USMLE (Fach) / Pharmacology - Endocrine (Lektion)

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• Metformin Biguanide. Oral drug. Inhibit hepatic gluconeogenesis and the action of glucagon, by inhibiting mGPD. ↓ gluconeogenesis, ↑ glycolysis, ↑ peripheral glucose uptake (↑ insulin sensitivity) Clinical use:- First-line therapy in type 2 DM, causes modest weight loss- Can be used in patients without islet function Risks/concerns:- GI upset- Lactic acidosis (thus contraindicated in renal insufficiency)- Vitamin B12 deficiency- Promote weight loss (often desired)
• Sulfonylureas 1st generation: Chlorpropamide, tolbutamide2nd generation: Glipizide (short-acting), glyburide, glimeperide (long-acting) Close K+ channel in β-cell membrane → cell depolarizes → insulin release via ↑ Ca2+ influx.- Simulate release of endogenous insulin in type 2 DM. Require some islet function, so useless in type 1 DM. Risks/concerns:- Hypoglycemia (↑ risk in renal failure, contraindicated in renal insufficiency). β-blockers may mask the warning signs of hypoglycemia, thus the combination of these two medications should be avoided.- Weight gain.- 1st generation: disulfiram-like effects
• Glitazones/thiazolidinediones Pioglitazone, rosiglitazone Binds to PPAR-γ nuclear transcription regulator → ↑ insulin sensitivity and levels of adiponectin → regulation of glucose metabolism and fatty acid storage. Used as monotherapy in type 2 DM or combined. Safe to use in renal impairment. Risks/concerns:- Weight gain- Fluid retention and edema- Hepatotoxicity → check liver function- Heart failure (contraindicated)- ↑ risk of fractures- Delayed onset of action (several weeks)
• Thioamides Propylthiouracil (PTU), methimazole Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis. Propylthiouracil also blocks 5'-deiodinase → ↓ peripheral conversion of T4 to T3. Clinical use: Hyperthyroidism- Propylthiouracil is used in the first trimester pregnancy (due to methimazole teratogenicity); methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity).- Not used to treat Graves ophthalmopathy (treated with corticosteroids). Adverse effects: Skin rash, agranulocytosis, aplastic anemia, hepatotoxicityMethimazole is a possible teratogen (can cause aplasia cutis).
• Cinacalcet Sensitizes Ca2+-sensing receptor (CaSR) in parathyroid gland to circulating Ca2+ → ↓ PTH Clinical use: Refractory hypercalcemia in 1° or 2° hyperparathyroidism, or parathyroid carcinoma Adverse effects: Hypocalcemia
• Fludrocortisone Synthetic analog of aldosterone with little glucocorticoid effects. Clinical use: Mineralocorticoid replacement in 1° adrenal insufficiency. Adverse effects: Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation.
• ADH antagonists Conivaptan, tolvaptan Clinical use: SIADH, block action of ADH at V2-receptor
• Desmopressin Clinical use: - Central (not nephrogenic) diabetes insipidus- von Willebrand disease- Sleep enuresis- Hemophilia A
• GH Clinical use: GH deficiency, Turner syndrome
• Oxytocin Clinical use: - Labor induction (stimulates uterine contractions)- Milk let-down- Controls uterine hemorrhage
• Somatostatin Ocreotide Clinical use: - Acromegaly- Carcinoid syndrome- Gastrinoma- Glucagonoma- Esophageal varices
• Demeclocycline ADH antagonist (member of tetracycline family) Clinical use: SIADH Adverse effects: Nephrogenic DI, photosensitivity, abnormalities of bone and teeth
• Glucocorticoids Beclomethasone, dexamethasone, hydrocortisone, methylprednisolone, prenisone, triamcinolone Inhibition of phospholipase A2 and inhibition of transcription factors such as NF-κB. Clinical use: Adrenal insufficiency, inflammation, immunosuppression, asthma Adverse effects:- Iatrogenic Cushing syndrome (hypertension, weight gain, moon facies, truncal obesity, buffalo hump, thinning of skin, striae, acne, osteoporosis, hyperglycemia, amenorrhea, immunosuppression), adrenocortical atrophy, peptic ulcers, steroid diabetes, steroid psychosis, cataracts- Adrenal insufficiency when drug stopped abruptly after chronic use
• Meglitinides Nateglinide, repaglinide Close K+ channel in β-cell membrane → cell depolarizes → insulin release via ↑ Ca2+ influx (binding site differs from sulfonylureas). Clinical use: Used as monotherapy in type 2 DM or combined with metformin.- Particularly suitable for patients with postprandial peak. - Should be taken shortly before meals. (In contrast to sulfonylureas, meglitinides are short-acting agents that primarily affect blood glucose levels shortly after intake.) Risks/concerns: Hypoglycemia (↑ risk with renal failure)- Weight gain.
• GLP-1 analogs Exenatide, liraglutide (sc injection) ↑ glucose-dependent insulin release, ↓ glucagon release, ↓ gastric emptying, ↑ satiety Clinical use: Type 2 DM Risks/concerns: Nausea, vomiting, pancreatitis. Promote weight loss (often desired).
• DPP-4 inhibitors Linagliptin, saxagliptin, sitagliptin Inhibits DPP-4 enzyme that deactivates GLP-1. ↑ glucose-dependent insulin release, ↓ glucagon release, ↓ gastric emptying, ↑ satiety. Use: Type 2 DM Risks/concern: Mild urinary or respiratory infections; weight neutral
• Amylin analogs Pramlintide (sc injection) ↓ gastric emptying, ↓ glucagon release, ↑ satiety Use: Type 1 DM, type 2 DM Risks/concerns: Hypoglycemia (in setting of mistimed prandial insulin), nausea
• Sodium-glucose co-transporter 2 (SGLT-2) inhibitors Canagliflozin, dapagliflozin, empagliflozin Block reabsorption of glucose in proximal convoluted tubule. Risks/concerns: Glucosuria, UTIs, vaginal yeast infections, hyperkalemia, dehydration (orthostatic hypotension), weight loss.- Check renal function (BUN, creatinine)
• α-glucosidase inhibitors Acarbose, miglitol Inhibit intestinal brush-border α-glucosidases → delayed carbohydrate hydrolysis and glucose absorption → ↓ postprandial hyperglycemia. Risks/concerns: GI disturbances- Not recommended if kidney function is impaired.
• Insulin - rapid acting Lispro, aspart, glulisine Alteration of the amino acid structure at the C terminal of the insulin B chain prevents polymerization and allows rapid absorption from the injection site.Binds insulin receptor (tyrosine kinase activity) rapidly. 1 hour peak. Liver: ↑ glucose stored as glycogenMuscle: ↑ glycogen, protein synthesisFat: ↑ TG storageCell membrane: ↑ K+ uptake Clinical use: Type 1 DM, type 2 DM, GDM (postprandial glucose control)
• Insulin - short acting 2-3 hour peak Regular Use: Type 1 DM, type 2 DM, DKA (IV), hyperkalemia (+ glucose), stress hyperglycemia
• Insulin - intermediate acting 4-10 hour peak NPH Composed of a crystalline suspension of insulin with protamine and zinc. This delays absorption of insulin from the subcutaneous injection site.
• Insulin - long acting Detemir, glargine No real peak Detemir – Has a fatty acid bound to one of the lysine amino acids on the insulin molecule. This fatty acid side chain allows detemir to bind to albumin and slowly dissociate, resulting in prolonged action. Glargine – Has a pH of 4 and forms a microprecipitate in the subcutaneous tissue after injection, resulting in a very slow release of insulin.
• Glipizide 2nd generation sulfonylurea - Short-acting
• Glyburide 2nd generation sulfonylurea - Long-acting
• Glimepiride 2nd generation sulfonylurea - Long-acting
• Nateglinide Meglitinide (sulfonylurea analog)
• Repaglinide Meglitinide (sulfonylurea analog)
• Injectible antidiabetic drugs - Insulin preparations - Amylin analogs - GLP-1 analogs
• -glitazone Glitazone/thiazolidinedione
• -gliptin DPP-4 inhibitors
• -gliflozin SGLT2 inhibitors
• Miglitol α-glucosidase inhibitor
• Levothyroxine (T4), Iiothyronine (T3) Thyroid hormone replacement Use: Hypothyroidism, myxedema.- May be abused for weight loss Adverse effects: Tachycardia, heat intolerance, tremors, arrhythmias
• Sevelamer Nonabsorbable phosphate binder that prevents phosphate absorption from the GI tract. Use: Hyperphosphatemia in CKD. Adverse effects: Hypophosphatemia, GI upset.
• Tesamorelin Growth-hormon-releasing-hormone analog Use: HIV-associated lipodystrophy
• Diabetes mellitus management All patients with diabetes mellitus should receive education on diet, exerise, blood glucose monitoring, and complication management. Treatment differs based on the type of diabetes:- Type 1 DM – insulin replacement- Type 2 DM – oral agents (metformin is first line), non-insulin injectables, insulin replacement; weight loss particularly helpful in lowering glucose- Gestational DM – insulin replacement if nutrition therapy and exercise alone fail Regular (short-acting) insulin is preferred for DKA (IV), hyperkalemia (+ glucose), stress hyperglycemia.
• Pramlintide Amylin analog
• Chlorpropamide 1st generation sulfonylurea
• Tolbutamide 1st generation sulfonylurea
• Linagliptin DPP-4 inhibitor
• Saxagliptin DPP-4 inhibitor
• Sitagliptin DPP-4 inhibitor
• Hyperthyroidism treatment Beta blockers (eg, propanolol): Blunt the adrenergic manifestations while awaiting definitve management (eg, surgery, radioiodine). Reduce conversion of T4 to T3, by inhibiting 5'-monodeiodinase in peripheral tissues. Thionamides (eg, propylthiouracil, methimazole): Decrease thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also decreases peripheral conversion of T4 to T3. Glucocorticoids can decrease production of TSH-receptor-antibodies. They also reduce conversion of T4 to T3. Potassium
• Major drug interactions of levothyroxine ↓ Levothyroxine absorption:- Iron, calcium, aluminum hydroxide- Bile acid binding agents (eg, cholestyramine)- Proton pump inhibitors, sucralfate ↑ TBG concentration:- Estrogen (oral), tamoxifen, raloxifen- Heroin, methadone ↓ TBG concentration:- Androgens, glucocorticoids- Anabolic steroids ↑ Thyroid hormone metabolism:- Rifampin- Phenytoin- Carbamazepine

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