Unit 2

Circulating epinephrine binds to beta 2 receptors

Acts as a bronchodilator which is why we use beta agonists for asthma treatment

Anticholinergics: Bind to muscarinic receptors on airway smooth muscle and thereby preventing the action of acetylcholine. Acetylcholine maintains bronchial smooth muscle tone. Ipratropium (Atrovent) Tiotropium (Spiriva)

Adverse Effects: Well tolerated by most patients - are inhaled medications that are poorly absorbed into the circulation from the lung, so you see few systemic adverse effects. Clinical Use: Not usually used in asthma because the beta2-agonists are much better bronchodilators. Used in COPD because some patients with COPD don't respond as well to the beta-agonists, but do respond to anticholinergic agents. Ipratropium plus albuterol (Duoneb) has been shown to improve pulmonary function and decrease hospitalization when used in the ED for moderate to severe asthma exacerbations. Tiotropium may be beneficial in patients with severe asthma who aren't controlled on high dose inhaled corticosteroids

Sucralfate Mechanism of action: Sucralfate (Carafate) is a non-systemic agent that is a complex of sulfated sucrose and aluminum which binds to protein at the site of the gastrointestinal mucosal lesion to create an adherent and protective barrier.

Adverse Effects: Sucralfate has little systemic absorption, so there are few systemic adverse effects. Adverse effects include: constipation (5-10%), metallic taste, nausea, fullness. It is a very large tablet - the patient can break in pieces if necessary or use the suspension formulation. Clinical Use: Treatment of ulcers: given twice daily, 30 minutes before meals. It is less effective than the PPIs or H2 antagonists, so is not used frequently. Might be a good choice in someone who does not want a drug that acts systemically.

inhaled cs

Adverse effects with inhaled steroids: minimal systemic side effects. At very high doses, all will be absorbed to some degree Local effects: Oral candidiasis. To avoid, be sure to rinse mouth (swish and spit) after each use. Dysphonia, reflex cough and bronchospasm. Spacer devices decrease the incidence of the local adverse effects.

oral steroids: Under normal conditions, the Hypothalamus releases corticotropin releasing hormone (CRH) which acts on the anterior pituitary to cause adrenocorticotropin hormone (ACTH) release which acts on the adrenal cortex to cause cortisol release. The cortisol then provides a negative feedback to the hypothalmus and anterior pituitary, thus keeping the system in balance. Patients who receive cortisol drugs (corticosteroids such as prednisone) have the HPA axis suppressed. This can cause problems when the patient is stressed because the body can not provide additional cortisol when needed. To minimize HPA-axis suppression, give corticosteroids in the morning and give every other day if possible (allows the HPA axis to recover/function on the days when the steroid is not taken). Tapering only necessary for dosing longer than > 5 days ( dosing p.246)

Adverse effects with oral steroids: Short bursts of oral corticosteroids to control acute exacerbations of asthma cause few adverse effects. However, long term daily use of oral steroids is associated with many adverse effects (see p. 818 in your textbook (Clinical Presentation of Cushing's Syndrome) for a more complete description of the potential adverse effects of continuous, long term administration of systemic corticosteroids : impaired glucose metabolism mood disturbances rounding of face (moon facies) acne osteoporosis growth retardation cataracts Hypothalamic pituitary adrenal (HPA)-axis suppression

Immunomodulators: Monoclonal antibody that inhibits the binding of IgE to mast cells and basophils. This limits the release of mediators of the allergic response. Omalizumb (Xolair)

Adverse effects: Anaphylaxis can occur, so the injections must be administered in the office or clinic and the patient observed afterward Pain and bruising at injection site in 5-20% of patients Clinical Use: Omalizumab is given by subcutaneous injection every 2 to 4 weeks. It is labeled for use in patients over the age of 12 with moderate to severe asthma who have had a positive skin test to perennial airborne allergens and who are not controlled with inhaled corticosteroids. It is very expensive (up to $24,000/year).

Mast Cell Stabilizers: Stabilize and prevent mediator release from mast cells - decreasing inflammatory response. Also affects other antiinflammatory cells including alveolar macrophages, thereby preventing inflammatory cell recruitment into the airway wall. Cromolyn Sodium for nebulizer (dosing p. 247)

Adverse effects: Few. 15-20% of patients may report a bad taste. Clinical Use: Used to decrease the inflammatory response in asthma. While this class of drugs has fewer adverse effects than the corticosteroids, they are also less effective as anti-inflammatory agents. No evidence that use of cromolyn sodium decreases the amount of inhaled corticosteroid needed for control Takes 4-6 weeks for maximal response. Seldom used

Antileukotrienes: Leukotrienes are potent biochemical mediators released from mast cells, eosinophils, and basophils that contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and activate inflammatory cells in the airways. Montelukast and zafirlukast antagonize the leukotriene receptor. LRTA = leukotriene receptor antagonist Zileuton inhibits 5-lipoxygenase which is a necessary enzyme in the formation of leukotrienes. Montelukast (Singulair) primarily used before the other antileukotrienes, cheaper, once daily, less interaction than the others Zafirlukast (Accolate) Zileuton (Zyflo)

Adverse effects: Well tolerated by most patients. Occasionally headache, nausea, and fatigue are reported. Suicide association - the FDA added a precaution about a possible increase in suicide with these drugs. The association appears to be weak and is not a reason to discontinue the drugs. Zileuton has been associated with liver function abnormalities. LFTs should be monitored regularly. Drug Interactions Zileuton is a CYP 1A2 inhibitor and can decrease the metabolism (increase the drug level) of drugs that are CYP 1A2 substrates. Zafirlukast is a weak CYP 2C9 inhibitor. Clinical Use: Montelukast is an oral, once a day medication designed to control the inflammatory process in asthma. The advantage is that it is easy and convenient to use The disadvantage is that they are not as effective as the inhaled corticosteroids.

Bismuth Subsalicylate (Pepto-Bismol) Mechanism of action: Has both antisecretory and antimicrobial activity. The bismuth has antimicrobial activity against bacterial and viral gastrointestinal pathogens. Clinical Use: Bismuth Subsalicylate is one of the components of the 4-drug Helicobacter pylori regimens. The dose for this indication is: 524 mg (2 tabs) four times a day. It is also used in the management of traveler's diarrhea.

Adverse effects: Contains salicylate, so should not be used in patients with salicylate allergy. High doses can cause salicylate toxicity (tinnitus is an early sign) -- use with caution in the very young, very old, and those with renal dysfunction. May cause blackened or gray tongue or black/gray stools

Methylxanthines: Theophylline inhibits the enzyme phosphodiesterase. Phosphodiesterase metabolizes the second messengers (i.e. cAMP and cGMP) involved in relaxing airway smooth muscle. Theophylline has also been shown to increase diaphragmatic contractility, improve mucociliary clearance, and increase respiratory drive. Theophylline (Theodur) Aminophylline- the intravenous form of theophylline

Adverse effects: Theophylline has a low therapeutic index; the toxic doses are close to the therapeutic doses. At higher serum levels, the adverse effects include: Nausea and vomiting Nervousness, tremor Seizures Tachycardia Serum levels: Traditional Target serum level (this is what you're likely to see as the target on the lab slip): 10 - 20 mcg/ml. Newer recommendations are for a target of 5-15 mcg/ml Drug Interactions: Theophylline is metabolized by CYP1A2 and CYP 3A4 so many agents will alter its metabolism. The following drugs inhibit CYP 1A2 and/or CYP 3A4 and will lead to increased theophylline levels. These are just a few examples (other drugs may do this also). Cimetidine (Tagamet) Ciprofloxacin Erythromycin Verapamil

Metoclopramide (Reglan) Mechanism of action: Blocks dopamine receptors thus decreasing nausea and vomiting. Also enhances GI motility, and gastric emptying. Clinical Use: Post-surgical gastric stasis and nausea and vomiting Diabetic gastric stasis Adjunctive therapy for GERD In high doses it has been used for chemotherapy induced nausea and vomiting, but at the high doses adverse effects are more likely to be seen, so is not used as much anymore for this.

Adverse reactions: Parkinsonian symptoms of muscle rigidity, akinesia, muscle spasm secondary to dopamine receptor blockade. Less likely to be seen with metoclopramide compared to the phenothiazines but is still a possibility, especially with high doses or long term therapy. Diarrhea - secondary to it's effect of increasing gut motility Sedation - in 10% of patients Tardive dyskinesia - repetitive, persistent movement may occur with long term chronic therapy with metoclopramide. It should be used for the shortest time possible.

Drug Interactions: The number of drug interactions differ between the drugs in this class. Cimetidine interacts with many drugs, ranitidine with fewer drugs, and famotidine and nizatidine with even fewer drugs. Cimetidine inhibits the clearance of drugs that are metabolized in the liver through the cytochrome P450 system, which may cause an increase in plasma concentrations of certain drugs metabolized by CYP 2D6, 3A4 and 1A2 isoenzymes. Ranitidine binds less intensely to the cytochrome P450 system and famotidine and nizatidine don't bind to the cytochrome P450 system. Cimetidine inhibits the metabolism of drugs such as: theophylline warfarin phenytoin

Clinical Use of the Histamine-2 receptor antagonists: Gastroesophageal reflux disease: The histamine-2 antagonists will treat GERD (but are less effective than the PPIs). They provide symptomatic relief for patient's with mild to moderate symptoms. In combination with antibiotics for H.pylori eradication.

Misoprostol (Cytotec) Mechanism of action: Misoprostol is an analog of prostaglandin E1. The prostaglandins stimulate gastric mucosa to secrete bicarbonate and mucus, thereby protecting the mucosa. There is also a prostaglandin receptor on the parietal cell and activation of this receptor causes inhibition of acid secretion by the parietal cell. Adverse reactions: Diarrhea - up to 40% (usually transient), menstrual bleeding and cramping. Contraindication: PREGNANCY - should not be used in a pregnancy that is to be continued. Misoprostol (Cytotec) is seldom used for gastrointestinal indications now. It is used in obstetrics/gynecology for cervical ripening in labor induction protocols, and for prevention or treatment of post partum hemorrhage. It is also a component (along with mifepristone) in medical termination of pregnancy regimens.

Clinical Use: Prevention of NSAID induced ulcers: will prevent ulcers and reduce serious GI complications by 40% in patients receiving NSAIDs. Does not seem to be effective in relieving GI pain that can occur with NSAID use. It is seldom used for this indication because PPIs are as effective and are better tolerated. Treatment of duodenal ulcers: Misoprostol can also be used in short term treatment of duodenal ulcers, but because of its many side effects other medications are preferred. Must be given 4 times a day so it is inconvenient.

Neurokinin Receptor Antagonist Drug in the Class: Aprepitant (Emend) Mechanism of action: Selectively antagonizes human substance P/neurokinin 1 receptors, thus decreasing the incidence of nausea and vomiting

Clinical Use: Prevention of chemotherapy-induced nausea and vomiting. Aprepitant is added to a regimen of a 5HT3 antagonist and a corticosteroid to prevent nausea and vomiting with certain highly emetogenic chemotherapy regimens. Post-operative nausea and vomiting. One dose 3 hours prior to anesthesia can be used to prevent post-op nausea and vomiting.

Corticosteroids Drugs in the Class: Dexamethasone Methylprednisolone Prednisone Mechanism of Action in Nausea and Vomiting : Uncertain, but perhaps secondary to inhibition of prostaglandins

Clinical Use: Adjunct to serotonin-3 antagonists in the treatment of chemotherapy-induced nausea and vomiting. The serotonin antagonist will prevent nausea and vomiting on the first day of chemotherapy and giving a corticosteroid will improve the control of the nausea over the subsequent days.

Serotonin-3 (5HT3 ) Receptor Antagonists Drugs in the Class: Dolasetron (Anzemet) Granisetron (Kytril) Ondansetron (Zofran) Palonosetron (Aloxi) Mechanism of action: Blocks serotonin-3 receptors in the chemoreceptor trigger zone and in the GI tract. Adverse reactions: Well tolerated by most patients Can cause headache, sensation of warmth or flushing

Clinical Use: Prevention of chemotherapy-induced nausea and vomiting. These agents are the most effective agents in preventing nausea and vomiting from even highly emetogenic cancer chemotherapy and are the drugs of choice for this indication. Ondansetron is now available as an inexpensive generic medication so the cost barrier to these medications has been alleviated. Post-operative nausea and vomiting. These drugs will work for post-op nausea and vomiting; doses used are smaller than for chemotherapy-induced nausea and vomiting.

Drug interactions Omeprazole inhibits CYP2C19 and thus may decrease metabolism of substrates of that enzyme: e.g. warfarin, theophylline, diazepam, phenytoin. Clopidogrel is metabolized to an active metabolite by CYP2C19; when omeprazole is given at the same as clopidogrel, the clopidogrel may be less effective. Since PPIs greatly reduce the acid production in the stomach, all of the PPIs can affect the absorption of drugs that require an acidic pH.

Clinical Use: Gastroesophageal reflux disease. Low dose over-the-counter PPIs can be used for mild-moderate heartburn; higher dose once/day or even twice/day therapy for esophagitis, or Barrett's esophagus. Active duodenal ulcers (4 weeks therapy will cure >90%) Active gastric ulcers (caution: symptoms may subside with this agent even if malignancy is present, so be sure to rule out malignancy) Pathological hypersecretory conditions In combination with antibiotics for H.pylori eradication Stress ulcer prevention Prevention of ulcers from NSAID use

Decongestants - The decongestants have alpha-1 adrenergic agonist activity which causes vasoconstriction in the nasal mucosa Relieve nasal congestion but do not help sneezing, itching, rhinorrhea Oral decongestants Phenylephrine Pseudoephedrine Nasal decongestants phenylephrine (Neo-synephrine) oxymetazoline (Afrin)

Clinical use: Pseudoephedrine is more effective as a decongestant compared to phenylephrine. It is used to cook methamphetamine and states are limiting its sales. Some states have made it a prescription only product; other states (e.g. Colorado, Wyoming) have made it a behind a counter drug that limits the amount sold and requires signatures and identification for purchase. Adverse effects are related to sympathetic nervous system stimulation: tachycardia, increased blood pressure, irritability Intranasal decongestants rapidly relieve nasal congestion but if used continuously can lead to a rebound congestion (rhinitis medicamentosa) when stopped. It is recommended to only use for 3 days or less.

longterm control medications are taken daily on a long-term basis to achieve and maintain control of persistent asthma. Most of these medications affect the underlying inflammatory process.

Corticosteroids (inhaled preferably, although daily oral steroids are used in severe, persistent asthma if the patient can't achieve control with inhaled corticosteroids). Cromolyn sodium Long-acting beta agonists (salmeterol or formoterol) - called long term control medications because they don't reverse acute bronchoconstriction but they also don't affect the underlying inflammation and thus should only be used in combination with another controller med (usually an inhaled corticosteroid) Theophylline Leukotriene modifiers Long acting anticholinergic - tiotropium Immunomodulator (omalizumab) - not a daily medicine but is a long term control med

Foods and Medications that may worsen GERD symptoms p. 286 has specifics

Decreased Lower Esophageal Sphincter Pressure Foods/Beverages Fatty meal Carminatives (peppermint, spearmint) Chocolate Caffeine Coffee, cola, tea Garlic Onions Chili peppers Medications Alcohol (wine) Nitrates Progesterone Tetracycline Theophylline Anticholinergics Barbiturates Benzodiazepines Dihydropyridine calcium channel blockers Dopamine Estrogen Nicotine Isoproterenol Opioids Phentolamine

Anticholinergic agents (Ipratropium) block the muscarinic receptors

Decreasing the contraction of Airway smooth muscle

The beta2-agonists bind with ß2 receptors and activate adenyl cyclase thus relaxing airway smooth muscle adverse effects: tachycardia tremor nervousness Meds dosing p.246-249

Drug Beta-2 Selective? Duration of Action Epinephrine No Short Metaproterenol (Alupent) No 2-3 hours Albuterol (Ventolin) Yes 3-4 hours Levalbuterol (Xopenex) Yes 3-4 hours Salmeterol (Serevent) Yes up to 15 hours Formoterol (Foradil) Yes up to 15 hours

Antihistamines-Anticholinergics: Mechanism of Action: Block the Histamine-1 receptors in the chemoreceptor trigger zone and blocks the cholinergic receptors in the CTZ. Clinical Use: Motion sickness - take 30 to 60 minutes before the car ride, boat ride, plane ride. Adverse Reactions: Sedation, drowsiness, confusion Dry mouth, blurred vision, urinary retention

Drugs in the Class: Dimenhydrinate (Dramamine) Diphenhydramine (Benadryl) Hydroxyzine (Vistaril, Atarax) Meclizine (Antivert) Scopalamine (Transderm-Scop)- blocks cholinergic receptors (also known as muscarinic receptor antagonist/antimuscarinic. It does not block histamine receptors.) Trimethobenzamide (Tigan)

Drugs Used for the Symptomatic Relief of Nausea and Vomiting Phenothiazines: Mechanism of Action: Blocks dopamine receptors in the chemoreceptor trigger zone thus decreasing nausea and vomiting. Clinical Use: Can be used as monotherapy for mild to moderate nausea and vomiting Are available in oral, injectable, and rectal forms Chlorpromazine, fluphenazine, perphenazine are not usually used for nausea and vomiting. They are traditional antipsychotic agents used in the treatment of schizophrenia.

Drugs in the Class: Prochlorperazine (Compazine) Promethazine (Phenergan) Chlorpromazine (Thorazine) Fluphenazine (Prolixin) Perphenazine (Trilafon) Adverse reactions: Parkinsonian symptoms of muscle rigidity, akinesia, muscle spasm secondary to the dopamine receptor blockade Sedation Anticholinergic side effects -- dry mouth, urinary retention (anticholinergic effects may also contribute to anti-emetic effect)

Histamine2-antagonists inhibit the action of histamine on H2 receptors on the parietal cells in the stomach, thus reducing gastric acid secretion. They reduce acid secretion by about 60%.

Drugs in the class: Cimetidine (Tagamet) Ranitidine (Zantac) Famotidine (Pepcid) Nizatidine (Axid) Adverse Effects: This class of drugs is well tolerated by most patients. The potential adverse effects include: GI discomfort - diarrhea, constipation CNS alterations - confusion, headache, drowsiness (rare at usual doses)

Over-the-counter proton pump inhibitors (PPIs): The over the counter proton pump inhibitors are labeled only for short term use (14 days) because patients should be evaluated if they have continuing symptoms(patient directed therapy). The products available include:

Esomeprazole (Nexium 24-hour) Omeprazole (Prilosec OTC) Omeprazole/sodium bicarbonate (Zegrid OTC) Lansoprazole (Prevacid 24 hr)

Spacer devices

Examples of spacer devices: Aerosol Cloud Enhancer, AeroChamber, Inspirese, Brethancer, Optihaler. They are especially useful in young children who have trouble coordinating MDI, and for the administration of corticosteroid by inhalation. Some of the spacer devices can be used with a face mask making them suitable for children <4 years old. St Louis Children's Hospital has a AeroChamber demonstration video posted on the web.

Antihistamines Antagonize the action of histamine at the H1-receptor site. First generation - cross the blood brain barrier and thus cause sedation as an adverse effect. Second generation - won't cross the blood-brain barrier and thus cause little sedation.

First generation Chlorpheniramine Chlortrimeton Diphenhydramine Benadryl Brompheniramine Dimetane Clemastine Tavist Second Generation Azelastine Nasal spray Astelin Cetirizine Zyrtec Fexofenadine Allegra Desloratidine Clarinex Loratidine Claritin Levocetirazine Xyzal Oloptadine nasal Patanol

short acting agents

For treatment of acute bronchospasm. Increased use of short acting inhalers may indicate that the asthma is getting worse and the clinician should consider increasing the use of anti-inflammatory therapy.

Signs and Symptoms of GERD

Frequent heartburn acid regurgitation epigastric pain belching hypersalivation Atypical Symptoms - also called extraesophageal symptoms Hoarseness Nausea Asthma, cough, wheezing (when evaluating a patient for new onset asthma or cough, GERD should be in your differential) Dental erosions Alarm Symptoms Substernal burning sensation after meals, when lying down, or bending over (need to consider cardiac origins for pain also) Continual pain Painful or difficulty in swallowing (need to rule out esophageal strictures, malignancy) Weight loss, anemia, bleeding (need to rule out malignancy)

Chemical transmitters mediating emetic stimuli Drugs used to treat nausea and vomiting affect the chemical transmitters and their receptors.

GI irritation, chemotherapy, radiation, infection, or drugs in the gut can cause inflammation leading to the release of prostaglandins, kinins, serotonin, and activation of the vagus nerve which releases acetylcholine. The chemoreceptor trigger zone (CTZ) is an area in the brain that mediates nausea and vomiting. Stimulation of the CTZ by acetylcholine, dopamine, histamine, or serotonin can trigger nausea and vomiting. The vomiting center (VC) is a second area that mediates nausea and vomiting. It receives inputs from the chemoreceptor trigger zone, from the GI tract via the vagus nerve, from the cardiovascular system, and from a variety of brain nuclei.

The promotility agent metoclopramide has been used as an adjunct to acid suppressing therapy for additional symptom relief. Clinical trials have shown little symptomatic benefit with this approach and metoclopramide can have significant adverse effects, so its use in GERD is discouraged.

Geriatric Note:Metoclopramide is on the Beers Criteria list of medications to be avoided or used with caution in the elderly because it can cause extrapyramidal adverse effects, including tardive dyskinesia. The risk is greater with frail older adults.

Herbal Medications Note:

Ginger is an herbal medication used as a digestive aid and antinausea remedy. It comes in many forms including fresh and dried root, tablets, capsules, and tinctures.Several studies have shown that it is effective in reducing the nausea and vomiting in pregnancy. Usual doses are 1 to 2 grams daily. Adverse effects include GI upset, bloating, heartburn. It may also inhibit platelet aggregation so should be avoided in patients taking anticoagulants and anti-platelet drugs.

Helicobacter pylori is a bacterium associated with ulcer disease. 90-100% of patients with duodenal ulcer and 70-90% patients with gastric ulcer harbor H.pylori; however, there are many more healthy people without any evidence of ulcer disease that also harbor this bacteria (up to 65% of individuals infected with the bacteria have no symptoms).

Helicobacter pylori (H. pylori) is a spiral shaped gram negative bacterium that burrows through the gastric mucous layer and causes tissue injury by producing various cytotoxins and proteases. Infection with H.pylori results in a life-long infection and chronic antral gastritis in almost all cases; the gastritis is usually asymptomatic. However, 10-20% of patients with H.pylori infection will develop peptic ulcer disease. Over 90% of duodenal ulcers and 80% of gastric ulcers are associated with H.pylori. It is now recommended that all patients with ulcers who are infected with H. pylori should be treated with antimicrobials and a proton pump inhibitor (PPI), regardless of whether they are suffering from the initial presentation of the disease or from a recurrence.

Pregnancy Note:

How to manage nausea and vomiting in pregnancy is a common clinical question. Non drug measures are recommended first - small meals, eat crackers, try ginger capsules. When that isn't enough, doxylamine (an antihistamine) 10 mg/pyridoxine (Vit B6) 10 mg (Diclegis) is a prescription only medication that is rated Category A for use in pregnancy. In the ensuing years it has become clear that the combination of doxylamine/pyridoxine does not cause birth defects and the FDA approved the combination in 2014 for use in the treatment of pregnancy induced nausea/vomiting. It is expensive ($200/30 tabs) but is recommended as first line therapy if non-drug measures don't help. Ondansetron has been used extensively in pregnancy and overall it appears to be unlikely to increase the risk for miscarriage, stillbirth, or major birth defects. It is labeled as an FDA pregnancy risk factor of B. There have been two case control studies that indicated there may be a slightly higher risk of cleft palate or heart malformation in infants exposed to ondansetron in the first trimester. Other studies indicate no increase in risk. Current guidelines suggest that ondansetron be avoided in first trimester unless there is significant nausea and vomiting not controlled by non-drug measures nor doxylamine/pyridoxine.

Treatment Approach to GERD: medication dosing p.288

If the patient's history is typical for uncomplicated GERD, an initial trial of empiric therapy is appropriate. If the empirical therapy is unsuccessful or the history suggests complicated GERD (i.e. alarm symptoms are present), further diagnostic testing is needed. Lifestyle modication should be initiated and continued through the course of GERD therapy. Antacids and over-the-counter acid suppressants are appropriate initial therapy for GERD. Antacids: Nearly 20% of the patients will have complete symptom relief with antacids alone. Patients should be instructed to take the antacid immediately after meals if symptoms occur.

Drug strategies for treating GERD are to either:

Increase the defensive factors - Metoclopropamide increases the lower esophageal sphincter pressure and increases gastric emptying. Bethanecol acts as a prokinetic agent to cause increased esophageal clearance. Neither drug is recommended now for the treatment of GERD because the adverse effects outweigh their effectiveness. Decrease the aggressive factors - antacids neutralize the acid, PPIs and H2-antagonists decrease the acid content of the gastric contents, alginic acid (component of the antacid Gaviscon) forms a foamy barrier for the acid contents.

Intranasal Corticosteroids: (dosing p.954) Adverse effects mild: nasal irritation, nose bleeds in 10% Beclomethasone Beconase Budesonide Ciclesonide Rhinocort Omnaris Flunisolide Nasarel Fluticasone Flonase Mometasone Nasonex Triamcinolone Nasacort

Intranasal corticosteroids are the most effective therapy for allergic rhinitis. If antihistamines don't relieve the symptoms, a nasal corticosteroid should be the next drug. All the nasal corticosteroid are approximately equal in efficacy. Most are given once a day, except flunisolide which should be given tow to three times a day. They take up to 12 hours to work and have maximum effects in a week, so work best when taken regularly throughout allergy season. If nasal congestion is severe, the drug may not reach the site of action. A decongestant nasal spray prior to the nasal corticosteroid may help.

Management of GERD

Lifestyle Modification is the cornerstone of therapy for the management of GERD and should be recommended for all patients, even those who need medications. Elevate head of the bed -- place 6-8 inch blocks under the head of the bed Diet: lose weight, decrease fat intake and avoid exacerbating foods Avoid lying down while eating and after meals Eat smaller meals and do not eat within 3 hours of bedtime Stop smoking and drinking alcohol

Geriatric Note:

Long term use (>8 weeks) of PPIs is on the Beers Criteria list of medications to be avoided or used with caution in the elderly because of the risk of C. difficile infections and bone loss and fractures. Only use for the long term in patients in whom it is absolutely necessary (e.g. chronic NSAID use, erosive esophagitis, failure with discontinuation trial).

Intranasal Cromolyn - is available over-the-counter but must be given three to four times a day and is most effective when started prior to allergen exposure.

Mast cell stabilizer that binds to mast cells and prevents the release of inflammatory mediatiors OTC Must be given 3 to 4 times daily and is most effective when started prior to allergen exposure. Not as effective as intranasal corticosteroids

NSAID gastropathy Prevention and Management of NSAID induced ulcers

Minimize NSAID use. Discontinue use if possible. If treating a patient with osteoarthritis, try acetaminophen as an analgesic. Use lowest dose possible of NSAID or shorter half-life NSAID (such as ibuprofen). Change risk factors if possible . Stop Smoking. If ulcer is present and NSAID discontinued, treat with a PPI (preferred) for 4 weeks. An H2-antagonist can be used but H2RAs are less effective than PPIs, especially with gastric ulcers or large ulcers. Third option is sucralfate four times daily, but it is also less effective than a PPI. If NSAID must be continued, use a proton pump inhibitor to treat a NSAID ulcer. For patients at high risk of developing ulcers from NSAIDs and who must take NSAIDs, consider anti-ulcer prophylaxis with a PPI. Misoprostol is also effective in preventing NSAID ulcers but it has significant adverse effects and is seldom used for this indication.

Monitoring history of asthma exacerbations

Monitor pharmacotherapy Adherence Inhaler technique Level of usage of medications Side effects Monitor patient-provider communication and patient satisfaction Environmental controls In addition to the medications used for asthma management, you should discuss environmental controls with your patients. Eliminating allergens can markedly improve the control of the asthma and lessen the need for medications. Patients with persistent asthma on daily medications: Identify allergen exposures (animals, house-dust mites, cockroaches, indoor molds, seasonal allergens) Use skin testing (or in vitro testing) to assess sensitivity to indoor allergens when patient has exposure to such allergens. Consider subcutaneous immunotherapy for patients with mild or moderate persistent asthma when there is a clear relationship between symptoms and exposure to an allergen. Patients with asthma at any level of severity should avoid: Exposure to allergens to which they are sensitive Tobacco smoke Exertion when air pollution levels are high Beta-blockers Sulfite containing foods Treat for rhinitis, sinusitis, gastroesophageal reflux, or obstructive sleep apnea if present Vaccines Annual flu vaccine Pneumococcal vaccine (age >18 yrs)

monitoring for asthma control should include:

Monitor signs and symptoms of asthma Daytime symptoms Nocturnal awakening from asthma Asthma symptoms not improved with beta-agonist inhalations Monitor pulmonary function: Spirometry: at time of diagnosis, after pharmacotherapy has been optimized, and every 1-2 years after that Peak flow monitoring: PEFR provides a simple, quantitative , reproducible measure of airway obstruction Home PEFR devices are available for <$20. Daily monitoring and recording of PEFR helps the clinician and patient in assessing therapy, detecting early stages of an exacerbation, and investigating specific allergens that may exacerbate symptoms. Personal best PEFR should be the standard with which to compare subsequent PEFRs. To establish personal best PEFR, record PEFRs twice a day while on optimized drug therapy, and use the highest value recorded. PEFR monitoring is especially useful for patients who have difficulty perceiving symptoms, a history of severe exacerbations, or who have moderate-severe persistent asthma. Monitor quality of life and functional status Missed school or work Reduction in usual activities Disturbances in sleep Change in caregiver activities due to child's asthma

Leukotriene Modifiers

Montelukast (Singular) will relieve nasal symptoms in allergic rhinitis and can be used in the treatment of allergic rhinitis. It is usually reserved as a second line agent because nasal corticosteroids are more effective in relieving symptoms It can be used in conjunction with other therapies.

Rhinitis is a syndrome with symptoms of rhinorrhea, itching, sneezing, congestion, and postnasal discharge. It can be either acute or chronic, allergic or non-allergic. We're going to focus in this section on allergic rhinitis. (routine therapy p. 959)

Nasal mucous membrane inflammation caused by a hypersensitivity response to foreign allergens mediated by IgE antibodies. Sensitization occurs after allergen exposure in susceptible patient and IgE antibodies are produced. Mast cells are sensitized. Early response occurs when the allergen, IgE and sensitized mast cells interact leading to the release of histamine, and other factors leading to itching, sneezing, and rhinorrhea. The late response occurs in up to one third of patients 8 hours after initial exposure to the allergen. Additional mediators of inflammation are recruited leading to nasal congestion. Grass, tree and weed pollens are the most common cause of intermittent allergic rhinitis. House dust mites, indoor molds, animal danders, and cockroach antigen are the most common causes of persistent allergic rhinitis.

Route of Administration

Nebulization: An air jet nebulizer causes particles of the drug to be suspended in a mist. It doesn't require the coordination of a metered dose inhaler (MDI); however, it requires a bulky, expensive device. Several studies have demonstrated equal efficacy between nebulized beta-agonists and beta-agonists delivered with a MDI plus spacer device in the acute treatment of asthma. Nebulization might be your only option for a very young child who can't coordinate MDI use. Parenteral: SQ epinephrine (Susphrine) used to be given as the treatment of choice for acute asthma attacks. We now know that inhaled beta-agonists are as effective as parenteral epinephrine and have fewer side effects. Also, epinephrine is very short acting and not selective, so you're more likely to see cardiac adverse effects. Oral: Inhaled therapy is preferred because there are fewer adverse effects. Oral terbutaline and metaprotenol are available but are not recommended for use in asthma. Metered Dose Inhalers: Proper technique is important and patients must receive instruction. MDIs are convenient to use and carry. Dry Powder Inhalers: A convenient drug delivery device; a capsule is inserted into the handheld device and when the patient inhales deeply and forcefully, a very fine powder is inhaled into the lungs, thus delivering the drug to the site of activity. Advantages: convenient, and doesn't take the same amount of coordination that an MDI does. Disadvantage: patient must inhale deeply and forcefully and some patients with asthma or COPD can't do this.

OTC histamine2-receptor antagonists (H2RAs): The H2-blockers are available without prescription and labeled for use in heartburn, acid indigestion, and sour stomach. The dose is half the dosage strength of the prescription products. They do not act as rapidly as the antacids but provide longer relief of symptoms. They are particularly useful when taken prior to an activity that may result in reflux symptoms (e.g. heavy meal or exercise). The agents available are:

Nizatidine (Axid AR) Famotidine (Pepcid AC) Cimetidine (Tagamet HB) Ranitidine (Zantac 75)

Benchmarks of good asthma control

No coughing or wheezing No shortness of breath or rapid breathing No waking up at night Normal physical activities No school or work absences (either by patient or caregivers) due to asthma

Risk factors for GERD

Obesity Pregnancy Dietary factors: caffeine, fatty foods, chocolate, spicy foods Smoking Ethanol use Drugs that decrease lower esophageal sphincter pressure: theophylline, nitrates, calcium channel blockers, beta -agonists, benzodiazepines, narcotics, progesterone, estrogen

The proton pump inhibitors are inactive pro-drugs and are converted at acidic pH to sulfenamide, which combines with a sulfhydryl group on the proton pump, thus irreversibly inhibiting the proton pump. They are given as enteric coated and slow release formulations to prevent the activation of the drug in the stomach lumen; instead the drug diffuses into the parietal cell where it is converted into the active form and thus inhibits the action of the proton pump, thereby stopping acid production. They inhibit over 90% of the 24-hr gastric acid secretion.

Omeprazole (Prilosec) Lansoprazole (Prevacid) Dexlansoprazole (Dexilant) Rabeprazole (Aciphex) Pantoprozole(Protonix) Esomeprazole (Nexium)

Clinical manifestations Up to 50% of chronic NSAID users will exhibit minor mucosal erosions (not ulcers). These superficial erosions are usually transient and resolve spontaneously through gastric adaptation even with continued NSAID use. Many of these patients will experience minor subjective symptoms such as dyspepsia and abdominal pain; these symptoms are not accurate predictors of more serious lesions. NSAID induced ulcers can present with typical ulcer symptoms, but up to 20% are asymptomatic. Bleeding from the ulcer may be the first manifestation

Patients at higher risk for NSAID induced ulcers Age over 60 History of peptic ulcer disease Smokers NSAID used (dose and compliance) Long acting therapy can put patient at increased risk Concurrent therapy with corticosteroids Use of more than one NSAID concomitantly Ethanol abuse

If there is treatment failure for h. pylori after first-line treatment: Use different antibiotics (continue the PPI) Example: PPI twice daily + bismuthsubsalicylate + metronidazole + tetracycline four times daily x 14 days. Duration of Therapy Duration of therapy needed is controversial. Standard recommendation is for a 14 day course as listed above but some of the regimens were studied with a 10 day course of therapy.

Pharmacoeconomics Note: Pylera is a commercially available drug that contains bismuth subcitrate, metronidazole, and tetracycline in one capsule. The patient is instructed to take 3 capsules four times daily for 10 days, along with omeprazole 20 mg twice daily. Pylera is expensive (about $700 for a 10 day course). It costs less to use generic bismuth subsalicylate, metronidazole, and tetracycline although it is more complicated for the patient. In a similar fashion, PrevPac is a blister pack with lansoprazole 30 mg/amoxicillin 1 gram/clarithromycin 500 mg as individual components conveniently packaged so that the patient takes one blister pack of meds twice a day for 14 days. The convenience comes at a price - brand name PrevPac costs about $800 and the generic form costs $400-500. The individual ingredients as separate prescriptions cost about $125 for a 14 day supply.

Scheduled pharmacologic therapy with an acid suppressing drug is required in patients who have moderate to severe symptoms with or without documented erosive esophagitis

Proton pump inhibitors: The PPIs provide rapid, symptomatic relief and healing of esophagitis in the highest percentage of patients. Symptomatic relief will occur in up to 83% of the PPI treated patients and esophagitis will be healed in 78% of the PPI treated patients. Initially start with one dose per day; if symptoms are still present after 4 to 8 weeks, either increase to twice daily or change to a different PPI; if symptoms are still present after two weeks of the second PPI, increase the dose of the second PPI to twice daily. Histamine2-antagonists: Histamine2-antagonists in prescription doses (double the OTC dose) given two or more times a day can also be used for patients with less severe GERD. Symptomatic relief will occur in 60% of H2-antagonist treated patients and esophagitis will be healed in 50%.

Corticosteroids have two roles in asthma: Interfere with inflammatory mediators (leukotrienes, prostaglandins) Prevent migration and activation of inflammatory cells Increase responsiveness of beta-receptors of the airway smooth muscle

Quick Relief: Oral or IV steroids (systemic corticosteroids) can be used for short periods of time (<2 weeks) to treat acute exacerbations. This is considered quick relief because you are treating existing bronchospasm. Long Term Control: Inhaled corticosteroids are used as long term control medications. Inhaled steroids are chemically modified to maximize topical effectiveness while decreasing systemic absorption

Pediatric Note:

Regurgitation is common in children and should be managed with non-pharmacologic measures if possible. Smaller, more frequent feedings and positioning the infant in an upright position after eating are tried first. If this doesn't help and the infant is vomiting, showing poor weight gain, and/or refusing to eat, an H2RA or a PPI can be used. Ranitidine is available as an oral syrup; esomeprazole, omeprazole, lansoprazole, and pantoprazole are available as oral suspensions.

Inhaled steroids: All the corticosteroid inhalers are expensive ($150/inhaler or more) so you will want to use the inhaler that is preferred on their insurance plan. p. 248

Relative Daily Dosing for > 12 years (<12 years doses are lower) Low Dose High Dose Beclomethasone QVAR 1-3 puffs BID >4 puffs BID Budesonide Pulmicort Turbuhaler (90 mcg or 180 mcg) 1-2 90-mcg puffs BID >3 180 mcg puffs BID Pulmicort Respules (soln for nebulizer) Ciclesonide Alvesco 80 or 160 mcg 1-2 80 mcg puffs once or twice/day >2 160-mcg puffs BID Flunisolide AeroBid 1-2 puffs BID >4 puffs BID Fluticasone Flovent HFA - 44, 110 or 220 mcg 1-3 puffs BID of lower dose inhaler > 2 puffs of the high dose inhaler Flovent Diskus 50, 100 or 250 mcg 1 blister BID of low dose 1- 2 blister BID of high dose Mometasone Asmanex 220 mcg 1 puff daily 3 puffs daily

Long acting agent

Salmeterol (Serevent) or Formoterol (Foradil) can be useful when added to inhaled corticosteroid therapy, especially to control nighttime symptoms; monotherapy with a long-acting beta agonist is not recommended; the patient must also be taking a controller medication such as an inhaled corticosteroid. They are not to be used for treatment of acute symptoms. Your patient must understand this and must be aware that a short-acting inhaler must be used to treat acute symptoms. Both long-acting beta agonists are available in combination inhalers with a corticosteroid (salmeterol/fluticasone = Advair; formoterol/budesonide = Symbicort; formoterol/mometasone = Dulera);

Clinical Use of Antihistamines (dosing p.955)

Second generation agents are recommended over first generation. They are as effective and cause less drowsiness. Loratidine is available as inexpensive OTC generic. Cetirizine and fexofenadine are also available OTC. The oral antihistamines will relieve sneezing, itching and rhinorrhea but are less effective for nasal congestion Intranasal antihistamine better if nasal congestion is the primary complaint. The intranasal antihistamines are prescription only products

Assessment and monitoring of asthma therapy

Severity is assessment by looking at both impairment and risk. Impairment is looking at how the current symptoms of asthma are affecting the patient. Risk looks at how often the patient has exacerbations and how serious are the exacerbations. • The initial assessment of severity helps determine the initial course of therapy. Control is assessed after treatment has begun. The control assessment also considers impairment and risk. • The degree of control helps decide whether therapy should be stepped up, left the same, or stepped down.

Step-Wise Approach to Asthma Drugs This step-wise approach comes from the 2007 National Asthma Education Program Expert Panel Report. First: Classify the initial severity of the asthma. Second: Decide on initial therapy. In addition to drug therapy, add patient education, environmental control, and management of co-morbidities if present. Third: Assess control of asthma and either step up the therapy or step down.

Severity of Asthma (>12 yrs of age) Symptoms [Recommended Step for Initiating Treatment] Severe Persistent Daytime symptoms and frequent nighttime symptoms (up to 7 x/week). Short acting beta agonists used several times per day. Daily activities are extremely limited by symptoms. [Step 4 or 5 (may also need to add a short course of oral corticosteroids)] Moderate Persistent Daily daytime symptoms and nighttime symptoms more than once per week. Daily use of short acting beta agonists. Some limitation of daily activities. [Step 3 (may also consider adding a short course of oral corticosteroids)] Mild Persistent Daytime symptoms >2x/week but < 1x/day, nighttime symptoms more than twice a month. Use of short acting beta agonists > 2 days/week, but not daily. Minor limitation of daily activities [Step 2] Intermittent Daytime symptoms less than twice a week and nighttime symptoms less than twice a month. Use of short acting beta agonists <2 days/week. No limitations in daily activities. [Step 1]

Quick-relief medications are taken to provide prompt reversal of acute airflow obstruction and relief of accompanying bronchoconstriction.

Short-acting beta-agonists Anticholinergics (inhaled ipratropium) Systemic corticosteroids (used for short term -- several days -- to bring an exacerbation of asthma under control)

Mechanism of action: Antacids neutralize the gastric acid. Clinical Use: Treatment: If used in appropriate doses, antacids are as effective as histamine antagonists in the treatment of duodenal or gastric ulcers, but appropriate doses are expensive and inconvenient. You must use 150 mEq/dose given 7 times per day (1 and 3 hours after meals and at bedtime). This will cost the patient more than histamine2 antagonist therapy and compliance is difficult to achieve. Symptom relief: The usual use for antacids is for symptomatic relief of ulcer pain and dyspepsia while the other medications are curing the ulcer.

Sodium bicarbonate: baking soda acts quickly but has a high sodium content and can cause systemic alkalosis when used for a long time. It should not be recommended routinely for use as an antacid Aluminum hydroxide and phosphate: aluminum salts are usually combined with magnesium salts, because aluminum causes significant constipation. In patients with renal impairment, the aluminum can accumulate. Despite this, it is sometimes used in chronic renal failure to bind phosphate. Magnesium hydroxide: magnesium produces diarrhea. It can also accumulate in patients with renal failure and should be avoided. Calcium carbonate: high doses can cause milk-alkali syndrome, leading to hypercalcemia. Can also cause constipation. Good choice for women since it provides calcium supplementation as well.

Direct Irritants to the Esophageal Mucosa

Spicy foods Aspirin Orange juice Bisphosphonates Tomato juice Nonsteroidal antiinflammatory drugs (NSAIDs) Coffee Iron Tobacco Quinidine Potassium chloride

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Ulcer Disease. The NSAIDs inhibit the cyclooxygenase enzymes and thus reduce prostaglandin formation. Cyclooxygenase enzymes (COX-1 and COX-2)

The traditional NSAIDs (ibuprofen, naproxen, ketoprofen, etc.) are non-specific COX inhibitors (block both COX-1 and COX-2), so in addition to the beneficial effect on inflammation, you see adverse effects related to prostaglandin inhibition from COX-1 inhibition. Two newer NSAIDs (etodolac and nabumetone) have improved COX-2 selectivity, and appear to cause less mucosal damage. Selective COX-2 inhibitors are even more selective for COX-2 than are etodolac and nabumetone. Celocoxib (Celebrex) only inhibits COX-2 and has a theoretically lower incidence of GI adverse effects.

Pathophysiology of ulcer disease

The two primary causes of peptic ulcers are infection with Helicobacter pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Therapy for peptic ulcers is directed at eradicating H.pylori (if present) and either reducing gastric acid secretion or enhancing gastric mucosal defense.

Allergic Conjunctivitis - Conjunctivitis with watery discharge, itching, eyelid edema (dosing p.958)

Topical Ophthalmic Medications Commonly Used for Allergic Conjunctivitis Antihistamines Alcaftadine (Lastacaft) Emedastine (Emadine) Bepotastine (Bepreve) Epinastine (Elesat) Antihistamine/Decongestant Combinations Antazoline + Naphazoline (Vasocon-A) - OTC Pheniramine + Naphazoline (Naphcon-A) - OTC Antihistamine/Mast Cell Stabilizers Azelastine (Optivar) Bepotastine (Bepreve) Ketotifen (Zaditor, Claritin Eye, Zyrtec Itchy Eye) - OTC Olopatadine (Patanol) Mast Cell Stabilizers Cromolyn Sodium (Crolom) Lodoxamide (Alomide) Nedocromil (Alocril) Pemirolast (Alamast) Nonsteroidal Anti-Inflammatory Drugs (NSAID) Ketorolac (Acular) Corticosteroids - avoid long term use Loteprednol (Alrex)

Nasacort and Flonase

Triamcinolone (Nasacort Allergy 24 hour) and fluticasone (Flonase Allergy Relief) are now available over the counter and are very cost effective choices of therapy (<$20/nasal inhaler vs $100-150 for prescription flunisolide or ciclesonide)

Nausea and the Emetic Reflex: When emesis starts, the glottis reflexively closes, thereby preventing the passage of vomit into the lungs The abdominal muscles contract in rhythmic, retching movements which compresses the stomach, increases intragastric pressure and sends the stomach contents up and out of the esophagus

What causes Nausea and Vomiting? Gastrointestinal irritation from stimulation of mechanoreceptors in the gut from distension or obstruction, or from stimulation of chemoreceptors by bacterial endotoxins, or irritation from toxic materials such as alcohol. Motion sickness occurs when there is a sensory conflict between visual, vestibular, and place sensations. Pregnancy sickness occurs in up to 80% of pregnant women in the first trimester. The causes of nausea and vomiting in pregnancy is unknown but may involve the following factors: delayed gastric emptying, changes in intra-abdominal pressure, metabolic changes, changes in hormone function, psychogenic influences. Intracranial pathology can cause a sudden bout of vomiting associated with a severe headache secondary to either inflammation or increased intracranial pressure. Migraine headache can also cause vomiting secondary to alterations in serotonin levels in the brain. Metabolic disorders can cause nausea and vomiting (e.g. hypoglycemia or uremia) Psychogenic causes of vomiting can include nervous dyspepsia, bulimia, anxiety, anticipatory nausea and vomiting (can occur in patients who had nausea and vomiting with a previous episode of chemotherapy) Pain can induce nausea and vomiting Drug and Radiation-Induced Emesis from cancer chemotherapy and radiation opioid analgesics (e.g. morphine, meperidine) Postoperative Nausea and Vomiting occurs because of several reasons including the use of anesthesia, gastrointestinal irritation with GI surgery, pain, hypoxia, pre and post-op drugs such as meperidine or morphine.

anticholinergic nasal spray- Ipratropium (Atrovent)

can be used to decrease watery nasal secretions