Practical Medical Pharmacology Study Guide 2023-2024 PDF

Practical Medical Pharmacology For 3rd Year Medical Students Soha Aly Elmorsy, MD, PhD, Head of Medical Pharmacology Department Faculty of Medicine, Cairo University BY Staff Members of Medical Pharmacology Department Faculty...

Practical Medical Pharmacology For 3rd Year Medical Students Soha Aly Elmorsy, MD, PhD, Head of Medical Pharmacology Department Faculty of Medicine, Cairo University BY Staff Members of Medical Pharmacology Department Faculty of Medicine - Cairo University 2023-2024 I II  Practical Medical Pharmacology To the doctors in the making, Printed future…. those who will give us a bright in February 2023 Editors: Prof. Dr. y Medical Pharmacology Department Faculty of Medicine - Cairo university III IV  Contents Diabetes mellitus 1 Endocrinal emergencies 8 Drugs and obesity 15 Management of sleep disorders 19 Pain management 24 Drugs and CNS emergencies 30 Intravenous fluid therapy 35 Antimicrobial prophylaxis 44 Treatment of selected infections (typhoid, UTIs, rheumatic fever) 52 Some selected infections (CAP, HAP, meningitis, encephalitis) 59 MCQs (Endocrine) 70 MCQs (Endocrine CNS) 85 Mock exam (EOM) 101 Mock exam (EOY) 111 V Important notes: - This book is intended for studying for the practical exam in clinical pharmacology, for third year medical students of the Faculty of Medicine, Cairo University in the academic year 2023-2024. - Answering the questions at the end of each topic will greatly help in grabbing the most important concepts towards the practical exam. - For the purpose of that exam, all areas with a blue/grey background in this book are intended for reading for the student to have a complete understanding of the topic and will not be addressed by direct questions in the pharmacology exam. VI  Diabetes Mellitus DM is metabolic disorder due to Absolute or Relative insulin deficiency Laboratory tests: - HbA1C > 6.5% - The test reflects the average plasma glucose concentration over a 2-3 month period of time. - It measures the amount of glucose activity associated with red blood cells over a 3 month time period (equal to the lifespan of the red blood cell). - Fasting plasma glucose > 126 mg/dL (7.0 mmol/l). (Fasting is defined as no caloric intake for at least 8 h). - Two hours postprandial plasma glucose > 200 mg/dL Treatment of Diabetes Mellitus Physiological insulin replacement therapy 1- Basal insulin - To control fasting glucose and suppress overnight hepatic glucose production - Given as NPH BID (twice daily), glargine OD (once daily), or detemir OD-BID. 2-Prandial insulin (Nutritional insulin” or “Bolus insulin) - To control post-prandial glucose spikes - It is given with each meal. - Given as a rapid-acting insulin analogue. - Regular insulin is considered a pre-prandial insulin because it takes about 30 minutes to start working. - Prandial insulins such as insulin lispro, insulin aspart, and insulin glulisine start working in 5 to 10 minutes. - Physiological insulin replacement therapy 3-Correction insulin “sliding scale insulin” - Given to reduce an elevated blood glucose level to a normal range. - Giving correction insulin is the worst way to manage diabetes. - Rather than maintaining normal blood glucose levels, we're actually waiting until hyperglycemia occurs, and then trying to bring it down to normal. - Regular insulin is used. Common insulin regimens used for treatment of type 1 DM Total daily insulin requirement = 0.5 ˣ total weight in kgs For premixed insulin= 0.5 ˣ total weight in kgs Step 1: calculate total daily insulin requirement; body weight (kg) ̸ 2 (e.g.: for 60 kg pt., total = 30 units) Step 2: then divide this dose into 3 equal parts; (10+10+10) Step 3: give 2 parts in the morning and one part in the evening (morning= 20 U and evening= 10 U) Basal-Bolus insulin regimen: Using Long-acting insulin (glargine/detemir or NPH), once or twice a day with short acting insulin (aspart, glulisine, lispro, Regular) before meals. 1  Example: 60 kg adult with moderate Ketones Total Insulin dose: 30 units Divide Insulin as following: Insulin Glargine (Lantus): 15 units at bedtime Insulin Lispro: 15 units total divided over meals Before breakfast: 5 units, Before lunch: 5 units, Before dinner: 5 units Factors affecting Insulin Requirements: Factors that INCREASE: i) Infection, operation, pregnancy and trauma ii) Treatment with counter-regulating hormones and drugs: - Thiazide diuretics and Diazoxide vasodilator - Sympathomimetics. - Oral contraceptives (and estrogens) - Corticosteroids iii) Specific antagonists e.g., insulinase enzyme and insulin antibodies. Factors that DECREASE: i) Physical exercise (Daily insulin requirements are inversely proportional to degree of physical activity). ii) Decrease in caloric intake. Insulin delivery devices: Insulin syringes Insulin pen Insulin jet Insulin pump Common injection sites Abdomen: most preferred site Other sites: Buttocks, thighs and arms. Site Rotation is essential 2  Patient Education Sample of Patient Education and Counseling A) Teach the patient: 1-Diabetes is a lifelong disease that requires lifestyle changes. 2- Early signs and symptoms of hypoglycemia and hyperglycemia. 3- Hypoglycemia is more dangerous, keep a source of sugar. 4- To wear a medical identification bracelet. B) Regular exercise: Exercise program must be individualized and built up slowly. C) Diet Regulation: Important to all diabetic patients. I- Total Caloric Intake: 1- Depends on Age, Physical activity & Deviation form ideal weight: a- Average weight (30 C/kg). b- Underweight (40 C/kg). c- Overweight (20 C/kg). 2- Weight reduction by caloric restriction in obese type II diabetics → Restore sensitivity to circulating Insulin. 3- Type I diabetics are seldom obese. Adequate diet is essential for growing children. II- Dietary Composition: 1- CHO: 50% of total caloric intake, mainly complex. 2- Proteins: 20% of total caloric intake. 3- Fat: < 30% of total caloric intake (Plant oil is better than Animal fat): a- Unsaturated fat e.g., Olive oil & Palm oil. b- Saturated fat e.g., Butter & Ghee. c- Cholesterol intake < 300 mg/day. 4- Dietary fibers e.g., Bran, green vegetable & fruits → ↓↓Absorption of glucose & cholesterol. III- Timing & Size of Meals: Breakfast should be eaten within 1/2 h after the morning insulin dose. 3 Main meals + 3 Snacks in between and at bed time. VI- Sweeteners: Aspartame, 2 amino-acids (Aspartic acid and Phenylalanine). V- Vitamins: Especially Vit B-1 & B-12. 3  D) Insulin Injection Instructions 1- If meal is OMITTED: Do Not Take Medication. 2- Protect insulin from Heat & Freezing. 3- Store insulin that has not been opened in the Refrigerator. 4- Do Not Shake insulin because of: a- The resulting froth prevents withdrawal of an accurate dose. b- May damage protein molecules. Management of Diabetes Mellitus I- Treatment Type 1 DM: - Life style Modification (Diet regulation + Exercise) + Insulin II- Treatment of Type 2 DM: Step 1 - Life style modifications = Diet + Physical activity Tried for 1 – 3 Months. - If Still Hyperglycemia (HBA1C ≥ 6.5%) → Step 2 - Life style modifications + Monotherapy: Metformin - If Still Hyperglycemia (HBA1C ≥ 6.5%) → Step 3 - Life style modifications + Dual therapy: 1- Metformin + Sulfonylurea (e.g. Glibenclamide or Glipizide) OR 2- Metformin + DPP-4 Inhibitor (Gliptins e.g., Sitagliptin) OR 3- Metformin + SGLT2 inhibitors e.g Dapagliflozin - If Still Hyperglycemia (HBA1C ≥ 6.5%) → Step 4 - Life style modifications + Triple therapy: 1- Metformin + Sulfonylurea + DPP-4 inhibitor (Gliptin) OR 2- Metformin + Sulfonylurea + GLP-1 analogs e.g. Exenatide OR 3- Metformin + Meglitinides (Glinides) + DPP-4 inhibitor OR 4- Metformin + Meglitinides (Glinides) + GLP-1 agonist. - If Still Hyperglycemia (HBA1C ≥ 6.5%) → Step 5 - Life style modifications + Insulin 4  Case No 1 An obese female aged 42 years complained of polyuria and polydipsia. After clinical examination and laboratory investigations, her 2 hour post prandial blood glucose was found 300 mg/dl and was diagnosed as type 2 diabetes mellitus (NIDDM). Hyperglycemia persisted despite control of diet and exercise for several weeks. How to manage this case? 1- The most suitable drug treatment of diabetes mellitus in this female is to be started with: a- insulin b- glibenclamide c- metformin d- carbimazole e- thyroxine 2- The drug selected in Q1 is: a- a sulphonylurea b- a biguanide c- a meglitinide d- a glitazone e- an α-glucosidase enzyme inhibitor must convert onto insulin therapy 3- The drug selected in Q1 may produce the following adverse effect: a- hypoglycemia b- myopathy c- alopecia d- lactic acidosis e- pancreatitis 4- Hyperglycemia persisted despite the proper use of the drug selected in Q1. What drug do you like to add? a- insulin b- glibenclamide c- metformin d- carbimazole e- thyroxine 5- The drug selected in Q4 is given by the following route of administration: a- Subcutaneous b- Intramuscular c- Intravenous d- Oral e- Rectal 6- Which of the following is expected adverse effect of the drug selected in Q4: a- hypoglycemia b- myopathy c- alopecia d- lactic acidosis e- pancreatitis 5 7- If the female got pregnant, which of the following is most appropriate? a. She can continue any sulfonylurea drugs she is taking. b. She must convert onto insulin therapy. c. She can use a combination of two oral antidiabetics. d. She will stop all treatment. e. She will convert to diet only. C-B-D-B-D-A-B Case No 2 A 57-year-old obese man presented with a three-week history of polyuria and polydepsia. Clinical features and laboratory findings confirmed a diagnosis of type 2 diabetes mellitus. Hyperglycemia and obesity persisted despite diet control and exercise for several weeks. How would you manage this patient? 1- Which of the following drugs would you like to start with? a- carbimazole b- glucagon c- hydrocortisone d- metformin e- hydrochlorothiazide 2- Regarding the selected drug in Q1, the following THREE statements are CORRECT: a- It is a biguanide b- It is a sulphonylurea c- It is considered as an oral euglycemic drug d- It is considered as an oral hypoglycemic drug e- It inhibits intestinal α-glucosidase enzyme f- It stimulates insulin secretion from pancreatic β-cells g- It can cause lactic acidosis especially in patients with renal impairment D,A-C-G 3- After 4 weeks of treatment with the drug selected in Q1, hyperglycemia was not adequately controlled. Which of the following drugs would you like to add: g- furosemide b- glibenclamide c- methimazole d- bromocriptine e- ephedrine 4- Regarding the selected drug in Q3, the following THREE statements are CORRECT: g- It is a biguanide b- It is a sulphonylurea c- It is considered as an oral euglycemic drug d- It is considered as an oral hypoglycemic drug e- It inhibits intestinal α-glucosidase enzyme f- It stimulates insulin secretion from pancreatic β-cells g- It can cause lactic acidosis especially in patients with renal impairment B, B-D-F 6 5- One day the patient took his medication but he missed his meal and played a football game. He felt very hungry, drowsy, his face was pale and sweaty and there was tachycardia. The urine was free of glucose. The most appropriate management of this situation is to give the patient: a- oral sweets b- intravenous glucose c- subcutaneous isophane insulin d- intravenous soluble insulin e- oral acarbose 6- Hyperglycemia was adequately controlled for several months. The patient is going to undergo a surgical operation. How would you like to modify the anti-diabetic medication: a- Decrease the dose of the oral anti-diabetic drugs b- Increase the dose of the oral anti-diabetic drugs c- Stop oral anti-diabetic drugs and give insulin d- Stop oral anti-diabetic drugs and give dexamethasone e- Continue oral anti-diabetic drugs but add atropine A, D Questions 1. Mention 3 types of insulin that can be used for basal blood glucose control and mention the administration frequency for each of them. 2. What is the functional of basal insulin injections? 3. What is the function of prandial insulin and when should it be given? 4. Mention 3 types of insulin for prandial blood glucose control. 5. When should insulin glulisine be given in relation to meals and how would it be administered? 6. Why is regular insulin considered pre-prandial and not prandial insulin? 7. What would happen if a diabetic patient took his regular insulin just before the meal? 8. What is the aim of giving insulin in a sliding scale and what is its disadvantage? 9. For an 80 kg diabetic patient, dependent on insulin, suggest his total daily insulin requirement and how it could be divided between two dose per day. 10. Suggest a basal-bolus regimen with glargine and lispro for a 70 kg patient. 11. Mention factors that increase and factors that decrease insulin requirements. 12. Mention items you should teach your diabetic patient. 13. Mention insulin injection and insulin use instructions. 14. Mention the HbA1c value at or above which oral diabetic therapy should be escalated to the next step. 15. For a Type 2 diabetic patient who remains uncontrolled on metformin and sulfonylurea, which of the following would NOT be added as a third drug? a. Sitagliptin b. Canagliflozin c. Repaglinide d. Liraglutide 7  Endocrine Emergencies-Diabetes mellitus emergency cases I- Hypoglycemic coma: - Results in Neuro-glyco-penia: Hunger, headache, irritability, weakness, blurring of vision, confusion, convulsions & coma. - If prolonged → Sweating, pallor, tachycardia & tremors → Permanent brain damage & Death. - Hypoglycemic Coma is the MOST Serious & Common coma in DM - It is due to: 1- Excess insulin 2- Too little meal 3- Excess exercise Management of hypoglycemic coma: If patient is conscious → Oral glucose or sweets If patient in Coma = Unconscious → I.V. Glucose 50 ml 25% → Life-saving. If sterile glucose is not available → Glucagon 1 mg S.C. or I.M II- Hyperglycemic coma: 1-DKA: diabetic ketoacidosis: more in T1DM 2-Euglycemic DKA (E-DKA): more with SGLTi 3-HONK (HyperOsmolar Non Ketotic Hyperglycemia): more in T2DM Diabetic ketoacidosis Treatment: 1- Soluble insulin: 0.1 U/kg/hr IV of Regular Insulin - continue IV insulin until the glucose and acidosis are corrected then switch to SC insulin. 2- Saline [0.9 %NaCL] IV infusion: Rehydration 3- Glucose 5% IV infusion when blood glucose is < 250 mg/dl to avoid hypoglycemia 4- NaHCO3 for severe metabolic acidosis (pH < 7.1; HCO3 < 5). 5- KCl added to IV fluids to avoid hypokalemia during insulin therapy. 6- Antibiotics for infection. Non-Ketotic Hyperosmolar Diabetic Coma - Occurs in Mainly T2DM with bad compliance. - Severe Hyperglycemia→ Polyuria→ Dehydration→ ↑ Osmolarity of Blood→ disturbed conscious level & coma BUT: No ketone bodies formation → no acidosis - Same lines of treatment for DKA But no need to alkalis. - After recovery →Resume Oral anti-diabetic therapy. 8  Thyroid Emergencies Myxedema Coma Definition: severe, long-standing hypothyroidism Treatment: 1-ttt of symptoms: Supportive care 2-ttt of the cause and ppt factor: Abs for infection 3-ttt of myoxedma: a- Loading dose of I.V levothyroxine: usually loading dose of 300–400 mcg initially, followed by 50–100 mcg daily. OR Liothyronine (T3) I.V: 5–20 mcg initially, followed by 2.5–10 mcg every 8 hours, but may be more cardiotoxic and more difficult to monitor. N.B. Intravenous therapy is mandatory because of impaired absorption of drugs in this condition. b- Hydrocortisone: i.v. is also needed, as adrenocortical insufficiency is usually present. Thyroid crisis (storm) - It is a rare but severe and potentially life-threatening complication occurring in untreated hyperthyroid patients; precipitated by surgery, severe infection or illness. - During thyroid storm, an individual's heart rate, blood pressure, and body temperature can increase to dangerously high levels. Management: 1. Methimazole blocks hormone synthesis while propylthiouracil in addition Prevent conversion of T4 to T3 2. K Iodide to inhibit release of thyroid hormones 3. Beta blockers IV without sympathomimetics activity (propranolol): If BB is contraindicated diltiazem can be used 4. Hydrocortisone IV: Protect against shock & Prevent conversion of T4 to T3 5. Supportive therapy is essential to control fever, heart failure, and any underlying disease process that may have precipitated the acute storm. 9  Adrenal Emergencies- Acute Adrenal Insufficiency Clinical Picture of Addisonian crisis: Acute Adrenal Insufficiency- History Investigations: Weakness-Fatigue-Anorexia-Dizziness/ I- Main & Initial Investigations Syncope Blood glucose (both bedside and Nausea / vomiting-Weight loss formal): low in cortisol deficiency Confusion-Seizure Electrolytes: ↑K &↓Na indicates Screen for infective symptoms or injury as a mineralocorticoid deficiency trigger for presentation ABG: Acidosis indicates Examination mineralocorticoid deficiency Hypotension, tachycardia II- Additional investigations: if first Pigmentation in skin creases, nail bed or scars presentation (prior to steroid (may be present in primary adrenal failure) administration if possible): Cortisol Confusion → coma level, ACTH level Acute Adrenal Insufficiency-treatment: 1- Steroid replacement - Give IV bolus/I.M of 50-100 mg/m2 hydrocortisone (Solu-CortefTM) immediately (dose for age shown below). - Follow with hydrocortisone 6 hourly IV - Once stable, 1- Reduce the IV dose, 2- Switch to oral maintenance dose 3-Mineralocorticoid replacement: fludrocortisone (0.05 - 0.1 mg daily). 2- Intravenous fluids: Indication: Shock or moderate to severe dehydration Bolus: 0.9% sodium chloride (normal saline) 10-20 mL/kg during the first hour of treatment. Maintenance: 0.9% sodium chloride and 5% glucose Monitor: RBG (Random Blood Glucose) & Electrolytes (Na+, K+) 3- To Treat hypoglycemia: Bolus: IV of 10% dextrose 2-5 mL/kg and recheck RBG (random blood glucose) after 30 min Maintenance: 10% dextrose in 0.9% sodium chloride to maintain normoglycaemia 4- To Treat Hyperkalemia: monitor by ECG: If Potassium is >7.0 mmol/L + ECG changes (peaked T waves ± wide QRS) → Arrhythmia → Treat with either calcium gluconate or insulin infusion Replacement Therapy in Addison’s disease a- Acute Addisonian Crisis: - Cortisol I.V. → I.V. infusion / 6 hours - Saline + Glucose 5% + Blood transfusion +Vasopressors. b- Chronic Addison’s Disease:→ Orally - Glucocorticoids: hydrocortisone (identical to natural cortisone) ) + Generous salt & sugar diet. - Mineralocorticoids: Fludrocortisone (Mineralocorticoid + some glucocorticoid activity) 10  Calcium Emergencies Hypercalcemia Manifestations: CNS effects: Lethargy Weakness, Confusion Coma Renal effects: Polyuria- Dehydration, Renal stones Gastrointestinal: Constipation, Nausea-Anorexia, Pancreatitis-Gastric ulcer Cardiac effects → syncope from arrhythmias Bone → Bony pains Treatment: Mild hypercalcemia, tends to be asymptomatic. If symptoms are present, they tend to be nonspecific and do not require immediate treatment. Moderate to severe hypercalcemia →immediate attention. 1- The first step is I.V FLUIDS -Intravenous fluid with isotonic saline is the fluid of choice because it helps to facilitate urinary calcium excretion. - Within the first few hours 500 mL then 150 to 200 mL/hour till euvolemia 2- Furosemide: can be considered in certain situations to further increase urinary calcium excretion (especially if renal impairment or cardiac dysfunction is present) 3- Calcitonin (S.C or IM) Dose: 200 units every 8 to 12 hours. M.O.A: Calcitonin reduces bone resorption, Advantages: Rapid onset -within 12 hours Disadvantages: - It is NOT very potent (reduces the serum Ca by no more than 1 to 2 mg/dL) & short- lived. 4- Bisphosphonates M.O.A.: inhibitor of osteoclast-mediated bone resorption Because intravenous or parenteral therapy is required, the two choices are: Dose: pamidronate (30, 60, or 90 mg) or zoledronic acid (4 mg) Advantage: more potent than calcitonin Disadvantages: delayed onset, be cautious or better avoided in renal impairment and follow up kidney function highly recommended 5- Cytokine (RANKL inhibitor) → denosumab - RANK ligand is a powerful bone-resorbing cytokine. It is often stimulated in the context of acute hypercalcemia. M.O.A: The RANK ligand inhibitor, denosumab Dose: (60 or 120 mg given subcutaneously; 120 mg is the approved dose for Hypercalcemia of malignancy) Advantage over the bisphosphonates is that renal dysfunction is not a contraindication. Disadvantages: delayed onset like the bisphosphonates, requires 24 to 48 hours. What are the practitioners doing? - Because both the bisphosphonates and denosumab are not immediately acting a standard of many practitioners faced with this situation is to use combination therapy with calcitonin and either a bisphosphonate or denosumab. - In this way one takes advantage of the rapid but weak effects of calcitonin while waiting for the more delayed but more powerful anticalcemic effects of pamidronate, zoledronic acid, or denosumab to manifest themselves. 11  HypoCalcemia Main causes: Postoperative hypocalcemia, (post-thyroidectomy or post-parathyroidectomy) Assessment Measuring PTH and Ca postoperatively. Treatment Indications: - Total Ca< 7 mg/dL - Ionized calcium < 1.1 mmol/L - Carpopedal spasm - Perioral numbness, - Positive Chvostek’s sign (twitching facial muscles) Chvostek’s sign Trousseau's sign (Carpopedal sapsm) Treatment: Mild: Supplementing with oral calcium (1 to 3 g daily of elemental calcium Moderate: Ca< 7 mg/dL despite calcium supplementation Ca escalated to include up to 6000 mg calcium per day, Vit D-( 0.5 -1 μg of calcitriol twice daily can be added. IV calcium if severe symptoms are present. IV Mg of 1 mg/kg / hour if patients remain symptomatic and hypocalcemic. In severe Refractory hypocalcaemia: Bolus IV injection: 1 to 2 g of calcium in 50 mL of 5% dextrose over 20 min Maintenance IV infusion: 11 g of calcium gluconate in 1000 isotonic saline or D5W. Over 24 Hrs Precaution for Calcium Infusion 1-Slow infusion 2-Clinical Monitoring: pulse and cardiac auscultation to detect early tachycardia 3-ECG: continuous ECG monitoring, as rapid replacement can elicit cardiac arrythmias. 4-Magnesium levels should also be checked Hypomagnesemia (serum magnesium level is below 1.7 mEq/L) and corrected ROLE Of Vitamin D3 Mild: follow up Moderate: calcitriol therapy at 0.25 μg once or twice a day for moderate Severe hypocalcemia: 0.5 μg once or twice a day or if 1-hour postoperative parathormone level is less than 15 pg/mL. Precaution for Vitamin D3: 1- Patients with borderline renal function 2- Elderly. - In these latter two situations, hypercalcemia can occur rather quickly especially when taken with Ca supplement. 12 Questions 1. Outline the management of hypoglycemia and hypoglycemic coma. 2. Outline the management of diabetic ketoacidosis. 3. Which of the following is a difference between the management of diabetic ketoacidosis and HyperOsmolar Non Ketotic Hyperglycemia (HONK)? a. Because the presence of ketone bodies is not a feature of HONK, we do not classically need to give NaHCO3. b. In HONK, no need to worry about hypoglycemia even with prolonged insulin infusion. c. In HONK, there will always be an excess of potassium in the blood we we don’t usually need to supplement insulin with KCl. d. Subcutaneous Mixtard insulin can be used instead of regular insulin for the management of HONK. 4. Regarding the treatment of myxedema coma, indicate whether each of the following is True or False: a. T3 has a longer t1/2 than T4 and so a loading dose is usually needed. b. T4 is more cardiotoxic than T3. c. Hydrocortisone is needed to manage the expected unmasking of adrenocortical insufficiency. d. Antibiotics are needed in every case. e. Only intravenous thyroxine is reliable. 5. Regarding the treatment of thyroid crisis, match the following phrases in column A with the best choice of drugs from column B. Column A Column B 6. Anti-shock a. Diltiazem 7. Controls the heart rate b. Hydrocortisone 8. For hyperthermia c. K iodide 9. Prevents conversion of T4 to T3 d. Methimazole 10. Prevents thyroid hormone e. Paracetamol release f. Prazosin g. Propylthiouracil 11. Enumerate the lines of management of acute adrenal insufficiency. 12. Explain each of the following: a. A patient with acute adrenal insufficiency will have hypoglycemia, yet he might need insulin infusion. b. Patient with moderate hypercalcemia is given NaCl solution for fluid replacement. c. Combined treatment of moderate hypercalcemia with calcitonin and pamidronate. d. Caution with vitamin D3 therapy with elderly patients. 13 13. Regarding the treatment of hypercalcemia, match the following phrases in column A with the best choice of drugs from column B. Column A Column B 14. A monoclonal anti-body a. Calcitonin 15. Contraindicated in renal b. D5W (glucose 5% solution) impairment c. Denosumab 16. Of limited potency d. Frusemide 17. Preferred in cardiac failure e. Hydrocortisone f. Teriparatide g. Zoledronic acid 18. A patient with acute adrenal insufficiency might need supplementation with all of the following EXCEPT: a. Ca b. Glucose c. K d. Na 19. Describe precautions with calcium infusion. 14  Drugs and Obesity It is said that much of the world is experiencing an “epidemic of obesity.” Obesity is often associated with the metabolic syndrome and increased risks of cardiovascular disease and diabetes. Since eating behavior is an expression of endocrine, neurophysiologic, and psychological processes, prevention and treatment of obesity are challenging. Even a 5–10% loss of weight is associated with a reduction in blood pressure and improved glycemic control. The definition of obesity according to the WHO: it is "a condition in which percentage body fat (PBF) is increased to an extent in which health and well-being are impaired“ Classification of obesity is being done most commonly according to the "Body Mass Index" (BMI) BMI is calculated as weight in kilograms divided by the height in metres squared Normal weight BMI is between 18.5 - 24.9 Overweight BMI is between 25 - 29.9 Obesity BMI is over 30 Severe (morbid) obesity BMI is over 40 Indications of obesity pharmacotherapy For patients who have failed to achieve clinically significant weight loss, defined as ≥ 5% of baseline weight after 6 months of lifestyle interventions The Obesity Society, the Endocrine Society, and the American Association of Clinical Endocrinologists recommend AOMs (anti-obesity medications) for individuals with: - BMI ≥ 30 kg/m: Drug therapy is adjunctive to lifestyle intervention. - BMI ≥ 27 kg/m in presence of concomitant obesity-related diseases and for whom dietary and physical activity therapy has not been successful. 15 N.B: Undeclared ingredients: Many products in market are sold for being pure herbs yet to make them effective they may be adulterated by adding medicines. 16 Kinetic changes with morbid obesity Effects on absorption: Effects on distribution: The gastrointestinal transit is accelerated, The drug distribution is probably the and the gastric empty time is shortened, most impacted by the obesity-related that can reduce the solubilization and changes because the fat mass (FM) absorption of some oral drugs. increases leading to an important Absorption from the subcutaneous issue increase of the volume of distribution for will be slowed due to poor blood flow to lipophilic drugs. subcutaneous fat. Effects on metabolism: Effects on Excretion: Hepatic metabolism is slowed not only Obesity and its complications as diabetes by decreased cardiac output but also due tends to damage kidneys, decreasing the to fatty infiltration of the liver. renal clearance. Bariatric surgery and absorption Dumping syndrome is the syndrome in which food, especially food high in sugar, moves from the stomach into the small intestine too quickly after its intake, sometimes also called the rapid gastric emptying syndrome. Compensatory intestinal release of Peptide YY (PYY) and glucagon-like-peptide-1 (GLP-1) and water and electrolyte absorption in the colon occurs. All of which can increase or decrease the absorption of therapeutic drugs. Extended-release drugs may have reduced bioavailability as a result of a significant portion of the gastric tract being bypassed. This can be important in critical drugs such as anti-epileptics. Possibly, switch oral solid medications doses to - liquid formulation, - using non-oral dose forms - immediate-release formulations. After bariatric surgery, patients may be more prone to rapid gastric emptying time, higher absorption rates and, consequently, higher and earlier peak concentrations (Cmax) (resulting from lower Vd) which causes a quicker drug onset. This may be of relevance for sedatives or opioids such as midazolam and morphine. Drugs more soluble at an acidic pH are absorbed in the stomach, whereas those soluble in an alkaline environment are absorbed in the small intestine. Bariatric procedures such as gastric bypass or sleeve gastrectomy, lead to decreased production of HCl and an increase in gastric pH. This might increase solubility of certain medications (e.g. allopurinol, i.e. basic drugs), and decrease solubility and absorption of medications dependent on an acidic environment (e.g. acetylsalicylic acid). Bariatric surgery and drug distribution Decrease in fat decreases the Vd of fat-soluble drugs Many patients experience hypoalbuminemia after bariatric surgery, with decreased plasma protein binding of drugs and this increases the free plasma fraction and causes decrease in the volume of distribution (Vd). 17  Nutritional deficiencies post-bariatric surgeries are common and are affected by the type of surgery performed. Nutritional Supplementation (B-Ca-D) should include 1–2 adult multivitamin-plus-mineral supplements, 1200–2400 mg elemental calcium, 3000 IU vitamin D (titrated to therapeutic amounts), and 250–350 mg vitamin B-12/d or 1000 mg vitamin B-12/wk Thiamin: Thiamin deficiency may appear due to a combination of rapid weight loss, decrease in consumption, and persistent vomiting postoperatively Zinc: Zinc deficiency induces hair loss, impaired sense of taste, and sexual dysfunction Selenium is absorbed primarily in the duodenum; therefore, patients after malabsorptive procedures such as RYGB and BPD are at risk of selenium deficiency The separation of calcium and iron supplements is recommended. If iron concentrations continue to remain low with oral supplementation, intravenous iron is recommended Summary Drug treatment is just one part of obesity management and it is not the main one. Many approved drugs might still have adverse effects that remain to be discovered so post-marketing surveillance is always a must. Drug treatment for obesity should always be under specialist supervision. Undeclared ingredients of commercially available anti-obesity products may lead to serious health outcomes and so only highly trusted products should be consumed. Obesity may affect kinetics of and response to drugs taken of other medical indications. Bariatric surgeries may also affect drug kinetics and hence drug response. Special vitamin and mineral supplementation may be needed after bariatric surgery according to its type. Questions 1. Mention indications of pharmacotherapy in obesity. 2. For each of the following anti-obesity drugs mention the mechanism of action and one important side effect: - Orlistat phenteramine/topiramate naltrexone/buproprion - Semaglutide liraglutide setmelanotide 3. Within the context of obesity treatment, explain the term, undeclared ingredients. 4. Mention the effect of morbid obesity on drug: absorption and distribution. 5. Explain the pharmacological basis of each of the following observations after bariatric surgery: - Impaired absorption of extended -release preparations - Decreased absorption of acetyl salicylic acid - Increased absorption of allopurinol - More rapid onset of orally administered morphine and midazolam 6. Explain the rational for each of the following: - Caution is necessary when prescribing an oral opioid or midazolam. - It is better to give liquid formulation after bariatric surgeries. 7. In general, what supplements are usually needed after bariatric surgery? 8. How can bariatric surgery affect drug distribution. 18  Management of Sleep Disorders Insomnia is defined by the presence of an individual’s report of difficulty with sleep. Difficulty falling asleep ➔ sleep latency Difficulty in staying asleep Prolonged periods of wakefulness during the sleep period Frequent transient arousals 19 Mechanism of action of Benzodiazepines - They bind to GABAA receptors at a site different from where GABA binds. - The site of binding is named the “Benzodiazepine receptor- BZ”, and there are BZ1 and BZ2 receptors. - Binding of a benzodiazepine to its receptor site increases the affinity of GABA for the GABA-binding site - This increases the frequency of the opening of the ion channel controlled by the GABAA receptor. - Opening of the central ion channel, allows chloride entry. - This causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials. - Thus, benzodiazepines allosterically modify GABA action. Benzodiazepine dependence - Psychological and physical dependence can be worse than that of opioids. - If large doses are given for long periods (more than a week) - Mostly pharmacodynamic- due to changes in responsiveness of the CNS - Can cause withdrawal symptoms such as: Anxiety, Restlessness, Confusion, Insomnia, Orthostatic hypotension, hyperactive reflexes and generalized seizures. - Withdrawal is more common with the short acting - All of them are controlled substances. - Cross tolerance with alcohol ➔ unsatisfactory therapeutic response when standard doses are used in a patient with a recent history of excessive use of alcohol OTHER HYPNOTIC AGENTS- Zolpidem Zaleplon: It has a chemical structure different from Fewer effects on cognitive function benzodiazepines but binds to a sub-type of compared to zolpidem or the benzodiazepine receptors. benzodiazepines Rapid onset of action and hypnotic effect for Minimal tolerance, half-life of one approximately 5 hours hour No anticonvulsant or muscle-relaxing properties. Eszopiclone: Tolerance less than that Few withdrawal effects and little tolerance occurs of zaleplon, half-life of six hours with prolonged use. Melatonin and melatonin receptor agonists Orexin antagonists Ramelteon and Tasimelteon are agonists at MT1 & Suvorexant block these OX 1 & MT2 receptors. 2 receptors to reduce Mainly for difficulty of falling asleep (increased sleep wakefulness and enhance latency). normal sleep. Least potential for abuse, dependence or withdrawal Suvorexant is an orexin effects. Can be administered long term. antagonist that improves sleep May increase prolactin levels. duration. Antidepressants Antihistamines Doxepin: An older tricyclic agent with an SNRI Some antihistamines with sedating mechanism properties, such as Approved at low doses for the management of Diphenhydramine, insomnia. Hydroxyzine Mirtazapine: An older tricyclic antidepressant Promethazine Strong antihistamine properties, Used off-label Anticholinergic effects for the treatment of insomnia Some are marketed in over-the- counter (OTC) products. 20 21 Strategy for treatment of sleep disorders Treatment of underlying medical conditions or psychiatric illness Non-pharmacologic therapies are very important. Some patients will still need and should be given a sedative-hypnotic for a limited period. Abrupt discontinuance of many drugs in this class can lead to rebound insomnia The failure of insomnia to remit after 7–10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Long-term use of hypnotics is an irrational and dangerous medical practice. Treatment of sleep disorders-Cautions A dose that does not impair mental activity or motor functions during waking hours. Prescriptions should be written for short periods Assess the efficacy of therapy from the patient’s subjective responses. Combinations of antianxiety agents should be avoided Patients should be cautioned about the consumption of alcohol and the concurrent use of over-the-counter medications containing antihistaminic or anticholinergic drugs Excessive CNS effects in the elderly: “The most common reversible cause of confusional states in the elderly is overuse of sedative/hypnotics.” Increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment Controlled use of sedatives and hypnotics and notes about addiction Most sedative-hypnotic drugs are classified as Schedule III or Schedule IV drugs Consequences of abuse are both psychological and physiologic. “Physiologic dependence can be described as an altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome” Withdrawal symptoms depend on the magnitude of the dose used immediately before cessation of use. Less symptoms with longer acting agents Management Of Circadian rhythm sleep disorders Sleep Hygiene Pharmacologic management of Jet lag Establish a set bedtime routine. Timed melatonin or melatonin agonist ramelton—To Set a regular sleep and wake time. help advance the circadian phase after eastward travel Go to bed when tired & get out of across up to seven time zones, to be started on the bed if unable to sleep within 15 evening of arrival and continued for up to 5 days. minutes. Hypnotics — benzodiazepines and non- Reduce noise, light, stimulation, & benzodiazepine, not for routine use, can cause next- temperature in bedroom. day performance deficits. Restrict activities in bed to those that Temazepam, midazolam, and triazolam; May cause help induce sleep. and anterograde amnesia. Avoid using caffeine & nicotine 6 The non-benzodiazepine zolpidem and zopiclone hours before bedtime. Caffeine and other stimulants — Judicious use of caffeine is generally safe and can help offset daytime sleepiness associated with jet lag, but may lead to sleep disruption in some cases. 22  Questions Which of the following is a recommendation with the use of hypnotics? a. They can be used for as long as requested by the patient. b. Elderly patients should be warned and monitored for the risk of falls c. Hypnotics should always be combined with anti-anxiety agents to enhance effectiveness. d. Patients with hepatic disease would require higher doses because of diminished activation of hypnotics in the liver. e. Patients with respiratory disease would require higher doses because they find it more difficult to sleep. Answer: B 1. How do benzodiazepines produce CNS depression? 2. Explain each of the following: Benzodiazepines are considered allosteric modifiers of GABA. Unsatisfactory response to benzodiazepines might be seen in patient with recent history of alcohol consumption. It is recommended to prescribe benzodiazepines for the shortest duration possible. Tolerance to benzodiazepines is considered dynamic in nature. The anti-depressant, mirtazapine might be effective as a hypnotic. 3. Describe withdrawal to benzodiazepines. 4. Based on kinetic properties, why would eszopiclone cause less tolerance (milder withdrawal) than that caused by zaleplon? 5. Classify the following hypnotics as either suitable to improve sleep latency or sleep duration: Eszopiclone lorazepam ramelteon Suvorexant triazolam zaleplon 6. Mention the name and the mechanism of action of an over-the-counter OTC product for insomnia. 7. Mention three cautions with writing hypnotic prescriptions. 8. Describe a strategy for management of jet-lag. 23  Pain management Definition of pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage. Categories of pain: (onset) Acute: Trauma, injury and inflammation Chronic: Malignant and Non -malignant as with: Sickle cell anemia, rheumatoid arthritis, fibromyalgia and AIDS. Categories of pain: (pathophysiology) Nociceptive pain (stimuli from somatic &visceral structure) Neuropathic pain (stimuli abnormally processed by nervous system) Chronic pain is experienced by approximately one-third of all cancer patients and as many as 70 to 90% of those with advanced disease. Although established pharmacotherapeutic strategies have been demonstrated to benefit most patients, undertreatment remains common. This unacceptable situation must be remedied; relief of cancer pain is an ethical imperative and clinicians have to maximize the knowledge and skills needed to attend to this task. 24  Pain management strategies: Non Pharmacological intervention Pharmacologic intervention WHO Analgesic Ladder The original ladder mainly consisted of three steps: First Step - Mild pain: non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen with or without adjuvants Second Step - Moderate pain: weak opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics and with or without adjuvants Third Step - Severe and persistent pain: potent opioids (morphine, methadone, fentanyl, oxycodone, buprenorphine, tapentadol, hydromorphone, oxymorphone) with or without non-opioid analgesics, and with or without adjuvants The opioid conversion table The opioid conversion table can be used to shift between different opioids or formulations of the same opioid Adjuvants, also called co-analgesics, include Tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine. Anticonvulsants like gabapentin and pregabalin Topical therapies (e.g., capsaicin) 25  The three main principles of the WHO analgesic ladder are: “By the clock, by the mouth, by the ladder.” This means that drugs should be taken regularly and at regular intervals, orally whenever possible, and analgesics should be prescribed starting at Step 1 (nonopioid analgesics) and titrated upward as needed. Patient-Controlled Analgesia (PCA) It has been utilized to optimize pain relief since 1971, with the first commercially available PCA pump appearing in 1976. The goal of PCA is to efficiently deliver pain relief at a patient's preferred dose and schedule by allowing them to administer a predetermined bolus dose of medication on-demand at the press of a button. PCA is used to treat acute, chronic, postoperative, and labor pain. These medications can be administered intravenously, epidurally, through a peripheral nerve catheter, or transdermally. Drugs commonly administered are opioids and local anesthetics. PCA has proven to be more effective at pain control and results in higher patient satisfaction. Drug abuse & addiction Theories of addiction Negative reinforcement (pain avoidance) Positive reinforcement (pleasure seeking) Incentive salience (craving) Stimulus response learning (habit) Inhibitory control dysfunction (impulsivity) THE DOPAMINE HYPOTHESIS OF ADDICTION Dopamine in the ventral tegmental area and the nucleus accumbens of the mesolimbic system appears to play a primary role in the expression of “reward,” and excessive dopaminergic stimulation may lead to reinforcement such that the rewarded behavior may become compulsive—a common feature of addiction. Though not the only neurochemical characteristic of drugs of abuse, it appears that most addictive drugs have actions that include facilitation of the effects of dopamine in the CNS. 26 Opioids Addiction— The euphoria, indifference to stimuli, and sedation usually caused by the opioid analgesics, especially when injected intravenously, tend to promote their compulsive use. These factors constitute the primary reasons for opioid abuse liability and are strongly reinforced by the development of physical dependence. The primary targets underlying the actions of the opioid analgesics are the μ, κ, and δ receptors. However, the opioids have other actions including disinhibition in dopaminergic pathways in the CNS. Opioids Addiction— Acute Effects: Euphoria (rush), Apathy: drowsiness & hypo activity. Risks of Chronic Abuse 1. Fatal overdose - homicide - suicide - accidents. 2. Risk of infections due to syringes (hepatitis, AIDS). Withdrawal Syndrome: Craving for the drug - anxiety - insomnia - tremors. Piloerection – mydriasis - lacrimation - rhinorrhea. Tachycardia - hypertension - hot & cold flushes. Abdominal cramps - vomiting – diarrhea. How to minimize problems presented by tolerance and dependence when using opioid analgesics: Establish therapeutic goals before starting opioid therapy. The patient and his or her family should be included in this process. Once an effective dose is established, attempt to limit dosage to this level. Instead of opioid analgesics—especially in chronic management—consider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discontinuance. Frequently evaluate continuing analgesic therapy and the patient’s need for opioids. Management of Opioid Abuse: Methadone or buprenorphine: Replace heroin or morphine by methadone. Gradual withdrawal of methadone (longer-acting) is less severe. Naltrexone: Given chronically after detoxification to block opioid receptors, loss of euphoric effects of opioids, loss of desire to take the drug. Symptomatic treatment of withdrawal symptoms: Anxiolytics - antiemetics – antispasmodics. Clonidine: inhibits sympathetic discharge. Fentanyl Addiction The opioid crisis just keeps getting worse, in part because new types of drugs keep finding their way onto the streets. Fentanyl, heroin’s synthetic cousin, is among the worst offenders. 27 Cannabis addiction (Strox, voodoo) The most prominent effects are Euphoria and relaxation. Feelings of well-being, grandiosity, and altered perception of passage of time. Dose-dependent perceptual changes (e.g., visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Heavy cannabis consumption is associated with chronic bronchitis and airway injury. Symptoms of cannabis withdrawal appear after 24 hr of abstinence, reach their peak around 2-6 days and remit within 2 weeks but impaired sleep pattern may persist for longer periods. Withdrawal symptoms: Irritability, anger, aggression, insomnia, depressed mood, weight loss, loss of appetite, difficulty in concentration and headache. Management of Cannabis addiction Psychosocial treatment Pharmacotherapy: (Potential treatments) Cannabinoid agonist as dronabinol and nabilone, reduce withdrawal manifestations Gabapentin and naltrexone also show promise Therapeutic uses of cannabinoids 28 Questions 1. Describe the sequence of use of analgesics according the WHO’s analgesic ladder. 2. What is the function of the opioid conversion table? 3. Mention three examples of analgesic adjuvants. 4. Mention the basic principles of the WHO analgesic ladder. 5. What is the goal for PCA (patient-controlled analgesia). 6. For which type/s of pain can PCA (patient-controlled analgesia) be used? 7. Which administration routes can be used for PCA (patient-controlled analgesia)? 8. Which drugs are commonly used for PCA (patient-controlled analgesia)? 9. Why do you think does PCA (patient-controlled analgesia) increase patient satisfaction? 10. What feelings promote compulsion on the use of opioids? 11. Describe the main features of opioid withdrawal. 12. How to minimize problems presented by tolerance and dependence when using opioid analgesics? 13. Outline the management of opioid addiction. 14. Chronic bronchitis and airway injury is a feature of the heavy consumption of which of the following? a. Cannabis b. Clonidine c. Fentanyl d. Morphine 15. Match each of the following drugs used in the management of opioid addiction with its most likely function: 1. Clonidine a. Control vomiting 2. Methadone b. Decrease withdrawal manifestations 3. Naltrexone c. Maintain abstinence d. Prevent tachycardia 16. Describe the effects of cannabis on mood and perception. 17. Describe physical and psychological changes with cannabis withdrawal. 18. Outline the management of cannabis addiction. 19. Some countries legalize cannabis and approve it for some indications. Mention three examples of such indications. 29  Drugs and CNS Emergencies Status Epilepticus Definition: - Status epilepticus is greater than 5 minutes of continuous seizure activity or greater than two episodes without return to baseline. Classification: - Depending on how long status epilepticus lasts and how it responds to treatment, four stages of SE have been suggested: Early SE consists of SE that responds to first-line treatment with benzodiazepines (BZDs). Established SE refers to SE that persists after treatment with first-line therapy. Refractory SE occurs when SE fails to stop after first and second-line anti-seizure drugs (ASDs) have been given. Super-refractory SE is defined as SE that continues or recurs 24 h or more after the onset of ‘anesthetic’ treatment. Status Epilepticus- Drug treatment Stage 1: Early SE -time period t1, prolonged seizure 5′–10′ Benzodiazepines; IV lorazepam can be repeated if necessary, once Stage 2: Established SE- time period t2, for GTCS −10′–30′ Non-sedating IV Anti-Epileptic Drugs Phenytoin 18 mg/kg IV bolus infusion at a maximum rate of 50 mg/min OR Fosphenytoin 15 mg PE/kg IV bolus infusion at a maximum rate of 100 mg/min OR Valproate 30 mg/kg bolus infusion at a rate of 3–6 mg/kg/min OR Levetiracetam 30 mg/kg (range 30–60) bolus infusion over 10 min Stage 3: refractory SE-−30′–60′ EEG monitoring—IV anesthetic agents Propofol: 2 mg/kg IV bolus infusion (can be repeated if necessary) OR Midazolam: 0.1–0.3 mg/kg IV infusion OR Thiopental: 100–250 mg IV bolus infusion over OR Pentobarbital: 5–15 mg/kg IV bolus, followed by IV infusion Doses to be adjusted and continued based on EEG monitoring Stage 4: super-refractory SE (>24 h) EEG monitoring—IV anesthetic agents (propofol/midazolam) + IV ketamine Doses to be adjusted and continued based on EEG monitoring Emerging treatments of epilepsy: Ketogenic diet, immunotherapy, epilepsy surgery, IV magnesium, treat the cause. Ketogenic diet in the treatment of epilepsy It is an eating pattern that includes high amounts of fat, low to moderate amounts of protein, and very little carbohydrates. The keto diet is typically rich in foods like butter, cheese, eggs, meat, nuts, oils, seafood, and seeds. “Ketogenic diet, initially described by Hugh Conklin, has been used for the treatment of medically refractory childhood epilepsy since the 1920s. Although its use became less frequent with the introduction of anticonvulsant medications, the diet has regained recognition over the past 15 to 20 years.” The mechanisms underlying the clinical efficacy of the ketogenic diet remain unknown. May act by: modification of the tricarboxylic acid cycle to increase γ-aminobutyric acid synthesis in the brain, limiting reactive oxygen species generation, and boost energy production in brain tissue. As a result, hyperpolarization of neurons occurs, stabilizing synaptic function and increasing resistance to seizures throughout the brain.” 30  Serotonin Syndrome Mechanism: Increased stimulation of postsynaptic 5-HT2A and 5-HT1A for a single or multiple drugs Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter that is derived from tryptophan. Serotonin is found primarily in the gastrointestinal tract, the central nervous system, and platelets. It is metabolized by monoamine oxidase in the liver. Serotonin modulates: attention, mood, appetite, sleep as well as some cognitive functions, thermoregulation and promotes platelet aggregation, uterine contraction, bronchoconstriction, vasoconstriction, and gastrointestinal motility. Clinical Picture: 1- Agitation. 2- Hypertonia, hyperreflexia, clonus ( an abnormal reflex response to a muscle stretch that involves rhythmic movement.) 3- Hyperthermia (temperature over 38 ºC) 4- Diaphoresis. 5- Diarrhea. Serotonin Syndrome- causes Serotonin syndrome may occur as a consequence of therapeutic medication use, drug interactions, or intentional overdose. Drugs implicated in serotonin syndrome  serotonin synthesis Serotonin receptor agonists Increase serotonin release L-Tryptophan (dietary - Triptans - Amphetamines supplement) - Ergot derivatives - Cocaine - Buspirone Inhibit serotonin uptake Inhibit serotonin - Amphetamines metabolism - Cocaine - MAO inhibitors - Antidepressants (SSRIs, TCSs, atypical- duloxetine, - Linezolid venlafaxine) - Dextromethorphan - Meperidine & tramadol - St. John’s wort Serotonin syndrome is often precipitated by the addition of one or more of these medications in patients who were previously stable on a serotonergic agent. Since there are so many drugs that may cause serotonin syndrome, it is important for providers to take a careful medication history when adding new medications Serotonin Syndrome Management: Prompt recognition External cooling Supportive care to control agitation, Muscular paralysis with neuromuscular hyperthermia, and autonomic blocking agents dysfunction Mechanical ventilation Discontinuation of all serotonergic Sedation and muscle relaxation with i.v bz agents Nonspecific serotonin receptor blockers, Intensive care unit monitoring, if such as cyproheptadine, chlorpromazine, needed and methysergide 31 1- Benzodiazepines, such as lorazepam or diazepam, are integral to the treatment of mild-to-moderate serotonin syndrome. 2- Oral Cyproheptadine: - Cyproheptadine, an antihistamine with nonselective antiserotonergic effects, may be considered in patients with moderate or severe symptoms 3- Paralysis with nondepolarizing agents, immediately followed by orotracheal intubation and mechanical ventilation, should be considered for patients with hyperthermia (temperature >38.5 °C), severe truncal rigidity. Neuroleptic Malignant Syndrome Definition: - A severe drug reaction associated with dopamine receptor blocking agents used primarily as antipsychotics. Drugs causing NMS: 1- Typical neuroleptics: e.g. haloperidol, chlorpromazine. 2- Atypical neuroleptics: e.g. olanzapine, clozapine, risperidone 3 Anti-dopaminergic antiemetics: e.g. metoclopramide 4- Withdrawal of dopaminergic agents: e.g. levodopa Clinical picture: Treatment lines 1- Discontinue, switch or reduce antipsychotics depending on severity 2- Anticholinergics are contraindicated in NMS, unless very mild with only rigidity. 3- Lorazepam for stupor or confusion 4- fluids and cooling 5- Bromocriptine and amantadine may be used in moderate case 6- Dantrolene for sever cases (blocker of ryanodine receptor, preventing Ca release from the sarcoplasmic reticulum) 32  Guillain-Barré Syndrome Definition: - GBS is an acute inflammatory polyrneuropathy characterized by ascending weakness and areflexia. - It is thought to be caused by anti-bodies against the myelin sheath and Schwann cells. Up to two-thirds of patients report a preceding infection: Influenza, Campylobacter jejuni, Cytomegalovirus, Epstein-Barr virus Mycoplasma pneumoniae, Zika virus, Hepatitis E Systemic compilations are very common in GBS patients admitted to the ICU from prolonged immobilization and mechanical ventilation Management: It is imperative to initiate therapy as early as possible to minimize nerve damage. A) IVIG: The dosage regimen recommended is daily intravenous infusions of immunoglobulin (0.4 g/kg/day) for 5 days, to a total dosage of 2 g/kg. - Intravenous immunoglobulin (IVIG) is prepared from fractionated pooled human sera derived from thousands of donors with various antigenic exposures. - Preparations of IVIG are composed of more than 90% IgG. - Although the mechanism of action of IVIG is not understood fully, proposed mechanisms include suppression of IgG production, accelerated catabolism of IgG, neutralization of complement-mediated reactions, neutralization of pathogenic antibodies, down-regulation of inflammatory cytokines and inhibition of autoreactive T lymphocytes B) Plasma Exchange: - In patients with hyperviscosity, congestive heart failure, chronic renal failure or IgA deficiency, plasma exchange should be preferred. - It is recommended that five single plasma volume exchanges (40–50 ml/kg) are given with a continuous flow machine on alternate days using saline and albumin as replacement fluid. 33 Questions 1. Status epilepticus is classified depending on how long status epilepticus lasts and how it responds to treatment. In the table below suggest one drug for each stage: Stage 1 Stage 2 Stage 3 Stage 4 2. Match each of the following drugs in column A with their relation to serotonin in column B 1. Antidepressants (SSRIs, TCSs, atypical- a.  serotonin synthesis duloxetine, venlafaxine) b. Serotonin receptor agonist 2. Buproprion c. Increase serotonin release 3. Buspirone d. Inhibit serotonin uptake 4. Dextromethorphan e. Inhibit serotonin 5. Ergot derivatives metabolism 6. L-Tryptophan (dietary supplement) f. No known relation to 7. Linezolid serotonin 8. Lamotrigine 9. MAO inhibitors 10. Meperidine 11. Phenytoin 12. St. John’s wort 13. Tramadol 14. Triptans 3. Outline serotonin syndrome management. 4. Mention two examples of drugs or drug classes that can cause neurolept malignant syndrome. 5. Outline the treatment of neurolept malignant syndrome. Explain the mechanism of action of IVIG in the treatment of Guillain-Barré Syndrome. 34  Intravenous Fluid Therapy Fluid Replacement Therapy Is the medical practice of replenishing fluid lost through sweating, bleeding, fluid shifts or other pathologic processes. Fluids can be replaced with: – Oral rehydration therapy(drinking). – Intravenous therapy. – Rectally. – Or by hypodermoclysis the direct injection of fluid into the subcutaneous tissue. – Fluids administered by the oral and hypodermic routes are absorbed more slowly than those given intravenously. Introduction Total Body Water (TBW) 50 -70% of total body wt. Water represents the large constitute of the body Average is greater for males. Highest in newborn, 75 -80%. By first year of life TBW ~ 65%. Most in muscle, less in fat. What is fluid balance? Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly. Important to remember A patient deprived of all external access to water must still excrete a minimum of 500- 800 ml urine/day in order to excrete products of catabolism In addition to: Mandatory insensible loss. *The most common uses for IVF: ❑ Acutely expand intravascular volume in hypovolemic states. ❑ Correct electrolyte imbalances. ❑ Maintain basal hydration. 35 When?  This requires an evaluation of: ❑ The patient’s hemodynamic. ❑ Organ perfusion. ❑ Cardiac function. ❑ An assessment of “fluid responsiveness” in addition to understanding the patients’ clinical condition. (Fluid Challenge Test) ❑ The nature and severity of the electrolyte imbalance must be assessed from: Three elements to assessing fluid balance and hydration status which are: ✓ Clinical assessment, body weight and urine output. ✓ Review of fluid balance charts. ✓ Review of blood chemistry. *Clinical Assessment Dehydration is defined as a 1% or greater loss of body mass as a result of fluid loss. Symptoms include: – Impaired cognitive function. – Headaches, fatigue. – Dry skin. – Severe dehydration can lead to hypovolaemic shock, organ failure and death. The signs of hypoperfusion include: – Mean arterial pressure (MAP) < 65 mmHg. – Tachycardia. – Decreased urine output. – Altered mentation – Poor capillary refill. – Skin perfusion/mottling. – Cold extremities. – It should be noted that hypotension and tachycardia reflect significant volume depletion. – A blood loss of about 1 L is required before a patient develops a tachycardia and about 1.5 L before the blood pressure begins to drop. – Postural hypotension. *Biochemical investigations ❑ Sodium. ❑ Potassium. ❑ Chloride. ❑ Magnesium. ❑ Phosphate. Normal Serum Osmolailty 280 – 300 mosm /kg. 36  Type o I luids Blood Crystalloids Colloids products Isotonic Hypertonic Hypotonic *Crystalloids Balanced salt/electrolyte solution; forms a true solution and is capable of passing through semipermeable membranes. Crystalloid solutions contain water, electrolytes, and/or glucose. In general, isotonic solutions are used to treat extracellular fluid (ECF) volume depletion. Hypotonic solutions to replace (ECF) and intracellular fluid (ICF) water loss. ▪ Hypertonic solutions are considered plasma expanders as they act to increase the circulatory volume via movement of intracellular and interstitial water into the intravascular space. *Free H2O solutions Provide Water that is not bound by macromolecules or organelles, free to pass through. Include : D5W (5% dextrose in water), D10W, D20W, D50W, and Dextrose/crystalloid mixes. *Colloids High-molecular weight solutions, draw fluid into intravascular compartment via oncotic pressure (pressure exerted by plasma proteins not capable of passing through membranes on capillary walls). Plasma expanders, as they are composed of macromolecules, and are retained in the intravascular space. Include mostly albumin, Hetastarch , Pentastarch (Pentaspan ), Plasma, Dextran. 37  A) Intravenous Sodium Chloride NaCl is available as : ▪ 0.225 %, containing 38.5 mEq of Na+ ▪ 0.45 %, containing 77 mEq of Na+ ▪ 0.9 %, containing 154 mEq of Na+ ▪ 3 % and containing 513 mEq of Na+ ▪ 5 % containing 1250 mEq of Na+ & (An equal amount o CL− in 1 L) solutions. 0.9 % NaCl solution is commonly referred to as normal or isotonic saline. But normal is misname better is isotonic saline. NOW, with new evidence was named abnormal saline). Indication of Isotonic (0.9 %) saline 1. To expand ECF volume in a hypovolemic patient. 2. To treat hyponatremia in a hypovolemic patient. 3. To treat hypernatremia in a patient with hypotension. 4. To treat saline-responsive metabolic alkalosis. 5. Preferred solution in a patient requiring contrast study. 6. Second preferred solution in critically ill patients with shock, ARDS, and at times burned patient. 7. Use cautiously in patients with Na+ overload such as CHF and liver failure. Hypotonic (0.45 %) saline *Indications 1. To maintain basic requirements of Na+. 2. To treat hypernatremia in a hypovolemic patient who has greater water than solute deficit. Hypertonic (3 %, 5 %, 7.5 %) saline 1. To treat symptomatic hyponatremia. 2. To treat hypotension and muscle cramps in hemodialysis patients. However, if sodium chloride is required for acute or chronic hyponatraemia, regardless of the cause, the deficit should be corrected slowly to avoid the risk of: Osmotic Demyelination Syndrome The rise in plasma-sodium concentration should not exceed 10- 12 mmol/litre in 24 hours. Hypertonic Saline in Head Trauma - Hypertonic saline is often used in trauma settings because it decreases the intracranial pressure in patients with head trauma and for patients following burns. - Offers some advantage over conventional therapy with mannitol: ❑ Greater magnitude of ICP reduction. ❑ Longer duration of action. ❑ No rebound increase in ICP. Adverse Effects Hyperchloremic Metabolic Acidosis and DEATH due to increasing chloride levels. Does not provide free water or calories. Interstitial edema Possible Acute renal injury (Cl causes renal vessel Vasoconstriction). 38  B) Balanced Electrolyte Solutions There are a number of “balanced” electrolyte solutions such as: – Ringer’s lactate (also called Lactated Ringer). – Plasma-Lyte 148. – Normosol R. – Isolyte S. * Ringer’s Lactate The most frequently used solution in fluid therapy because of its consideration as physiologic saline. Since Ringer’s lactate contains less Na+ than normal saline, it is less effective as a volume expander compared to normal saline. Ringer’s lactate is slightly hypotonic, with osmolality 273 mOsm. One liter contains: – 130 mEq /L Na+. – 109 mEq /L Cl -. – 28 mEq /L lactate. – 4 mEq /L K+. – 1.5 mEq Ca+2. Lactate is used instead of bicarb because it is more stable in IVF during storage. Lactate is converted into HCO3 − in the liver. Lactate needs oxygen to be converted into HCO3 − in the liver, so, it will not act as buffer in case of tissue hypoxia e.g circulatory shock. More closely resembles the electrolyte composition of normal blood serum. So as minimal effects on normal body fluid composition and pH. Does not provide calories. Indication ((Surgeons Fluid)) Used instead of isotonic sodium chloride solution during or after surgery. In the initial management of the injured, burned or wounded. It may reduce the risk of hyperchloraemic acidosis. To correct metabolic acidosis with hypokalemia (infrequently)- contains potassium Ringers Lactate and Coagulopathy ❑ Studies in surgical patients have demonstrated that as compared to LR volume replacement with NS results in greater blood loss with a greater need for blood transfusion. ❑ The cause of the coagulopathy is unclear, and is only explained by the difference in Ca++ partly between the two solutions. Lactate as a Metabolic Fuel The proportion of lactate uptake by the myocardium and its use a metabolic fuel increases during. Exercise. β-adrenergic stimulation. Elevated afterload. During shock. ❑ During shock the heart undergoes a major shift in substrate utilization such that it oxidizes lactate for the majority of its energy needs. ❑ Similarly, during increased demand on brain metabolism, lactate is increasingly utilized as an energy substrate. 39 *Cautions with Ringer’s lactate Use cautiously in renal failure patients because of potential development of hyperkalemia. Use cautiously in a patient with hepatic failure. (Impairs lactate metabolism) Ringer's Solution for Infusion contains insufficient concentration of potassium and calcium to be used for maintenance of these ions or to correct their deficits. Adverse effects Being slightly hypotonic (avoid in Closed Head Injury due to Increased Intracranial Pressure risk → cerebral edema). Lactate may accumulate in a preexisting Lactic Acidosis, and cannot initially be cleared. Calcium in RL can bind the citrated anticoagulant in blood product. (For this reason ringer lactate are contraindicated as dilution fluid for blood products). Drug interactions (e.g. not campatible with Ceftriaxone). Recommendation : At least 24- 48 h separation time between administration. Medications incompatible with the Ringer's Solution: - Amphotericin B- Cortisone. C) Intravenous Glucose (Dextrose in Water) Feature of Intravenous Glucose – Contains no Sodium or chloride. – Osmolality: 278 mOsm/L. (Isosmotic solution) *Composition of Intravenous Glucose Dextrose in water is available as: – 2.5%. (containing 25 g dextrose in 1 L of water, respectively) solutions – 5%. (containing 50g dextrose in 1 L of water, respectively) solutions – 10%. (containing 100g dextrose in 1 L of water, respectively) solutions – 50 %. (containing 500 g dextrose in 1 L of water, respectively) solutions *Intravenous Glucose in The Body The dextrose is metabolized to water and CO2, and the water is distributed between ECF and ICF compartments. In clinical management, the most commonly used solution is 5 % dextrose in water, which is usually abbreviated as D5W. This solution provides 170 kcal/L Indication of Intravenous Glucose D5W primary expands the intracellular volume AND should never be used as plasma expander. Indication of Intravenous Glucose Water depletion (dehydration) tends to occur when these losses are not matched by a comparable intake, as may occur in: - Coma or - Dysphagia or - In the elderly or - Apathetic who may not drink enough water on their own initiative. 40  Prevents excess catabolism and limits proteolysis (Protein sparing effect) Primarily used to deliver intravenous medications in small volume fluid infusions. The recommended dosage when used as a vehicle or diluent ranges from 50 to 250 ml per dose of medicinal product to be administered. Glucose solutions are also used to correct and prevent hypoglycaemia and to provide a source of energy in those too ill to be fed adequately by mouth. Glucose solutions are a key component of parenteral nutrition (TPN). Glucose solutions are given in regimens with calcium and insulin for the emergency management of hyperkalaemia. Why not to give water? Pure water causes hemolysis, if given IV; therefore, D5W is given to provide pure water. Infusion Rate Infusion rate should not exceed the patient's glucose oxidation capacities in order to avoid hyperglycaemia. Therefore, the maximum dose ranges from 5mg/kg/min for adults to 10-18 mg/kg/min for babies and children depending on the age and the total body mass. Adverse Effects Dilution and other effects on serum electrolytes Electrolyte disturbances such as: – Hyponatraemia. – Hypokalaemia. – Hypophosphataemia. – Hypomagnesaemia. Hypoosmolality. The above effects do not only result from the administration of electrolyte-free fluid but also from glucose administration. Hyperosmolality, osmotic diuresis and dehydration. Hypervolaemia and, for example, congested states, including pulmonary congestion. Enhance lactate production, more in tissue hypo-perfusion. In severe malnutrition (risk of precipitating a refeeding syndrome) *Refeeding Syndrome Characterized by the shift of – Potassium. – Phosphorus. – Magnesium. intracellularly as the patient becomes anabolic. Adverse effects Hyperglycemia. Aggravation of ischemic brain injury & increase mortality rate. Blood: – (electrolyte-free glucose solution) should not be administered simultaneously with, before or after an administration of blood through the same infusion equipment, because haemolysis and pseudoagglutination can occur. 41  Contraindications Uncompensated Diabetes. Other Known Glucose Intolerances (Such as metabolic stress situations). Hyperosmolar Coma. Hyperglycemia. Hyperlactatemia. Hypersensitivity to the active substance. Recommendation: not to be routinely used as they offer no benefit but can be harmful. Questions 1. Hypertonic electrolyte solutions… a. Mainly distribute intracellularly b. Are considered plasma expanders as they contain proteins. c. Replace lost interstitial fluid. d. Exert osmotic power on interstitial water. 2. Giving which of the following solutions is equivalent to giving pure water? a. D5W b. Lactated Ringer c. Saline 0.45% d. Saline 0.9% 3. Enumerate indications of isotonic saline. 4. Ensuring a gradual rise in plasma concentration of NaCl is important to avoid …………………………..syndrome. 5. Explain the following: - Hypertonic saline may be preferred over mannitol in head trauma. - Lactated Ringer will not act as a buffer in hypoxia. - We use lactated Ringer cautiously in hepatic impairment. - We use lactated Ringer cautiously in renal impairment. - We use lactated Ringer cautiously in calcium or potassium deficiency. - Lactated Ringer may lead to cerebral edema in cases of closed head injury. - Lactated Ringer cannot be used to dilute blood products. - D5W cannot be used as a plasma expander. - We cannot directly give pure water intravenously. 6. Mention adverse effects of giving NaCl solution. 7. Which of the following is regarded as a balanced electrolyte solution? a. Dextran b. D5W c. Isotonic saline d. Lactated Ringer solution 8. Enumerate indications of lactated Ringer solution. 9. Mention 3 medications that can’t be used with lactated Ringer. 10. How would excess D5W change the following in plasma? a. Na, K, Mg, P b. Osmolarity c. Lactate d. Glucose 42 For each phrase in column A, choose a suitable solution from column B. Column A Column B 11. Plasma expander colloid a. Dextran 12. Serves as pure water b. Glucose 5% in water 13. Most liable to cause demyelination c. Lactated Ringer’s 14. Provides calories d. Saline 0.45% 15. Acts as a buffer e. Saline 0.9% 16. Treats some cases of metabolic alkalosis f. Saline hypertonic 17. Used in hypernatremia 18. Isotonic but may cause hyperchloremic acidosis 19. Might cause refeeding syndrome with starvation 20. Incompatible with amphotericin 21. Has protien-sparing effect 22. Provides bicarbonate 23. Component of parenteral nutrition 24. Preferred in surgeries and burn 25. May treat hyper as well as hyponatremia 43  Antimicrobial Prophylaxis Stewardship Program Healthcare system that promotes and monitors judicious use of antimicrobials, to optimize clinical effectiveness and minimize misuse and overuse, which confer resistance to their effect. By 2050, if pattern of antimicrobial use continues the same way, deaths attributed to antimicrobial resistance will exceed those caused by vehicle accidents and cancer. Antibiotic A substance produced by a living microorganism to kill or inhibit the growth of other living microorganisms. Gram +ve = Bluish Gram –ve = Reddish Aerobic Anaerobic Obligate: TB Obligate: C. perfringens Microaerophilic: H. pylori Fucultative: E. coli Aerotolerant: Streptococci Classification of Antimicrobials Narrow- spectrum Broad- spectrum Vancomycin Broad spectrum & antipseudomonal penicillins Erythromycin, clarithromycin, Tetracyclines azithromycin ▪ Inhibition of normal flora > Aminoglycosides Chloramphenicols Intestine Pseudomembranous Sulfonamides Clindamycin colitis + Vagina Candidiasis Trimethoprim ▪ Inhibition of vitamin B synthesis ▪ Inhibition of vitamin K synthesis Bactericidal Bacteriostatic Bacteriostatic (low conc.) & Bactericidal (high conc.) Inhibitors of cell wall Tetracyclines Erythromycin synthesis Aminoglycosides Macrolides Chloramphenicol Co-trimoxazole Clindamycin Quinolones Sulfonamides Rifampicin Trimethoprim Metronidazole 44 AVOID the following combinations: Bactericidal + Bacteriostatic A bactericidal antimicrobial will not act effectively EXCEPT with actively- growing micro- organisms Penicillins + Aminoglycosides NOT in same syringe → Precipitate each other Nephrotoxic antimicrobials + Nephrotoxic drugs   Penicillins Thiazide diuretics Cephalosporins NSAIDs Vancomycin Aminoglycosides Ototoxic antimicrobials Vancomycin ! Aminoglycosides Sulfonamides + Sulfur- containing drugs Cross allergy  Thiazide diuretics Loop diuretics Diazoxide Sulfonylureas (Antidiabetics) Aminoglycosides + Neuromuscular blockers Curare- like effect Beware Sulfonamides Drink plenty of fluids + Urinary alkalinization HME inhibitors Chloramphenicol Quinolones Metronidazole ! HME inducer Rifampicin Outdated tetracyclines Fanconi syndrome Chloramphenicol IN premature babies Gray baby syndrome Metronidazole Disulfiram- like effect Cross- allergy & Cross- resistance Penicillins Cephalosporins Carbapenems No systemic effect if given orally Acid- labile penicillins Vancomycin Some oral sulfonamides (Sulfasalazine) Aminoglycosides Biliary excretion Cefoperazone (3rd generation cephalosporin) Ceftriaxone (3rd generation cephalosporin) Doxycycline (Highly Lipid soluble tetracycline) Moxifloxacin (Fluoroquinolone) 2nd line treatment of TB (Resistant TB) Aminoglycosides Fluoroquinolones   Streptomycin Ciprofloxacin Kanamycin Levofloxacin Amikacin Gatifloxacin, Moxifloxacin 45 Damage of growing cartilage Fluoroquinolones QT prolongation Fluoroquinolones Fatal aplastic anemia (Idiosyncratic, Irreversible) Chloramphenicol Antimicrobial Prophylaxis Surgical prophylaxis Types of Wounds Clean Clean- Contaminated Dirty contaminated Expected infection 20% Expected infection 40% Elective Urgent Open wound Purulence Closed Open procedure Inflammation Abscess procedure Spill form hollow organ Perforated organ Penetrating trauma < 4 Penetrating trauma > 4 hours hours Indications of Surgical Prophylaxis Contaminated & clean- contaminated. Operations lasting more than 2 hours. Unclean wound. At least THREE medical diagnoses (Diabetic + Cardiac + Hypertensive). No Justification for Antimicrobial Prophylaxis Neurosurgery Clean wound. Cardiac catheterization. Head & Neck surgery No prosthesis. Tonsillectomy. Endoscopic sinus procedures. Gastrointestinal & Splenectomy Elective, low risk. Orthopedic Clean involving knee, hand, foot + No prosthesis. General Rules Duration Up to 24- 48 hours. Selection According to suspected micro-organisms, depending on site of operation. Gram- positive Suspected Site of Type of operation Antimicrobial Alternative micro-organisms Operation Prophylaxis Penicillin allergy Staphylococci Cardiac Coronary artery 1st generation Macrolide: Closed bypass cephalosporin: Clindamycin procedure Cefazolin 2nd generation cephalosporin: Cefuroxime Orthopedic Spinal procedures 1st generation Hip fracture cephalosporin: Type I: Clean wound < 1 cm. long Total joint Cefazolin replacement Type II: Laceration > 1 cm. long Open fracture WITHOUT soft tissue damage (Types I & II) 46  Gram- negative & Anaerobes ADDED TO Staphylococci Site of Operation Type of Antimicrobial Alternative operation Prophylaxis Penicillin allergy Orthopedic Open fracture 3rd generation Macrolide: (Type III) cephalosporin: Clindamycin Ceftriaxone + Anaerobes Levofloxacin Contaminated 3rd generation Fluoroquinolone: open fracture cephalosporin: Levofloxacin (Type III) Ceftriaxone + Anaerobes + Anaerobes Metronidazole Type III: Open segmental fracture Metronidazole OR : Open fracture WITH extensive Ceftriaxone soft tissue damage + Metronidazole : Traumatic amputation + Antipseudomonal / Beta- lactamase inhibitor Piperacillin / tazobactam Gastrointestinal Appendicectomy 1st generation Macrolide: Open or Perforated cephalosporin: Clindamycin laparoscopic appendicitis Cefazolin + High risk: Colorectal + Anaerobes Aminoglycoside: >70 years old surgery Metronidazole Gentamicin Diabetic OR OR Pregnant 2nd generation Metronidazole Immunocompromi cephalosporin + + Gentamicin sed Anaerobes: Cefoxitin Acute + Macrolide + Gram- cholecystitis Obstructive positive + Anaerobes: jaundice Erythromycin No Justification for Antimicrobial Prophylaxis Urinary catheter. Gynecological Diagnostic laparoscopy. Intra-uterine device. Endometrial biopsy. 47 Rheumatic Fever Group B streptococci (gram- positive) Antimicrobial Prophylaxis Alternative Duration Penicillin allergy Benzathine penicillin G Azithromycin No rheumatic endocarditis: Weight ≤ 27 kg: Weight ≤ 27 kg: 5 years after acute rheumatic 600,000 units IM q3-4 5 mg/kg PO once daily fever or until 21 years of age, weeks Weight > 27 kg: whichever is longer. Weight > 27 kg: 250 mg/kg PO once daily Carditis with no residual heart 1.200,000 units IM q3-4 disease: weeks 10 years after acute rheumatic fever or until 21 years of age, whichever is longer. Carditis with residual heart Penicillin V Erythromycin disease: 250 mg PO twice daily 10 mg/kg twice daily (up 10 years after acute rheumatic to 250 mg twice daily) fever or until 40 years of age, whichever is longer. Lifetime prophylaxis may be needed. Infective Endoca