Unit 4

Sinusitis Rhinosinusitis is a term that covers a group of inflammatory processes, usually caused by bacteria or viruses, that occur within the sinus cavity. The sinuses are normally sterile. The sterility is maintained by the mucociliary clearance system and immunologic defense mechanisms. When the sinus ostia (the openings between the sinuses and the nasal cavities) are obstructed, the sinuses can become infected. Viral upper respiratory infections, allergic and nonallergic rhinitis can cause edema that obstructs the ostia. If ostial obstruction is severe, a condition of negative pressure may occur and infectious nasal secretions may be drawn into the sinuses during nose blowing, sneezing, or coughing. The environment within the enclosed sinus cavities then becomes hypoxic and acidic, thus providing a good medium for the growth of bacteria. The maxillary and ethmoidal sinuses are mostly developed in childhood; the sphenoidal and frontal sinuses are very small at birth and enlarge with age, becoming well developed between ages 7-12.

Acute Bacterial Rhinosinusitis Acute bacterial rhinosinusitis typically is preceded by a viral upper respiratory infection or occurs in conjunction with allergic rhinitis. Signs and Symptoms mucoid, purulent nasal discharge malodorous breath facial pain over sinuses periorbital swelling headache fever, malaise Microbiology of acute sinusitis: The most common bacterial organisms that cause acute sinusitis: Streptococcus pneumoniae - up until the mid-1990s, in the U.S. nearly all strains of streptococcus pneumoniae were sensitive to penicillin and amoxicillin. However, in other countries, streptococcus pneumoniae was showing resistance to penicillin, and in the U.S., by the mid-1990s, the problem of drug-resistant S.pneumoniae was becoming an increasing problem. Today, up to 30% of the streptococcus pneumoniae isolates in this country are either resistant to penicillin and amoxicillin or show intermediate sensitivity to penicillin and amoxicillin. Haemophilus influenzae - about 60% of the strains of H.influenzae in the U.S. are sensitive to penicillin and amoxicillin, while 40% produce a beta-lactamase enzyme and are thus resistant to amoxicillin. Moraxella catarrhalis - in the U.S., up to 90% of moraxella catarrhalis are beta-lactamase producing strains. A significant number of cases of acute sinusitis are caused by viral infections and thus won't respond to antibiotics, but clinically, it is often difficult to tell which are viral and which are bacterial.

Somogyi effect and Dawn phenomenon: You should consider both the Somogyi effect and the Dawn phenomenon when evaluating a patient with persistent morning hyperglycemia. Somogyi effect Rebound hyperglycemia in the morning secondary to nocturnal hypoglycemia. You can evaluate this by looking at the 3 a.m. glucose. If it's a consideration, ask your patient to get up and check the middle of the night glucose for several nights. Dawn Phenomenon Rise in the blood glucose concentration between 4 & 8 a.m. secondary to increasing growth hormone levels Geriatric Note: Sliding scale insulin is on the Beers Criteria list of medications to be avoided or used with caution in the elderly. The sliding scale insulin specifically refers to the sole use of short or rapid acting insulin to manage hyperglycemia.

Adjusting Doses You should look at the usual onset and duration of the insulins your patient is using to determine how to adjust doses based on blood glucose values.

Sulfonylureas Drugs in the class: First Generation: chlorpropamide (Diabinese) tolazamide (Tolinase) tolbutamide (Orinase) Second Generation glyburide (Micronase, Diabeta) glipizide (Glucotrol) glimepiride (Amaryl) Mechanism of Action: The sulfonylureas work by inhibiting the potassium channel in the pancreatic beta cell, thus resulting in depolarization and activation of calcium channels which results in enhanced insulin secretion. Even though insulin levels tend to return to baseline values after a few months of continued sulfonylurea use, a continued clinical response is usually seen and is thought to be secondary to a normalization of hepatic glucose production and improved tissue response to endogenous insulin.

Adverse Effects Hypoglycemia: This is an extension of the pharmacologic effect. The longer acting agents are more likely to cause clinically significant hypoglycemia. Skin reactions: Pruritis and rash are the most common side effect of the sulfonylureas. GI effects: Mild GI symptoms can be experienced. Take with food if necessary. Hepatotoxicity: Elevated liver function tests have been reported with all the sulfonylureas. Hepatoxicity with jaundice has also occurred; if this happens another class of drugs should be used. Weight gain: Because these agents increase the secretion of insulin, they can cause weight gain in some patients. Cardiovascular effects: The UGDP study (University Group Diabetes Program - 1970) found more cardiovascular deaths in the tolbutamide treated group versus the insulin treated group, and since then, the sulfonylureas have carried a warning in the package insert regarding a potential for increased cardiovascular mortality. This study has been widely criticized and it appears that the benefits from the sulfonylureas in lowering blood glucose clearly outweighs the risks. Geriatric Note: Chlorpropamide, and glyburide are on the Beers Criteria list of medications to be avoided or used with caution in the elderly. Both chlorpropamide and glyburide can cause prolonged hyperglycemia in older adults.

Thiazolidinediones (TZDs) Drugs in the class: Rosiglitazone (Avandia) Pioglitazone (Actos) Mechanism of action: Bind and activates a nuclear receptor that increases peripheral tissue sensitivity to insulin. Clinical Use: The TZDs may be added to metformin to provide additional glucose lowering. They may also be used as monotherapy in patient's who can't take metformin. Reduce HgB A1C by 1 to 1.5% and Fasting Plasma Glucose by 60 to 70 mg/dl. Maximal effect may not be seen until 3-4 months on therapy. Low hypoglycemic risk Convenient to use (one dose per day) and can be used in patients with renal dysfunction.

Adverse Effects: Well tolerated by most patients. Rare cases of severe idiosyncratic hepatocellular injury were reported with the use of troglitazone (Rezulin), the first drug in this class and it was removed from the market in 1999. The newer agents don't appear to have the same risk for hepatoxicity, but just to be safe, it is recommended at this time that LFTs be monitored regularly with rosiglitazone and pioglitazone. Exacerbation of congestive heart failure can occur due to fluid retention. Should not be used in patients with preexisting Class III or IV heart failure. Weight gain from fluid retention and fat accumulation. TZDs cause preadipoctyes to differentiate into mature fat cells in subcutaneous fat stores. This contributes to the 1.5 to 4 kg weight gain commonly seen with these drugs. Increased bone fracture rate; may relate to TZD effects on the pluripotent stem cell and shunting of new cells to fat instead of osteocytes as well as altering osteoblasts/osteoclasts. The fracture rate may be increased by 25% as compared to other diabetes medications. Rosiglitazone was reported to increase myocardial infarction rates and for a number of years its use was limited; it was only available through a speciality pharmacy and patients and prescribers were required to document that they understood the risks versus benefits. In 2013, the FDA lifted these restrictions and stated that a re-evaluation of trial data caused this action.

Alpha-glucosidase Inhibitors Drugs in the class: Acarbose (Precose) Miglitol (Glyset) Mechanism of action: Inhibits the alpha-glucosidase enzymes in the small intestine. This slows carbohydrate digestion in the small intestine thereby delaying glucose absorption. They lower postprandial glucose levels.

Adverse Effects: The adverse effects are mostly gastrointestinal and are secondary to the increased amounts of undigested sugars that pass into the large intestine. They present as abdominal pain (21%), diarrhea (33%), flatulence (77%). Doses >100 mg tid of acarbose caused increases in serum transaminase levels in 15%. Clinical Use: These drugs need to be given three or more times a day (just prior to each meal) and cause significant GI side effects, so are generally used as a second line agent. They can be used as monotherapy in patients who have post-meal hyperglycemia or as an additional drug in combination with metformin, or a sulfonylurea. Patients using these in combination with other agents should be warned that they will need to treat hypoglycemia with glucose tablets or glucagon injection (sucrose containing candy won't be absorbed).

Biguanides Drug in the Class: Metformin (Glucophage) Mechanism of action: Increases peripheral utilization of glucose by increasing tissue sensitivity to insulin. Decreases hepatic gluconeogenesis thus decreasing hepatic glucose output. It does not cause the weight gain that can be a problem with the use of insulin and sulfonylureas. Metformin is only drug at this time in the biguanide class -- it is an antidiabetes agent not an oral hypoglycemic because it does not provoke hypoglycemia. Clinical use: Metformin should be included in the therapy for all patients with Type 2 diabetes, unless it is not tolerated or is contraindicated. It was the first antidiabetes medication proven to reduce the risk of total mortality. The United Kingdom Prospective Diabetes Study (UKPDS) was a 20 year study involving over 4000 patients with Type 2 diabetes mellitus. One part of the study looked at the use of metformin in overweight patients with Type 2 diabetes mellitus. It found that intensive blood glucose control with metformin in these patients decreased diabetes related deaths by 42%, decreased MIs by 36%, and decreased overall mortality by 36%. Metformin will reduce HgbA1C by 1.5 to 2% and fasting plasma glucose by 60 to 80 mg/dl.

Adverse effects: Gastrointestinal: diarrhea, metallic taste, nausea, and anorexia can occur in up to 20%. Taking the drug with meals can minimize this. Lactic acidosis can occur with metformin. A related drug, phenformin, was used in the 1960s and the 1970s and was removed from the market because of cases of fatal lactic acidosis. Metformin can also cause lactic acidosis but it is less likely to occur with metformin. The patients at risk for the development of lactic acidosis include those with hepatic failure, cardiac failure and renal failure. The package labeling says that it should not be used in patients with estimated CrCl <30 ml/min. Additionally metformin should be avoided in patients at risk of developing acute renal failure - shock, acute CHF, MI, septicemia, liver disease, contrast agents. Vitamin B12 deficiency Long term use of metformin is associated with Vitamin B12 deficiency and the ADA 2017 Diabetes standards recommends that B12 levels should be tested periodically (annually is reasonable), especially in patients with anemia or peripheral neuropathy. Note: For years, the package labeling indicated that it was necessary to stop metformin in women with sCr >1.4 and men with sCr >1.5. However, there is new evidence that metformin may be fairly safe in moderate renal insufficiency. The package labeling was recently changed to say that avoiding metformin is only necessary when estimated CrCl is less than 30 ml/min. Other authors have given recommendations for reducing doses in mild-moderate renal dysfunction: CrCl 45-60 ml/min - max daily dose 2000 mg; CrCl 30-45 ml/min max daily dose 1000 mg

Bisphosphonates Mechanism of Action: Bisphosphonates have a strong affinity for calcium phosphate and inhibit osteoclast formation, thus slowing bone loss. They bind to the bone and thus have a long duration of action. Drugs in the Class: Alendronate (Fosamax) Ibandronate (Boniva) Risedronate (Actonel) Zoledronic Acid (Reclast) Drug Daily dose Weekly dose Monthly dose Quarterly dose Yearly dose Alendronate (Fosamax) 5-10 mg oral 35-70 mg oral NA NA NA Ibandronate (Boniva) 2.5 mg oral NA 150 mg oral 3 mg IV NA Risedronate (Actonel) 5 mg oral 35 mg oral 150 mg oral NA NA Zoledronic Acid (Reclast) NA NA NA NA 5 mg IV

Adverse effects: GI - heartburn, nausea, abdominal pain Esophagitis - when given orally Osteonecrosis of the jaw is a rare adverse effect that has been associated with bisphosphonates. Clinical Use: The bisphosphonates have a low bioavailability and must be taken on an empty stomach to ensure absorption. To prevent esophagitis, the patient should be told to take with a full glass of water and then remain upright for 30-60 minutes after ingestion. The bisphosphonates can be given either daily, weekly, monthly, quarterly or yearly depending on the product and the dose. All appear to relatively equal in efficacy. They can be used to prevent osteoporosis or treat patients who already have osteoporosis. The bisphosphonates have been shown to decrease the incidence of vertebral, nonvertebral, and hip fractures.

Glucagon-Like Peptide 1 (GLP-1) Agonists Drugs in the class: Albiglutide (Tanzeum) - SQ once weekly Dulaglutide (Trulicity) SQ once weekly Exenatide (Byetta) - SQ twice daily Exenatide QW (Bydureon) - SQ once weekly Liraglutide (Victoza) - SQ once daily Lixisenatide (Adlyxin) - SQ once daily Mechanism of action: Mimic the action of the incretin hormone called glucagon-like peptide-1 (GLP-1). This enhances glucose-dependent insulin synthesis and secretion from the pancreas while suppressing inappropriately high postmeal glucagon secretion resulting in decreased hepatic glucose production.

Adverse effects: Low hypoglycemic risk except when added to a regimen containing a sulfonylurea or basal insulin. Consider decreasing the dose of the sulfonylurea or basal insulin when starting a GLP-agonist. Nausea - in up to 30-40%. This generally subsides with continuing therapy. The once weekly extended release exenatide injection causes less nausea than the twice daily shots. Pancreatitis - post-marketing reports have associated this class of drugs with pancreatitis; if pancreatitis occurs, the drugs should be stopped and not re-started. Liraglutide and extended release extenatide caused an increased risk of thyroid cancer in mice; all of of the drugs in this class should not be used in patients with a history of thyroid cancer. Clinical Use: They tend to increase satiety, slow gastric emptying and promote weight loss. The GLP-1 receptor agonists are used as an adjunct to improve glycemic control in patients with type 2 diabetes mellitus who are not achieving optimal control with oral medications. Especially effective in reducing postprandial glucose levels They are injectable medications

Dipeptidyl Peptidate-4 inhibitors (DPP-4 inhibitors) Drugs in the class: Sitagliptin (Januvia. Also in combo with metformin as Janumet) Saxagliptin (Onglyza) Linagliptin (Tradjenta. Also in combo with empagliflozin as Glyxambi) Alogliptin (Nesina) Mechanism of action: Dipeptidyl Peptidate-4 (DPP-4) is an enzyme that breaks down glucagon-like peptide-1 (GLP-1). When DPP-4 is inhibited, then GLP-1 levels rise. GLP-1 is an incretin hormone; when the gastrointestinal tract senses glucose, it secretes GLP-1 which causes increases insulin release from the pancreas, increased uptake of glucose into tissues, decreased gastric emptying, and increased satiety and fullness.

Adverse effects: Well tolerated with few reported adverse effects Severe, disabling joint pain has been reported; this is a rare occurence Low hypoglycemic risk except when added to a regimen containing a sulfonylurea or basal insulin. Consider decreasing the dose of the sulfonylurea or basal insulin when starting a DPP-4 inhibitor Rare serious skin reactions such as Stevens-Johnson syndrome have been reported Clinical Use: Can be added to improve glucose control in patients with Type 2 diabetes already receiving metformin or a TZD. They are a once day tablet. Weight neutral, They may be especially useful for the patient with continued post prandial hyperglycemia.

Strategies for using Insulin and other injectables in the Patient with Type 2 diabetes

Also: Patients with a cardiovascular risk score of >5-10% in 10 years should receive 75 to 162 mg aspirin daily. The AHA/ACC Treatment of Cholesterol to Lower Cardiovascular Risk guidelines recommend that patients age 40-75 with diabetes should receive either moderate intensity or high intensity statin therapy Blood pressure should be < 140/90

Antibiotic therapy for Acute Otitis media You will note that azithromycin (Zithromax) is not listed as a treatment option. This drug is labeled for use in acute otitis media, but the group writing the guidelines chose to not include it because it does not achieve bacteriocidal levels in the middle ear fluid. Amoxicillin within last 30 days, or concurrent purulent conjunctivitis present, or history of recurrent otitis media unresponsive to amoxicillin Initial Therapy If the first agent hasn't worked at 48-72 hours No Amoxicillin 80-90 mg/kg per day Amoxicillin-clavulanate (Augmentin) Yes Amoxicillin-clavulanate: 90 mg/kg per day of amoxicillin with 6.4 mg/kg per day clavulanate Ceftriaxone 50 mg/kg IM x 3 days The authors of the guidelines chose amoxicillin as the first line agent based on its general effectiveness when used at appropriate doses, safety, cost, taste, and narrow microbiologic spectrum. Duration of treatment Children < 2 yrs, and children with severe illness: 10 days of therapy is recommended. Children age 2 to 5 years: 7 days of therapy Children > 6 yrs with nonsevere illness: 5-7 days of therapy is adequate.

Alternative antibiotics Other appropriate antibiotics can be used to treat acute otitis media when modifying factors are present: Modifying Factors Daycare center attendance Recent antibiotic use (within 30-60 days) Resistance suspected/documented Bilateral disease Conjunctivitis-otitis syndrome Recurrent AOM/otitis prone Past/current amoxicillin failure AOM in patient with chronic OME TM perforation/tympanostomy tubes Immunosuppression Infant <6 months old Useful Antibiotics When Modifying Factors Present Cefpodoxime 10 mg/kg/day PO BID Cefdinir 14 mg/kg/day QD Cefuroxime 30 mg/kg/day PO BID Amoxicillin/clavulanate 90/6.4 mg/kg/day PO BID Ceftriaxone 50 mg/kg/dose IM ×3 days Levofloxacin 10 mg/kg/day PO BID (not FDA-approved for AOM) Clindamycin 30 mg/kg/day PO TID (lacks activity against H. influenzae and M. catarrhalis)

Management of Acute Sinusitis Antibiotic Therapy' The following recommendations are taken from the 2012 IDSA guidelines. They differ from older guidelines because they recommend Augmentin as a first line agent (older guidelines recommended amoxicillin as the first line agent). First line antibiotic: Standard dose Amoxicillin - Clavulanate is recommended as the first line agent for both children and adults. Standard dose: 45 mg/kg/day in children, 500 mg tid or 875 mg bid in adults Use high dose amoxicillin-clavulanate as the alternative first line for patients more likely to be infected with a resistant bacteria or who are at risk of serious complications if there is a treatment failure: High dose: 90 mg/kg/day in children, 2 grams twice daily in adults Candidates for high dose amoxicillin/clavulanate as empiric therapy include: those who come areas with a high prevalence of invasive, resistant S.pneumoniae, those with severe infection (e.g. fever >102°F), attendance at daycare, age <2 or >65 yrs, recent hospitalization, antibiotic use within last month, or those who are immunocompromised.

Alternative first line agents for patients allergic to amoxicillin: Respiratory fluoroquinolone (levofloxacin or moxifloxacin) can be used. Either is as effective as amoxicillin/clavulanate. It is recommended that they NOT be used first line to help slow the development of resistance to the fluoroquinolones. Drugs that have been used, but are not preferred: Trimethoprim/sulfamethoxazole (Bactrim DS) - is inexpensive, but limited coverage against H. influenzae and S. pneumoniae and failure rates can be up to 25%. Doxycycline 100 mg twice daily - is inexpensive, and can be used as an alternative for adults. Should not be used in children or pregnant women. Azithromycin and clarithromycin - H. influenzae and S. pneumoniae are increasingly resistant to the macrolides and treatment failures may occur. Second and third generation oral cephalosporins are no longer recommended as first line therapy because of increasing rates of resistance: cefuroxime, loracarbef, cefprozil, cefdinir Adjunct therapy In addition to antibiotics, the following medications have been recommended as useful adjuncts: Nasal Saline Irrigation - may be useful in adults. There is less evidence of its usefulness in young children. Decongestants - these are commonly recommended and patient's may tell you that they notice an improvement in breathing because of less nasal stuffiness, but clinical trials do not show that they help shorten the course of the disease. The IDSA guidelines say to not recommend or prescribe them. Topical anticholinergic - ipratropium nasal spray - may help with a runny nose Nasal corticosteroids - flunisolide, fluticasone, mometasone - have been shown to be a useful adjunct in patients with recurrent acute rhinosinusitis or chronic sinusitis.

Combination Injectable Medications Insulin degludec and liraglutide (Xultophy) - combines the long acting insulin degludec (Tresiba) and liraglutide (Victoza) in a fixed ratio combination containing 100 units degludec and 3.6 mg liraglutide per ml. Supplied in pens where the dosing is in units. Insulin glargine and lixisenatide (Soliqua) - combines the long acting insulin glargine (Lantus) and lixisenatide (Adlyxin) in a fixed ratio combination containing 100 units glargine and 33 units lixisenatide per ml. Supplied in pens where the dosing is in units. The advantages of the combination products is that it decreases the number of injections each day for patients who need both a long acting insulin and a GLP-1 Receptor Agonist. The disadvantage is that the doses of each medicine can't be titrated individually. Instructors Note: Empaglifozin (Jardiance) in the EMPA-REG Outcome trial and Liraglutide (Victoza) in the LEADER trial have both been shown to lower the death rate from cardiovascular disease. The ADA 2017 Medical Care of Diabetes Standards of Care suggests clinicians consider adding one of these drugs to the regimens of patients with established cardiovascular disease.

Amylin Analog Drugs in the class: Pramlintide (Symlin) - SQ injection Mechanism of action: Pramlintide is a synthetic analog of human amylin. Amylin is a hormone secreted from pancreatic beta cells that contributes to glucose control during the postprandial period. It slows gastric emptying and suppresses glucagon secretion. Adverse effects: Hypoglycemia - pramlintide alone does not cause hypoglycemia. However, if used with insulin therapy, it increases the risk of severe insulin-induced hypoglycemia. It is recommended that the pre-meal dose of insulin be decreased by 50% when first starting pramlintide. Nausea -- occurs in up to 30%. Tends to decrease with time. Clinical Use: Pramlinitide is an injectable agent that can be used as adjunct treatment to insulin in patients with either Type 1 or Type 2 diabetes who are using mealtime insulin therapy and continue to have post-prandial hyperglycemia. It is given subcutaneously prior to each meal and must be administered as separate injection from the mealtime insulin.

Common Causes of Failure of Antimicrobial Therapy Drug Inappropriate drug Inadequate dose Improper route of administration Malabsorption Accelerated drug excretion or inactivation Poor penetration of drug into site of infections Host Poor host defenses Undrained pus Retained infected foreign body Dead tissue Pathogen Development of drug resistance Superinfection by other pathogens Dual infection initially - only one of the pathogens treated Laboratory Erroneous report of susceptible pathogen

Bacterial Cell Wall Inhibitors Bacteria have a rigid outer layer, the cell wall, which maintains the bacterial shape and contains the contents of the bacterial cell. The bacterial cell has a high internal osmotic pressure, with the internal pressure being 3-5 times greater in gram-positive than in gram-negative bacteria. If the cell wall is damaged or its formation is inhibited, the cells will lyse. The two primary classes of antibiotics that inhibit bacterial cell wall synthesis are the beta-lactam antibiotics and the glycopeptide, vancomycin. Beta-lactam Antibiotics Beta-lactam antibiotics all contain a beta-lactam ring in their structure. The side chains off the beta-lactam ring vary among the agents. The four classes of antibiotics in the beta-lactam group are: Penicillins Cephalosporins Carbapenems Monobactams

Tetracyclines The tetracyclines bind to the 30S subunit of bacterial ribosomes and inhibit bacterial protein synthesis. The drugs in this class include: Doxycycline Tetracycline Minocycline Spectrum of activity: Tetracyclines are active against many organisms, although increased resistance limits their use now in infections that used to be commonly treated by these agents (ie UTIs). They are active against chlamydia, mycoplasma, Borrellia burgdorferi (Lyme disease), rickettsia rickettsia (Rocky Mountain Spotted Fever). Resistance: Resistance occurs most commonly when the organism develops an efflux pump. The pump protein is encoded on a plasmid and may be transmitted to other types of bacteria; thus tetracyline resistance is often a marker for resistance to multiple drugs. Adverse reactions Deposition in bone and primary teeth (when used in pregnant women and young children). The tetracyclines are contraindicated in pregnancy and in children under age 9. Erosive esophagitis if taken at bedtime (doxycycline) Photosensitivity (mostly with tetracycline Dizziness - with minocycline and high doses of doxycycline

Bacterial Folate Inhibitors - Sulfonamides Sulfonamides - such as sulfamethoxazole Trimethoprim Trimethoprim-sulfamethoxazole in combination (Septra, Bactrim) Antibacterial spectrum: Some gram negative organisms (E.coli), chlamydia, and Pneumocystis. Clinical Uses: Pneumocystis pneumonia (PCP) prophylaxis and treatment in immunocompromised patients Urinary tract infections (UTIs) prophylaxis and treatment. Resistance occurs when organisms develop a pathway to synthesize their own folate, or the bacteria produce a different protein target site or reduce permeability to the antibiotic. Adding trimethoprim to sulfamethoxazole inhibits another pathway in the formation of folic acid, and the two drugs act synergistically together. Adverse effects: Gastrointestinal: Nausea, vomiting, diarrhea Hypersensitivity: The sulfonamides are one of the most allergenic classes of antibiotics. The allergic reactions are frequently manifested as a diffuse, maculopapular rash, but rarely, can also present as Stevens-Johnson syndrome or toxic epidermal necrolysis. Kernicterus: Sulfonamides can displace bilirubin from binding sites on serum albumin and cause kernicterus in newborns. They should be avoided in neonates. Hematologic: Leukopenia, hemolytic anemia can occur rarely.

Parathyroid Hormone Mechanism of Action: Endogenous parathyroid hormone and analogues of parathyroid hormone directly stimulate osteoblastic bone formation thus increasing bone density. Drug in the Class: Teriparatide (Forteo) Abaloparatide (Tymlos) Adverse effects: muscle cramps risk of hypercalcemia nausea very high doses caused osteosarcoma in rats Clinical Use: Daily subcutaneous injection. Because of the theoretical risk of osteosarcoma, and the fact that they require a daily injection, and they are very costly, they are reserved for the treatment of women with severe osteoporosis who are at high risk of fracture. Labeled for use for 2 years only. There is evidence that there is no benefit for using teriparatide or abaloparatide and a bisphosphonate concurrently, so if teriparatide is begun, the bisphosphonate should be stopped.

Calcitonin Mechanism of action: Calcitonin acts on a calcitonin receptor to inhibit the osteoclasts and thus decrease bone resorption. The reduction in bone turnover with calcitonin is much less than with other anti-resorptive agents such as the bisphosphonates. Drugs in the Class: Calcitonin (Miacalcin) - injectable - SQ or IM Calcitonin (Miacalcin) - nasal Adverse effects: flushing - 2% incidence with injectable nausea, vomiting, diarrhea nasal irritation (for the nasal prep) Clinical Use: May be used to treat osteoporosis in women who are > 5 years beyond menopause. It has been shown to decrease the evidence of vertebral fractures, while having no effect on the incidence of nonvertbral fractures. Injectable calcitonin may decrease bone pain immediately after a vertebral compression fracture, but has not been shown to be effective for reducing chronic pain. Because it reduces bone turnover less than the other available classes of drugs, it is recommended that it be used only in women who can not or choose not to take one of the other drugs. Seldom used anymore in the management of osteoporosis

Drug Interactions with Hormonal Contraceptives Oral Contraceptive Drug Interactions Interacting Drug Net Effect Drugs that increase or may increase the metabolism of OCs - These drugs increase the metabolism of the hormones and thus decrease the levels. We don't measure blood levels so it is difficult to assure that effective contraception is occurring and it is prudent to not use hormonal contraception in women taking enzyme inducing drugs chronically. Spotting, breakthrough bleeding, or pregnancy - consistent spotting or breakthrough bleeding is a hint that the hormone levels are decreased, so the contraceptive efficacy may be decreased. Aprepitant Bexarotene Bosentan Carbamazepine Darunavir Felbamate Fosphenytoin/Phenytoin Griseofulvin Modafanil Mycophenolate mofetil Nevirapine Oxcarbazepine Phenobarbital Pioglitazone Primidone Rifabutin Rifampin Ritonavir Secobarbital St John's Wort Topiramate Miscellaneous drug interactions with OCs Cyclosporine Doubling of cyclosporine level Warfarin Increase or decrease in anticoagulation - check INRs Antibiotics Contraceptive hormones are conjugated in the liver and excreted in the bile. Bacteria in the gut cleave the conjugated product and then the hormone is reabsorbed. This is called enterohepatic circulation. If you kill the bacteria with a broad spectrum antibiotic, you interrupt the cycle (the conjugated hormone is fecally excreted without being reabsorbed) and you decrease the amount of hormone in the body. Thus it is recommended that women taking COCs use a backup form of contraception while they are also taking an antibiotic.

Choosing Hormonal Contraception • First look at adherence factors -- If consistent daily use isn't likely to occur, choose an injectable product (DMPA), a transdermal patch, or the vaginal ring (or IUD - either progesterone implant or copper T IUD). Then decide: Combination contraception or Progestin Only?? Avoid estrogen - Use Progestin Only In: Thromboembolic Disorders Hypertension Migraines - particularly those with focal neurologic symptoms Smokers >35 yrs Breast feeding History of or multiple risk factors for heart disease If you decide a Combination Product will work then choose any of the low dose estrogen products and adjust by adverse effects. You might consider starting with 20-30 mcg for women <70kg and the 35 mcg product for women >70 kg. Instructors Note: The CDC has handy tools for clinicians prescribing contraception. The CDC Reproductive Health website has links to the PDF version of the latest Medical Eligibility for Contraception document and the latest Selected Practice Recommendations. In addition, you will find links to CDC Contraception App for IOS and Android and also links to epub format of the same information (epub opens as an iBook on an Apple device).

Progestin Only Contraceptives The regular progestin only pills can theoretically be used in emergency contraception but it isn't very practical because you have to take 20 pills now and 20 pills 12 hours later (or 40 pills all at once). Next Choice One Dose and Plan B One Step are progestin only products specifically packaged and labeled for use as an emergency contraceptive. Both contain one 1.5 mg levonorgestrel tablet with the instructions to take one pill as soon as possible after unprotected intercourse. Progesterone-receptor Agonist/Antagonist Ulipristal acetate (Ella) is a progesterone receptor modulator that is available by prescription only and is a single 30 mg tablet that should be taken within 120 hours of unprotected intercourse. It is appears that the primary mechanism of action is to delay or prevent ovulation; the studies used to bring the drug to market suggest that it retains efficacy up to the 120 hours after intercourse. It is a pregnancy category X drug so the patient should have a negative pregnancy test before it is prescribed.

Choosing a Product The COCs cause more nausea and vomiting. An antiemetic should be recommended or prescribed at the same time. The advantage for the patient of using this method would be that they may be able to use one of their packs of pills that they already have at home. The Next Choice and Plan B one step can be purchased without a prescription. They cost about $50. Ella needs a prescription and also costs about $50. Some reviews suggest that it may be a little more effective as you approach 120 hours as compared to Next Choice or Plan B. Other emergency contraceptive methods: • Insertion of a copper IUD within 120 hours of unprotected intercourse will also prevent pregnancy • Mifepristone (Mifeprex, RU-486) is an antiprogestin drug that is labeled for use in terminating pregnancies of up to 49 days in duration (it is used in combination with misoprostol for pregnancy termination). However, if given as a single dose within 120 hours of unprotected intercourse, it will also prevent a pregnancy from occurring. It is not commonly available in pharmacies and is very expensive (several hundred dollars) so is rarely used as an emergency contraceptive. Effectiveness of Emergency Contraception • With either combination contraceptives or progestin only contraceptives, the pregnancy rates of <2-3% when taken within 72 - 120 hours of unprotected intercourse. If pregnancy occurs, the fetus does not appear to be harmed. • The insertion of the Copper IUD is 99% effective in preventing pregnancy. • In studies, the mifepristone was 100% effective in preventing pregnancy when given within 72-120 hours of intercourse. Instructors Note: Progestin only (e.g. Plan B ) emergency contraception does not work as effectively in women with higher BMI (>30). Ulipristal (e.g. Ella) appears to be effective in BMI up to 35. Above that, an IUD is recommended for emergency contraception. Some centers recommend a second dose of EC for women with high BMIs but that has not been studied.

Cephalosporins Like the penicillins, the cephalosporins interfere with the last step of bacterial cell wall synthesis, thus leaving the cell membrane exposed and cell lysis occurs. They are only active against organisms with a peptidoglycan cell wall; thus they don't have activity against protozoa, fungi, or viruses. Classification of Cephalosporins Cephalosporins are classified into generations based on their spectrum of activity against aerobic gram-negative bacilli. The activity against gram-negative bacteria increases from first to third generation. The activity against gram-positive bacteria decreases from first to third generation. Adverse reactions: Adverse reactions with the cephalosporins are similar to those with the penicillins (hypersensitivity, diarrhea, rash). Hypersensitivity: There is about a 10% risk of cross-allergenecity between the penicillins and the cephalosporins, which means that 90% of the patients with a penicillin allergy won't show sensitivity to the cephalosporins. However, if the reaction to penicillin was anaphylaxis, the cephalosporins should usually be avoided because the potential reaction is so severe.

Classification of Cephalosporins Classification Examples Overview of antimicrobial activity First generation Cefazolin Cephalexin Streptococci, staphylococci, and some gram-negative organisms. Useful for skin and soft tissue infections and for surgical prophylaxis Second generation with Haemophilus influenzae activity Cefaclor Cefuroxime Gram-positive organisms such as streptococcus pneumoniae, and Haemophilus influenzae (a respiratory pathogen). Second generation with Bacteroides fragilis activity Cefotetan Cefoxitin Aerobic gram negative bacilli such as E.Coli, plus the anerobic B. fragilis. Used for intra-abdominal infections. Third generation Cefotaxime Ceftriaxone Ceftizoxime Aerobic gram negative bacilli such E. Coli and H. influenzae. Third generation (Oral broad-spectrum) Cefixime Cefpodoxime Increased gram-negative activity as compared to the first generation cephalosporins, but not as much coverage as the parenteral third generation cephalosporins Third and fourth generation with Pseudomonas aeruginosa activity Ceftazidime Cefeipime Aerobic gram negative bacilli plus activity against pseudomonas

(Ch.56, p. 863) Osteoporosis is a thinning of normal bone. It occurs with aging. More than 10 million people in the U.S. have osteoporosis, and 80% of these are women. Bone fracture is major cause of morbidity and mortality in patients with osteoporosis. Patients who suffer a hip fracture have a 12-20% higher mortality rate compared to a patient of the same age and sex. Bone physiology There are two types of bone: Cortical - Cortical compact bone makes up 80% of the skeleton. It is the main component of long bones and provides strength when torsion is the dominant force. Trabecular - Trabecular bone makes up 20% of the skeleton. It is more porous and resists compressive forces. It is found at the ends of long bones and predominates in the vertebral body. Bone Mass is determined by the net effect of two ongoing processes - bone formation and bone resorption. Bone is continuously formed and continuously resorbed throughout life. The two cells involved in these processes are: Osteoblasts - form bones Osteoclasts - resorb bones Age Related Decrease in Bone Mass: In both men and women, there is a gradual loss of bone mass after age 35-40 years. After menopause: Women lose up to 15% of trabecular bone during the first 5 to 7 years after menopause.

Classification of Osteoporosis Type I "Post Menopausal Osteoporosis" is associated with increased trabecular bone loss. Occurs in postmenopausal women between 51 and 75 years of age. Bone loss is accelerated in the first 5 to 7 years after menopause -- by 20 years after menopause, the rate of bone loss slows. The most common fractures are vertebral fractures, distal radius fractures, and tooth loss. Decline in estrogen levels leads to greater osteoclast activity and osteoblasts are unable to refill the bone resorption cavities completely. Type II "Senile Osteoporosis" occurs in both men and women over age 70 leading to both cortical and trabecular bone loss. The most common fractures are hip, pelvis, vertebral fractures. Type III "Secondary Osteoporosis" occurs secondarily to various medications or diseases. Examples of causes of secondary osteoporosis:chronic corticosteroid therapy lithium therapy.

Glinides The drugs in this class structurally consist of the non-sulfonylurea part of glyburide and have a very similar mechanism of action. Drugs in the class: Repaglinide (Prandin) Nateglinide (Starlix) Mechanism of action: Interact with binding sites on the potassium channels in the pancreatic beta cell membrane, thus inducing insulin secretion (similar mechanism to the sulfonylureas). They have a rapid onset of action and a short duration of action.

Clinical efficacy: As effective as glyburide or glipizide in lowering blood glucose levels, and also provides synergistic activity when used in combination with metformin. They are administered 15-30 minutes before each meal to decrease meal related increases in blood glucose. Clinical use: These drugs need to be given three times or more per day (just before meals) so are inconvenient for most patients. They can be useful for patients with meal-related hyperglycemia who haven't responded to other agents.

Ovarian Changes in Menopause (Ch. 50, p. 775) Throughout a woman's life, the number and function of ovarian follicles decreases. As menopause approaches, the remaining follicles require higher concentrations of FSH for follicular maturation. At menopause, the follicles remaining in the ovaries no longer respond to FSH and no longer produce 17B-estradiol. Because of the lack of feedback inhibition on the hypothalamic-pituitary-ovarian axis, the FSH concentrations increase. As the ovarian function declines, the woman experiences changes in her menstrual pattern. The menstrual interval may increase; menstrual blood flow may either increase or decrease, both in quantity and in number of days of bleeding. Changes in Hormone Production after Menopause Estradiol: Pre-menopausal average estradiol concentrations are 120 ng/L; this falls to 18 ng/L after menopause. Estrone: The primary estrogen after menopause is estrone, which is derived from the peripheral conversion of androstenedione. Estrone is a less potent estrogen than estradiol. The aromatase enzyme responsible for this conversion is found in fat and liver tissue and increases with age and body weight. Progesterone: Progesterone production is also decreased after menopause. Progesterone concentrations after menopause are unmeasurable. Androgens: Overall concentration of androgens decreases from 1500 pg/ml premenopausally to 800 pg/ml post-menopause.

Clinical symptoms of Menopause - The clinical symptoms of menopause are primarily related to a lack of estrogen on target tissues Hot Flashes - Nearly 75% of women will experience hot flashes during menopause. Symptoms include a sudden feeling of warmth in chest, neck, and face. The woman can also experience headache, dizziness, diaphoresis, night sweats. The prevalence of hot flushes is highest during the 2 years after menopause and declines over time. The hot flush results from changes in the hypothalamic thermoregulatory center in the brain. Estrogen withdrawal causes a downward resetting of the central hypothalamic thermostat that leads to heat dissipation through vasodilation and perspiration at relatively low body temperatures. Urogenital atrophy - The tissues of the vagina, urethra, vulva and trigone of the bladder have large numbers of estrogen receptors and these tissues atrophy when estrogen level is reduced. Vaginal walls become thin, and lose elasticity. The urethra is easily irritated and dysuria occurs. Psychologic function This is a controversial area, but there is some evidence that depression can be related to menopause. There is also some evidence that in some women, menopause can adversely affect short-term memory (estrogen therapy may help). Cardiovascular Disease Premenopausal women have a lower incidence of cardiovascular disease than men. As a woman ages, the risk curves for men and women converge and become nearly the same after age 70. For many years, clinicians assumed that hormone therapy would prevent cardiovascular disease, but it now appears that hormone therapy does not prevent cardiovascular disease. Osteoporosis We'll discuss this later in the unit.

Choosing Contraception There are two major types of hormonal contraception: Combination products that contain both estrogen and progestin and progestin only products. First, we'll look at how the hormones exert their contraceptive effect. Estrogen Contraceptive Effect Suppresses hypothalamic release of FSH-RF (follicle stimulating hormone releasing factor), and LH (luteinizing hormone), thus preventing the development of the dominant follicle. It also stabilizes the endometrial lining which minimizes the breakthrough bleeding see with oral contraceptive use. Progestin Contraceptive Effect thicken cervical mucus which impairs the transportation of sperm inhibit implantation of the ovum by causing alterations in the endometrial lining inhibit ovulation by suppressing luteinizing hormone (LH) secretion

Combination Contraceptive Products - Combination contraception contains both estrogen and progestin together. Initially, the only combination products were oral contraceptive pills, but now a transdermal patch and a vaginal ring are also available. Combination Oral Contraceptive (COC) Pills The first oral contraceptive products contained 50-100 mcg of estrogen and 1-10 mg progestin, and were associated with numerous adverse effects. "Low Dose" combination oral contraceptives contain <35 mcg of ethinyl estradiol. The newest oral contraceptive pills are multiphasic products designed to mimic the hormonal fluctuations of the normal menstrual cycle. Monophasic - All 21 active pills contain same amount of estrogen/progestin Biphasic - 21 active pills contain 2 different estrogen/progestin combinations Triphasic - 21 active pills contain 3 different estrogen/progestin combinations asic - 21 active pills contain 3 different estrogen/progestin combinations Quadriphasic - contains 4 different estrogen/progestin combinations

Management of Selected Complications of Diabetes Mellitus

Complications are macrovascular (accelerated risk of heart disease) and microvascular (retinopathy, nephropathy, peripheral vascular disease, gastropathy). Two landmark trials demonstrated that lowering blood glucose levels decreases the risk of developing complications. The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that in Type 1 diabetes tight control of glucose will decrease the microvascular complications. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive blood glucose control in patients with Type 2 diabetes mellitus decreases microvascular complications such as retinopathy and nephropathy; the 10 year UKPDS follow-up also showed a decrease in cardiovascular (macrovascular) disease in the intensive treatment group. We will review the pharmacotherapy of the following microvascular complications of diabetes: nephropathy, peripheral neuropathy, and gastropathy.

Choosing a Hormone Therapy Product Women without uterus : May receive estrogen on a continuous basis. If a woman has primarily urogenital symptoms, topical vaginal estrogen may be adequate for treatment. The cream should be administered vaginally on a daily basis for 1 to 3 months then intermittently for relief of symptoms. Some of the estrogen is absorbed systemically but the amount absorbed is less than with transdermal or oral estrogen administration. For women with significant vasomotor symptoms, oral or transdermal estrogen will alleviate the symptoms. The lowest dose of estrogen that relieves the symptoms should be prescribed. Oral products are convenient (once a day tablet) and in addition to the vasomotor symptoms, will also relieve urogenital symptoms. Transdermal estrogen is a patch that is applied to the skin. It will relieve vasomotor and urogenital symptoms. An advantage to the transdermal dosage form is that the drug is absorbed directly into the blood and doesn't go through the liver first (doesn't have a hepatic first pass effect). This may decrease the risk for cholecystitis since it does not increase the biliary cholesterol saturation as much as oral estrogen therapy. Disadvantage for the patch is a risk of skin irritation and the cosmetic issues of having a patch on the skin. Women with intact uterus : Must receive a progestin for at least 12 days/month. There are several regimens that can be used. Regimen 1: Estrogen Day 1-25 with Progestin Day 13-25 Regimen 2: Estrogen Daily with Progestin Day 1-12 each month Regimen 3: Estrogen and Progestin each taken daily Regimen 1 and 2 lead to regular uterine bleeding. Usually it is light and predictable. Regimen 3 leads to less uterine bleeding but irregular spotting is common especially at the beginning of therapy.

Contraindications to Hormone Therapy Absolute Contraindications Active thromboembolic disease or history thereof (e.g., DVT, PE, stroke, MI) Undiagnosed abnormal genital bleeding Known, suspected or history of estrogen dependent neoplasia (e.g., breast cancer, endometrial cancer) Impaired liver function Known or suspected pregnancy Relative Contraindications (diseases that may be (exacerbated by estrogens/progestins) Gallbladder Disease Hypertriglyceridemia Asthma Migraine headache Epilepsy Systemic lupus erythematosus Porphyria

Insulin Effects on Carbohydrates, Fats, and Proteins

Counter-regulatory hormones from the pancreas, pituitary, adrenal cortex, and adrenal medulla protect against hypoglycemia If the plasma glucose falls below a critical concentration, a number of counter-regulatory responses occur: Pancreatic glucagon release Sympathetic nervous system activation Hypothalamic-pituitary-adrenal release of growth hormone, cortisol, and epinephrine

Bile Acid Sequestrant Drug in the Class: Colesevelam (Welchol) Mechanism of Action: Acts in the intestinal lumen to bind bile acid. It is unknown exactly how this causes it to lower blood glucose levels but it has been shown to decrease fasting plasma glucose by 5-10 mg/dl Adverse Reactions: Constipation (11%) Alters the absorption of numerous drugs and fat-soluble vitamins Clinical Use: Must be given two to three times/day Not commonly used - statins are preferred for cardiovascular protection and other drugs are more effective in lowering blood sugar

Dopamine Agonist Drug in the Class: Bromocriptine (Cycloset) Mechanism of Action: Dopamine agonist that works in the brain.The exact mechanism of how bromocriptine improves glycemic control is unknown. Low hypothalamic dopamine levels, especially on waking, are augmented, which may decrease sympathetic tone and output. These effects are speculated to improve hepatic insulin sensitivity. Adverse Effects: Not well tolerated. Up to 24% of patients discontinue because of adverse effects. Nausea and vomiting, rhinitis, headache Clinical Use: Not commonly used because of small effect on blood glucose and high incidence of adverse effects HgbA1C lowering: 0.3 to 0.6%

Drug Therapy The NAMS position statement recommends treating women with osteoporosis drug therapy if they have had an osteoporotic vertebral fracture, or have a BMD consistent with osteoporosis (T score < -2.5) or a T score < -2 and they have risk factors. It is not recommended to use hormone therapy for primary prevention of osteoporosis. If HT is being used for treatment of menopausal symptoms, it will decrease the rate of bone loss. Bisphosphonates are the first-line drugs. The bisphosphonates have been shown to reduce the incidence of both spinal fractures and non-spinal fractures, while raloxifene has only been shown to reduce the incidence of spinal fractures.

Drug Therapy cont. Denosumab injections are safe and effective but are expensive. They can be used in patients who can't take an oral bisphosphonate. Raloxifene has the theoretical benefit of estrogen receptor antagonism in the breast so may be appropriate for the patient with breast cancer history. Teriparatide is reserved for use in women with severe osteoporosis and a high risk of fracture. Calcitonin is reserved for use in patients with established osteoporosis (it is not used as a preventive agent). It is less effective than other available agents so should not be used as a first line agent. It is seldom used anymore.

Risk Factors for Osteoporosis Age Female gender Caucasian or Asian Small stature Low Body weight Early menopause Sedentary Lifestyle Decreased mobility Low calcium intake Smoking Excess Ethanol intake Medical Conditions: chronic liver disease, renal failure, hyperthyroidism Drugs: corticosteroids, phenytoin, furosemide, excessive thyroid replacement therapy

Drugs Used in the Management of Osteoporosis Estrogen Therapy or Estrogen-Progestin Therapy Estrogen therapy will help prevent osteoporosis in post-menopausal women. When compared to placebo, or calcium/Vitamin D alone, estrogen use results in improved bone density. Estrogen inhibits the effect of osteoclasts on bone resorption. The greatest benefit occurs when therapy is started soon after menopause. Recent recommendations from the US Preventive Services Task Force (USPSTF) and the American College of Obstetrics and Gynecology suggest that hormone therapy not be continued long term for the prevention of osteoporosis because the risks of HT outweigh the potential benefits.

Overview of Female Sex Hormones Estrogens - There are three endogenous estrogens that a woman produces. 17-B Estradiol is the most potent endogenous estrogen and is the principal ovarian estrogen. Estriol is the principal placental estrogen. Estrone is a metabolite of 17B-estradiol and has about one-tenth the potency of estradiol. In the post-menopausal woman (who is not producing 17B-estradiol from the ovaries any more), estrone becomes the primary endogenous estrogen because it is also formed from androstenedione, which is secreted from the adrenal glands.

Effects of Estrogens - The beneficial effects of hormone therapy and the adverse effects all are secondary to the biologic effects of the hormones. Female Sexual Characteristics - Estrogens mediate the development of female sexual characteristics such as female shape and breast development. Epiphysis closure - The increase of estrogen secretion at puberty causes closure of the epiphysis of long bones and cessation of growth in height. Uterine cell growth - Without estrogen (as in menopause), there is a lack of uterine endometrium cell proliferation. Thicken vaginal cell mucosa -After menopause, vaginal epithelium thins. Maintain bone mass - Estrogens decrease the rate of resorption of bone by decreasing the activity of osteoclasts. Enhance the coagulability of blood - Estrogens stimulate production of factor VII to X, and inhibit antihrombin III; this may be why one of the risks of hormone therapy is increased thromboembolism.

Skin infections (ch.73, p.1093) Cellulitis is an acute spreading infection of the skin and subcutaneous tissue. It occurs when the skin barrier is broken, such as from a cut or abrasion Most common organisms Group A streptococci Staphylococcus aureus Hemophilus influenzae (children) Signs and symptoms • usually history of prior minor trauma, ulcer, surgery • erythema and edema of skin • nonelevated lesion with poorly defined margins • commonly tender lymphadenopathy • malaise, fever, chills Empiric treatment for outpatients (mild to moderate cases) 1st generation cephalosporin (ie Keflex) for 10-14 days OR Penicillinase-resistant penicillin (ie Dicloxacillin) for 10 - 14 days) OR Erythromycin 500 mg qid x 10-14 days (for penicillin allergic patient) Patients with diabetes or who have been hospitalized are more likely to have a gram-negative infections. They should receive a second or third generation cephalosporin. There is an increasing incidence of community-acquired methicillin resistant staphylococcus aureus. If a cellulitis doesn't respond within 24-48 hours to one of the above antibiotics, you should reevaluate the patient.

Fungal Infections Tinea Pedis - Athlete's foot • most common dermatophytosis in the U.S. • most commonly seen in young males • induced by tight fitting footwear which produces warm, moist environment Two main clinical types: Interdigital - begins between the 4th and 5th toes. Symptoms include: malodor, hyperkeratosis, maceration, scaling, intense pruritus Moccasin appearance - scaling around heel and sole. Variable pruritus. Tinea Corporis - ringworm of the body typically involves the smooth skin of the trunk and extremities most common presentation is ring-shaped lesion with a scaly erythematous border and central clearing. Tinea cruris - jock itch occurs in the groin area in men often associated with a concomitant athlete's foot lesions have sharply demarcated, erythematous borders. Asymmetric scaly plaques with central clearing. Very pruritic. Penis and scrotum usually not involved. Treatment - same agents are used for all three types Over the counter preparations: Clotrimazole 1% - Lotrimin Miconazole 2% - Micatin Tolnaftate 1% - Tinactin, Aftate Undecylenic Acid and Undecylenate Salts - Desenex, Cruex All the above meds are about equal in efficacy. • For active infection, use cream preparation. Wash the affected area with soap and water and dry thoroughly. Apply cream sparingly and rub in completely. • Make take several days before improvement is seen and two to four weeks for complete disappearance of signs and symptoms. • Preventative measures should also be discussed with patient: i.e. change socks daily, allow shoes to dry between wearings, wear shower shoes, switch to boxer shorts for jock itch, etc. Talcum powder can be used as drying agent. Can also use medicated antifungal powders - not as effective for treatment of active infection, but may be useful in prevention in patient with recurrent infections.

Incretin Based Therapy Incretin System. In healthy patients the ingestion of food results in the release of gastrointestinal peptides, including GLP-1 (Glucagon Like Peptide 1), GIP (Gastric Inhibitory Peptide)(not shown), as well as the pancreatic beta cell hormones insulin and amylin. GLP-1 is released from "L cells" located in the small bowel & colon. Following the absorption of food, GLP-1 promotes insulin secretion, otherwise known as the incretin effect. As illustrated, GLP-1 (and its mimetics, such as exenatide) have at least 4 mechanisms by which they can reduce plasma glucose levels. Both GLP-1 and amylin mimetics have inhibitory effects on gastric emptying, and appetite. (Amylin mediates its effects by different receptors than GLP-1). After secretion, GLP-1 is rapidly metabolized by the enzyme DPP-4 (dipeptidyl peptidase-4) in the liver. The plasma half-life of GLP-1 is ~ 2 minutes. DPP-IV inhibitors such as sitagliptin inhibit the breakdown of GLP-1 by DPP-4. Note that DPP-IV inhibitors will only produce an effect when blood sugar is elevated, causing the release of GLP-1 from the small intestine.

GLP-1 agonists (exenatide & liraglutide) result in stimulation levels that are >5-fold higher compared to peak physiologic levels of GLP-1. In contrast, DPP-4 inhibition only results in about a ~2-fold increase in GLP-1, within the physiologic range. DPP-4 inhibitors do not inhibit gastic emptying, while GLP-1 agonist do. GLP-1 agonists, but not DPP-4 inhibitors, have been observed to increase satiety, decreased food intake and a reduced preference for fat & simple carbohydrates in animal models. As an expected result, DPP-4 inhibitors have been found to be weight neutral in clinical trials, compared to weight loss seen with GLP-1 receptor agonists. Diagram and description from

Pharmacoeconomics Note: Pregabalin (Lyrica) is widely studied and labeled for use in DPN, is given twice daily, and does not need to be dose adjusted in renal dysfunction. Why would you ever want to use gabapentin (Neurontin) instead? Both drugs have the similar mechanisms of action, but gabapentin must be given three times a day, must be dose adjusted for renal dysfunction, and takes longer to titrate up to an effective dose. The answer: Cost! Pregabalin is only available as the brand name Lyrica and costs $400/month. Gabapentin is available as an inexpensive generic that costs $20-30/month.

Gastroparesis Diabetic gastroparesis is a common complication of diabetes. It is caused by delayed gastric emptying and presents as early satiety, bloating, nausea, vomiting and abdominal pain. Management: Eat several small meals each day. Metoclopropamide (Reglan) may stimulate motility. Metoclopropamide stimulates cholinergic receptors in the g-i tract and acts centrally as an anti-emetic. Metoclopropamide also inhibits dopamine activity in the CNS and can have extrapyramidal side effects (similar to the antipsychotic drugs but to a lesser degree) including the development of tardive dyskinesia. Long term therapy with metoclopropamide should be avoided unless absolutely necessary. It is given three to four times a day, usually 30 minutes prior to meals. Erythromycin is an antibiotic that stimulates gastric motility by binding to motilin receptors in the gastrointestinal tract. The g-i side effects of erythromycin are the most troublesome side effects when it is used as an antibiotic. It has been studied in limited numbers of patients for use in gastroparesis with some success, and is another alternative for the management of gastroparesis.

Glargine (Lantus), Detemir (Levemir), Insulin Degludec (Tresiba) are long-acting insulin analogues.

Glargine has a different amino acid at position 21, thus changing the insulin's absorption characteristics. It is in solution in the bottle, but precipitates at physiologic pH in the subcutaneous tissue when injected. It is long-acting, with no peak, and is usually given at night. It is designed to mimic the body's basal insulin secretion. Detemir has a free fatty acid attached to the insulin molecule which causes it to bind to albumin the subcutaneous tissue. It is slowly released from the albumin and thus provides a slow and consistent release of insulin. It is also a basal insulin; it needs to be given twice daily in many patients. Degludec has a different amino acid at position 30 and a fatty acid attached. It forms multiple hexamers in the subcutaneous tissue after injection and thus has a delayed duration of action. It's duration of action is longer than the other two insulins in this class.

Insulin receptor stimulation activates glucose transporters on the plasma membranes of insulin-sensitive tissues

Glucose and amino acids from food stimuli in the gut sends signals to the pancreatic beta cells. These signals lead to the depolarization of the beta cells and the release of insulin into the portal vein. The insulin travels in the portal vein through the liver before being diluted in the general circulation. The insulin binds to insulin receptors on various tissues and cells and affects the storage and use of carbohydrate, fat, and protein.

Inhaled Insulin (Afrezza)

Has as onset of action similar to lispro. Duration is a little shorter than lispro Can be used to provide premeal insulin Advantage: Not injected (but patient's will still need to inject a long acting basal insulin) Disadvantages: Twice as expensive as Humalog, only available in 4 and 8 unit doses so can't finely tune the amount of insulin given, may cause bronchospasm and shouldn't be used in patients with lung disease

Risks of HRT Endometrial Cancer Prolonged unopposed estrogen therapy causes hyperplasia of the endometrium and increases the risk of endometrial cancer by 4-6 times. Adding progestin for at least 12 days each month negates this risk by decreasing the endometrial hyperplasia. Breast Cancer Breast cancer risk increases in EPT users beyond 5 years. The Women's Health Initiative (WHI) progestin/estrogen trial (see below) found an 26% higher risk of breast cancer in patients taking EPT for > 5 years versus those taking placebo. In the ET arm of the trial, women taking estrogen alone had no increased risk of breast cancer after an average 7 years of use. Coronary Heart Disease For a long time, it was assumed because post-menopausal women have a much higher incidence of CHD than pre-menopausal women, that replacing the estrogen would decrease the risk of heart disease. However in the last several years, two large scale, well done trials have been reported in which women receiving hormone replacement therapy (estrogen/progestin) not only didn't have a reduced risk of heart disease, they had an increased risk of heart disease. Thromboembolism and Stroke The use of HT is associated with an increase in the risk of stroke and a larger increase in the risk of thromboembolism. The WHI progestin/estrogen trial found a 41% increase in the risk of stroke (29 cases of stroke/10,000 women/year in the treatment group versus 21 cases/10,000 women/year in the placebo group), and a two fold increase in risk of thromboembolism (34 cases/10,000 women/year in the treatment group versus 16 cases/10,000 women/year in the placebo group). The WHI estrogen alone trial had similar results (44 cases of stroke/10,000 women/year in the treatment group versus 32 cases/10,000 women/year in the placebo group).

Hormone Therapy Products Estrogens Conjugated Estrogens (Premarin) Estropipate (Ogen) Ethinyl estradiol (Estinyl) Micronized estradiol (Estrace) Esterified estrogens (Estratab) Estradiol transdermal system (Estraderm) Progestins Medroxyprogesterone (Provera and other brands Norethindrone/norethindrone acetate Combination Products Conjugated estrogens plus medroxyprogesterone (Prempro) Esterified estrogens plus methyltestosterone (Estratest) Estrogen plus methyltestosterone (Estratest) : May provide additional benefit in women who have vasomotor symptoms refractory to estrogen alone, or for women with decreased libido after menopause. Adverse effects of the methyltestosterone include mild facial hair in 10-20%, acne.

Usual Daily Doses of Insulin Insulin dosing regimens are initiated empirically then adjusted according to blood glucose results. The following table lists usual total daily doses of insulin. It is useful to have this information so that you can quickly assess -- is this patient using a low, normal, or high amount of insulin daily? Usual Daily Doses of Insulin Type1: Initial Dose 0.5-0.8 u/kg/day Type 1: with ketosis, during illness, during growth spurt 1-1.5 u/kg/day Type 2: with insulin resistance 0.7-1.5 u/kg

Insulin Regimens Intensive insulin therapy is preferred for most patients with Type 1 diabetes. The ideal insulin regimen will mimic normal insulin secretion as closely as possible; it will deliver a basal (continuous) amount of insulin throughout the day and night with increases in insulin for each meal. Insulin pump therapy Insulin pumps are portable, programmable pumps designed to deliver regular insulin, insulin lispro, insulin aspart, insulin glulisine from a reservoir to a subcutaneously inserted catheter or needle. They can be programmed to deliver a continuous, basal amount of insulin and the user can deliver pre-meal bolus amounts of insulin. The pre-meal bolus amount is determined by the number of carbohydrates in the meal. The pumps are expensive and require a motivated, well educated patient. Multiple Daily Injections of Insulin Your book discusses various strategies to provide a physiologic insulin regimen. It will require multiple daily injections of insulin. A traditional approach was to give a dose of NPH insulin mixed with regular insulin in the morning and in the evening. While this approach is convenient for the patient because it requires only two injections a day, it won't achieve blood glucose goals for most patients with Type 1 diabetes. It may be enough for patients with Type 2 diabetes who are secreting their own endogenous insulin.

Management of Hypothyroidism (ch.44, p. 679) Thyroid hormone pathophysiology Thyroid hormone controls the metabolic activity of all tissues by regulating genes whose protein products are critical for cellular respiration. Physiologic effects of thyroid hormone include: Fetal development (physical and cognitive) Metabolic rate Body temperature Cardiac rate and contractility Peripheral vasodilation Red cell mass and circulatory volume Respiratory drive Peripheral nerve reflexes Hepatic metabolic enzymes Bone turnover Skin and soft tissue effects

Iodide is actively transported into thyroid epithelial cells. Thyroid peroxidase catalyzes the iodination of tyrosine, creating monoiodotyrosine and diiodotyrosine in thyroglobulin. Thyroid-stimulating hormone (TSH) causes stored thyroglobulin to undergo exocytosis and release thyroid hormone. A large proportion of the circulating T-3 and T-4 is bound to proteins; only the free (unbound) hormone is active but older T-3 and T-4 lab tests measure both the bound and unbound hormones. Thyroxine (T-4) undergoes deiodination to triiodothyronine (T-3) in peripheral sites such as the liver. T-3 acts at it's various target sites.

Glycopeptides - Vancomycin The only glycopeptide available in the U.S. is vancomycin. Vancomycin inhibits bacterial cell wall synthesis by interfering with an early step in the peptidoglycan formation of the cell wall. Antibacterial spectrum: Vancomycin can't cross the cell membrane of gram-negative bacteria and thus is only active against gram-positive bacteria. It isn't a beta-lactam antibiotic so it is not affected by beta-lactamase enzymes. Vancomycin also binds to a different site from the beta-lactams. It is active against bacteria that are resistant to beta-lactam antibiotics, such as methicillin-resistant staphylococcus aureus (MRSA). Vancomycin is almost always given parenterally but can be given orally to treat Clostridium difficile. Adverse reactions: Red neck syndrome -- when vancomycin is infused rapidly, it can trigger a release of histamine which leads to a flushing sensation and transient rash. This can be prevented by infusing the vancomycin over 2 hours. High serum levels of vancomycin may cause nephrotoxicity or ototoxicity, particularly in patients receiving concomitant aminoglycosides. Vancomycin levels are often drawn to determine the correct dose in patients with renal insufficiency.

Macrolides The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting protein synthesis. The drugs in this class include: Erythromycin Azithromycin (Zithromax) Clarithromycin (Biaxin) Spectrum of activity: Erythromycin is effective against the same organisms as penicillin G, and is a good alternative in patients allergic to penicillin. In addition, it provides coverage against chlamydia, mycoplasma, and legionella. Clarithromycin provides the same coverage plus H. influenzae. Azithromycin has less activity against streptococci and staphylococci, but more activity against H. influenzae and Moraxella catarrhalis. The macrolides are often used in the management of respiratory infections. Resistance to the macrolides: Alteration in the bacterial ribosome -- resistance to the macrolides develops when the bacterial ribosome changes so that the macrolide can't bind to it. Adverse reactions: Gastrointestinal: Erythromycin activates motilin ( a gastric hormone) receptors, thus initiating gastric peristalsis. The incidence of anorexia, nausea, vomiting is about 20-25% This occurs much less often with clarithromycin or azithromycin (less activation of motilin receptors). Drug Interactions: Erythromycin (and to a lesser degree clarithromycin) inhibits the cytochrome P-450 3A4 and will decrease the metabolism of several drugs such as theophylline, warfarin, and carbamazepine. Azithromycin has negligible effects.

Signs and Symptoms of acute otitis media fever otalgia lethargy irritability anorexia tugging of ear lobes fluid in middle ear opaque, bulging tympanic membrane Diagnosis of acute otitis media To diagnosis acute otitis media, the clinician should confirm a history of acute onset, identify signs of middle-ear effusion, and evaluate for the presence of signs and symptoms of middle-ear inflammation. Signs of middle-ear inflammation include: distinct erythema of the tympanic membrane, and distinct otalgia. Diagnostic Criteria for Acute Otitis Media A diagnosis of AOM requires a history of recent, usually acute, onset of signs and symptoms of middle ear inflammation and effusion in the presence of either distinct erythema of the tympanic membrane or distinct otalgia (discomfort clearly referable to the ear that results in interference with, or precludes, normal activity or sleep). The presence of middle ear effusion can be present as bulging of the tympanic membrane, limited or absent mobility of the tympanic membrane, air-fluid level behind the tympanic membrane, or otorrhea. Consensus Recommendations A diagnosis of otitis media can be established if purulent otorrhea of <24 hours (not otitis externa), or if two of four tympanic membrane abnormalities (i.e., middle ear effusion) are present as: (a) Marked decrease or absent mobility; (b) Yellow/white discoloration; (c) Opacification (other than from scarring); (d) Air-fluid interfaces WITH One indicator of inflammation as: (a) New ear pain (± unaccustomed ear pulling); (b) Marked tympanic membrane redness; or (c) bulging tympanic membrane From: American Academy of Pediatrics and the American Academy of Family Practitioners (AP/AAFP) Subcommittee on Management of Acute Otitis Media as presented in Table 96-1 Applied Therapeutics The Clinical Use of Drugs 9th edition. Microbiology of acute otitis media. The organisms that cause acute otitis media are similar to those that cause acute bacterial rhinosinusitis. Streptococcus pneumoniae (33%) Hemophilus influenzae (20-30%) Moraxella catarrhalis (up to 16%)

Management of Acute Otitis Media Assess and treat pain Acetaminophen or ibuprofen can be used for mild to moderate pain associated with acute otitis media. Topical benzocaine (similar to Auralgan - order the generic because it is much cheaper) provides additional but brief benefit over acetaminophen. Is only labeled for use in patients > 5 yrs; there is no evidence of harm in children less than 5. The main disadvantage is that a few patients exhibit a contact allergy to benzocaine. Opioid analgesics such as acetaminophen with codeine (Tylenol 3) may be needed for moderate or severe pain. Watchful waiting Whether treated or not, about 60% of children who have acute otitis media are symptom-free within 24 hours. Antibiotic use in the other 40% reduces the duration of symptoms by about one day. American Academy of Pediatrics: Clinical Practice Guideline: The Diagnosis and Management of Acute Otitis Media Pediatrics February 25, 2013 http://pediatrics.aappublications.org/content/early/2013/02/20/peds.2012-3488.full.pdf html Age Diagnosis is Certain Diagnosis is Uncertain <6 mo Start antibiotics immediately Start antibiotics immediately 6 mo to 2 yr May start antibiotics immediately or offer watchful waiting for non-severe illness Watchful waiting for non-severe illness (mild otalgia, fever <39°C).Start antibiotics immediately for severe illness (moderate to severe otalgia, fever >39°C) >2 yr Start antibiotics immediately for severe illness. May start antibiotics immediately or offer watchful waiting if illness is nonsevere. Watchful waiting Watchful waiting: Defer antibiotic therapy for 48-72 hours. Only appropriate when follow-up can be ensured and antibiotics started if symptoms persist or worsen. The prescription can be called into a pharmacy, thus avoiding the need for another clinic visit. Certain Diagnosis: 1) Rapid onset 2) signs of middle ear effusion 3) signs and symptoms of middle-ear inflammation

Upper Respiratory infection (also known as the Common Cold) (Ch. 72, p. 1077) The common cold is an acute, communicable, viral illness which lasts about seven days. Children ages 2 to 5 yrs have up to 8.3 colds per year. Clinical presentation Nasal congestion, watery rhinorrhea, sneezing Sore throat - present in 50% of patients Headache, general malaise Management of Nasal Congestion Normal Saline Nose drops Humidification of inspired air (vaporizers) Increased fluid intake Sympathomimetics (Decongestants) Antibiotics are not indicated unless secondary bacterial infection is present. Sympathomimetic Decongestants Drugs in the Class: Pseudoephedrine (Sudafed) Phenylephrine (Neo-synephrine) Naphazoline (Privine) Oxymetalozone (Afrin) Tetrahydrozoline (Tyzine) Mechanism of action: Sympathomimetics directly stimulate a -adrenergic receptors resulting in vasoconstriction. This results in decreased tissue hyperemia, decreased tissue edema, decreased nasal congestion, and improved nasal airway patency. Adverse effects: Oral : can cause nervousness, irritability, insomnia. Topical: Continued use can lead to severe rebound congestion.

Management of Cough Cough is a reflex triggered by mechanical or chemical stimulation of the upper respiratory tract, or by central stimuli. It serves to expel foreign bodies and unwanted material from the airways. First generation antihistamine/decongestant (e.g. brompheniramine plus pseudoephedrine - Dimetapp) - This combination is recommended by American College of Chest Physicians in recently published guidelines (see link above) to treat an acute cough associated with the common cold in adults. The assumption is that the cough is due to a combination of post-nasal drip, direct irritation, and inflammation of cough receptors in the upper airway. The FDA has issued an advisory recommending that over-the-counter cough and cold products NOT be used for infants and children under the age of 2 because serious and potentially life-threatening side effects can occur; they also urge caution if these products are used in older children. Expectorants are used to increase respiratory tract secretions and increase productive cough Good hydration is best expectorant. Guafenesin (Robitussin) is marketed as expectorant but has not been shown to be efficacious in objective studies. Cough suppressants/Antitussives - decrease the frequency of cough, but also decrease the clearance of secretions Use cough suppressants only when dry, non-productive cough disturbs sleep. Dextromethorphan is the d-isomer of levorphanol and has antitussive properties without analgesic properties. Codeine is also used as an antitussive in prescription cough syrups Taylor, et. al. looked 49 children ages 18 months to 12 years who had a significant night cough of less than 14 days duration. The children were randomized into three groups: codeine, dextromethorphan, placebo. The results found that all three groups were equal with regard to reduction in cough score. (Taylor, Novack, et al. Efficacy of cough suppressants in children. J Pediatrics 1993; 122: 799-802) The recent ACCP guidelines for the diagnosis and management of cough specifically say that cough suppressants are not recommended for an acute cough associated with an upper respiratory infection because of limited efficacy.

Nephropathy Diabetes is now the most common single cause of end stage renal disease (ESRD) in the U.S. This is due to the fact that diabetes is increasing in prevalence, diabetic patients now live longer than in the past, and patients with diabetic renal disease are now being accepted for treatment in ESRD programs. Manifestation of Diabetic Renal Disease: Nephropathy first manifests as microalbuminuria (>30 mg/day urinary albumin excretion). This progresses over 10-15 years to overt nephropathy or clinical albuminuria (>300 mg albumin/24 hr) with hypertension also developing. Once overt nephropathy develops, 50% of patients with Type 1 diabetes will have ESRD within 10 years and 75% by 20 years. Patients with Type 2 diabetes are less likely to develop ESRD even if they have overt nephropathy.

Management of Diabetic Renal Disease: Annual urinalysis and screening for microalbuminuria Blood Glucose control - the DCCT trial has shown that intensive diabetes therapy will reduce the risk of developing nephropathy. Hypertension Control - hypertension will markedly accelerate the progression of diabetic nephropathy and appropriate antihypertensive therapy will greatly decrease the progression of the renal disease. Goal blood pressure should be <140-130/80, according the American Diabetes Association guidelines ACE inhibitors and Angiotensin Receptor Blockers Many studies have shown that in patients with Type 1 diabetes and hypertension, ACE inhibitors or ARBs can reduce the rate of progression of renal disease to a greater degree than other antihypertensive agents that lower the blood pressure by an equal amount. It has also been shown that ACE inhibitors or ARBs will reduce the progression of microalbuminuria in patients with Type 1 diabetes and normotension. It is postulated that this is because once the nephrons are damaged by the diabetes they becomes more sensitive to Angiotensin II, which further damages the nephrons. Therefore it is recommended that all hypertensive diabetic patients should receive ACE inhibitors or ARBs as their first antihypertensive drug. Furthermore, ACE inhibitors or ARBs should also be given to patients with Type 1 diabetes and microalbuminuria even if normotensive.

Treatment Approach to Type 2 Diabetes ADA Standards of Medical Care in Diabetes 2017 Each year the American Diabetes Association publishes standards of care regarding diagnosis and treatment of diabetes. It is a long document and you don't need to print but should be aware that this is a great resource for updated information about diabetes. Two algorithms from this document are presented below and you can find more information by going to the original document.

Management of hyperglycemia in type 2 diabetes,2015: A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Inzucchi SE et al. Diabetes Care 2015 Jan; 38 (1):140-149. provides additional nomograms for special circumstances (you'll find them in the supplementary data section of the guidelines): If it is necessary to minimize cost, Metformin plus a Sulfonyurea are the preferred two drug combination, and NPH and regular insulin are the preferred insulins. Metformin and a second generation sulfonylurea such as glipizide or glyburide are available as generics and are inexpensive (as low as $4/month). NPH insulin and regular insulin cost $150/vial compared to Humalog and Lantus at $300/vial. The other newer oral agents cost $300-400/month each. If avoiding hypoglycemia is important, insulin and sulfonylureas are removed from the nomogram. If avoiding weight gain is important, sulfonylureas, TZDs, and insulin are removed from the nomogram.

Peripheral Neuropathy Painful diabetic peripheral neuropathy is a common complication of diabetes. It usually involves the lower extremities and ranges from mild paresthesias to severe pain. It can be a difficult management problem -- drugs have been used to treat the symptoms with varying degrees of clinical efficacy.

Management: Maximize glucose control: It is thought that the peripheral neuropathy is secondary to an accumulation of sorbitol and fructose in peripheral nerve cells. It appears that intensive glycemic control will decrease the onset and progression of the neuropathy Simple Analgesics: Simple analgesia with NSAIDs should be the first line of therapy. When these no longer work, then other avenues should be explored Antidepressants:TCAs have been shown to be effective in the management of peripheral neuropathy, in patients with or without depressive symptoms; the most commonly used TCA in this setting is amitriptyline. The SNRI, duloxetine is a dual acting antidepressant (effects both serotonin and norepinephrine reuptake) that has also been shown to be effective in treating the symptoms of painful peripheral neuropathy. Duloxetine is labeled for use in treating painful diabetic neuropathy. Other SNRIs, venlafaxine and desvenlafaxine have also been used in the treatment of neuropathy but are considered second-line after duloxetine. Anticonvulsants: Pregabalin (Lyrica) or Gabapentin (Neurontin). Pregabalin is labeled for use in the treatment of painful diabetic neuropathy and has been shown in clinical trials to provide consistent pain relief. The dose needed for relief is usually 150 mg twice daily. Gabapentin has a similar mechanism of action and has also been used; the dose needed for relief varies widely, from 400 mg three times daily to 1200 mg three times daily. Capsaicin: Capsaicin-P is a non-prescription cream that contains the active ingredient in hot peppers. Capsaicin impedes the conduction and transmission of peripheral pain impulses. It is used with limited success in the management of shingles, and can be tried in diabetic peripheral neuropathy. Topical Lidocaine: The lidocaine 5% patch (Lidoderm) is labeled for use in post herpetic neuralgia but may also provide relief for painful diabetic neuropathy. Opioid-like Medications:Tramadol (Ultram) and tapentadol (Nucynta) have both shown some effectiveness in managing diabetic peripheral neuropathy pain. Tramadol is available as a generic and is inexpensive ($20/month); tapentadol is only available as the brand name Nucynta and is expensive ($500/month).

Sodium Glucose Transporter 2 (SGLT2) Inhibitors The kidney normally filters about 180 g/day of glucose in the glomerulus and less than 0.5 g/day is excreted in the urine. Glucose is not excreted in the urine until the blood glucose levels rise above 180 mg/dl (renal threshold). Glucose reabsorption occurs in the proximal tubule through the action of glucose transporters, SGLT1 and SGLT2. The SGLT2 inhibitors stop the action of the SGLT2; glucose is excreted in the urine when the blood glucose is >80 mg/dl. Overall glucose loss is 80-100 g/day. Drugs in the Class: Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empaglifozin (Jardiance) Also Glyxambi - empaglifloxin/linagliptin combination, and Synjardy XR - empagliflozin/metformin combination Clinical Use: Once daily oral medicine Easy to take, well tolerated in most patients Lower postprandial hyperglycemia and will reduce Hgb A1c by about 1% Promotes weight loss through excretion of glucose

Mechanism of Action: Increases excretion of glucose in urine through inhibition of SGLT2 Adverse effects: Genitourinary yeast infections - related to increases in glucose in urine Hypotension related to volume depletion - particularly in elderly, patients with impaired renal function, patients on diuretics. Make sure patient is well hydrated before starting drug. Hyperkalemia in patients taking ACE inhibitors or ARBs Increased risk of amputations - specific to canagliflozin (Invokana) - in 2017, the FDA added a boxed warning to the label of canagliflozin saying that it increases the risk of amputations. The warning comes because of data from two trials (CANVAS and CANVAS-R) showed a doubled rate of leg and foot amputations in patients receiving canagliflozin as compared to placebo. It is unclear at this time why this was seen with canagliflozin and not seen in the other SGLT2 inhibibitor trials.

Progestins Progesterone is the primary endogenous progestin. The functions of the progestins include: Mammary gland development and ductal growth Maintain uterine lining (in combination with estrogens) Help maintain pregnancy Inhibit uterine contractions Decrease HDL, Increase LDL

Menstrual Cycle Follicular phase The follicular phase begins at the onset of menstruation and lasts about 14 days. Estrogen levels begin to increase, and follicles mature, producing increasing estrogen. Ovulatory Phase Estrogen levels rise to above 200 pg for at least 50 hours, thus stimulating the pituitary to release a surge of luteinizing hormone. This triggers ovulation Luteal or Secretory Phase The luteal phase the progesterone dominant phase. The corpus luteum produces progesterone and estrogen, thus thickening the endometrium in preparation for implantation of the fertilized ovum. If implantation doesn't occur by day 23 to 25, the corpus luteum regresses and estrogen and progesterone levels decrease and the endometrium sloughs (menstruation).

Levothyroxine Dosing Guidelines for Hypothyroidism in Adults Non pregnant patients 1.6 mcg/kg ideal body weight /day initial dosing; titrate to TSH [male IBW = 50 + 2.3 kg for each inch over 5 feet; female IBW = 45 + 2.3 kg for each inch over 5 feet] Older adults; adults with CVD 25 or 50 mcg/day initially, increase by 25 mcg/day at monthly intervals until 1.6 mcg/kg/day dose is achieved Pregnant patients already being treated with levothyroxine Increase to nine doses weekly (one extra dose two days/wk) at the earliest knowledge of pregnancy. Dose will be titrated to trimester specific TSH ranges Patients with subclinical hypothyroidism TSH <10 mIU/L. Start with 50 mcg/day; increase by 25 mcg/day every 6 weeks until TSH within lab normal range.

Mild (Subclinical) Hypothyroidism TSH > lab limits of normal but below 10 mIU/l and no signs or symptoms of hypothyroidism May be a risk factor for cardiovascular mortality, elevated LDLs, mood changes, and decreased exercise tolerance. Thyroid replacement therapy should be considered for those with non-specific or subtle symptoms such as fatigue or lethargy, elevated cholesterol, heart disease, high cardiovascular risk, positive antithyroid peroxidase antibodies (because this indicates that they have a high likelihood of progressing to symptomatic hypothyroidism), infertility, or pregnancy. May not need a full dose of levothyroxine initially because thyroid gland is still producing some of its own thyroid hormone

Carbapenems The carbapenems also interfere with the last step of bacterial cell wall synthesis. There are two drugs in this class: Imipenem with cilastin (Primaxin) Meropenem Antibacterial spectrum: The carbapenems are broad spectrum antibiotics with activity against streptococci, staphylococci, enterobacteraciae, Pseudomonas aeruginosa, H. influenzae, and anaerobic bacteria. They are reserved for treatment of life-threatening infections in hospitalized patients. Adverse reactions: Imipenem with cilastin Nephrotoxicity - imipenem is broken down in the kidney to a nephrotoxic metabolite. The cilastin inhibits the formation of the metabolite, and thus prevents the nephrotoxicity. Seizures - imipenem can cause seizures, especially in patients with renal insufficiency or pre-existing seizure disorders. Meropenem - does not cause nephrotoxicity or seizures.

Monobactams The only available monobactam is aztreonam (Azactam). Antibacterial spectrum: Aztreonam is active against gram-negative aerobic bacilli and has no activity against gram-positive bacteria. The spectrum of activity is similar to that found with the aminoglycosides. Adverse effects: Aztreonam has few adverse effects and can be used in patients with penicillin or cephalosporin allergy.

Managing the Patient - Preventing and Treating Osteoporosis Screening for Osteoporosis: Evaluate all women at time of menopause for risk factors for osteoporosis. It is suggested a bone mineral density (BMD) measurement for post menopausal women with medical causes for bone loss regardless of age, and for all postmenopausal women at age 65 regardless of other risk factors. Consider bone density measurements at an earlier age if a postmenopausal woman has risk factors such as a history of a fracture, is thin, a smoker, or has a family history of osteoporosis in a parent. BMDs are generally done with a dual-energy x-ray absorptiometry (DEXA) scan. Results are reported as T scores, which is the number of standard deviations above or below the mean bone mineral density for sex and race matched to young controls. Patients are divided into the following categories: Normal - a T score that is 0 to -1 (within one standard deviation of the young adult reference mean) Osteopenia - low bone mass - A T score between -1 and -2.5 (between one s.d. and 2.5 s.d. below the young adult reference mean) Osteoporosis - a T score less than -2.5

Non Drug Management good for all patients Exercise - Weight bearing exercise - slows bone loss and increases strength and flexibility Minimize risk of falls - Anchor rugs, minimize clutter, remove loose wires, use nonskid mats, install handrails Decrease Modifiable Risk Factors - Stop smoking and drinking alcohol Vitamin D intake - 400 IU per day w/calcium can reduce rate of bone loss. Vitamin D enhances the small bowel absorption of calcium and is especially important if the calcium intake is marginal. Supplementation with a multi-vitamin is essential if the woman doesn't drink fortified milk or doesn't spend 30-60 minutes per day in the sun. Calcium Intake - Postmenopausal women should routinely ingest at least 1200 mg/day of elemental calcium. If a woman is diagnosed with osteopenia or osteoporosis, the treatment dose of calcium is 1500 mg/day. Calcium carbonate 500 mg tabs contain 200 mg elemental calcium each. Medications - evaluate dosages and discontinue if possible any drugs with sedative effects. Be cautious about prescribing drugs that cause orthostasis.

Combination Contraceptive Patch (Ortho-Evra) Delivers ethinyl estradiol 20 mcg/day plus norelgestromin 150 mcg/day Patch is applied once a week for 3 weeks, then a patch-free week Is useful for women who can't or won't take a pill on a daily basis but want regular monthly periods and the efficacy of a combination contraceptive Combination Vaginal Ring (Nuvaring) Releases ethinyl estradiol 15 mcg/day plus etonorgestrel 120 mcg/day into the vagina The ring is inserted high into the vagina and remains there for 3 weeks. It is removed for one week (the woman then has a menstrual period) Efficacy is comparable to oral contraceptives Good for women who can't or won't take a daily pill

Non-Contraceptive Benefits of combination oral contraceptives (COCs) Decrease menstrual flow and decrease menstrual cramps. Menstrual blood loss decreases from an average of 35 ml/mo to 20 ml/mo. COCs can also be used to treat menstrual cramps in women who don't respond to NSAIDs and non-drug therapy. Women taking COCs are less likely to have iron-deficiency anemia because they have less menstrual blood loss. Protect against ovarian and endometrial cancer. Women taking COCs have a 40-80% decrease in risk of developing endometrial cancer (because they have a decrease in endometrial hyperplasia). This decrease in risk increases with duration of therapy and persist for at least 10-15 years after stopping OC. There is also a good deal of evidence to suggest that COCs reduce the risk of developing ovarian cancer. By suppressing ovulation or altering hormonal levels throughout the menstrual cycle, it appears that COCs alter the conditions that favor development of ovarian cancer. COCs may also reduce the opportunity for cells to mutate by decreasing the number of ovarian cell divisions. Finally, a 1998 animal study suggests that progestin may cause the death of damaged ovarian cells before they become cancerous. The magnitude of the reduction in risk appears to depend on the duration of pill use—those women using the pill for a longer period of time (e.g., > 5 years) have a larger reduction in risk. Studies also suggest that the protective effect lasts for at least 10 to 15 years. Decrease benign breast disease - There is a 50-75% reduction in risk of fibroadenomas and chronic cystic breast disease in COC users. The bulk of the evidence indicates that the currently used COCs do not increase the risk of breast cancer. Improve acne (some products) - Some oral contraceptives with low androgenic activity (Ortho Tri-Cyclen is one) have been shown in controlled trials to decrease acne and are marketed for this. Any product with a low androgenic effect should provide comparable results.

Managing Menopausal Symptoms There are two issues in the management of menopause: 1) Alleviating the symptoms - primarily vasomotor and genitourinary 2) Decreasing the incidence of long term risks of menopause - increases in cardiovascular disease and osteoporosis. Short-term Management of Symptoms Estrogen therapy will relieve hot flushes and genitourinary symptoms. It is now recommended that if estrogen replacement is used for the alleviation of these symptoms, the lowest dose possible for the shortest period of time be used. If the symptoms are primarily genitourinary, consider using topical estrogen only. Some of the estrogen is absorbed systemically but the amount is small and even women with an intact uterus can receive vaginal estrogen for genitourinary symptoms (without progestin). Many clinicians recommend that when discontinuing estrogen, you should taper the dose. Taper by lowering the dose to the lowest dosage strength available and then decrease the number of days per week the drug is taken (i.e. go to every other day therapy, every third day, etc).

Non-estrogen therapy for vasomotor symptoms (hot flushes): SSRIs - venlafaxine and paroxetine have been used with some success. The dose is half the dose used in the management of depression. Clonidine (Catapres) is more effective than placebo in reducing menopausal flushes but is less effective than estrogen therapy. Gabapentin (Neurontin) has been shown in one study to decrease the number of hot flushes. Soy - it appears that consumption of soy protein may decrease the incidence and severity of hot flushes. Herbal medicines - black cohosh, yam root, Chasteberry have been used. Long-term Prevention of Disease It is recommended that neither estrogen and progestin nor estrogen alone be used for solely for the prevention of chronic conditions in postmenopausal women. There is fair to good evidence that HT decreases the risk for osteoporosis and colon cancer, there is also fair to good evidence that EPT increases the risk for breast cancer, and HT increases the risk of venous thromboembolism, coronary heart disease, stroke, and cholecystitis. The harmful effects of HT are likely to exceed the chronic disease prevention benefits in most women Potential Long-Term Benefits of HRT Osteoporosis Estrogen therapy decreases the rate of bone loss after menopause. We'll talk more about this in the osteoporosis section of the module. Colorectal Cancer Estrogen/progestin therapy will decrease the risk of colorectal cancer by 20%. This finding has been consistent in most studies that have looked at this.

Emergency Contraception - is the use of a method after intercourse to prevent pregnancy. Also Known As: Morning after pills Postcoital contraception Secondary contraception These terms do not convey the correct timing of use nor that they should only be used for emergencies, so the preferred term is emergency contraception Candidates for Emergency Contraception Women of reproductive age who've had unprotected intercourse within the last 72 - 120 hours. (The sooner the better but there is evidence that the pregnancy rate is decreased even when taken 120 hours after intercourse) How does emergency contraception work? Emergency contraception is thought to prevent pregnancy by disrupting ovulation, fertilization, gamete transport, and/or implantation. (This is a controversial statement - see: NY Times article) Emergency Contraception Methods Combination Oral Contraceptives The Yuzpe method of emergency contraception involves giving ethinyl estradiol 100 mcg and levonorgestrel 6.5 mg (or an equivalent amount of another progestin) twice 12 hours apart. You can use regular combination oral contraceptives to achieve this dose. Many references tell the appropriate dose (e.g. Lo/Ovral 4 white (active) pills now and 4 pills 12 hours later).

Oral Contraceptive Pills That May Be Used As Emergency Contraception Brand Tablets per Dose Color Alesse 5 Pink Aviane 5 Orange Cryselle 4 White Enpresse 4 Orange Lessina 5 Pink Levlen 4 Light-orange Levlite 5 Pink Levora 4 White Lo-Ovral 4 White Low-Ogestrel 4 White Nordette 4 Light-orange Ogestrel 2 White Ovral 2 White Ovrette 20 Yellow Plan B 1 White Portia 4 Pink Preven 2 Blue Tri-Levlen 4 Yellow Triphasil 4 Yellow Trivora 4 Pink Nausea and vomiting is a significant problem with this method. It is recommended that an antiemetic be administered just before each dose. You can give meclizine 50 mg or metoclopramide 10 mg.

Alternative or Herbal Remedies for Colds Coltsfoot - herbal antitussive Has a mucilage component which is a polysaccharide secreted by plant cells that when dissolved in water forms a viscous gel that coats the surface of mucous membrane - thus perhaps soothing it. Contains pyrrolizidine alkaloids (Pas) which have been associated with hepatoxicity. The Pas attack hepatic cellular nucleophiles - toxicity has not been reported with coltsfoot specifically but it is a possibility because of the presence of the Pas Echinacea was a traditional medicine of Native Americans in the Central Plains of this country. In laboratory animals it has been shown to increase the phagocytic and bacteriocidal activity of macrophages (WBCs). The exact active ingredient is not known - several alkaloids have been isolated but it is not clear if one is responsible for the activity or if it is the combination together that provides benefit. It appears to be safe. A Cochrane review (Linde 2006) concluded that some preparations of Echinacea may be effective for the early treatment of colds in adults, but results from clinical trials are not consistent.

Otitis Media Although otitis media is predominantly seen in the pediatric population, we have included this content in this course because it underscores the importance of using antibiotics in a prudent and cost effective manner. Otitis Media is the presence of fluid in the middle ear caused by infection, allergy or anatomic or functional alterations of the middle ear or eustachian tube. It is divided into 2 syndromes: Acute Otitis Media (AOM) - an acute disease that produces signs and symptoms of local or systemic infection such as earache, fever, and a bulging yellow or red tympanic membrane. Otitis Media with Effusion (OME) - is characterized by fluid buildup in the middle ear and the patient is asymptomatic aside from diminished hearing. Often OME follows an episode of AOM. It is important in treatment to distinguish between the two syndromes because in most cases of OME, antibiotics are not indicated. Acute Otitis Media Epidemiology 71% will have at least one episode by age three 33% will have three or more episodes by age three Most cases occur between six and 36 months of age Seasonal variation: AOM occurs more often in winter months Pathophysiology The health of the middle ear is dependent on the drainage and aeration provided by the eustachian tube. The eustachian tube is shorter and more flattened in infants and young children and is more susceptible to clogging than in adults. Any factor that induces inflammation of the upper respiratory tract with the resultant blockage of the eustachian tube can lead to infection in the middle ear. Conditions that cause inflammation of the upper respiratory tract and predispose to blockage of the eustachian tube include: viral respiratory infections, second hand smoke. Blockage of the eustachian tube can also lead to otitis media with effusion -- the middle ear isn't acutely infected with a bacterial pathogen but it is full of non-infected fluid.

Community Acquired Pneumonia (Ch. 71, p. 1065) Pneumonia is an inflammation of lung parenchyma which is most commonly caused by infection. The focus of this section will be on the treatment of community-acquired pneumonia. Pneumonia is the sixth most common cause of death in the United States Community acquired pneumonia is more likely to present in the winter months. Mortality rate in patients hospitalized with community acquired pneumonia is about 15% and the mortality rate is <1% in non-hospitalized patient. Clinical Presentation Community Acquired Pneumonia (CAP) is defined as an acute infection of the lungs that is associated with symptoms of acute infection and is accompanied by an infiltrate on the chest X-Ray in a patient not hospitalized or residing in a long term care facility for > 14 days before the onset of symptoms. Signs and symptoms include: fever tachycardia tachypnea productive cough change in the amount or character of the sputum pleuritic (knife-life) chest pain inspiratory lag on affected side decreased breath sounds infiltrate on chest x-ray Management of Community Acquired Pneumonia The decision about whether or not to hospitalize a patient with community acquired pneumonia is a clinical challenge. The IDSA 2007 guidelines suggest that severity-of-illness scores, such as the CURB-65 criteria (confusion, uremia, respiratory rate, low blood pressure, age 65 year or greater), or prognostic models such as the Pneumonia Severity Index be used to help decide where to treat a patient with CAP.

Pathogen Comments Streptococcus pneumoniae Most common cause of community acquired pneumonia. Is the cause of 2/3 of cases of bacteremic pneumonia. Haemophilus influenzae More commonly seen in patients with COPD Mycoplasma pneumoniae Can cause pneumonia in healthy adults of any age Chlamydia pneumoniae Respiratory viruses Legionella spp Generally doesn't cause pneumonia in healthy young adults; is associated with epidemic legionaire's disease Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella spp. are often called atypical organisms. This is because they are not detectable on Gram stain nor are they cultured using standard bacterial culture media.

Resistance to the beta-lactam antibiotics There are four primary ways that bacteria become resistant to the beta-lactam antibiotics: Production of bacterial enzymes that destroy the beta-lactam ring. These enzymes are called beta-lactamases. For example, most staphylococcus aureus bacteria are resistant to penicillin G because they produce a beta-lactamase enzyme that destroys the Pen G. Alteration of the target site where the antibiotic binds to the bacteria. For example, penicillin-resistant streptococci have altered penicillin-binding proteins, and the penicillin can't bind to the bacteria and thus can't kill the bacteria. Reduced bacterial cell membrane permeability. Gram negative organisms develop resistance to the beta lactam antibiotics through this mechanism. Presence of an efflux pump. Gram negative organisms may develop an efflux pump which transports the beta-lactam antibiotic back across the cell membrane before it can damage the bacteria. The penicillins interfere with the last step of bacterial cell wall synthesis, thus leaving the cell membrane exposed and cell lysis occurs. They are only active against organisms with a peptidoglycan cell wall; thus they don't have activity against protozoa, fungi, or viruses. Adverse reactions The penicillins are very well tolerated by most patients; they have a high therapeutic index. Hypersensitivity (a true allergy): Anaphylaxis in 0.05%. Ampicillin rash: Maculopapular rash (not a true penicillin allergy) can occur with concurrent allopurinol or with viral illness such as mononucleosis. Diarrhea: Can occur with the use of any antibiotic. Clostridium difficile can emerge as a result of disruption of normal microorganisms.

Penicillins Antibacterial spectrum: The antibacterial spectrum varies, with the side chains of the various penicillins. Classification of Penicillins Classification Examples Overview of Microbial activity Standard penicillins Penicillin G (IV) Penicillin VK (PO) Gram-positive organisms, such as streptococcus pneumoniae. Common dental organisms such as actinomycosis Treponema pallidum (organism that causes syphilis) Aminopenicillins Ampicillin (IV/PO) Amoxicillin (PO) Gram positive organisms such as streptococcus pneumoniae, and enhanced activity against aerobic gram-negative bacilli, such as Haemophilus influenzae. Used to have activity against E.Coli, but now more than 50% of E.Coli strains are resistant. Antistaphylococcal penicillins Methicillin Nafcillin (IV) Oxacillin Dicloxacillin (PO) Staphylococcus aureus. These penicillins are not destroyed by the beta-lactamase enzyme produced by staph. aureus. Antipseudomonal penicillins Ticarcillin (IV) Piperacillin (IV) Gram-negative organisms, including pseudomonas aeruginosa. Will not kill bacteria that produce the beta-lactamase enzyme. Combinations with beta-lactamase inhibitors Ticarcillin plus clavulanic acid (Timentin) Piperacillin plus tazobactam (Zosyn) Ampicillin plus sulbactam (Unasyn) Amoxicillin plus clavulanic acid (Augmentin) Clavulanic acid, tazobactam, and sulbactam inhibit the beta lactamase enzyme produced by bacteria, This allows the ticarcillin, piperacillin, ampicillin or amoxicillin to work. The antimicrobial spectrum thus includes gram-positive organisms plus the organisms that produce beta-lactamases, such as staph. aureus, haemophilus influenzae.

The table below lists the available insulin preparation with their usual onset, peak and duration times. These times can vary from individual to individual and are just a guideline to use in planning an insulin administration strategy.

Premixed Insulin Combinations - onset and duration depends on each ingredient Insulin Type Trade Name 50% NPH: 50% Regular Humulin 50/50 70% NPH: 30% Regular Humulin 70/30 or Novolin 70/30 50% lispro protamine: 50% lispro Humalog Mix 50/50 75% lispro protamine: 25% lispro Humalog Mix 75/25 70% aspart protamine: 30% aspart Novolog Mix 70/30 70% insulin degludec; 30% aspart Ryzodeg 70/30 **lispro protamine, aspart protamine have durations of action similar to NPH insulin

Insulin consists of two polypeptide chains which are connected by two disulfide bonds. Insulin is secreted initially from the pancreas as proinsulin. While in the storage granule of the beta cell, the connecting peptide (C-peptide) is cleaved, leaving equal amounts of insulin and C-peptide. Concentration of Insulin Commercially available insulin is U-100 - 100 units insulin per ml. U200, U300, and U500 are also available as options for patients with Type 2 diabetes who have high insulin requirements (decreases the volume with each injection). The newer U200 and U300 products are only available in prefilled pens that deliver the dose in units. Species differences Historically, the insulin used for diabetes therapy was isolated from beef and pork pancreas. Beef insulin differs in structure from human insulin by 3 amino acids and pork insulin differs by 1 amino acid. Now, insulin can be made biosynthetically (usually using recombinant DNA technology) to be identical to human insulin, and human insulin has now replaced beef/pork insulin in therapy.

Prescription and Non-Prescription Insulin Older insulins are over-the counter products. When prescription laws were made, the legislators considered insulin to be so "life-sustaining" that they didn't want to provide any barriers to its accessibility, so you don't need a prescription to obtain these insulins. (It is an interesting concept, given the number of other medications that are prescription only and are similarly "life-sustaining" -- back when the original prescription laws were formulated insulin was in a class by itself). Newly developed insulins, such as lispro (Humalog), glulisine (Apidra), or glargine (Lantus), etc are prescription products because they weren't "grandfathered" like the other insulins. Onsets and Duration of Action Insulin is not stable in the gastrointestinal tract and must be administered parenterally. Insulin preparations have been formulated to provide various onsets and duration of action. A new inhaled insulin (Afrezza) was released in the past year; another inhaled product (Exubera) was available a few years ago and had such disappointing sales that it was removed from the market by its manufacturer. It remains to be seen if Afrezza will succeed.

Progestin-Only Injectable Contraceptives Depo-Provera (DMPA) - medroxyprogesterone actetate. Is given as an IM shot once every 12 weeks. Is very effective (0.3% pregnancy rate in 1st year) Disadvantages include: irregular bleeding and spotting. By one year, about 50% are amennorheic. Weight gain can also be a problem. When women become amenorrheic with DMPA, it indicates that they are in a hypoestrogenic state. This is a concern, especially in adolescents, because this is the time that bone density is built up and the hypoestrogenic state may adversely affect their bone mineral density. Depo-provera causes a delay in return of fertility after the last injection. With DMPA, there is generally a 4 month delay in the return to fertility after stopping use; by 10 months, 50% of former users will be fertile. Progestin Subdermal Implants Nexplanon is a single rod implanted system containing etonogestrel (active metabolite of desogestrel) that provides contraception for 3 years Only cost effective if used for the entire 3 years Advantages: No user effort is required Disadvantages: If you remove because of side effects, it becomes a very expensive method of contraception. Side effects are similar to the other progestin only products.

Progestin Intrauterine Device Mirena is an intrauterine device containing a reservoir with levonorgestrel It is implanted in the uterus and provides contraception for up to 5 years; it is labeled for use in women who have already had at least one child. Skyla and Liletta are intrauterine devices that contain lower doses of levonorgesterel, provide contraception for three years, and are labeled for use in either primigravida women or in women who have already had a child. As with the subdermal implants, the cost effectiveness depends on them being in place for several years

The list below gives some symptoms associated with various components of the oral contraceptive. You can use this to help switch to a different product if needed. Estrogen Excess Symptoms • Nausea, bloating • cervical mucorrhea • Chloasma • Headaches • Breast fullness, tenderness • Edema • Hypertension Estrogen deficiency Symptoms • Early or midcycle breakthrough bleeding • Increased spotting • Hypomenorrhea Progestin Excess Symptoms • Increased appetite/Weight gain • Tiredness, fatigue • Acne, oily scalp, hirsuitism (androgenic effect) • Depression • Breast regression Progestin Defiency Symptoms • Late breakthrough bleeding • Amenorrhea Progestin Only Contraceptives - there are three types of progestin only contraceptives: • Progestin Only Pills • Progestin injectable (DMPA, Depo-provera) • Subdermal implants - Implanon

Progestin Only Advantages Can be used by women who shouldn't receive estrogen - such as those with thromboembolic disease. Can be used in breast feeding - progestin has no effect on quality of breast milk (may increase quantity), or long term growth and development of fetus. Does not inhibit the binding of prolactin to its receptors, so doesn't interfere with quantity of milk. The injectable progestin (Depo-provera) provides 3 months of contraceptive activity - a good alternative for women in whom daily adherence may be an issue. The subdermal implants provide even longer contraceptive activity. Progestin Only Disadvantages Cause menstrual bleeding irregularities in most women initially If pregnancy occurs, more likely to be ectopic. Progestins decrease tubule motility which may alter egg or zygote transport and thus lead to ectopic pregnancies. Weight gain - of over 5 lbs occurs in up to 2/3 of the clients. Long term use may adversely affect bone mineral density. The package labeling for Depo-provera suggests that therapy be limited to 2 years. Progestin-Only Pills Micronor (Norethindrone 0.35 mg) Ovrette (Norgestrel 0.075 mg) Nor-QD (Norethindrone 0.35 mg Progestin only pills are only effective if taken VERY consistently. They must be taken EVERY day at the same time. This is not a good choice of contraception for a woman or girl who might have adherence problems. If a progestin only pill is missed or taken more than 3 hours late, a backup method of contraception should be used for the next 48 hours.

Choosing a Combination Oral Contraceptive Estrogen Dose - All the available products contain either ethinyl estradiol or mestranol (which is converted to ethinyl estradiol in the body) as the estrogen. You just have to decide what dose of estrogen to use. Initial dose is usually 35 mcg or less -- you might consider starting with 20-30 mcg for women <70kg and the 35 mcg product for women >70 kg. All of the commercially available oral contraceptives are similar in effectiveness. You could prescribe any of them as a first choice and then, switch if a woman is not tolerating it.

Progestin dose and progestin type - the progestins vary in their biologic effect and adverse effect profile.

Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra) are rapid acting insulins.

Regular insulin forms hexamers that diffuse slowly from the subcutaneous space; lispro, aspart, and glulisine insulin don't form the hexamers to the same extent and thus are absorbed more rapidly when injected subcutaneously. Patients find rapid acting insulins more convenient than regular insulin -- you can inject just before a meal, whereas with regular insulin you must inject it then wait a half hour or more to eat. Human insulin has an amino acid structure that includes the following sequence: Phe-Tyr-Thr-Pro-Lys-Tyr. Lispro insulin reverses the prolinelysine structure so that the amino acid sequence includes the following pattern: Phe-Tyr-Thr-Lys-Pro-Tyr. Aspart insulin differs by one amino acid different from human insulin - it has an aspartic acid on B28 position. Glulisine differs by two amino acids at the B3 and B29 position.

Contraindications to Combination Oral Contraceptive Therapy - The contraindications are related to the adverse effects and risks of hormone therapy. Over age 35 and smokes >15 cigarettes/day Thromboembolic disorder - the estrogen component puts a woman at increased risk of thromboembolic disease. The overall risk is very low in a woman without risk factors, but COCs should be avoided in a woman with a history of thromboembolic disorder (current or previous history of DVT/PE). Uncontrolled Hypertension- BP >160/100 or with evidence of end organ damage from hypertension. Known hyperlipidemia Breast cancer - even though COCs don't increase the risk of breast cancer they shouldn't be used in a woman with pre-existing breast cancer. Estrogen dependent neoplasm Liver tumor Pregnancy Active hepatitis or severe cirrhosis Migraine headaches with focal neurologic symptoms

Relative Contraindications - use with caution; the theoretical or proven risks usually outweigh the benefits. Migraine Headaches without focal neurologic symptoms- COCs can make headaches worse, particularly in women >35 yrs of age Hypertension- the older COCs with higher doses of hormones caused a significant increase in blood pressure in some women. The incidence of this is much less with today's products, but you must still monitor blood pressure. Diabetes (>20 years duration or with diabetes complications) - COCs are okay in women with uncomplicated diabetes but should be avoided in women with complications of diabetes. Active gallbladder disease - the older, high dose COCs caused an increased in gallbladder disease but the lower dose products only increase the risk slightly, if at all. Still, it is prudent to avoid their use in patients with active gallbladder disease. Major surgery planned w/in 4 weeks Major injury to lower leg Multiple risk factors for coronary artery disease (e.g. older age, smoking, diabetes, hypertension) Over age 35 and smokes (<15 cigarettes/day) Use of certain interacting drugs (we'll discuss this later)

Fluoroquinolones The quinolones enter the bacterial cell by passive diffusion and inhibit bacterial DNA gyrase, which is an enzyme involved in the bacterial DNA replication process. They can be divided into generations according to their antimicrobial spectrum of activity. Classification of the Quinolones Classification Agents Antimicrobial spectrum General Clinical Indications First generation Nalidixic Acid (NegGram) Gram-negative organisms (but not Pseudomonas) Uncomplicated urinary tract infections Second generation Norfloxacin (Noroxin) Ofloxacin (Floxin) Ciprofloxacin (Cipro) Gram-negative organisms (including Pseudomonas), some gram-positive (including Staph aureus but not Strep pneumoniae) and some atypical pathogens Uncomplicated and complicated urinary tract infections and pyelonephritis, STDs, prostatitis, skin and soft tissue infections Third generation Levofloxacin (Levaquin) Moxifloxacin (Avelox) Same as for second generation agents plus expanded gram-positive coverage (penicillin-sensitive and penicillin-resistant S. pneumoniae) and expanded activity against atypical pathogens Acute exacerbations of chronic bronchitis, community-acquired pneumonia

Resistance to the quinolones: Resistance occurs because of either modification in bacterial DNA leading to altered targets in the bacteria or decreased permeability of the bacterial cell membrane. Adverse effects GI: nausea, vomiting, diarrhea (5-10%) CNS: headache, restlessness, insomnia (0.4%) Musculoskeletal: arthralgia, joint pain, joint stiffness (<1%) In animal studies, the quinolones caused joint damage and arthropathies in young animals of various species. The labeling of these drugs says that safety in human children has not been established and use should be avoided in children and pregnancy. Despite the fact that the package insert for the quinolones still says that use should be avoided in children and pregnancy, they have been used successfully for a number of years in children with cystic fibrosis. Children with cystic fibrosis often develop pseudomonas lung infections and the quinolones are the only oral antibiotics that can treat them. Drug interactions: Inhibition of the cytochrome p-450 system -- ciprofloxacin and levofloxacin inhibit CYP 1A2 in the cytochrome P-450 system. Drugs such as theophylline and warfarin that are metabolized by this enzyme will have increased serum levels. Decreased absorption -- Ciprofloxacin concentrations will decrease by up to 90% when administered at the same time as antacids or other cations (Ca, Mg, Fe ). The other quinolones will show some decreased absorption with antacids also, but not to the same degree. The third generation quinolones (e.g. levofloxacin), are sometimes called the "respiratory quinolones" because they can be used to treat respiratory infections. The second generation quinolones, e.g. ciprofloxacin, don't cover Streptococcus pneumoniae well and shouldn't be used in respiratory infections.

Antibiotic Resistance When organisms aren't killed by an antibiotic, they are said to have antibiotic resistance. This resistance is classified as: Innate Innate resistance is intrinsic resistance based on the mechanism of the drug. For example, vancomycin can't cross the cell membrane of gram-negative bacteria and thus is only active against gram-positive bacteria. Therefore, gram-negative bacteria are innately resistant to vancomycin. or Acquired Acquired resistance occurs when the bacteria mutates or acquires a resistance gene from another bacteria. The bacteria changes so that it is no longer killed or inhibited by the antibiotic. Biochemical Mechanisms of Acquired Resistance Acquired resistance occurs when bacteria develop one of the following: Reduced permeability. Gram-negative bacteria are surrounded by an outer lipopolysaccaride membrane which presents a barrier for many antibiotics. The outer membrane has channels (porins) through which lipophilic or small drugs can enter. Resistant strains of bacteria have less permeable outer membranes or porin channels. This is why pseudomonas aeruginosa is resistant to gentamicin. Production of bacterial enzymes that destroy or alter the antibiotic. Some strains of Haemophilus influenzae produce a beta-lactamase enzyme that destroys penicillin and ampicillin. These strains of H.influenzae are resistant to ampicillin. Alteration of target site. The bacteria produces a different protein target site where the antibiotic normally binds and thus the antibiotic can not bind to the bacteria nor kill it. An example of this is with methicillin-resistant Staph.aureus (MRSA). The MRSA has altered penicillin binding proteins, so the methicillin can no longer bind with Staph. aureus and will no longer kill the bacteria. Presence of an efflux pump. Gram negative bacteria may develop an efflux pump, which transports the antibiotic back across the cell membrane before it can damage the bacteria.

Selecting Antibiotic Therapy Empiric Therapy This is antibiotic therapy before a pathogen is identified. Consider the following things when choosing the appropriate antibiotic: Organisms most likely to be causing the infection at this site in this patient. Usual susceptibility patterns of organisms to antibiotics. Patient characteristics such as allergies and renal status. Ideally, empiric therapy should cover 90% of the suspected organisms. There are several useful references for determining empiric therapy. One is Sanford's Handbook of Antimicrobial Therapy. It lists infectious sites, with their usual organisms, and recommended treatment. It is updated annually and costs about $20. It is usually given away for free by several drug companies each year. You'll find this pocket reference in many primary care clinics. http://www.sanfordguide.com/ Johns Hopkins University Division of Infectious Diseases has an on-line and mobile device antibiotic guide; it costs about $30/year. It gives similar recommendations for empiric therapy -- you can look up the site of infection, and then see the most common infecting organisms, and see recommendations for therapy. http://prod.hopkins-abxguide.org/ Definitive Therapy When culture and sensitivity results are available, switch to the most cost-effective, narrowest spectrum antibiotic. The gram stain gives you an initial idea of the organism. The lab report will then tell you the infecting organism with a list of antibiotics that are going to be effective against this pathogen.

RANKL inhibitor Mechanism of action: Denosumab (Prolia) inhibits the action of RANKL (nuclear factor kappa B ligand). When this ligand is inhibited, osteoclast formation and function are inhibited and thus bone resorption is decreased. Drug in the class: Denosumab (Prolia) - a monoclonal antibody that is given as subcutaneous injection every 6 months. Adverse effects: Hypocalcemia - patients should have a normal calcium level prior to treatment and be instructed to take calcium and vitamin D supplements. Clinical Use: Can be used as an alternative to the bisphosphonates, especially in patients who can't take an oral bisphosphonate because of gastrointestinal contraindications. Are much more expensive than a generic bisphosphonate. Annual cost for two injections of denosumab is in the $2000-3000 range as compared to $120/year for a generic bisphosphonate.

Selective Estrogen Receptor Modulators (SERMs) Mechanism of Action: Selective estrogen receptor modulators (SERMs) have estrogen-like effects on bone, but act as estrogen antagonists in the endometrium and breast. Drugs in the Class: Raloxifene (Evista) Tamoxifen (is not used for osteoporosis, but is used as an adjunct in breast cancer treatment) Adverse effects: hot flashes leg cramps increased risk of thromboembolism Clinical Use: Raloxifene can be used to prevent and treat post-menopausal osteoporosis. It has been shown to decrease the incidence of vertebral fractures, but has no effect on the incidence of nonvertebral or hip fractures. May be especially useful in the women with a history of breast cancer. Disadvantage: does not treat the other symptoms of menopause and in fact, may make the hot flushes worse.

Hypothyroidism - Hypothyroidism is a relatively common clinical entity, occurring in up to 6% of women. Causes of Hypothyroidism Primary Hypothyroidism - inadequate secretion of thyroid hormones from the thyroid gland. Common causes: Autoimmune (Hashimoto's) thyroiditis Iatrogenic (radiation or surgery to treat thyroid cancer) Medications (amiodarone, lithium, tyrosine kinase inhibitors) Secondary Hypothyroidism - Hypothalamic or pituitary malfunction Pituitary or hypothalamic disease

Signs and Symptoms of Hypothyroidism Many patients with mild or subclinical hypothyroidism present with a normal physical exam. As the hypothyroidism progresses, the symptoms include: Fatigue Constipation Menorrhagia Weight gain Cold intolerance Mental sluggishness Dry skin

Carbohydrate Metabolism (ch. 43, p.651)

The endocrine functions of the pancreas controls carbohydrate metabolism in the body. The function of carbohydrate metabolism is to deliver energy for use, to store energy after eating, and to mobilize energy stores when needed. The maintenance of adequate levels of circulating glucose is essential for brain tissue and red blood cell metabolism since these tissues depend on circulating glucose for their energy supply.

(Ch. 48, p. 747) The ovary synthesizes hormones for reproductive tissues and maintains the secondary female sex characteristics The two most important hormones from the ovary are the sex steroids estrogen and progesterone. The production of these hormones is controlled by the hypothalamic-pituitary axis.

The hypothalamus secretes gonadotropin-releasing hormone (GnRH). GnRH acts on the pituitary to stimulate the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH act on specific receptors in the ovary to stimulate the production of estrogen and progesterone. The estrogen and progesterone produced act in a feedback inhibition mechanism on the hypothalamus and pituitary to decrease production of GnRH, LH and FSH. As a woman ages, the function and number of ovarian follicles decreases. The follicles become less responsive to follicle-stimulating hormone (FSH, and fail to mature. Without follicle maturation, estradiol-17B production, ovulation, and progesterone secretion do not occur.

Thyroid Stimulating Hormone test TSH is a hormone released from the pituitary gland; it stimulates the thyroid gland to release thyroid hormone. More TSH is released when the body is hypothyroid and less is released when the body has enough or too much thyroid hormone present. It is the recommended test to monitor thyroid function and thyroid replacement therapy. The TSH will elevate prior to the serum T-4 decreasing. Monitor serum TSH Every 6-12 months in a stable patient 6-8 weeks after a dose or product change Monthly during pregnancy

Thyroid Replacement Therapy The primary treatment of hypothyroidism is thyroid replacement therapy. There are four thyroid hormone products available in the US. It is recommended that levothyroxine be the preferred product for all patients. Levothyroxine - synthetic t-4 Liothyronine - synthetic T-3 Thyroid dessicated - dried pork thyroid glands Liotrix - synthetic t-4/t-3 combination product. Pharmacoeconomics Note: Levothyroxine is a drug with a narrow therapeutic index; small changes in doses can cause marked changes in the TSH. A concern is that the bioavailability of various levothyroxine products may differ enough that changing brands may change therapeutic outcome. There are generic products available that meet the FDA criteria for generic equivalence to brand name Synthroid (AB rating) but the AACE and American Thyroid Association say that the FDA studies were not sensitive enough to detect important differences between the products. They recommend that if a patient changes brands of levothyroxine, the TSH should be checked in 6-8 weeks. The Synthroid brand of levothyroxine costs about $30/month; generic levothyroxine $5-10/month.

Drug Therapy If influenza is suspected, a rapid flu test should be performed. If positive and the symptoms have been present for <48 hours, treatment with an antiviral is recommended. Before the culture and sensitivity results are back, the clinician must decide on empiric therapy. Empiric therapy must cover streptococcus pneumoniae and should cover the atypical pathogens such as mycoplasma pneumoniae.IDSA recommendations for initial therapy for the non-hospitalized patient are one of the following: Macrolides, such as erythromycin, azithromycin, or clarithromycin. The macrolides will cover both streptococcus pneumoniae and mycoplasma. Erythromycin is inexpensive but causes GI upset in a signficant number of patients. Azithromycin or clarithromycin are much more expensive but are easier to take and provide better coverage against H. influenzae. Doxycycline - is less effective than the other two choices against S.pneumoniae so would not be a good choice for an acutely ill person. However, it is effective against atypical organisms such as mycoplasma or chlamydia, and is inexpensive, so it can be used in the younger, less ill patient. Beta-lactam PLUS a macrolide -- Preferred oral beta-lactams are high-dose amoxicillin (1 gram three times daily) or amoxicillin/clavulanic acid (Augmentin) 2 grams twice daily. Alternatives include ceftriaxone intramuscularly, cefpodoxime, or cefuroxime. The beta-lactam will provide coverage against resistant streptococci, while the macrolide provides coverage for atypical organisms. Respiratory fluroquinolones (Quinolones with enhanced streptococcus pneumoniae coverage such as levofloxacin 750 mg, moxifloxacin, or gemifloxacin). -- these drugs provide coverage against strep, including strep that aren't sensitive to penicillin or amoxicillin and will also cover the atypical organisms such as mycoplasma. They are expensive and if they are over used, resistance will develop. Ciprofloxacin used to be effective against strep. pneumoniae but the strep. pneumoniae organisms quickly developed resistance so cipro is not a good drug for community acquired pneumonia now. You will see that these guidelines suggest broader spectrum antibiotic therapy for the hospitalized patient. The hospitalized patient is sicker and you want to make sure that you cover for the less common organisms, including gram negative aerobic bacteria. Thus they recommend that you include a beta-lactam antibiotic with coverage against gram negatives that will also cover streptococcus pneumoniae, in addition to a macrolide or fluroquinolone to cover the atypical organisms. After the culture and sensitivity results are back and the pathogen is defined, you should switch to pathogen specific therapy.

Treatment recommendations from the IDSA 2007 community acquired pneumonia guidelines The 2007 Infectious Disease Society of America guidelines suggest that sputum culture and sensitivity tests are optional for outpatients with CAP. Most patients admitted to the hospital should have a sputum culture and some should have a blood culture (see the guidelines Table 5 for the specifics). Patient variable Preferred treatment options Outpatient Previously healthy and no recent use of antimicrobials Macrolide (preferred) or doxycyline Comorbidities (COPD, diabetes, renal or congestive heart failure, or malignancy, asplenia, immunospressing conditions), or use of antimicrobial within the past 3 months Respiratory fluoroquinolone or A beta-lactam plus a macrolide Inpatient Non-ICU Respiratory fluoroquinolone or A beta-lactam plus a macrolide ICU Intravenous beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus azithromycin or a respiratory fluouroquinolone If pseudomonas infection is a concern, use piperacillin-tazobactam, cefepime, imipenem, or meropenem plus levofloxacin. Pseudomonas infections are more likely in patients with COPD, If MRSA is a concern, add vancomycin or linezolid. The best indicator of staphylococcus aureus is a gram stain showing gram-positive cocci in clusters.

Non Insulin AntiDiabetes Drugs There are nine classes of non insulin antidiabetes drugs. Up until mid 90's, there were only two classes of non-insulin drugs (sulfonylureas and biguanides); In the last ten years, the additional classes of drugs have been added. Biguanides (metformin) Sulfonylureas and Glinides Thiazolidinediones (TZDs) Inhibitors of intestinal alpha-glucosidase Incretin Based Therapy - Dipeptidyl Peptidate-4 inhibitors (DPP-4) and GLP-1 agonists Sodium Glucose Transporter2 Inhibitors Dopamine agonists - Bromocriptine Bile Acid Sequestrants Amylin Mimetics

Type 2 Diabetes

Antimicrobial Mechanisms of Action The ideal antibiotic interferes with a vital function of bacteria without affecting host cells; this is called selective toxicity. There are 5 main mechanisms of action: (Ch.69, p. 1033) Inhibition of Cell Wall Synthesis (Cephalosporins, Penicillins,Vancomycin) Bacteria have a rigid outer layer, the cell wall, which maintains the bacterial shape and contains the contents of the bacterial cell. The bacterial cell has a high internal osmotic pressure, with the internal pressure being 3-5 times greater in gram-positive than in gram-negative bacteria. If the cell wall is damaged or its formation is inhibited, the cells will lyse and die. Inhibition of Cell Membrane Function (Amphotericin B, Nystatin, Imidazoles (eg miconazole) All living cells are bounded by a cytoplasmic membrane which serves as a selective barrier and controls the internal composition of the cell. Damaging the cytoplasmic membrane causes cell damage and death. This type of antibiotic damages the cytoplasmic membrane of certain fungi. Inhibition of Protein Synthesis (Chloramphenicol, Macrolides, Tetracyclines, Aminoglycosides) These antibiotics inhibit the replication of bacteria by disrupting the normal action of RNA and inhibiting protein synthesis Inhibition of Nucleic Acid Synthesis (Quinolones, Rifampin) Antibacterial action of the antibiotics occurs through inhibition of DNA synthesis. Inhibition of Bacterial Folic Acid Metabolism (Sulfonamides, Trimethoprim) The antibiotics prevent bacteria from synthesizing folic acid, thus interrupting RNA and DNA synthesis.

Whether an antibiotic inhibits or kills bacteria depends on its concentration Minimum inhibitory concentration (MIC) is defined as the lowest concentration of antibiotic that inhibits the growth of an organism. Minimum bacteriocidal concentration (MBC) is defined as the lowest concentration of antibiotic that kills the bacteria. For most antibiotics, the MBC is 2-8 times greater than the MIC. Killing by bacteriocidal drugs can be concentration-dependent or time-dependent. Some antibiotics such as aminoglycosides or quinolones have concentration-dependent killing. At greater concentrations, greater bacteriocidal activity is found. For antibiotics with time-dependent killing such as the penicillins, the more time that the concentrations are above the MBC, the more bacteriocidal activity is noted. Post-antibiotic Effect is when normal bacterial replication is delayed after administration of an antibiotic is stopped. This is why some antibiotics can be dosed at longer dosing intervals, even though they have short half-lives.

Clinical Strategies to Decrease Resistance The frequency of resistance in bacteria and the number of drugs to which they are resistant is increasing. Overuse of antibiotics contributes to the development of resistance. Practitioners should exercise restraint in prescribing antibiotics according to the following guidelines: Do not prescribe antibiotics for colds Do not routinely prescribe antibiotics for uncomplicated acute bronchitis unless the cough has persisted for more than 10 days. Do limit antibiotic use for pharyngitis to cases of documented strep throat. Do not treat chronic otitis media with effusion unless the effusion has persisted for three or more months. Do not prescribe antibiotics for sinus symptoms during the common cold unless the symptoms are severe, with pain and/or fever, or the symptoms persist for two weeks or more.

dentifying the Pathogen Gram Stain useful for rapid characterization of an organism by cell wall structure and cell morphology. Culture and Sensitivity Minimum Inhibitory Concentration lowest concentration of antibiotic that inhibits growth of a microorganism. Definitions Susceptible: Infecting organism is inhibited by levels of antibiotic attained in the blood or tissue by usual dosage, including oral administration when applicable. Moderately Susceptible (Intermediate): Infecting organism is inhibited only by blood levels achieved by maximum dosages indicated in pharmaceutical package literature. Resistant: Infecting organism is resistant to usually achievable blood levels of the antibiotic.