Lect_ES Pharmacology PDF

1 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 11/11/2024 Common Drugs Used in Endocrine Disorders  Common Drugs Used in Endocrine Disorders 2 Outline  Drugs used in thyroid disorder (*)  Antidiabetic drugs (*)  Sex hormones and hormonal contraceptives (*)  Oxytocic drugs: (ergometrine,...

1 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 11/11/2024 Common Drugs Used in Endocrine Disorders  Common Drugs Used in Endocrine Disorders 2 Outline  Drugs used in thyroid disorder (*)  Antidiabetic drugs (*)  Sex hormones and hormonal contraceptives (*)  Oxytocic drugs: (ergometrine, oxytocin)  Corticosteroids (*) 11/11/2024  3 DRUGS USED IN THYROID DISORDER 11/11/2024 Thyroid & Antithyroid Drugs  Thyroid & Antithyroid Drugs 4 Biosynthesis of Thyroid Hormones  Transport of iodide into the thyroid gland (by sodium/iodide symporter)  Oxidation of iodide (I-) into iodine (I) by thyroidal peroxidase  Iodination of tyrosine residues within the thyroglobulin molecule to form  Monoiodotyrosine (MIT) and diiodotyrosine (DIT). This (a process called iodide organification) 11/11/2024  Biosynthesis….Cont’d 5 Figure showing biosynthesis of thyroid hormones. The sites of action of various drugs that 11/11/2024 interfere with thyroid hormone biosynthesis are shown  Biosynthesis….Cont’d 6  Two molecules of DIT combine within the thyroglobuline to form L-thyroxine (T4)  One molecule of DIT combines with one molecule of MIT to form triiodothyronine (T3)  Thyroxine, T3, MIT, and DIT are released from thyroglobulin by proteolysis and leave the cell by exocytosis  Most of the hormone released during exocytosis is thyroxine (T4) but most of the circulating T3 is derived from T4 (by deiodination) 11/11/2024  7  Most of the effect of circulating T4 is due to T3 (greater potency of T3 and deiodination of T4 to T3) 11/11/2024 Figure: Peripheral metabolism of iodine (deiodination of T4 into T3)  Pharmacokinetics 8  Absorbed best in the duodenum and ileum  Absorption is modified by food, drugs, gastric acidity, and intestinal flora  Oral bioavailability:  L -thyroxine (80%) while T3 is almost completely absorbed (95%)  Parenteral route: IV route is preferred for both T3 & T4  Plasma protein binding: T4 & T3 are reversibly bound to protein, primarily to thyroxine-binding globulin (TBG) 11/11/2024 9  Clearance: metabolic clearances of T4 & T3 are increased in hyperthyroidism but decreased in hypothyroidism  Half-lives: half-lives of T4 & T3 are decreased in hyperthyroidism but are increased in hypothyroidism 11/11/2024 10 Mechanism of Action  Binding of T3 with thyroid receptor in the nucleus→ expression of genes responsible for many metabolic process (Na+/K+ ATPase, enzymes structural proteins, etc) 11/11/2024 Figure: Action of thyroid hormones:interaction with their receptors in the nuclus  Functions of Thyroid Hormone 11  Depend on the protein synthesis and potentiation of the secretion and action of growth hormone 1. Effects on growth and development  Is critical for the development and functioning of nervous, skeletal, and reproductive tissues.  Thyroid deprivation in early life results in irreversible mental retardation and dwarfism—typical of congenital cretinism. 2. Effects on metabolism  Carbohydrates, fats, proteins, and vitamins 11/11/2024  Thyroid Preparations 12  Synthetic: levothyroxine, liothyronine, liotrix  Of animal origin: desiccated thyroid  levothyroxine used for thyroid replacement and suppression therapy b/c of its:  Stability  Low cost  Lack of allergenic foreign protein  Long half-life (7dys) → permits once-daily administration  T4 is converted to T3 intracellularly (producing both hormones) 11/11/2024 13  T3 is 3-4x more potent thanT4, it is not recommended for routine replacement therapy because of:  Its shorter half-life (24 hours) → requires multiple daily doses  Its higher cost  Greater difficulty of monitoring its adequacy of replacement  Greater risk of cardiotoxicity (more potent) → T3 should be avoided in cardiac disease 11/11/2024 14  The use of desiccated thyroid preparations is never justified (antigenicity, instability, variable hormone concentrations and difficulty in laboratory monitoring) Clinical Uses of Thyroid Hormone  Hormone replacement therapy in hypothyroidism or cretinism  TSH suppression therapy in thyroid cancer or nontoxic goiter (occasionally) 11/11/2024  Special conditions 15 1. Myxedema and Coronary Artery Disease  Frequently occur together in older persons  Correction of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or acute myocardial infarction  Thyroid hormones → ↑ metabolism (↑ O2 demand)→ angina & myocardial infarction in coronary artery disease  Low levels of circulating thyroid hormone protect the heart against increasing demands (angina pectoris or myocardial infarction) 11/11/2024  Special conditions…Cont’d 16 2. Myxedema Coma  Refers to an end state of untreated hypothyroidism  Is a medical emergency warranting treatment in intensive care unit  Give all preparations IV due to poor drug absorption from other routes in myxedema coma  Give a loading dose of levothyroxine IV—usually 300–400 mcg initially, followed by 50–100 mcg daily 11/11/2024  Special conditions…Cont’d 17 3. Hypothyroidism and Pregnancy  Early development of the fetal brain depends on maternal thyroxin  Higher dose of levothyroxine is required in pregnant hypothyroid patient (many factors decrease the plasma level of levothroxine)  After delivery the need for increasing dose decreases 4. Congenital Hypothroidism (cretinism)  Requires early full maintenance therapy to improve the prognosis for mental and physical development 11/11/2024  Antithyroid agents 18  Reduction of thyroid activity and hormone effects can be accomplished by  Agents that interfere with the production of thyroid hormones  Agents that modify the tissue response to thyroid hormones  Glandular destruction with radiation or surgery  Antithyroid drugs used clinically include: thioamides, iodides, and radioactive iodine 11/11/2024  Antithyroid…Cont’d 19 1. Thioamides:  Include: methimazole, propylthiouracil (PTU) & carbimazole  Carbimazole is prodrug & converted to methimazole in vivo  Methimazole is about 10 times more potent than propylthiouracil  The thiocarbamide group is essential for antithyroid activity 11/11/2024  Antithyroid…Cont’d 20 Figure: Structure of thioamides, the thiocarbamide moiety 11/11/2024 is shaded in color.  Pharmacokinetics 21 Absorption:  Propylthiouracil (PTU): rapidly absorbed bioavailability of 50-80% (incomplete absorption or hepatic first-pass metabolism).  Methimazole: Absorption is complete (F = 100%) but at variable rate. Distribution:  Both drugs accumulate in the thyroid gland Excretion:  Most of PTU is excreted by the kidney within 24 hrs  Excretion of methimazole is slower than that of PTU 11/11/2024 22  Both have short plasma half-life  1.5 hrs for propylthiouracil & 6 hrs for methimazole.  A single 100 mg dose of propylthiouracil can inhibit iodine organification by 60% for 7 hrs  Propylthiouracil is given every 6–8 hrs  A single 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 hrs  A single daily dose is effective in the management of mild to moderate hyperthyroidism 11/11/2024 23 Cautions:  Both thioamides cross the placental barrier and are concentrated by the fetal thyroid (risk of fetal hypothyroidism).  Are classified as pregnancy category D (evidence of human fetal risk)  But PTU (more strongly protein-bound) is preferable in pregnancy & nursing infants than methimazole 11/11/2024  Pharmacodynamics 24  The thioamides act by multiple mechanisms:  Inhibition of thyroid peroxidase-catalyzed reactions → blocking iodine organification  Blockade of coupling of the iodotyrosines (I with Tyr)  Inhibition of peripheral deiodination of T4 into T3  Onset of effects of these agents is slow (inhibit the synthesis and presence of T4 stores) 11/11/2024  Toxicity 25  Nausea and gastrointestinal distress  Maculopapular pruritic rash (4–6%) → commonest  Hepatitis (more common with PTU) and cholestatic jaundice (with methimazole) can be fatal  Agranulocytosis (infrequent but potentially fatal ) 11/11/2024  Iodides 26  Now days iodides are rarely used as sole therapy.  The gland may escape iodide block and in 2-8 wks with consequent exacerbation of thyrotoxicosis. Pharmacodynamics  Iodides have several actions on the thyroid  Inhibition of organification → blocks iodination of tyrosine  Blockade of hormone release → inhibits thyroglobuline proteolysis  Onset of action occurs rapidly (within 2-7 days)  Hence, useful in the management of thyroid storm 11/11/2024  Contraindications 27  Initiate iodides therapy after onset of thioamide therapy  iodide therapy may increase intraglandular stores of iodine which may delay onset of effects of thioamide therapy.  Avoid iodide therapy if treatment with radioactive iodine seems likely.  may delay onset of effects radioactive iodine (↑ intraglandular stores)  Iodide should not be used alone  exacerbation of thyrotoxicosis 11/11/2024 28  Avoid chronic use of iodides in pregnancy  Cross the placenta and cause fetal goiter Toxicity  Adverse reactions to iodine (iodism) are uncommon and in most cases reversible upon discontinuance 11/11/2024  Radioactive Iodine 29  I is the only isotope used for treatment of thyrotoxicosis Pharmacokinetics  Rapidly absorbed after oral administration  Concentrated by the thyroid  Larger enough dose can be given to severely damage the gland without harming other tissues  Its therapeutic effect depends on emission of β rays  Destruction of the thyroid parenchyma becomes evident within a few weeks after administration 11/11/2024 Radioactive…… Cont’d 30 Advantages  Easy administration, effectiveness, low expense and absence of pain Contraindication:  Avoid use of radioactive iodine in pregnant women or nursing mothers  Crosses the placenta to destroy the fetal thyroid gland  Excreted in breast milk. Clinical Uses  Graves‘ Disease (for destruction of the gland)  Toxic nodular goiter 11/11/2024  Adrenoceptor-blocking agents (β-blockers) 31 -blockers: metoprolol, propranolol, atenolol  Mainly to control symptoms associated with thyrotoxicosis  Mimic symptoms of sympathetic stimulation  Do not typically alter thyroid hormone levels  Propranolol is the most widely used in thyrotoxicosis as adjunct therapy 11/11/2024  β-blockers…Cont’d 32 Clinical uses  Are effective therapeutic adjuncts with other antithyroid drugs  Subacute thyroiditis  Acute phase of a viral infection of the thyroid gland (release of T3 and T4)  Early stage of Hashimoto‘s thyroiditis 11/11/2024  Clinical Uses of Antithyroid Drugs 33 1. Hyperthyroidism (thyrotoxicosis)  High levels of thyroid hormone A. Graves’ disease: most common form  Is an autoimmune disorder in which the body produces antibody against TSH receptor.  Stimulates secretion of thyroid hormone (TSI) Management: #3 primary methods A. Antithyroid drug therapy: Methimazole, propylthiouracil  Methimazole is preferable to propylthiouracil (except in pregnancy) as it can be administered once daily (enhances adherence) 11/11/2024 34 B. Radioactive Iodine C. Thyroidectomy: of choice for very enlarged gland 11/11/2024  Special problems i.35 Thyroid Storm: thyrotoxic crisis  is sudden acute exacerbation of all of the symptoms of thyrotoxicosis (life-threatening).  Requires vigorous intervention:  control the severe cardiovascular manifestations using propranolol  Inhibition of release of thyroid hormones using potassium iodide  Blockade of hormone synthesis using propylthiouracil and methimazole  Hydrocortisone to control shock (may also block conversion of T4 to T3) 11/11/2024 36 ii. Thyrotoxicosis during pregnancy  Never use radioactive iodine → crosses the placenta and may injure the fetal thyroid.  Preparation of the patient with propylthiouracil (1st trimester) and a subtotal thyroidectomy (mid trimester). 2. Nontoxic goiter  is a syndrome of thyroid enlargement without excessive thyroid hormone production.  Causes:  iodide deficiency (commonest), mutations in genes involved in hormone synthesis (Dyshormongenesis), dietary goitrogens and neoplasms 11/11/2024  Nontoxic goiter…..cont’d 37  In goiter due to iodine deficiency:  Prophylactic administration of iodide  Goiter due to ingestion of goitrogens:  elimination of the goitrogen or by adding sufficient thyroxine to shut off TSH stimulation.  Dyshormonogenesis  adequate thyroxine therapy to suppress pituitary TSH 11/11/2024  38 PANCREATIC HORMONES & ANTIDIABETIC DRUGS 11/11/2024 Antidiabetic Drugs 39 The pancreas: # 2 portions (Figure below)  Exocrine pancreas:  Acinar cells: produce an enzyme-rich juice used for digestion (exocrine).  Endocrine pancreas:  Pancreatic islets (islets of Langerhans): produce hormones involved in regulation of glucose storage and use. 11/11/2024 40 11/11/2024 Figure showing the exocrine and endocrine portions of the pancreas.  Islets of Langerhans 41 11/11/2024  Hormones of the endocrine pancreas 1. Insulin 42  is a peptide hormone  is synthesized in  cells of pancreatic Islet. Biosynthesis of Insulin (See figure below)  Transcription of insulin gene  Translation and post-translational processing  Preproinsulin: Removal of the signal peptide ↓  Proinsulin: Removal of C peptide ↓  Insulin: biologically active hormone 11/11/2024 43 11/11/2024  Chemistry insulin  Proinsulin is hydrolyzed into insulin and C-peptide (C-peptide 44 has no known physiologic function but dx).  Insulin 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. Figure: Structure of human proinsulin and insulin. Insulin is shown as the shaded (green color) 11/11/2024 peptide chains, A and B.  Insulin Secretion  Insulin release: 45  Low at basal rate  Much higher at stimulated rate ( in response stimuli like glucose, certain amino acids (eg, leucine, arginine), hormones like glucagon, etc.).  Inhibitory signals include somatostatin, leptin, and chronically elevated glucose and fatty acid levels. Mechanism of stimulated insulin release:  Hyperglycemia → ↑intracellular ATP levels → closure of ATP dependent K-channels →↓outward K efflux → depolarization of β cell → opening of voltage-gated Ca- channels→ ↑intracellular calcium triggers secretion of insulin. 11/11/2024  Insulin Secretion…..cont’d  The insulin secretagogue drug group (sulfonylureas, 46 meglitinides, and D-phenylalanine) exploits parts of this mechanism. 11/11/2024 Figure: Control of insulin release from pancreatic β cell by glucose & by sulfonylurea drugs.  Circulating Insulin Basal insulin values in normal humans: 30–90 pmol/L 47  Insulin peak during meals: 360–540 pmol/L Insulin Degradation  The liver and kidney are the two main organs that remove insulin from the circulation.  The liver (60%) & the kidney (35–40%)  Parenteral injection reverses this ratio: kidney (60%) & liver ( ≥ 30–40%).  The half-life in plasma: about 5 to 6 min. 11/11/2024  Mechanisms of action of insulin I. Regulation of Glucose Transport & metabolism: 48  Cells uptake glucose only through facilitated diffusion  requires transporters (glucose transporter)  Insulin acts on cells though insulin receptors on plasma membrane  Binding of insulin to insulin receptors causes expression of glucose transporters (glut-1, glut-4) on the plasma membrane (Fig.)  translocation of intracellular vesicles containing GLUT4 & GLUT1 glucose transporters to the plasma membrane.  Glucose then enters into the cell through GLUT-1 &GLUT-4 (facilitated diffusion).  insulin also activates hexokinases which convert glucose into glucose-6-phospahte (g-6-p). 11/11/2024 MOA of Insulin…… Cont’d 49 11/11/2024 II. Regulation of Gene Transcription: 50  More than 100 genes are known to be regulated by insulin although the mechanisms of regulation are still being worked out. 11/11/2024 Figure: Pathways of insulin signaling.  Effects of Insulin on Its Targets 51 1. Decreases blood glucose concentration  ↑glucose transport into muscle, adipose and many other tissues but not brain  Stimulates glycogenesis  inhibits glycogenolysis (liver & skeletal muscle) & gluconeogenesis (liver) 2. Decreases blood amino acid concentration  ↑protein synthesis and inhibits protein breakdown  Promotes growth by inhibiting protein degradation 11/11/2024  Effects of Insulin ….Cont’d 3. 52 Decreases blood fatty acid and ketone concentrations  Facilitates FFAs transport into cells (stimulates lipoprotein lipase).  Promotes formation of fatty acids & glycerol from glucose.  Promotes synthesis of triglyceride & inhibits their breakdown ( inhibits hormone sensitive lipase).  ↓Ketone formation (↓acetyl-CoA substrate for Ketone bodies) 11/11/2024  Summary of metabolic effects of insulin 53 11/11/2024  Diabetes mellitus (DM)  Diabetes is not a single disease 54  consists of a group of syndromes characterized by hyperglycemia; altered metabolism of lipids, carbohydrates, and proteins; and an increased risk of complications from vascular disease.  Can be due to absolute insulin deficiency or relative insulin deficiency with peripheral tissue resistance to insulin  Main types:  Type I DM: insulin-dependent DM  Type II DM: non-insulin-dependent DM  Other types  Maturity-onset DM of the young (MODY)  Gestational diabetes, etc 11/11/2024  Antidiabetic drugs 55 I. Insulin Preparations II. Non-insulin antidiabetic agents I. Insulin Preparations Goals of insulin therapy:  To control both basal and postprandial (after meal) glucose levels while minimizing the risk of hypoglycemia Production:  Produced by rDNA techniques  The human or a modified human proinsulin genes are inserted into E. coli or yeast  The proinsulin is then extracted and further processed to 11/11/2024 form the insulin or insulin analogs Classification of Insulin Preparations 56  Based on the source, strength and rates of onset and duration of actions  Four principal types of injectable insulins are available: 1. Rapid acting insulin: insulin lispro, insulin aspart, and insulin glulisine 2. Short-acting insulin: Regular insulin 3. Intermediate-acting insulin: Isophane (NPH) insulin 4. Long acting insulin: Insulin glargine & insulin detemir 11/11/2024  Classification…Cont’d 57 Figure: Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. 11/11/2024 58 1. Rapid-acting insulin: insulin lispro, insulin aspart, and insulin glulisine  injected rapid-acting insulin analogsare commercially available.  Also called ultra short-acting insulin  Rapid onset and early peaking of activities.  more closely mimic normal endogenous prandial insulin secretion than does regular insulin.  Control of postprandial glucose levels: injected immediately before meal.  For emergency treatment in uncomplicated11/11/2024 diabetic ketoacidosis.  Their duration of action is rarely more than 4–5 hours 59  Lowers the risk of late postmeal hypoglycemia.  Have the lowest variability of absorption of all available commercial insulins.  Insulin lispro (Humalog):  two amino acids are transposed ( proline from position B28 to B29 & lysine from position B29 to B28).  Insulin aspart (Novolog):  substitution of proline at B28 by aspartic acid.  Insulin glulisine (Apdira):  is formulated by substitution of lysine at B3 by asparagine and at B29 by glutamic acid. 11/11/2024 2.60 Short-acting insulin: Regular insulin  soluble crystalline zinc insulin made by recombinant DNA techniques (identical to human insulin).  After subcutaneous injection  Onset of action: within 30 minutes  peaks of action: between 2 and 3 hours  Duration of action: lasts 5–8 hours.  Regular insulin molecules self-aggregate to form dimers that stabilize around zinc ions to create insulin hexamers.  delayed onset and prolongs the time to peak action (hexameric nature). 11/11/2024  Hexamers →dimers →monomers→absorption (delayed) 61  Should be injected 30–45 minutes before the meal to minimize the mismatching.  Administrationat mealtime → Slow absorption of regular insulin → blood glucose rises faster than insulin level → early postprandial hyperglycemia & late postprandial hypoglycemia.  The time of onset, intensity of peak action and duration of action increase with dose  pharmacokineticsand pharmacodynamics of small doses of regular and NPH insulins differ greatly from those of large doses. 11/11/2024 62  Regular soluble insulin is the only type that can be administered IV.  Useful in the management of diabetic ketoacidosis as IV therapy 3) Intermediate-acting insulin: Isophane (NPH) insulin  NPH (neutral protamine Hagedorn) insulin:  Regularinsulin + Protamine (highly basic protein)  The combination delays the absorption and onset of action  Onset of action: 2–5 hrs  Duration of action: 4–12 hrs 11/11/2024  Administered only SC 63  Usually mixed with regular & rapid acting insulin and given two to four times daily for insulin replacement 4. Long-acting insulins: Insulin glargine & insulin detemir Must be given SC Provide a peakless basal insulin level (lasts > 20hrs)  Used to control basal glucose level without producing hypoglycemia 11/11/2024  64 i. Insulin glargine:  Is a peakless long-acting insulin analog.  Two arginines attached to the B-chain carboxyl terminal & glycine replacing asparagine at the A21.  Precipitates at the site of injection (after SC injection).  prolonged absorption and longer action  Onset of action: slow (1–1.5 hrs)  Maximum: after 4–6 hrs.  Duration of action: 11–24 hrs (maximum activity is maintained) 11/11/2024  Given once daily or doses are splitted and given 2x/day.  65 ii. Insulin detemir  Most recently developed long-acting insulin analog.  Terminal threonine is dropped from the B30 position and myristic acid (C-14 fatty acid chain) is attached to the terminal B29 lysine.  ↑both self-aggregation in subcutaneous tissue and reversible albumin binding in the circulation.  Onset of action: 1–2 hrs (dose-dependent)  Duration of action: > 24 hrs.  Dosing: twice daily to obtain basal insulin level. 11/11/2024  5) Mixtures of insulins 66  Intermediate-acting NPH insulins:  require several hours to reach adequate therapeutic levels  Thus, requires supplements of rapid- or short-acting insulin before meals  Premixed preparations:  lispro, aspart, and glulisine can be mixed just before injection with NPH insulin in same syringe (unstable) Remedy  Protamine + insulin lispro = neutral protamine lispro (NPL)  Protamine + insulin aspart = neutral protamine aspart (NPA)  NPL & NPA have the same duration of action as NPH insulin but faster onset of action 11/11/2024 67 Premixed formulation as remedy:  50%/50% NPL/insulin lispro or 75%/25% NPL/insulin lispro  70%/30% NPA/insulin aspart Clinical Uses of insulin and analogs  All patients with type 1 DM  Patients with type 2 DM: not responding adequately to oral hypoglycemic agents  Patients with postpancreatectomy diabetes  Gestational diabetes 11/11/2024  68 Special Circumstances i. Diabetic Ketoacidosis  Life-threatening medical emergency caused by inadequate or absent insulin replacement  occurs commonly in people with type 1 diabetes.  typically occurs in newly diagnosed type 1 patients or  in those who interrupted insulin replacement. Treatment: Aggressive insulin therapy, IV hydration and maintenance of potassium & other electrolyte levels. 11/11/2024 69 ii. Hyperosmolar Hyperglycemic Syndrome  Commonly seen in persons with type 2 diabetes  Characterized by profound hyperglycemia and dehydration. It is associated with inadequate  Treatment: aggressive rehydration and restoration of glucose and electrolyte homeostasis Complications of Insulin therapy  Hypoglycemia: brain damage (brain sensitive)  Treatment: glucose or glucagon (requires liver glycogen).  Immunopathology:  insulin allergy → immediate type HR.  immune insulin resistance: Anti-insulin antibody. 11/11/2024  2. Non-insulin antidiabetic agents 70  Are oral antidiabetic agents  used for the treatment of persons with type 2 diabetes:  Include insulin secretagogues, biguanides, thiazolidinediones, α-glucosidase inhibitors, incretin-based therapies, and amylin analog. 11/11/2024  Insulin secretagogues: 71  Include sulfonylureas, meglitinides, D-phenylalanine derivatives 1. Sulfonylureas: MOA:  Stimulation of release of endogenous insulin by promoting closure of potassium channel in the pancreatic β-cell membrane  Closure of ATP sensitive K-channel→ Depolarization→ opening of voltage gated Ca- channel→Ca2+ influx → Release of insulin  Not effective in patients who lack functional β-cells. 11/11/2024 i. First-generation sulfonylureas 72 Tolbutamide:  Well absorbed but rapidly metabolized in the liver.  Half-life: 4–5 hrs  Duration of effect is relatively short  Safe in elderly  Divided dose Chlorpropamide  Half-life: 32 hrs  Metabolized in the liver (slow):→active metabolites Contraindication  In elderly patients (prolonged hypoglycemia) 11/11/2024  In patients with hepatic or renal insufficiency 73 Tolazamide  Comparable potency to chlorpropamide  But has a shorter duration of action.  Generates active metabolites. 11/11/2024 74 ii. Second-generation sulfonylureas: Glyburide, glipizide & glimepiride Glyburide  Liver metabolism.  Contraindication:  Hepato-renal insufficiency Glipizide  The shortest half-life (2–4 hrs)  For postprandial hyperglycemia: Ingested 30 minutes before breakfast 11/11/2024 Shorter half-life → lower risk of hypoglycemia 75 Glimepiride  Is approved for once-daily use as monotherapy or in combination with insulin.  The most potent analogue 2. Meglitinide: Repaglinide  MOA: Same as that of sulfonylureas  Very fast onset of action → postprandial hyperglycemia  Peak effect within 1 hr after ingestion,  Duration of action: 5–8 hours  Hepatic metabolism (by CYP3A4 ) 11/11/2024 76 3) D-phenylalanine derivative: Nateglinide  MOA:  Same as that of sulfonyl ureas  Metabolized in the liver  Half-life: 1.5 hrs  Duration of action < 4 hrs 11/11/2024 4) Biguanides: metformin 77 Mechanisms of Action:  Reduction of hepatic glucose production through activation of AMP-stimulated protein kinase (AMPK).  Reduces gluconeogenesis  Enhanced insulin action (sensitivity) in peripheral tissues (muscle & fat).  ↑glucose uptake & glycolysis in peripheral tissues  ↓endogenous insulin production (insulin sparing effect)→ thus, no increment in weight unlike in insulin secretagogues.  Reduction of plasma glucagon levels  Reduced absorption of glucose absorption form the GIT 11/11/2024 78 Effects of metformin  Reduces postprandial & fasting glucose levels.  In fasting hyperglycemia: once-daily dose at bedtime.  In postprandial hyperglycemia: Once-daily dose before meal.  Generally, does not cause hypoglycemia, even at larger dose (does not cause insulin release).  Hence, melformin is called ―euglycemic agent‖. Pharmacokinetics:  Oral bioavailability: 50-60%  Not metabolized:  Excreted unchanged in urine.  Not bound to plasma proteins  Half-life: 1.5-3 hrs 11/11/2024  Clinical uses 79  First line therapy for type 2 DM.  No increment in weight nor hypoglycemia (spares insulin).  Prevention of new onset of type 2 DM (middle aged, obese). Toxicity  GI effects (most common): anorexia, nausea, vomiting, abdominal discomfort, and diarrhea.  Reduced absorption of vitamin B12 on long-term metformin therapy.  Lactic acidosis (less common in the absence of hypoxia or renal or hepatic insufficiency) 11/11/2024 80 Contraindication  Hepato-renal diseases, alcoholism, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction).  Increased risk of lactic acidosis induced by biguanide drugs. 11/11/2024  Thiazolidinediones (Tzds) 81  Include pioglitazone (Actos) & rosiglitazone (Avandia) 11/11/2024 82 MOA:  Major site of action is adipose tissues and minimal in liver & muscle.  Tzds act to decrease insulin resistance.  Tzds bind nuclear peroxisome proliferator-activated receptor- gamma (PPAR-γ) to modulate the expression of the genes involved in  Lipid and glucose metabolism,  insulin signal transduction, and  adipocyte and other tissue differentiation NB: Tzds require insulin to be present for their action.  Slow onset of action (Tzds involve gene activation)  Tzds are euglycemics 11/11/2024 83 Pioglitazone  Has PPAR-α & PPAR-γ activity  Metabolized to active metabolites.  Taken once daily  More significant triglyceride-lowering effect (PPAR-α-binding).  Reduces mortality and macrovascular events (myocardial infarction and stroke). Clinical uses  Treatment of type 2 DM: as monotherapy or in combination with metformin, sulfonylureas, and insulin.  Prevention of type 2 DM. 11/11/2024 84 Rosiglitazone (Avandia)  Rapidly absorbed  Highly proteinbound.  Metabolized less active metabolites  Administered once or twice daily Clinical uses  Treatemnt of type 2 DM: as monotherapy or combination therapy.  Prevention of type 2 DM. 11/11/2024 Adverse 85 effect of Tzds  Fluid retention  Risk of heart failure. Many  Dose-related weight gain  Increased bone fractures (women). Contraindication  Pregnancy  Liver disease  Heart failure 11/11/2024  α-glucosidase inhibitors: acarbose and miglitol 86 MOA:  competitively inhibit intestinal α-glucosidases and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides. Clincal Uses:  Type 2 DM: as monotherapy or in cobination with 11/11/2024 sulfonyureas (additive effect) ADRs 87  flatulence, diarrhea, and abdominal pain  Dueto undigested carbohydrate in the colon → fermentation →FFAs releasing gas Contraindication  Inflammatory bowel disease  Renal failure  Hepatic disease (used with caution) 11/11/2024  Pramlintide  88 Is an injectable synthetic analog of amylin  Actions:  suppresses glucagon release via undetermined mechanisms  delays gastric emptying, and  has CNS-mediated anorectic effects  rapidly absorbed after SC administration→ levels peak within 20 minutes  should be injected immediately before eating  duration of action: 2.5 hrs  metabolized and excreted by the kidney. 11/11/2024 Clinical uses  Type 1 diabetes 89  Type 2 diabetes: double of the dose for type 1. ADRs  Hypoglycemia  Gastrointestinal symptoms: nausea, vomiting & anorexia. Incretin mimics: A. Exenatide  Synthetic analog of glucagon-like-polypeptide 1 (GLP-1)  Adjunctive therapy to inadequate therapy with SU or metformin  Duration of action : 10 hrs  Excreted in urine. 11/11/2024  Injected Sc within 1 hr before a meal  Multiple actions: 90  Potentiation of glucose-mediated insulin secretion (by increasing beta-cell mass)  Suppression of postprandial glucagon release (unknown mechanisms)  Slowed gastric emptying  Central loss of appetite ADRs  Nausea, vomiting and diarrhea  Weight loss (due to nausea and anorectic effects)  Pancreatitis (may be severe and sometimes fatal). 11/11/2024  B. Sitagliptin  Oral bioavailability: 85%  Half-life: 12 hrs; the dosage is 100 mg 91  Given orally once daily MOA:  inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules. ↑levels of GLP-1 and GIP →↓postprandial glucose excursions( by ↓ glucose-mediated insulin secretion and decreasing glucagon levels). ADRs  Nasopharyngitis, upper respiratory infections & headaches.  Allergic reactions(rarely). 11/11/2024 92 11/11/2024  Summary…cont’d 93 11/11/2024  94 SEX HORMONES AND HORMONAL CONTRACEPTIVES 11/11/2024  Menstrual Cycle…Cont’d 95 Classification:  On the basis of ovarian changes: #3 phases  Follicular (or preovulatory) phase,  Ovulatory phase  Luteal (or postovulatory) phase  On the basis of uterine changes: #3 phases  Proliferative phase  Menstrual phase  Secretory phase  Review on the Female Reproductive Physiology 96 The Menstrual Cycle  begins with menarche, usually around age 12, and continues to occur in nonpregnant women until menopause; usually around age 50  Comprehension of the hormonal regulation of the normal menstrual cycle is essential to understanding contraception in women  Menstrual Cycle…Cont’d 97 A. The Follicular phase I. Recruitment of follicles:  First 4 days: ↑FSH levels → ↑growth & development II. Selection and dominance of follicles:  B/n days 5 & 7: one follicle becomes dominant → later rupture & release the oocyte III. Atresia of nondominant follicles:  The dominant follicle → ↑estradiol and inhibin secretion → inhibition of hypothalamic secretion of GnRH & pituitary secretion of FSH (negative feedback) → atresia of the remaining follicles recruited during the cycle (mainly due to lack of FSH)  Menstrual Cycle…Cont’d Atresia Recruitment Follicular Size Dominance Ovulation Selection FSH Sensitive Pool Ovulation 9 18 28 Day After Ovulation Figure showing Menstrual the follicular wave  Menstrual Cycle…Cont’d 99 B. Ovulatory phase:  Elevated levels of estradiol levels (from preovulatory dominant follicle) → LH surge → stimulation of the final stages of follicular maturation & ovulation (follicular rupture & release of the oocyte)  On average, ovulation occurs 24 to 36 hours after estradiol peak and 10 to 16 hours after the LH peak  Conception is most successful when intercourse takes place from 2 days before ovulation to the day of ovulation  Menstrual Cycle…Cont’d 100 C) Luteal phase:  After ovulation, the remaining luteinized follicles become the corpus luteum → synthesizes androgen, estrogen, and progesterone  Theca interna: work with the granulosa cells to produce steroids Androgen (Testosterone) E2 (Estradiol)   Aromatase Theca interna Granulosa cells   LH FSH  Menstrual Cycle…Cont’d 101  Progesterone:  Maintains the endometrial lining → essential for implantation and maintenance of pregnancy  Also inhibits GnRH and gonadotropin (FSH/LH) release → preventing the development of new follicles  If pregnancy occurs, hCG prevents regression of the corpus luteum until the placenta takes over the production of progesterone and estrogen (6 - 8 wks of gestation) 11/11/2024  Menstrual Cycle…Cont’d 102  Nofertilization or implantation → ↓levels of LH/hCG → Degeneration of corpus luteum → ↓progesterone production endometrial shedding ↑FSH levels → follicular (menstruation) recruitment for the next cycle begins  Hormonal regulation of the menstrual cycle 103 11/11/2024  Summary of the Menstrual Cycle 104 Figure showing the menstrual cycle, showing plasma levels of pituitary and ovarian hormones and histologic changes  The ovarian hormones 105 1. The estrogen I. Natural Estrogens  The major estrogens produced by women are  Estradiol (estradiol-17β, E2) → major product  Estrone (E1)  Estriol (E3)  Estrogen…Cont’d 106 II. Synthetic Estrogens  Steroidal estrogens: ethinyl estradiol, mestranol, quinestrol  Produced via chemical alterations of the natural estrogens → meant to increase their oral effectiveness  Nonsteroidal compounds with estrogenic activity: dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, methallenestril, and chlorotrianisene  Estrogen…Cont’d 107 Figure showing compounds with estrogenic activity  Estrogen…Cont’d Table: commonly used estrogens 108  Estrogen…Cont’d 109 Pharmacokinetics  Estradiol binds strongly to α2 globulin (sex hormone-binding globulin [SHBG])  Metabolism: Estradiol is converted by the liver and other tissues to estrone and estriol  Estrone and estriol have low affinity for the estrogen receptor.  Excretion: in bile (significant) and breast milk (small)  Undergoes enterohepatic recycling  Estrogen…Cont’d 110 MOA: similar to those of other steroides like cortisol  Estrogen binding with its receptors (α & β isoforms) → hormone receptor complex → binding to a specific sequence of nucleotides (estrogen response elements, EREs) → transcription → proteins synthesis  Estrogen…Cont’d 111 Clinical Uses A. Primary Hypogonadism  Characterized by estrogen deficiency  Requires estrogens replacement therapy (HRT)  Treatment usually begins at 11–13 years of age to stimulate the development of secondary sex characteristics and menses, to stimulate optimal growth, and to prevent osteoporosis  Estrogen…Cont’d 112  It is initiated with small doses of estrogen on days 1–21 each month and is slowly increased to adult doses and then maintained until the age of menopause (approximately 51 years of age) B. Postmenopausal Hormonal Therapy  Is a hormone replacement therapy (HRT)  Cessation of normal ovarian function is usually followed by:  Loss of periods, sleep disturbances, genital atrophy, accelerated loss of bone (osteoporosis) →leads to fractures, and lipid changes (↑ atherosclerotic cardiovascular disease) 11/11/2024  Estrogen…Cont’d 113  Estrogen replacement therapy may help avoid these sings and symptoms i.e.  Vasomotore symptoms: hot flashes alternating with chilly sensations, inappropriate sweating, and less commonly paresthesias  Osteoporosis  Vaginal dryness and urogenital atrophy  Cardiovascular disease: estrogens produce a favorable lipoprotein profile, promote vasodilation, inhibit the response to vascular injury, and reduce atherosclerosis  Estrogen…Cont’d 114 C) Other uses  Intractable dysmenorrhea or amenorrhea & hirsutism ( excessive androgens form ovary)  Estrogens combined with progestins can be used  to suppress ovulation (intractable dysmenorrhea)  to suppress ovarian function (hirsutism & amenorrhea)  Estrogen…Cont’d 115 ADRs  Uterine bleeding  Cancer → chronic estrogen therapy may increase the risk of breast cancer & endometirial carcinoma  Others: Nausea, breast tenderness, hyperpigmentation, migraine headaches, etc. Contraindications  Estrogen-dependent neoplasms such as carcinoma of the endometrium or breast cancer  Undiagnosed genital bleeding  Liver disease  Selective Estrogen Receptor Modulators (SERMs) and Anti- estrogens A. SERMs: Tamoxifen, Raloxifene, and Toremifene  SERMs are compounds with tissue-selective actions.  The pharmacological goal of these drugs:  To produce beneficial estrogenic actions in certain tissues like bone, brain, & liver  To produce antagonist activity in tissues such as breast and endometrium (where estrogenic actions might be deleterious → carcinogenesis)  Tamoxifen & toremifene → treatment of breast cancer  Raloxifene → prevention & treatment of osteoporosis 116  B. Anti-estrogens 117 B. Anti-estrogens  Include: Clomiphene and Fulvestrant  These compounds differ from the SERMs in that they are pure antagonists in all tissues studied.  Clomiphene → for the treatment of infertility in anovulatory women  Fulvestrant → for treatment of breast cancer  SERMs and anti-estrogens…Cont’d 118 Figure: The structures of the trans-isomer of tamoxifen, and of raloxifene, trans- clomiphene (enclomiphene), and fulvestrant  Therapeutic Uses 119  Breast Cancer: Tamoxifen is highly efficacious  Tamoxifen reduces the risk of developing contralateral breast cancer and is approved for primary prevention of breast cancer in women at high risk.  Prophylactic treatment should be limited to 5 years, as effectiveness decreases thereafter.  Toremifene has therapeutic actions similar to tamoxifen  fulvestrant may be efficacious in women who become resistant to tamoxifen  Therapeutic Uses…Cont’d 120  Osteoporosis: Raloxifene reduces the rate of bone loss and may increase bone mass  Infertility:  Clomiphene is used primarily for treatment of female infertility due to anovulation.  MOA: Blockade of ER → Inhibition of negative feedback effect of estrogen on the hypothalamus and pituitary → ↑gonadotropin levels (primarily FSH) → follicular recruitment →ovulation  It is relatively inexpensive, orally active, and requires less extensive monitoring than do other treatment protocols  ADRS 121  Tamoxifen  Hot flashes  Estrogenic activity in the uterus →↑risk of endometrial cancer,↑risk of thromboembolic disease  Raloxifene  Hot flashes  Deep vein thrombosis  Leg cramps. NB: Raloxifene does not appear to increase the risk of developing endometrial cancer  ADRS…Cont’d 122  Fulvestrant  Hot flashes, GI symptoms, headache, back pain & pharyngitis  Clomiphene  Ovarian hyperstimulation  Increased incidence of multiple births  Ovarian cysts  hot flashes  blurred vision  prolonged use (e.g., 12 or more cycles) may increase the risk of ovarian cancer  Estrogen-Synthesis Inhibitors 123  Include: GnRH agonists, Aromatase inhibitors GnRH agonists  Continued administration prevents ovarian synthesis of estrogens but not their peripheral synthesis from adrenal androgens Aromatase inhibitors: I) Non selective: Aminoglutethimide  Use of aminoglutethimide is limited by its lack of selectivity  Estrogen synthesis inhibitors…cont’d 124 II) Selective aromatase inhibitors: Steroidal (Type I) agents: formestane and exemestane are substrate analogs that act as suicide inhibitors to irreversibly inactivate aromatase Nonsteroidal (Type II) agents: Anastrozole, letrozole, & vorozole Interact reversibly with the heme groups of CYPs  Estrogen synthesis inhibitors…cont’d 125 Clinical Uses  May be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen  They are highly efficacious and actually superior to tamoxifen in some adjuvant settings but unlike tamoxifen, they do not increase the risk of uterine cancer or venous thromboembolism  Have potential use for the chemoprevention of breast cancer  ↓estrogen levels →blockade of hormonal effects as tumor promoters (by stimulation of cell proliferation)  Have a theoretical advantage over tamoxifen  2. The Progestins 126  Compounds;progestins, progestational agents, progestagens, progestogens, gestagens, or gestogens  The progestins include I) Natural Progestins: Progesterone  Progesterone is the most important progestin in humans Precursor: cholesterol  Sources:  Adrenal cortex, ovary (corpus luteum), placenta (during preganacy)  Progestins…cont’d 127  Blood levels  Low during the follicular phase of the menstrual cycle  Increases during the luteal phase of the cycle  Further elevated during pregnancy peaking in the third trimester  Role of progesterone:  Hormonal effects  Precursor to estrogens, androgens & adrenocortical steroids  Progestins…Cont’d 128 II) Synthetic progestins  Progesterone/ 17α-acetoxyprogesterone derivatives (the pregnane series): hydroxyprogesterone caproate, medroxyprogesterone acetate (MPA) and megestrol acetate  19-nortestosterone derivatives (estranes): norethindrone, norethynodrel, ethynodiol diacetate  Are also called third generation synthetic progestins  Lack the C19 methyl group  Were developed for use as progestins in oral contraceptives, and  They also exhibit androgenic and other activities  Progestins…cont’d 129  The gonane series: norgestrel , desogestrel, gestodene, & norgestimate  Are recently developed series of the 19-nortestesterone containing ethyl at 13-position rather than methyl substituent  Have lower androgenic effect than 19-nortestestrone  These two classes of 19-nortestosterone derivatives are the progestational components of all oral and some long acting injectable contraceptives  17-Ethinyl testosterone derivatives: dimethisterone  Progestins…cont’d 130 Figure: Structural features of various progestins  Progestins…cont’d 131 Mechanism of Action  Similar to that of other steroid hormones.  Progestins enter the cell and bind to progesterone receptors (PR, 2 isoforms(PR-A & PR-B)) in the nucleus → Binding of ligand-receptor complex to progesterone response element (PRE) → activation of gene transcription → Protein synthesis  Progestins…cont’d 132 Physiological and Pharmacological Actions  Neuroendocrine Actions:  ↓the frequency of GnRH pulses → the major mechanism of action of progestin-containing contraceptives.  Reproductive Tract:  ↓estrogen driven endometrial proliferation and leads to the development of a secretory endometrium  the abundant watery secretion of the estrogen-stimulated endocervical glands is changed to a scant, viscid material when stimulated by progesterone → ↓penetration of the cervix by sperm  Progestins…cont’d 133  Maintenance of pregnancy:  Progesterone suppresses menstruation and uterine contractility  Mammary Gland:  Development of the mammary gland requires both estrogen and progesterone  Proliferation of the acini of the mammary gland during pregnancy and luteal phase of the cycle  progesterone acting with estrogen  Progestins…cont’d 134 NB: During the normal menstrual cycle, mitotic activity in the breast epithelium is very low in the follicular phase but peaks in the luteal phase  Thus, progesterone may be responsible for the increased risk of breast cancer associated with estrogen-progestin use in postmenopausal women  Progestins…cont’d 135 Pharmacokinetics  Plasma protein binding (≥90%):  Progesterone: albumin and corticosteroid-binding globulin CBG, but is not appreciably bound to SHBG  19-Norcompounds: SHBG and albumin, and esters such as MPA bind primarily to albumin  Metabolism:  Progesterone: metabolized primarily in the liver to pregnanediol (major)  Synthetic progestins: primarily hepatic (although metabolism is not as clearly defined as that of  Progestins…cont’d 136  Elimination:  Progesterone: hydroxylated and conjugated metabolites are eliminated in urine  Synthetic progestins: generally via the urine as conjugates and various polar metabolites  The elimination half-life  Progesterone ≈ 5 min  Synthetic progestins have much longer half-lives (norethindrone ≈7 hrs, norgestrel ≈16 hrs, gestodene ≈12 hrs and MPA ≈24 hrs) Table: Properties of some progestational agents 137  Progestins…cont’d 138 Clinical Uses of Progestins A. Therapeutic Applications  Hormone replacement therapy (HRT) and hormonal contraception  Treatment of dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated  Progestins…Cont’d 139 B. Diagnostic Uses  Progesterone can be used as a test of estrogen secretion  The administration of progesterone, 150 mg/d, or medroxyprogesterone, 10 mg/d, for 5–7 days, is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens.  To test the responsiveness of the endometrium in patients with amenorrhea → combination of estrogen and progestin can be given  Anti-progestins and progesterone-receptor modulators (PRMs) Include: mifepristone, onapristone 140 Mifepristone:  is derivative of norethindrone (the 19- norprogestin) Predominant anti-progestin activity but some agonist activity Thus, considered PRM Onapristone: is pure progesterone antagonist  Anti-progestins and PRMs…Cont’d 141 Pharmacological Actions  Acts as a competitive receptor antagonist of PR In the early stages of pregnancy:  mifepristone → blockade of uterine PRs → decidual breakdown → detachment of the blastocyst → hCG production → degeneration of the CL →↓ progesterone secretion accentuating further decidual breakdown  Blockade of PRs + ↓endogenous progesterone → ↑uterine prostaglandin levels and sensitizes the myometrium ↑uterine contraction  Anti-progestins and PRMs…Cont’d 142  Mifepristone also causes cervical softening → expulsion of the detached blastocyst  Prevention of ovulation: due to actions of mifepristone on the hypothalamus and pituitary rather than the ovary ( via unclear mechanisms )  Mifepristone impairs the development of a secretory endometrium and produces menses if administered in the mid- to late luteal phase  Mifepristone also binds to glucocorticoid and androgen receptors and exerts anti-glucocorticoid and anti-androgenic actions  Anti-progestins and PRMs…Cont’d 143 Pharmacokinetics  Mifepristone is orally active with good bioavailability  Plasma half-life: 20 to 40 hrs  Plasma protein binding: binds to α1-acid glycoprotein → prolongs half-life  Metabolism: undergoes hepatic metabolism & enterohepatic circulation  Excretion: predominantly in the feces  Anti-progestins and PRMs…Cont’d 144 Therapeutic Uses and Prospects  Termination of early pregnancy: Mifepristone in combination with misoprostol or other prostaglandins  Prostaglandin further increase myometrial contractions and ensure expulsion of the detached blastocyst  The success rate >90% for pregnancies ≤ 49 days‘ duration ADRs  Vaginal bleeding (most severe) NB: major concern about long-term use mifepristone is the possibility of unopposed estrogenic effects  Other Ovarian Hormones 145  Androgens: testosterone, androstenedione, and dehydroepiandrosterone  The normal ovary produces small amounts of androgens  Of these, only testosterone has a significant amount of biologic activity  These small amounts of androgens may be partly responsible for normal hair growth at puberty, female libido, and for metabolic effects.  Androgen production by the ovary may be markedly increased in some abnormal states, usually in association with hirsutism and amenorrhea  Other Ovarian Hormones…cont’d 146  Inhibin and activin:  Inhibin inhibits FSH secretion while activin increases FSH secretion  Relaxin  Structurally similar to insulin, although the amino acid sequence differs  A physiologic role for this peptide has not been established.  Other nonsteroidal substances: corticotropin- releasing hormone, follistatin, and prostaglandins  These probably have paracrine effects within the ovary  Summary 147  Contraception 148 Desired Outcome  To avoid pregnancy  Other health benefits  Prevention of sexually transmitted diseases (condoms)  Improvements in menstrual cycle regularity (hormonal contraceptives)  Prevention of malignancies and other health conditions (OCs)  Management of perimenopause  Contraception Methods 1. Barrier Methods  Condom (male & female)  Diaphragm  Cervical cap 2. Surgical Methods  Laparoscopic sterilisation (Female)  Rings, clips, bipolar diathermy, laser  Tubal ligation (Female)  Vasectomy (Male)  Contraception Methods…Cont’d 3. Hormonal Methods  Oral contraceptive  Combined oestrogen/progestogen  Progestogen only  Depot progestogens  Injections  Subcutaneous silicone implants/norplant  Vaginal ring: Silicone rings releasing oestrogen & progestogen  Contraception Methods…Cont’d 151 4. Intra Uterine Devices (IUD)  Inert  Copper bearing  Progestogen releasing 5. Spermicides  Creams, Films, Foams, Jellies, Pessaries, Sponges  (All of these are mainly Nonoxynol-9 based.) 6. Natural Methods  Rhythm  Breast feeding (while baby is totally breast fed) 11/11/2024  Contraception…cont’d 152 Table: Pregnancy rates versus contraceptive methods  Pharmacologic therapy 153 I. Spermicides II. Hormonal contraceptives I. Spermicides  Spermicides: contain nonoxynol-9  are chemical surfactants that destroy sperm cell walls and act as barriers that prevent sperm from entering the cervical os  are available as creams, films, foams, gels, suppositories/pissaries, sponges, and tablets Spermicide-Implanted Barrier Techniques  The vaginal contraceptive sponge (Today) is pillow shaped and contains 1 g of the spermicide nonoxynol-9  The sponge comes in one size and is available over the  1. Oral contraceptives 154 A. Combination oral contraceptives (COP):  Also called the combined pill  Contains a combination of estrogen & progestin  Commonly used estrogens: Ethinyl estradiol (mostly used) and mestranol  Commonly used progestins: levonorgestrel, norethindrone, norethindrone acetate, norgestrel, desogestrel, norgestimate, and drospirenone Formulations:  Include: monophasic, biphasic, or triphasic pills are generally provided in 21-day packs.  Combined Oral Contraceptives…Cont’d 155  Monophasic preparations:  Fixed amounts of the estrogen and progestin are present in each pill  The pill is taken daily for 21 days followed by a 7-day ―pill-free‖ period  Biphasic preparations :  Provide two different pills containing varying amounts of estrogen & progestin  The amount/dosage of estrogen is fixed, while the progestin increases in the 2nd half of the 21-day cycle  Bleeding occurs during the 7-day ―off‖ period  Reduces the total amount of estrogen & progestin administered  Combined Oral Contraceptives…Cont’d 156  More closely approximates the physiologic estrogen-to- progestin ratios of the menstrual cycle  Triphasic preparations  Provide three different pills containing varying amounts of estrogen & progestin  Dosage of one or both components is changed twice during the during the 21-day cycle  Dose of estrogen may be fixed or variable, while that of progestin increases in 3 equal phases  Bleeding occurs during the 7-day ―off‖ period  Reduces the total amount of estrogen & progestin administered  More closely approximates the physiologic estrogen-to- progestin ratios of the menstrual cycle  Combined Oral Contraception…cont’d Table: some oral and implantable contraceptive agents in use1 157 Combined Oral Contraception…cont’d Table …cont’d 158 Combined Oral Contraceptives…Cont’d 159 Mechanism of action  Suppression of gonadotropin secretion  inhibition of ovulation (main mechanism)  Development of endometrial atrophy making it unreceptive to implantation  Production of viscous cervical mucous that impede sperm transport  Possible effect on the secretions & peristalsis of the fallopian tube interfering with ovum & sperm transport  Combined Oral Contraceptives…Cont’d 160 Absolute contraindications  < 6 Wk postpartum if breast feeding  Smoker ≥ 15 cigarettes/day, > 35 Y of age  HPT systolic ≥ 160 mm Hg or diastolic ≥ 100 mm Hg  History of venous thromboembolism (VTE)  Ischemic heart disease  Migraine headache  Current breast cancer  Severe liver cirrhosis  Combined Oral Contraceptive…cont’d Non-contraceptive benefits  Prevention of osteoporosis: ↑ bone mineral density  ↓dysmenorrhea  ↓peri-menopausal symptoms  ↓acne  ↓hirsutism  Prevention of ovarian and endometrial cancer  Possibly ↓ ovarian cysts  POP…Cont’d 162 B. Progestin-only pill (POP)/”mini-pill” Usually contains: norethindrone or norgestrel  Taken daily on a continuous schedule Limitations:  Less efficacious than combination oral contraceptives  May produce irregular menstrual cycles more frequently than the combination product Advantages:  May be used breast-feeding patient(no effect on milk production unlike estrogen)  In patient intolerant to estrogen  Used in smokers  In patient with contraindications to estrogen  2. Transdermal patch (Ortho Evra): 163  Contains ethinyl estradiol and norelgestromin  Applied on the abdomen, upper torso, or buttock  One patch replaced every week for 3 weeks with the 4th patch-free week (when withdrawal bleeding occurs)  Limitations:  less effective  in women weighing greater than 90 Kg  3. Vaginal ring (Nuvaring) 164  Composition: ethinyl estradiol and etonogestrel  The ring is inserted into the vagina and is left in place for 3 weeks with ring-free 4th week (when withdrawal bleeding occurs)  The ring releases estradiole & desogestrel (etonogestrel)  Efficacy, contraindications, and adverse effects: similar to those of oral contraceptives.  Limitation:  may occasionally slip or be expelled accidentally  4. Progestin implants 165  Include: Levonorgestril (Norplant), Etonogestrel (Implanon)  Progestin-only implanted contraceptive rod/capsule  inserted under skin of upper arm  Effective for up to 3 years  MOA: blocks LH surge & prevents ovulation, thickens cervical mucus, alters endometrial lining 5. Intrauterine device (IUD) 166  Small plastic objects inserted into uterus  Have fine plastic strings hanging→ for removal  #2 types  Hormone-releasing progesterone IUD (progestin IUD)/Mirena  Copper-releasing IUD Progestin IUD progesterone  Releases levonorgestrel (LNG)  Provides contraception for up to 5 yrs  IUDs…cont’d Copper T IUD Progestin IUD/Mirena  Causes migration of WBCs  Releases 20 mcg LNG per into the uterine cavity day into uterine cavity for 5 resulting in phagocytosis of years spermatozoa  MOA:  MOA:  Inhibits fertilization:  Copper ions seem to have anovulation, thickens direct toxic effect on cervical mucus, inhibits spermatozoa sperm and ovum motility  Phagocytosis by WBC and function  Can be left in place for 10  Can be left in place for 5 yrs years  6. Injectable Contraceptives 168 Combined Injectable Contraceptives  Monthly injectable contraceptive composed of 5 mg estradiole cypionate & 25 mg medroxyprogestrone acetate  Less breakthrough bleeding Injectable Progestin (Depo-Provera)  Is progestin-only: Depot- medroxyprogestrone acetate (DMPA) 150 mg given IM every 12 weeks  MOA: Alters endometrial lining, thickens cervical mucus and blocks LH surge preventing ovulation  7. Emergency/Postcoital Contraception (the “morning-after pill”) 169  Goal: to prevent pregnancy after unprotected intercourse  High-dose oral contraceptive  95% effective within 24 hrs; 75% effective within 72 hrs A) Plan B: two doses of minipill each containing 0.75 mg of levonorgestrel taken at 12 hrs interval or 1.5 mg as single dose  ↓the risk of pregnancy by 80% B) Yuzpe method/Preven: 2 doses of 0.1mg ethinyl estradiol plus 0.5 mg of levonorgestrel separated by 12 hrs  ↓the risk of pregnancy by 60%  Emergency …Cont’d 170 MOA:  Prevention of ovulation, fertilization and implantation (less imp‘t)  Copper-T IUD  99% effective if inserted within 5 days  Mifepristone: single dose of mifepristone has also been used for EC  For maximal efficacy emergency contraception (EC) must be started as soon as possible → max 5 days (before implantation)  Oxytocic Drugs  Oxytocic drugs are used for cervical ripening and labor induction  They stimulate the uterus to contract and relaxes the cervix  Include oxytocin, ergometrine and prostaglandins. Cervical ripening:  Throughout most of pregnancy, the cervix is closed & firm.  During the last few weeks of pregnancy, the cervix becomes softer and thinner in order to facilitate labor.  This process is mediated by hormonal changes, including final mediation by prostaglandins E2 and F2α, which cause increased collagenase activity in the cervix leading to thinning and dilation.  Oxytocic….Cont’d Labor Induction  Conditions warranting induction  Postdatism (>42 weeks),  Suspected fetal growth retardation  Maternal hypertension  Premature rupture of membranes with no active onset of labor  1. Oxytocin  is neurohypophyseal hormone oxytocin (an octapeptide)  Its release is stimulated by cervical dilatation, & by suckling  Oxytocin for clinical use is prepared synthetically Pharmacokinetics  Routes: can be given by IV (most often) or IM injection  Metabolism: inactivated in the liver and kidneys, and by circulating placental oxytocinase  Oxytocin….Cont’d Actions  On the uterus.: contracts the uterus  Other actions:  Mammary gland: contracts myoepithelial cells  causing ‗milk let-down‘  Vasodilatory action  Weak antidiuretic action  water retention (can be problematic in patients with cardiac or renal disease, or preeclampsia) Clinical uses of oxcytocin  Used to induce or augment labour  Treatment of postpartum haemorrhage  Oxytocin...Cont’d Unwanted effects of oxytocin  Dose-related hypotension (vasodilatory action),  Reflex tachycardia (due to hypotension)  Water retention (due to antidiuretic action)  Hyponatraemia (due to water retention)  2. Ergometrine  Isolated from the fungus Ergot (Claviceps purpurea) MOA: not understood (especially on smooth muscle)  Possibly acts partly on α-adrenoceptors & 5-HT receptors Actions  Uterus: contracts the human uterus  thus reducing bleeding from the placental bed  Blood vessels: moderate vasoconstrictor action Pharmacokinetics  Routes: can be given PO, IM or IV  Onset of action: very rapid  Ergometrine…Cont’d Clinical use of ergometrine  Treatment of postpartum haemorrhage  Combined oxytocin & ergometrine preparation is used for:  mgt of the third stage of labour  control of bleeding due to incomplete abortion prior to surgery Unwanted effects of ergometrine  Vomiting (effect on dopamine D2 receptors in the CTZ  Hypertension (BP)  due to vasoconstriction  Nausea, blurred vision and headache  associated with BP  Angina  vasospasm of the coronary arteries  3. Prostaglandins Endogenous prostaglandins:  Include: Prostaglandin (PG) F2α, PGE2 and PGI2 (prostacyclin)  The uterus has substantial prostaglandin-synthesising capacity Actions  PGF2α  implicated in the ischaemic necrosis of the endometrium that precedes menstruation (little vasoconstrictor action in human)  PGE2 and PGI2 (prostacyclin) are vasodilator prostaglandins  PGE2 and PGF2 contract the non-pregnant as well as the pregnant uterus and relaxe the cervix  the sensitivity of uterine muscle to PGs increases during gestation  Prostaglandins…Cont’d  Prostaglandins also play a part in two of the main disorders of menstruation:  Dysmenorrhoea (painful menstruation)  associated with  production of PGE2 & PGF2α  treated using NSAIDs (inhibit prostaglandin biosynthesis)  Menorrhagia (excessive blood loss)  may be caused by a combination of vasodilatation & haemostasis   PGI2 by the uterus vasodilaton/ inhibition of platelet aggregation  impaired haemostasis (bleeding)  Treated using NSAIDs  Prostaglandins…Cont’d Prostaglandin preparations  The prostaglandins used in obstetrics are:  Dinoprostone (PGE2): can be given intravaginally as a gel or as tablets, or by the extra-amniotic route as a solution  Carboprost (15-methyl PGF2α): given by deep IM injection  Gemeprost or misoprostol (PGE1 analogues): given intravaginally  Prostaglandins…Cont’d Clinical use  Carboprost:  can be used for treat postpartum haemorrhage if patients do not respond to ergometrine.  Dinoprostone:  Late (second trimester) therapeutic abortion  given by the extra-amniotic route  Cervical ripening and induction of labour  given as vaginal gel  Gemeprost (misoprostol):  Used as a medical alternative to surgical termination of pregnancy (up to 63 days of gestation)  given as vaginal pessary following mifepristone  Prostaglandins…Cont’d Unwanted effects  Uterine pain, nausea and vomiting  cardiovascular collapse  Phlebitis  at the site of IV infusion NB: Side effects can be reduced when PGs (e.g. misoprostol) are combined with mifepristone(a progestogen antagonist)  sensitizes the uterus to prostaglandins; thus lower doses of the PGs can be used to terminate pregnancy  Tocolytics  Are drugs that inhibit uterine contraction  delay labour  Clinical use:  Used to delay preterm labour/prevent preterm labor  Tocolytic agents include:  Oxytocin antagonist: atosiban  β2-adrenoceptor agonists: ritodrine, salbutamol,terbutaline  Cyclo-oxygenase inhibitors: NSAIDs (indomethacin)  Calcium channel blockers: nifedipine  Magnesium: magnesium sulfate  Ethanol: not effective  17α-hydroxyprogesteron caproate  1. Atosiban  Is an oxytocin receptor antagonist  Used as an alternative to β2-adrenoceptor agonists  Given as IV bolus followed by IV infusion (for  48 hrs) Adverse effects  Vasodilation, nausea, vomiting and hyperglycaemia 2. Cyclo-oxygenase inhibitors : indometacin  Inhibit PG synthesis and delay labour Adverse effects  Their use could cause problems in the baby including:  Renal dysfunction & delayed closure of the ductus arteriosus  both are influenced by endogenous PGs  3. β2-adrenoceptor Agonists Selective β2-adrenoceptor agonists: ritodrine, salbutamol, terbutaline  Inhibit spontaneous or oxytocin-induced contractions of the pregnant uterus  relaxation of the pregnant uterus  Used in selected patients to prevent premature labour occurring between 22 and 33 weeks of gestation in otherwise uncomplicated pregnancies  Risks to the mother:  pulmonary oedema  Reduced myometrial response  so avoid prolonged treatment with these drugs  4.17α-hydroxyprogesteron caproate A low level of maternal serum progesterone has been associated with miscarriage and preterm labor  Progestines are shown to prevent preterm labor Antenatal Corticosteroids  Important for fetal lung maturation → prevent respiratory distress syndrome, intraventricular hemorrhage, and death in infants delivered prematurely.  betamethasone: 12 mg IM every 24 hrs for two doses or  dexamethasone : 6 mg IM every 12 hrs for four doses (between 26 and 34 weeks‘ gestation)  187 ADRENOCORTICOSTEROIDS & ANTAGONIST 11/11/2024 Adrenocorticosteroids & Antagonists 188 11/11/2024  Adrenocorticosteroids 189  Steroid hormones produced & released by the adrenal cortex.  Classified as: 1. Glucocorticoides (cortisol): effects on intermediary metabolism & immune function. 2. Mineralocorticoides (aldosterone): salt retention 3. Sex hormones (androgene or estrogen) Biosynthesis of adrenocortical hormones  All adrenocortical hormones are synthesized from cholesterol (See figure below). 11/11/2024  Figure: Outline of major pathways in adrenocortical hormone biosynthesis 190 11/11/2024  Glucocorticoids 191 1. Cortisol (hydrocortisone)  Is a naturally occurring glucocorticoid Pharmacokinetics  Its synthesis and secretion are tightly regulated by the (HPA axis)  The rate of secretion follows a circadian rhythm governed by pulses of ACTH that peak in the early morning hours and after meals.  In plasma, about 90% are bound to corticosteroid-binding globulin (CBG).  CBG is increased in pregnancy and with estrogen administration and in hyperthyroidism 11/11/2024  Half-life of cortisol in the circulation: 1-1.5 hrs 192  Increased by exogenous hydrocortisone, stress, hypothyroidism, liver disease.  Metabolisim and excretion: Most cortsisol are metabolized by the liver and excreted in urine.  Only1% of cortisol is excreted unchanged. Mechanism of Action  Binding of cortisol with glucocorticoid receptors in the cytoplasm → transport of cortiso-receptor complex into the nucleus → Binding of cortisol-receptor complex to glucocorticoid response element (GRE) → activation of gene expression → initiation of protein synthesis → cellular response. 11/11/2024 193 Figure showing the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the 11/11/2024 subsequent events in a target cell.  Effects of cortsol 194 1. Metabolic effects  Carbohydrate metabolism:  ↑gluconeogenesis and glycogen synthesis  inhibit the uptake of glucose by muscle cells ↑serum glucose levels → stimulating insulin release  Insulin increases lipogenesis  Lipid metabolism  Stimulate hormone sensitive lipase → ↑ lipolysis  Protein metabolism:  ↑ release of amino acids (Via muscle catabolism)  NB: both lipogenesis and lipolysis are stimulated with net increase in fat deposition (in face, shoulder, etc). 11/11/2024 2. Anti-Inflammatory and Immunosuppressive Effects  Synthetic corticosteroids 195  Include prednisone, prednsiolone, dexamethasone, triamcinolone, etc.  Have similar mechanism of action to those of cortisol. 11/11/2024 Table: Some commonly used natural and synthetic corticosteroids for general use. 196 11/11/2024  Clinical pharmacology 197 1. Replacement therapy: Adrenal disorder  Adrenocortical insufficiency i. Acute adrenocortical insufficiency: Life threatening and requires immediate therapy with hydrocortisone (100mg IV every 8hrs) until the patient becomes stable. ii. Chronic adrenocortical insufficiency (Addison‘s disease):  Congentital adrenal hyperplasia  Genetic disorder in which the enzyme involved in the glucocorticoid synthesis is deficient.  Cushing’s syndrome: after surgical removal of pituitary 11/11/2024 tumor or adrenal glands  2. Therapeutic uses in non-endocrine diseases 198  Does not involve hypothalamic-pituitary-adrenal axis.  Attributed to the ability of cortisol to suppress inflammatory and immune responses.  Non endocrine disorders benefiting from glucocorticoids:  Transplant rejection  Rhematic disorders like rheumatoid arthritis  Inflammatory bowel diseases, etc.  Organ transplant rejection  Allergic reactions  Asthma, etc 11/11/2024  ADRs 199  Of two categories:  Those resulting from withdrawal of therapy and  those resulting from continued use at higher doses.  Withdrawal of therapy  Flare-up of underlying diseases  Suppression of HPA axis and acute adrenal insufficiency  Continued use of higher doses of glucocorticoides  Fluid and electrolyte abnormalities  Hypertension, hyperglycemia  Immunosuppression→ susceptibility to infection  Osteoporosis  Myopathy, etc. 11/11/2024  Contraindication & caution 200  Precaution:  Keep the dosage as low as possible with intermittent administration (eg, alternate-day)  Supplementary therapy at times of stress (surgery, intercurrent illness or accidents)  Contraindication  Peptic ulcer, heart disease or hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis, psychoses, diabetes, osteoporosis, or glaucoma 11/11/2024  Mineralocorticoids: aldosterone, deoxycorticosterone, fludrocortisone 201 A. Aldosterone  Isthe natural mineralocorticoid in humans.  Secretion is regulated by RAAS. Physiologic Effects  Reabsorption of sodium from the distal part of the DCT and cortical collecting renal tubules. B. Deoxycorticosterone (DOC):  Itis one of the minirealocorticoides formed in and released from the adrenal cortex in small amount. 11/11/2024  Mineralocorticoids...Cont’d 202 C. Fludrocortisone  Is a synthetic corticosteroid.  Has both glucocorticoid and mineralo corticoid properties.  Used in the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency. Corticosteroid antagonists  Refer to both mineralocorticoids and glucocorticoids. i. Receptor antagonists:  Spironolactone & eplerenone: aldosterone receptor antagonists (Shall be covered under diuretics).  Mifepristone (RU-486): competitive inhibitor of glucocorticoid receptor and also progesterone receptor. 11/11/2024  Used in the treatment of Cushing‘s syndrome.  Mineralocorticoids…Cont’d 203 ii. Synthesis inhibitors  Several drugs inhibit adrenal steroid synthesis. The most important ones are: 1. Ketoconazole: is an antifungal imidazole derivative.  Is a potent and non selective inhibitor of adrenal and gonaldal steroid synthesis.  Inhibits cytochrome P450 enzymes → important for synthesis of all steroids. Clinical use of Ketoconazole:  adrenal carcinoma (Cushing‘s syndrome), breast and prostate cancers. 11/11/2024  Aminoglutethimide 204  Blocks the conversion of cholesterol to and inhibits the synthesis of all hormonally active steroids Clinical uses  Adrenocorticalcancer (Cushing‘s syndrome) → given with metyrapone or ketoconazole 3. Metyrapone  isa relatively selective inhibitor of cortisol and corticosterone synthesis Clinical uses  Not been widely used alone for the treatment of Cushing‘s syndrome. 11/11/2024