Drug Acting on Endocrine System PDF

Drug Acting on Endocrine system 1 By: Alemseged.W, 2024 9/1/2024 Learning objectives 9/1/2024  Demonstrate an understanding of drugs acts on Endocrine system with respect to:...

Drug Acting on Endocrine system 1 By: Alemseged.W, 2024 9/1/2024 Learning objectives 9/1/2024  Demonstrate an understanding of drugs acts on Endocrine system with respect to: By: Alemseged.W, 2021  Drug classes & the specific mechanisms  Major PK characteristics of each drug class  Primary adverse effects of each drug class  Unique characteristics of individual agents 2 Outline 9/1/2024  Hypothalamic & pituitary hormones By: Alemseged.W, 2021  Antidiabetic drugs  Drugs for thyroid disorders  Adrenocorticosteroids & adrenocortical antagonists  The gonadal hormones & inhibitors 3  Introd.. Hypothalamic & pituitary hormones 9/1/2024  Endocrine system is a system of glands that secrete By: Alemseged.W, 2021 hormones into the bloodstream.  It consists of the glands that secrete hormones, chemicals that assist in regulating body functions.  Several organs act as endocrine glands as well as members of other organ systems. E.g the liver, stomach, pancreas, and kidneys are members 4 of the endocrine system as well as other organ systems.  Cont…….  Organs that belong primarily to the endocrine system include 9/1/2024 the pituitary gland, the adrenal glands, the thyroid gland, and the gonads (ovaries and testes). By: Alemseged.W, 2021  The anterior pituitary secretes six hormones. Including  Growth hormone(GH) , Prolactin,  Thyroid-stimulating hormone(TSH),  Follicle-stimulating hormone(FSH), luteinizing hormone(LH)  Adrenocorticotropic hormone(ACTH). 5  Posterior pituitary: Anti-diuretic hormone(ADH), (vasopressin) and Oxytocin.  Endocrine Glands, Hormones, and Their Functions and Structure 9/1/2024  Organ/tissue Hormone Major function Thyrotropin-releasing Stimulates secretion of hormone Thyrotropin-releasing hormone By: Alemseged.W, 2021 Corticotropin-R Causes release of ACTH Growth hormone–RH Causes release of GH Hypothalamus GH inhibitory Inhibits release of GH hormone(somatostatin Gonadotropin-(GnRH) Causes release of LH and FSH Dopamine or prolactin- Inhibits release of prolactin inhibiting factor Growth hormone 6  9/1/2024 By: Alemseged.W, 2021 7 Cont…..  9/1/2024 By: Alemseged.W, 2021 8 Cont……  9/1/2024 By: Alemseged.W, 2021 9 Cont……  9/1/2024 By: Alemseged.W, 2021 10 Cont……  Drugs Affecting the Endocrine System… 1. Antidiabetic drugs 11 By: Alemseged.W, 2021 9/1/2024 Overview of DM  DM is not a single disease entity but rather a group of 9/1/2024 metabolic disorders sharing the common underlying feature of hyperglycemia By: Alemseged.W, 2021  An ideal blood sugar level for anyone without diabetes or prediabetes, regardless of age, in the morning should be less than 100 mg/dL  A fasting blood sugar level of 99 mg/dL or lower is normal,  100 to 125 mg/dL indicates prediabetes, and 126 mg/dL or higher indicates you have diabetes. 12  Cont…..  Hyperglycemia in DM results from 9/1/2024  Defects in insulin secretion, insulin action, or, most commonly, both By: Alemseged.W, 2021  Upon ingestion of carbohydrates, insulin is released into the blood and promotes uptake and utilization of glucose in specific organs, namely, the heart, adipose tissue, and skeletal muscle. 13  Cont….. The etiologies (causative factors) include: o Obesity: chronic calorie intake and prolonged stimulation of β cell 9/1/2024 causes a decrease in insulin receptor and also adipose tissue and muscle are less sensitive. By: Alemseged.W, 2021 o Hereditary (from family) , damage of pancreatic tissue o Diabetogenic hormones (like growth hormone, thyroid, epinephrine), o Diabetogenic drugs like Thiazide diuretics, epinephrine, phenothiazines, o Other factors: Pregnancy The common signs and symptoms include o 1. Polyuria - inc. urine output 14 2. Polydipsia - inc. thirst 3. Polyphagia - inc. hunger Overview of DM … Type 1 DM : (or Juvenile type)  It is insulin dependent diabetes mellitus (IDDM) 9/1/2024  Due to due to autoimmune or viral diseases  An autoimmune disease in which islet destruction is caused primarily by  T lymphocytes reacting against as yet poorly defined β-cell antigens, resulting in a reduction in β-cell mass  Genetic susceptibility & environmental influences play important roles in the pathogenesis  Most commonly develops in childhood, becomes manifest at puberty & progressive with age 15  Overview of DM … Type 2 DM: or maturity onset type 9/1/2024  It is non-insulin dependent diabetes mellitus (NIDDM)  Environmental influences, such as a sedentary life style & By: Alemseged.W, 2021 dietary habits have a role  Genetic factors are more important than in type 1 DM  The 2 metabolic defects that characterize type 2 DM  Insulin resistance  ↓ed ability of peripheral tissues to respond to insulin 16 Overview of DM… The impaired insulin action also affects fat metabolism, 9/1/2024 result in By: Alemseged.W, 2021 increased free fatty acid flux and triglyceride levels and low levels of HDL  β-cell dysfunction  Manifested as inadequate insulin secretion in the face of insulin resistance & hyperglycemia NB: In most cases, insulin resistance is the 10 event & followed 17 by ↑ing degrees of β-cell dysfunction  Cont…..Type 2  Individuals with type 2 diabetes may not require insulin to 9/1/2024 survive, but 30% or more will benefit from insulin therapy to By: Alemseged.W, 2021 control blood glucose.  Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur as the result of  stress such as infection or  the use of medication that enhances resistance, eg, corticosteroids 18  Cont…..  Dehydration in individuals with untreated or poorly controlled type 2 diabetes can lead to a life threatening condition – non- 9/1/2024 ketotic hyperosmolar coma. If it’s > 600mg/dl  A blood sugar level more than 300 mg/dl will be dangerous By: Alemseged.W, 2021  Results in  the blood glucose may rise to 6–20 fold and  an altered mental state develops or lose of consciousness.  Urgent medical care and rehydration are required. Type 3 DM  The type 3 designation refers to multiple other specific causes of an elevated blood glucose:  Pancreatectomy , pancreatitis, non-pancreatic diseases, drug 19 therapy, etc  Overview of DM…  Type 4 DM (Gestational diabetes (GDM) ) 9/1/2024  is defined as any abnormality in glucose levels noted for the 1st time during pregnancy By: Alemseged.W, 2021  During pregnancy, the placenta & placental hormones create an insulin resistance (have a blocking effect on insulin) that is most pronounced in the last trimester  Risk assessment for DM is suggested starting at the 1st prenatal visit  High-risk women should be screened immediately  Screening may be deferred in lower-risk women until the 24th to 28th wk of gestation 20 Risks factors of GDM?  Although any woman can develop GDM during pregnancy, 9/1/2024 some of the factors that may ↑ the risk include the following:  Overweight or obesity By: Alemseged.W, 2021  Family history of DM  Having given birth previously to a very large infant, a still birth, or a child with a birth defect  Age (women who are older than 25 are at a greater risk for developing GDM than younger women)  Pre-diabetes 21  Diabetic complications ▲ Acute Diabetic ketoacidosis (DKA) : Type 1  the body's cells must use ketones (toxic acids) as a source of energy.  Ketoacidosis develops when ketones build up in the blood.  It can become serious and lead to diabetic coma or even death.  The hallmarks of ketoacidosis are:  High level of ketones in the urine  Shortness of breath  Fruit-smelling breath  Dry mouth  stomach pain, nausea, vomiting, and confusion  Cont…… 9/1/2024 Non-ketotic hyperosmolar coma ▲ Chronic Microvascular disease: By: Alemseged.W, 2021  impotence & poor wound healing  Atherosclerosis : Strokes, coronary heart disease  Renal failure, retinal damage, nerve damage  Infective disease: Tuberculosis 23  Treatment of DM  Antidiabetic drugs A. Injectable antidiabetic agents: Insulins B. Oral antidiabetic agents Both aim to produce normal blood glucose states  Proper dietary management.  Caloric restriction and weight loss are imp’t in obese DM patients.  Increase physical activity.  Oral Hypoglycemic agent Insulin secretagogues  Sulfonylurea drugs  Meglitinides  Incretin mimetics Insulin sensitizers  Biguanides  Thiazolidinediones Others Agents that reduce carbohydrate absorption  (Alpha glucosidase inhibitors). Agents that reduce glucose renal reabsorption  (SGLT-2, Sodium/glucose cotransporter 2 inhibitors) INSULIN  It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges;  there are species differences in the amino acids of both chains.  Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is  hydrolyzed into insulin and a  residual connecting segment called C-peptide Fig. Structure of human proinsulin (C-peptide plus A and B chains) source : Bertram katzung  Insulin Secretion  Insulin is released at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose),  Amino acids (especially gluconeogenic amino acids, eg, leucine, arginine),  Hormones such as glucagon-like polypeptide-1 (GLP-1),  Glucose-dependent insulinotropic polypeptide (GIP), glucagon, High concentrations of fatty acids, and  β-adrenergic sympathetic activity are recognized.  Cont……  One mechanism of stimulated insulin release is, hyperglycemia results in increased intracellular ATP levels,  which close the ATP-dependent potassium channels.  Decreased outward potassium efflux results in depolarization of the beta cell and opening of voltage- gated calcium channels.  The resulting increased intracellular calcium triggers secretion of the hormone (insulin) Fig. One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. source : Bertram katzung Insulin preparations… 9/1/2024  4 principal types of injected insulins are available: By: Alemseged.W, 2021  Rapid-acting→ very fast onset & short duration  Short-acting → rapid onset of action  Intermediate-acting → slow onset of action  Long-acting: → slow onset of action Insulin lispro: Pro at position B28 has been moved to B29, & Lys at position B29 has been moved to B28 Insulin aspart: substitution of the B28 Pro with a negatively charged Asp Insulin glulisine: substituting a Lys for Asn at B3 & Glu for Lys at B29 Insulin glargine: attachment of 2 Arg molecules to the B-chain carboxyl terminal & substitution of a Gly for Asn at the A21 31 position →soluble in an acidic Fig. Structure of human proinsulin (C-peptide plus A & B solution but ppt in the more chains) and insulin neutral body pH after SC inj Insulin detemir: terminal thr is dropped from the B30 position & myristic acid (a C-14 FA chain) is attached to the terminal B29 Lys →prolong the availability of the injected analog by ↑ing both self-aggregation in SC tissue & reversible albumin binding Insulin preparations… 9/1/2024 a) Rapid acting: Insulin aspart, lispro, & glulisine  Rapid onset (5-15 min) & shorter duration (2-4hr) By: Alemseged.W, 2021 b) Short acting: Regular insulin (R-Insulin)  Slow onset (~30 min) & prolonged duration (5-8hr)  The only insulin product that can be given by IV bolus, IV infusion, or even IM  NB: Injected rapid & short-acting insulins:  Dispensed as clear solutions at neutral pH &  Contain small amts of Zn to improve their stability & shelf life 32 Insulin preparations… 9/1/2024 c) Intermediate acting  Isophane insulin suspension (also called NPH) By: Alemseged.W, 2021  Insulin zinc suspension (also called Lente)  Both have a cloudy appearance  Slower in onset & more prolonged duration d) Long acting  Glargine: Clear, colorless solution  Extended insulin Zn suspension (Ultralente)  White, opaque solution 33 Insulin preparations… 9/1/2024  Combination Insulin products  NPH 70% & regular insulin 30% (70/30) By: Alemseged.W, 2021  NPH 50% & regular insulin 50% (50/50)  Insulin lispro protamine susp 75% & insulin lispro 25% (75/25) 34 Common Insulin Regimens 9/1/2024 (1) Split Mix Regimens  Two injections (intermediate + soluble) per day By: Alemseged.W, 2021  before breakfast & before bedtime  Proportion/dosage of insulins titrated based on BG profile  Drawback  Mixing insulins is tedious and problematic  Inaccuracy of dose  Not preferred –more problems for patients 35 9/1/2024 By: Alemseged.W, 2021 36  Cont…. - Before using insulin, need to ensure well mixed - always roll 9/1/2024 between hands - Do NOT Shake Vial = bubbles & inaccurate By: Alemseged.W, 2021 dose - insulin CANNOT be administered orally - GI tract secretions destroy insulin structure - Given subcutaneous at a 45 to 90 degree angle - Regular insulin ONLY can be given IV - Insulin sites need to be rotated to prevent lipodystrophy (tissue atrophy or hypertrophy) = interferes w/ insulin 37 absorption Insulin therapy: pt selection… 9/1/2024  Insulin therapy is often instituted for type 2 DM pts By: Alemseged.W, 2021 who:  Can't control their DM with diet & exercise alone  Are highly symptomatic  i.e. have glucose levels frequently > 250 mg/dl  Are newly diagnosed with very high glucose levels 38 Insulin regimens 9/1/2024  Conventional insulin therapy  Simpler non-physiologic insulin regimens, such as single By: Alemseged.W, 2021 daily inj, or 2 inj/day  Intensive insulin therapy  Tx with 3 or more inj/day or with continuous sc insulin infusion with an insulin pump  Dose of the pre-meal bolus is determined by  Ambient blood glucose level before the meal  Size & composition of the meal &  Anticipated activity levels 39 Factors that affect insulin absorpn & Action 9/1/2024  Factors that determine the rate of absorpn of insulin after sc admn include By: Alemseged.W, 2021  Site of inj, type of insulin, sc blood flow, smoking, regional muscular activity at the site of the inj, volume & conc of the injected insulin, & depth of injection  Factors that alter insulin action  Insulin requirements may be altered due to:  Diet, exercise, illness, emotional disturbances, or other stressors 40 9/1/2024 By: Alemseged.W, 2021 41  9/1/2024 Late meal, too little CHO, extra exercise, too much insulin By: Alemseged.W, 2021 42  Oral Hypoglycemic Classification  These agents are useful in the treatment of patients who have 9/1/2024 Type 2 diabetes but who cannot be managed by diet alone. By: Alemseged.W, 2021  Insulin Secretagogues: Sulfonylureas, Meglitinide analogs  Insulin Sensitizers. . Thiazolidinediones.  Biguanides : Metformin  α-Glucosidase Inhibitors 43 Anti Diabetic Drugs 9/1/2024  Sulfonylureas: Stimulate beta cells to release more insulin.  Meglitinides: Non-sulfonylurea insulinotropic agent. By: Alemseged.W, 2021  Biguanides: No effects on beta cells.  3 sites for work: peripheral tissue, liver, intestine.  Thiazolidinediones: Decrease insulin resistance in peripheral target tissue.  α-glucosidase inhibitor: Delay carbohydrate absorption from GI tract 44  Sulfonylureas  These agents promote the release of insulin from β-cells 9/1/2024 e.g. tolbutamide, glyburide, glipizide and glimepiride. By: Alemseged.W, 2021 Mechanism of Action: Effective only if have functional beta cells,  stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca2+ influx in the beta cells, which stimulates insulin release. 45 Cont……  Reduce glucagon secretion & increase the binding of insulin 9/1/2024 to target tissues.  Decrease production of glucose in the liver By: Alemseged.W, 2021  Increase the number of insulin receptors Pharmacokinetics of sulfonylureas: Orally, well absorbed. Reach peak concentration after 2-4 hr. All are highly bound to plasma proteins. Duration of action is variable. 46 Second generation has longer duration than first generation. cont/…..  Metabolized in liver 9/1/2024  Excreted in urine (elderly and renal disease)  Cross placenta, stimulate fetal β-cells to release insulin By: Alemseged.W, 2021 → fetal hypoglycemia at birth. Second generation sulfonylureas Long acting: Glyburide, Glimepiride  More potent than first generation  Have longer duration of action.  Less frequency of administration  Have fewer adverse effects & drug interactions. 47 9/1/2024 By: Alemseged.W, 2021 48 9/1/2024 By: Alemseged.W, 2021 49 Sulfonylureas……. Adverse effects 9/1/2024 1. Hyperinsulinemia & Hypoglycemia:  More common in long acting sulfonylureas. particularly By: Alemseged.W, 2021 (glyburide, and glimepiride). More in old age, hepatic or renal diseases. 2. Weight gain due to increase in appetite unless the diabetic diet and exercise program are followed. 50  Meglitinides 9/1/2024  Include Nateglinide&repaglinide  are non-sulfonylureas that lower blood sugar by stimulating pancreatic secretion of insulin. MOA is identical to sulfonylureas PK : Orally, well absorbed.  Very fast onset of action, peak  Short duration of action (4 h),  Metabolized in liver and excreted in bile.  Taken just before each meal (3 times/day) the dose should be skipped51 if the meal is missed.  Cont…..  Monotherapy or in combination with other oral hypoglycemic drugs  Should be taken 1 to 30 minutes before a meal Side effects : hypoglycemia and weight gain Incretins  are GI hormones secreted from intestine in response to food even before blood glucose level becomes elevated.  They are carried through circulation to pancreatic beta cells. Incretins regulate blood glucose by: Increase insulin secretion Decrease glucagon secretion  Cont….. Incretins include:  GLP-1 (glucagon-like peptide-1)  GIP (gastric inhibitory peptide) Both are inactivated by dipeptidyl peptidase-4 (DPP-4). Mechanism of Action of Incretin Mimetics  Cont…. Glucagon-like peptide-1 (GLP-1) agonists: Include: ▪ Dulaglutide , Liraglutide , ▪ Exenatide Liraglutide (Victoza, Saxenda ) MOA ▪ Binds to GLP-1 receptors & stimulates insulin secretion from β cells. ▪ It also reduces glucagon secretion by inhibiting alpha cells of the pancreas. ▪ Given s.c. once/day (single- dose pre-filled disposable pens) Used together with diet and exercise to treat type 2 diabetes and in patients who are not controlled with other oral anti diabetics. Not used in type I diabetes..  Cont….  It decreases appetite and inhibits body weight gain  As a treatment for adults who are obese or overweight with at least one weight-related comorbid condition (e.g. hypertension, type 2 DM, or dyslipidemia). Adverse effects o Nausea, vomiting and diarrhea (most common) o Hypoglycemia when combined with sulfonylureas or insulin. o Pancreatitis (rare) Dipeptidyl peptidase-4 inhibitor (DPP- 4 inhibitors) e.g. Sitagliptin, vildagliptin Sitagliptin (Januvia)  Inhibit DPP-4 enzyme thus increase incretin hormone (GLP-1).  Is given orally. Is given once daily. MOA: Inhibit DPP-4 enzyme and leads to an increase in incretin level. This results in an ↑ in insulin secretion & ↓ in glucagon secretion Use : Type II DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. Adverse effects Nausea, abdominal pain, diarrhea. Nasopharyngitis and headache.  Insulin sensitizers  Are drugs which increase the sensitivity of peripheral target organs to insulin. Include Biguanides e.g. metformin Thiazolidinediones e.g. pioglitazone Metformin MOA:  Reduces insulin resistance.  Increases sensitivity of liver, muscle & adipose tissues to insulin & increase peripheral glucose utilization (tissue glycolysis).  Inhibits hepatic glucose production (gluconeogenesis).  Impairs glucose absorption from GIT.  Improve lipid profile: ↓LDL, ↓VLDL , ↑HDL  cont…. PK : Orally, NOT bound to serum protein., NOT metabolized.  t ½ = 3 hours. Excreted unchanged in urine 9/1/2024  Use for obese type 2 diabetes  Used Alone or co-administered with insulin or Sulfonylureas By: Alemseged.W, 2021  It also used to treat atherosclerosis for down- regulation of LDL& VLDL Advantages of metformin  No risk of hypoglycemia, No weight gain Has prominent lipid-lowering activity Inexpensive 58  Adverse effect  GIT disturbances: Metallic taste in the mouth, nausea, vomiting, diarrhea.  should be taken with meals and should be started at a low dose to avoid intestinal side effects then increase gradually.  Interference with vitamin B12 absorption (long term use)  Lactic acidosis (very rare)  Serious lactic acid accumulation usually occurs only in the presence of a predisposing conditions  Renal insufficiency, Severe liver disease , Alcohol abuse.  Heart failure, Pulmonary insufficiency  Cardiogenic or septic shock Contraindications of metformin  Renal disease, Liver disease, Alcoholism.  Cardiopulmonary dysfunction, Pregnancy. Thiazolidinediones (glitazones): Pioglitazone, Rosiglitazone MOA:  Decrease insulin resistance, through binding with PPAR(Peroxisome proliferator-activated receptor-γ) lead to regulation adipocyte production and secretion of fatty acids as well as glucose metabolism,  resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle  Improve function of pancreas β cells  Ameliorating fat metabolic disorder  Preventing and treating type 2 diabetes mellitus and their cardiovascular complications  Cont….. Pharmacokinetics of glitazones 9/1/2024  Orally (once daily dose). Highly bound to plasma albumins (99%)  Slow onset of activity, Half life 3-4 h, Metabolized in liver, Excreted in bile and urine. Uses Type II DM with insulin resistance. Used either alone or combined with sulfonylurea, biguanides or insulin. No risk of hypoglycemia when used alone Adverse effects : Hepatotoxicity (liver function tests for 1st year of therapy)., Fluid retention (Edema), CHF, Mild weight gain. 61  Failure of estrogen-containing oral contraceptives  Alpha glucosidase Inhibitors 9/1/2024  Include acarbose and miglitol Mechanism of action:  Reversible inhibitors of intestinal α-glucosidases in intestinal brush border cells that are responsible for carbohydrate digestion.  ↓ carbohydrate digestion & glucose absorption in SI (lower postprandial glucose level).  Can be combined therapy with sulfonylurea Acarbose: Given orally, Is not absorbed., Excreted in feces 62  Taken just before meals., No hypoglycemia if used alone.  Cont…. Use: Effective alone in the earliest stages of impaired glucose tolerance  Not recommended alone as therapy for moderate to severe hyperglycemia  Most useful in combination with other oral hypoglycemic drugs or with insulin.  GIT side effects: Flatulence, bloating, diarrhea, abdominal pain. Contraindicated: in malabsorption, severe renal impairment, Irritable bowel syndrome  Inflammatory bowel disorders , Intestinal obstruction.  combination medications for type 2 diabetes  Metformin and glipizide (Metaglip)  Rosiglitazone and glimepiride (Avandaryl)  Pioglitazone and metformin (ACTOplus Met)  Metformin and glyburide (Glucovance)  Rosiglitazone and metformin (Avandamet)  Pioglitazone and glimepiride (duetact)  2. Drugs for thyroid disorders 65 By: Alemseged.W, 2021 9/1/2024  CA S E S T U D Y 9/1/2024  A 33-year-old woman presents with complaints of fatigue, sluggishness, weight gain, cold intolerance, dry skin, and By: Alemseged.W, 2021 muscle weakness for the last 2 months. She is so tired that she has to take several naps during the day to complete her tasks. These complaints are new for her since she used to feel warm all the time, had boundless energy causing her some insomnia, and states she felt like her heart was going to jump out of her chest. She also states that she would like to become pregnant in the near future. Her past medical history is significant for radioactive iodine therapy (RAI) about 1 year ago after a short trial of methimazole and66 propranolol therapy. Cont…..  She underwent RAI due to her poor medication 9/1/2024 adherence and did not attend routine scheduled appointments afterward. On physical examination, her By: Alemseged.W, 2021 blood pressure is 130/89 mm Hg with a pulse of 50 bpm. Her weight is 136 lb (61.8 kg), an increase of 10 lb (4.5 kg) in the last year. Her thyroid gland is not palpable and her reflexes are delayed. Laboratory findings include a thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL and a free thyroxine level of 8 pmol/L. Evaluate the management of her past history of hyperthyroidism. Identify the available treatment options for control of her current thyroid status. 67 Overview 9/1/2024  The thyroid gland is located in the neck in front of the trachea  This highly vascular gland manufactures & secretes 2 hormones: By: Alemseged.W, 2021 thyroxine (T4) & triiodothyronine (T3)  Iodine is an essential element for the manufacture of both of these hormones  The activity of the thyroid gland is regulated by thyroid- stimulating hormone, produced by the anterior pituitary gland 68 Overview… 9/1/2024  Two diseases are related to the hormone-producing activity of the thyroid gland: By: Alemseged.W, 2021  Hypothyroidism—a decrease in the amt of thyroid hormones manufactured & secreted  Hyperthyroidism—an ↑ in the amt of thyroid hormones manufactured & secreted  A severe form of hyperthyroidism, called thyrotoxicosis or thyroid storm, is characterized by high fever, extreme tachycardia, & altered mental status 69  9/1/2024 By: Alemseged.W, 2021 Causes of thyrotoxicosis: Graves’ disease (60-80%) - Multinodular goitre (14%)- Adenomas /carcinoma note : All patients with hyperthyroidism have thyrotoxicosis but Not all patients with thyrotoxicosis have hyperthyroidism 70 Cont…. features of Graves Disease(Diffuse Toxic Goiter) 9/1/2024  Caused by thyroid stimulating immunoglobulins that stimulate TSH receptor , resulting in sustained thyroid over activity By: Alemseged.W, 2021 71 A. Drugs for Hypothyroidism 9/1/2024  Thyroid hormone influences many systems & processes in the body, including the following: By: Alemseged.W, 2021  Metabolic: energy levels, body temp, wt, lipids, appetite  CV: HR, heart rhythm, BP, fluid distribution  Skin & hair: composition, thickness, texture  GI: motility  Musculoskeletal: bone growth, tendon reflexes  Hematologic: erythropoiesis  Reproductive: ovulation & spermatogenesis 72 9/1/2024 By: Alemseged.W, 2021 73 Drugs for Hypothyroidism… 9/1/2024  Thyroid hormone preparations include:  Levothyroxine Na(T4 By: Alemseged.W, 2021  Others: Liothyronine(T3) , liotrix (mix T4 ,T3, Levothyroxine Na  Dosage Forms: Tabs, injection  Indication: Hypothyroidism from any cause 74 Drugs for Hypothyroidism… 9/1/2024  Levothyroxine Na…  Adverse reactions: most common By: Alemseged.W, 2021  Fatigue, ↑ed appetite, wt loss, heat intolerance, hyperhidrosis  Adverse reactions: rare/severe/important  Hair loss, menstrual irregularities, nervousness, irritability, insomnia  C/Is:  Caution must be exercised in conditions in which tachycardia is dangerous (CAD, aortic stenosis, mitral stenosis) 75 B. Drugs for Hyperthyroidism 9/1/2024  Drugs for Hyperthyroidism Anti-thyroid drugs include: thioamides, iodides, and radioactive By: Alemseged.W, 2021 iodine(RAI), (131I).  Thioamides: propylthiouracil(PTU), methimazole, carbimazole,  Non-radioactive Iodine: Strong Iodine Solution (Lugol's Solution), Na Iodide (IV), K Iodide  Beta blockers: , propranolol, metoprolol  can suppress tachycardia & other symptoms of Hyperthyroidism 78 THIOAMIDES  The thioamides methimazole and propylthiouracil(PTU) are 9/1/2024 major drugs for treatment of thyrotoxicosis.  carbimazole, which is converted to methimazole in vivo, By: Alemseged.W, 2021  Methimazole is more potent than PTU and is the drug of choice in adults and children.  Due to a black box warning about severe hepatitis, PTU should be reserved for use during the first trimester of pregnancy, 79 9/1/2024 By: Alemseged.W, 2021 80 Cont……  Both thioamides cross the placental barrier and are 9/1/2024 concentrated by the fetal thyroid, so that caution must be employed when using these drugs in pregnancy. By: Alemseged.W, 2021  Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D  Of the two, PTU is preferable during the first trimester of pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily.  In addition, methimazole has been associated with congenital malformations.  Both thioamides are secreted in low concentrations in breast milk but are considered safe for the nursing infant. 81 Drugs for Hyperthyroidism... 9/1/2024 1. Thionamides: propylthiouracil (PTU)  Act primarily by blocking the synthesis of thyroid hormone By: Alemseged.W, 2021 Adverse Effects:  The most common (in 6% to 10% of pts) are skin rash, fever, & arthralgia (sore joints)  Serious, Rare Side Effects : Agranulocytosis, Hepatotoxicity, Vasculitis 82 Drugs for Hyperthyroidism... 9/1/2024  PTU has 4 therapeutic applications in hyperthyroidism: By: Alemseged.W, 2021  Reduction of thyroid hormone production in Graves' disease  Control of hyperthyroidism until the effects of radiation on the thyroid become manifest  Suppression of thyroid hormone production prior to subtotal thyroidectomy  Treatment of thyrotoxic crisis 83 Drugs for Hyperthyroidism... 9/1/2024 2. Radioactive iodine (131I)  Destroys the thyroid gland via radiation By: Alemseged.W, 2021  Indications: Hyperthyroidism, Thyroid cancer  Adverse effects:  Hypothyroidism: Almost all pts require lifelong thyroid replacement after radioactive ablation  Sialadenitis: Inflammation of the salivary glands occurs b/c of uptake of 131I  Salivary damage can result in xerostomia (dry mouth), altered taste, ↑ed dental caries, & pain  Cancer: Although very small, a risk of cancer arises from the radiation from the 131I 84 Drugs for Hyperthyroidism... 9/1/2024  C/Is:  Absolutely C/I in pregnancy & lactation By: Alemseged.W, 2021  Furthermore, pregnancy must be avoided for 6 months following administration of 131I  Relatively contraindicated in children: There is a small risk of cancer 85 Thyrotoxicosis during pregnancy  Better to start therapy before pregnancy with radioactive Iodine  During pregnancy radioiodine is contraindicated,  Propylthiouracil is the drug of choice during pregnancy. 9/1/2024 By: Alemseged.W, 2021 87 Drugs for Hyperthyroidism... 9/1/2024 3. Strong iodine solution (lugol's solution)  Suppression of thyroid hormone production in preparation By: Alemseged.W, 2021 for subtotal thyroidectomy  Also used to suppress thyroid hormone release in pts experiencing thyroid storm  Obtain tests of thyroid function  Advise pts to dilute strong iodine solution with fruit juice or some other beverage to increase palatability 88 Drugs for Hyperthyroidism... 9/1/2024  Mild Toxicity  Inform pts about Sx of iodism (brassy taste, burning sensations in the mouth, soreness of gums & teeth), & instruct them to discontinue Tx & By: Alemseged.W, 2021 notify the prescriber if these occur  Symptoms fade upon drug withdrawal  Severe Toxicity  Iodine solution can cause corrosive injury to the GIT  Instruct pts to discontinue the drug & notify the prescriber immediately if severe abdominal distress develops  Tx includes gastric lavage & giving Na thiosulfate 89  Thyroid storm  sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life threatening syndrome.  There is hyper metabolism, and excessive adrenergic activity, death may occur due to heart failure and shock.  It is a medical emergency.  should be treated in an ICU for close monitoring of vital signs and for access to invasive monitoring Cont…..  Correct electrolyte abnormalities, Treat cardiac arrhythmia ( if present ) & Aggressively control hyperthermia by applying ice packs  administer antiadrenergic drugs (e.g. propranolol) to minimize sympathomimetic symptoms  High-dose Propylthiouracil (PTU) is preferred because of its early onset of action  Administer iodine compounds (Lugol's iodine or potassium iodide) orally or via a NG tube  Hydrocortisone 50 mg IV every 6 hours to prevent shock.