mgt of prediabetes) 2. Mgt. of polycystic ovarian syndrome (PCOS) 3. Useful as 1st line therapy in the obese, and are recommended as 1st line therapy in non-obese subjects in some country. ADVERSE EFFECTS: - Diarrhea (most common) - Nausea and vomiting - GI effects is resolved after chronic use and taken before meals - Decrease absorption of Vit. B12 (long term use) CONTRAINDICATIONS: - renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg. chronic cardiopulmonary dysfunction) - increased risk of **[lactic acidosis]** induced by biguanide ***[THIAZOLIDINEDIONES]*** (INSULIN SENSITIZERS) Mechanism of Action: - **Activate PPAR-y,** a nuclear transcription factor for fat cell differentiation and fatty acid metabolism. - Enhance insulin sensitivity in muscle, liver and fat tissues. Site of action: **Adipose tissues** - where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation. 1. Rosiglitazone (Avandia) 2. Pioglitazone (Actos) 3. Troglitazone- banned due to hepatoxicity S/E: Hepatoxicity, fluid retention and weight gain *[MISCELLANEOUS AGENTS]* 1. **[ALPHA GLUCOSIDASE INHIBITORS]** - Retards absorption CHO by preventing the breakdown of sucrose and complex CHO in the intestines. - Use to prevent postprandial hypergylcemia - **Take with first bite of meal** - A/E: Flatulence, Diarrhea, Abdominal pain 1. Acarbose (Precose, Glucobay, Gluconase) 2. Voglibose (Basen) 3. Miglitol (Glyset) 2. **[INCRETINS]** - GI hormones secreted in response to oral glucose load. - Effects: increase insulin secretion and decrease glucagon secretion - Example: **GLP-1 (Glucagon like polypeptide)** **3.** **[AMYLIN ANALOGUE]** ***Pramlintide (SQ)*** - Given as an add on to patients on insulin - For type 1 DM A/E: increase risk of hypoglycemia - Synthetic analog of amylin - Modulate postprandial glucose levels - Suppress glucagon release - Slows gastric emptying and promotes satiety **[SGLT2 INHIBITORS]** - Dapaglifozin -- 1st drug developed - Canglifozin -- 1st drug approved - Empaglifozin - Improve glycemic control - Inhibit glucose absorption in the renal proximal tubule **[GLUCAGON]** - Glucagon is synthesized in the α cell of the pancreatic islets of Langerhans Metabolic Effects: Physiologic Effects: 1. **[Cardiac Effects]** - Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism. 2. **[Effects on Smooth Muscle]** - produce profound relaxation of the intestine. Uses: 1. Emergency tx of severe hypoglycemic reactions in patients with type 1 diabetes 2. Used in overdosage of beta blockers 3. as an aid to x-ray visualization of the bowel because of its ability to relax the intestine. **DRUGS FOR BONE & JOINT DISORDERS** **[GOUTY ARTHRITIS]** GOUT - Associated with hyperuricemia (increase uric acid) - Uric acid is a waste product created during the normal breakdown of purines, naturally occurring substances found in foods such as liver, mushrooms, anchovies, mackerel and dried beans **[CAUSES OF GOUT]** **1. Abnormalities in enzyme** Increase levels of: a. PRPP (Phosphoribosyl pyrophosphate) Deficiency of: a. HGPRT (Hypoxanthine-guanine phosphoribosyltransferase) b. G6PT (Glucose-6-Phosphatase) c. Uricase- a digestive enzyme **2. Increased breakdown of nucleic acids** - Patients with leukemia undergoing chemotherapy **3. Increase dietary purines** **4. Drugs that decrease clearance of uric acid** **[SPECTRUM:]** 1. Hyperuricemia 2. Acute gouty attack 3. Tophi 4. Podagra 5. Big ear, elbow, wrist & hands 6. Nephrolithiasis **Drugs for [Acute] Gouty Attacks** 1. **Indomethacin** - An NSAID that is potent inhibitor of COX enzyme. - As effective as colchicine but less GI toxicity - S/E: GI ulcer and bleeding 2. **Colchicine** - Microtubule synthesis inhibitor - Inhibit macrophage migration & phagocytic activity - May be given oral or IV (less GI toxicity) 3. **Corticosteroids** - For resistant patients - Example: Prednisone, ACTH, Triamcinolone **Drugs for [Chronic] Gouty Attacks** 4. **Allopurinol** - Xanthine analog - Xanthine oxidase inhibitor - Indicated for patients with renal failure and leukemias - S/E: leucopenia, rashes, GI toxicity, acute gouty attack with initiation 5. **Uricosuric agents** - Probenecid, Sulfinpyrazone - Inhibit renal tubular reabsorption of uric acid - Maintain adequate urine flow, alkalinize urine with NaHCO3 - S/E: GI irritation, rashes, renal stones **[OSTEOARTHRITIS]** - **Slowly progressive disorder** characterized by deterioration and loss of articular cartilage. - **Articular cartilage** - white tissues that covers the end of bones where they come together to form joints. **RISK FACTORS:** 1. Age 2. Sex 3. Obesity 4. Joint injuries (sports, accident) 5. Genetics 6. Bone deformities (people that are born with malformed joints or defective cartilage) **Symptoms:** - Pain during activity - Tenderness (joint may feel tender when you apply pressure) - Stiffness - Loss of flexibility - Grating sensation (you may hear grating sensation) - Bone spurs (extra bits of bones) - Bouchard's nodes and Heberden's nodes **[DIAGNOSIS:]** 1. Joint xray 2. Subchondral bony sclerosis (increase bone density) 3. Osteophytes (bony projections that form along joint margins) **[Non Pharmacological Tx]** 1. Dietary counseling 2. Physical therapy 3. Assistive devices 4. Surgery (if unresponsive to medication) **[Pharmacologic Tx]** 1. **Acetaminophen** 2. **NSAIDs** 3. **Capsaicin** - inhibit substance P 4. **Glucosamine & Chondroitin** dietary supplements shown to alleviate pain, slows down loss of cartilage 5. **Corticosteroids** - only the intraarticular route is effective for osteoarthritis 6. **Hyaluronate injection** Hylan GF20, reported to decrease pain 7. **Narcotic analgesics** for unresponsive patients, and contraindicated to NSAIDs. activation of mu receptor **[RHEUMATOID ARTHRITIS]** - Chronic progressive inflammatory disorder of joints of unknown etiology. - Inflammation leads to tissue proliferation - The onset of RA is insidious (cause harm that is not easily noticed) **SYMPTOMS:** 1. malaise (feeling of not being healthy) 2. anorexia 3. accompanied by symmetrically tender and swollen joints 4. Pain in the joints is common and aggravated by movement **[Drugs:]** 1. **[SALICYLATES & NSAIDs]** - NSAIDs and COX-2 Inhibitors reduce joint pain and swelling but they do not alter the course of the disease or prevent joint destruction. 2. **[CORTICOSTEROIDS]** - It can work well either orally or parenterally. - They have excellent anti-inflammatory activity and are immunosuppressants. - Used as bridging therapy (as long as DMARD are taking effect) - **Prednisone (oral)** - **Methylprednisolone (IM)** - **Triamcinolone (intraarticular)** 3. **[DMARDs: (Disease Modifying Anti-Rheumatic Drugs)]** - The objective of the DMARD therapy is to **reduce or prevent joint damage** and preserve joint function - Inflammatory factors are reduced significantly by DMARDs but not by NSAID's - Mechanism of action is not clearly defined but they act at different stages in the pathogenesis to control symptoms and modulate immune response. 1. **LEFLUNOMIDE** - It inhibits pyrimidine synthesis and is indicated as monotherapy for RA. - Hepatotoxity is associated with this agent. - Contraindications include patients with impaired liver function and concomitant use with methotrexate. - Liver function tests **Should** be performed. - **Significant weight loss** and immunosuppression may occur with the therapy 2. **ETANERCEPT** - It binds to TNF-alpha and beta, inhibiting the inflammatory response mediated by immune cells. - It is indicated as a monotherapy or in conjunction with methotrexate. 3. **INFLIXIMAB (Remicade)** - It binds to TNF-alpha - Superior than methotrexate alone - The newest DMARD is an interleukin-1 receptor antagonist. - **Interleukin** - class of glycoprotein that is produced by leukocytes for regulating immune response 4. **METHOTREXATE** - DHF reductase inhibitor - Rapid onset (2-3 weeks) - S/E: Stomatitis, nausea and vomitting, diarrhea, leukopenia, thrombocytopenia, liver cirrhosis, teratogenic (monitor ALT & AST regularly) **[LESS FREQUENTLY USED:]** 1. **Gold preparations** The mechanism of action is unknown. Dermatologic reactions are the most common side effect and are seen in approximately 15% of patients. 1. Aurothioglucose (IM) 2. Gold Na thiomalate (IM) 3. Auranofin (oral) S/E: NV, diarrhea, stomatitis, anemia and leukopenia 2. **Azathioprine** - converted to **6-mercaptopurine** in the body and is a non-specific purine synthesis inhibitor - Bone marrow suppression is a major adverse effect. In addition, xanthine oxidase inhibitor allopurinol inhibits azathioprine metabolism 3. **Penicillamine** - The mechanism of action of penicillamine in rheumatoid arthritis is unknown but it may be related to reduction of collagen formation. (Collagen is a type of tissue compound that forms as part of scar tissue that result from inflammation. - S/E: rashes, metallic taste, hypoguesia 4. **Cyclosporine** - It binds to intracellular receptor, cyclophiline. - This complex inhibits calcineurin. **OSTEOPOROSIS** - **Decrease bone mass/ density** - **Osteomalacia** - softening of bones - **Rickets** - decrease calcification of bones (children) **[Types:]** 1. Post-menopausal (estrogen def. increases bone resorption) 2. Age related 3. Drug-induced **[S/Sx of Osteoporosis]** 1. Short stature 2. Kyphosis 3. Lordosis 4. Bone pain 5. Bone fractufre **[Non-pharmacologic Tx]** 1. Adequate calcium intake 2. Vitamin D intake 3. Smoking cessation 4. Weight bearing exercises **[CALCIUM CARBONATE]** - Salt of choice - Taken with meals (acid dependent) - S/E: constipation, flatulence **[BIPHOSPHONATES]** Examples: Alendronate, Risedronate, Ibandronate **MOA:** Bind to hydroxyapatite in bone and inhibits osteoclast adherence. - Greatest bone density increase and fracture risk reduction - Taken at morning w/ plain tap water **[SERMS: Selective estrogen receptor modulators]**