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What is the half-life of propylthiouracil?
What is the half-life of propylthiouracil?
Which of the following is a synthetic progestin that is a 19-nortestosterone derivative?
Which of the following is a synthetic progestin that is a 19-nortestosterone derivative?
What is the function of the "islets of Langerhans" in the pancreas?
What is the function of the "islets of Langerhans" in the pancreas?
The most potent analogue used as monotherapy or in combination with insulin is?
The most potent analogue used as monotherapy or in combination with insulin is?
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Which of the following is a contraindication to the use of metformin?
Which of the following is a contraindication to the use of metformin?
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What is the primary mechanism of action of the "combined pill" oral contraceptive?
What is the primary mechanism of action of the "combined pill" oral contraceptive?
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T3 is 3-4x more potent than T4, why is it not recommended for routine replacement therapy?
T3 is 3-4x more potent than T4, why is it not recommended for routine replacement therapy?
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Which of the following is the most common cause of nontoxic goiter?
Which of the following is the most common cause of nontoxic goiter?
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The half-life of insulin is 5 to 6 mins.
The half-life of insulin is 5 to 6 mins.
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The progestin-only pill (POP) or "mini-pill" is less efficacious than combined oral contraceptives.
The progestin-only pill (POP) or "mini-pill" is less efficacious than combined oral contraceptives.
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What are the two main hormones that are produced by the "islets of Langerhans"?
What are the two main hormones that are produced by the "islets of Langerhans"?
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What are the two main categories of anti-diabetic drugs?
What are the two main categories of anti-diabetic drugs?
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What are the three primary methods used to manage Graves’ Disease?
What are the three primary methods used to manage Graves’ Disease?
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What is the primary use of the "Yuzpe method" for emergency contraception?
What is the primary use of the "Yuzpe method" for emergency contraception?
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What are the two primary classifications of progestins?
What are the two primary classifications of progestins?
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What are the two main types of "intrauterine devices" (IUDs)?
What are the two main types of "intrauterine devices" (IUDs)?
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What are the most common side effects of metformin?
What are the most common side effects of metformin?
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What are the two main types of "anti-estrogens"?
What are the two main types of "anti-estrogens"?
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What are the two main types of "selective estrogen receptor modulators" (SERMs)?
What are the two main types of "selective estrogen receptor modulators" (SERMs)?
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What are the two main types of "progesterone receptor modulators" (PRMs)?
What are the two main types of "progesterone receptor modulators" (PRMs)?
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What are the two primary clinical uses for "corticosteroids"?
What are the two primary clinical uses for "corticosteroids"?
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What are the three main categories of "adrenocorticosteroids"?
What are the three main categories of "adrenocorticosteroids"?
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What is the primary action of "oxytocin"?
What is the primary action of "oxytocin"?
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What is the primary use of "ergometrine"?
What is the primary use of "ergometrine"?
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What is the primary action of "prostaglandins" in relation to the uterus?
What is the primary action of "prostaglandins" in relation to the uterus?
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What are the two main types of "tocolytic agents"?
What are the two main types of "tocolytic agents"?
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What is the primary action of "corticosteroid antagonists"?
What is the primary action of "corticosteroid antagonists"?
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What is the primary clinical use of ketoconazole?
What is the primary clinical use of ketoconazole?
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What is the primary clinical use of "progestin implants"?
What is the primary clinical use of "progestin implants"?
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Match the following contraceptive methods with their descriptions:
Match the following contraceptive methods with their descriptions:
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Study Notes
Pharmacology of the Endocrine System
- This topic covers common drugs used in endocrine disorders.
- Subtopics include drugs used in thyroid disorders, antidiabetic drugs, sex hormones and hormonal contraceptives, oxytocic drugs (ergometrine, oxytocin), and corticosteroids.
Drugs Used in Thyroid Disorder
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Biosynthesis of Thyroid Hormones:
- Iodide is transported into the thyroid gland by a sodium/iodide symporter.
- Iodide (I-) is oxidized to iodine (I) by thyroidal peroxidase.
- Tyrosine residues within thyroglobulin are iodinated to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
- Two DIT molecules combine to form L-thyroxine (T4).
- One DIT molecule and one MIT molecule combine to form triiodothyronine (T3).
- Thyroxine (T4), T3, MIT, and DIT are released from thyroglobulin by proteolysis and leave the cell by exocytosis.
- Most of the circulating T3 is derived from T4 by deiodination.
- Most of the effect of circulating T4 is due to T3 (greater potency of T3 and deiodination of T4 to T3).
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Pharmacokinetics:
- Absorption is best in the duodenum and ileum, but absorption is modified by food, drugs, gastric acidity, and intestinal flora.
- Oral bioavailability of L-thyroxine is 80%, while T3 is almost completely absorbed (95%).
- The IV route is preferred for both T3 & T4.
- T4 & T3 are reversibly bound to protein, primarily to thyroxine-binding globulin (TBG). Metabolic clearances of T4 & T3 are increased in hyperthyroidism but decreased in hypothyroidism. Half-lives of T4 & T3 are decreased in hyperthyroidism but increased in hypothyroidism.
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Mechanism of Action:
- Binding of T3 with thyroid receptor in the nucleus leads to expression of genes responsible for many metabolic processes (Na+/K+ ATPase, enzymes, structural proteins, etc.).
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Functions of Thyroid Hormone:
- Depend on protein synthesis and potentiation of growth hormone secretion and action.
- Affects growth and development, critical for the development and functioning of nervous, skeletal, and reproductive tissues.
- Thyroid deprivation in early life results in irreversible mental retardation and dwarfism (congenital cretinism).
- Affects metabolism of carbohydrates, fats, proteins, and vitamins.
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Thyroid Preparations:
- Synthetic: levothyroxine, liothyronine, liotrix
- Of animal origin: desiccated thyroid
- Levothyroxine (T4) is used for replacement and suppression therapy because of its low cost, stability, and lack of allergenic foreign protein. T4 is converted to T3 intracellularly producing both hormones. – T3 is 3-4x more potent than T4, but due to shorter half life and higher cost it's not often used for routine replacement therapy. T3 has greater risk of cardiotoxicity in patients with cardiac disease.
- Desiccated thyroid is not recommended due to its variable hormone concentrations and the difficulty in monitoring.
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Clinical Uses of Thyroid Hormone:
- Hormone replacement therapy in hypothyroidism or cretinism.
- TSH suppression therapy in thyroid cancer or nontoxic goiter (occasionally).
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Special Conditions:
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Myxedema and Coronary Artery Disease
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Myxedema Coma
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Hypothyroidism & Pregnancy
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Congenital Hypothroidism (cretinism)
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Additional Information:*
- Antithyroid agents reduce thyroid activity and hormone effects.
- These agents interfere with thyroid hormone production (e.g., thioamides, iodides, radioactive iodine), modify tissue response to thyroid hormones, or cause glandular destruction (with radiation or surgery).
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Antithyroid agents (thioamides):
- Include methimazole, propylthiouracil (PTU), and carbimazole.
- Carbimazole is a prodrug, converted to methimazole in vivo.
- Methimazole is about 10 times more potent than propylthiouracil. – The thiocarbamide group is essential for antithyroid activity.
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Pharmacokinetics
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Absorption: Propylthiouracil (PTU) is rapidly absorbed but with a bioavailability of 50-80% due to incomplete absorption or hepatic first-pass metabolism.
- Methimazole has a complete absorption (F = 100%).
- Both drugs accumulate in the thyroid gland.
- Most of PTU is excreted by the kidney within 24 hrs, excretion of methimazole is slower than that of PTU – Both have short plasma half lives, PTU having 1.5 hours and methimazole having 6 hours
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Pharmacodynamics: – Thioamides act by multiple mechanisms: inhibition of thyroid peroxidase-catalyzed reactions, blockade of coupling of the iodotyrosines, and inhibition of peripheral deiodination of T4 into T3. – Onset of effects of these agents is slow (inhibit the synthesis and presence of T4 stores).
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Toxicity: nausea, and gastrointestinal distress, maculopapular pruritic rash, hepatitis, cholestatic jaundice, and agranulocytosis which is infrequent but potentially fatal
Antidiabetic Drugs
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Pancreatic Hormones:
- The pancreas has exocrine and endocrine portions.
- Exocrine: acinar cells produce enzymes for digestion.
- Endocrine: pancreatic islets (Islets of Langerhans) produce hormones involved in regulating glucose storage and use.
- The pancreas has exocrine and endocrine portions.
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Insulin:
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A peptide hormone synthesized in β cells of pancreatic islets.
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Biosynthesis involves transcription of insulin gene, translation and post-translational processing of preproinsulin.
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Proinsulin is hydrolyzed into insulin and C-peptide.
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Insulin contains 51 amino acids arranged into two chains (A and B).
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Insulin has a short half-life (approximately 5-6 minutes) degraded primarily by the liver and the kidney.
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Insulin Secretion:
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Released at basal and stimulated rates (in response to glucose, amino acids, glucagon).
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Inhibitory signals include somatostatin, leptin, and chronically elevated glucose and fatty acid levels.
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Mechanism: 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.
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Insulin Action:
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Regulates glucose transport and metabolism which involves the uptake of glucose through facilitated diffusion, using glucose transporters (GLUT).
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Insulin also activates hexokinases which converts glucose into glucose–6–phosphate
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Regulates gene transcription through 100+ genes in various metabolic pathways (e.g., mitogenesis, protein synthesis, glycogen synthesis)
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Effects of Insulin on its targets
- Decreases blood glucose levels (↑ transport to muscle, adipose tissue).
- Stimulates glycogenesis, inhibits glycogenolysis / gluconeogenesis.
- Decreases blood amino acid levels, promotes protein synthesis. Inhibits protein breakdown.
- Decreases blood fatty acid & ketone concentrations, promotes synthesis of triglycerides, inhibits their breakdown (inhibits hormone sensitive lipase). ↓ Ketone formation.
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Diabetes Mellitus:
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Diabetes is a group of syndromes characterized by hyperglycemia, altered metabolism of lipids, carbohydrates, and proteins, vascular disease, and increased complications risk. It may be caused by absolute or relative insulin deficiency with peripheral tissue resistance to insulin.
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Types include Type I (insulin-dependent), Type II(non-insulin dependent). Maturity-onset DM of the young (MODY), and gestational diabetes (occurs during pregnancy), etc.
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Antidiabetic Drugs (Non-Insulin): – Are used to treat type 2 diabetes. – Include sulfonylureas, meglitinides, D-phenylalanine derivatives, biguanides, thiazolidinediones, a-glucosidase inhibitors, incretin-based therapies, amylin analogues.
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Examples include: sulfonylureas-to increase insulin release (e.g., Glipizide). Meglitinides- similar action to sulfonylureas, but faster action (e.g. Repaglinide. Thiazolidinediones-decrease insulin resistance (e.g. Pioglitazone, rosiglitazone). Biguanides(e.g. Metformin):reduce hepatic glucose production. a-glucosidase inhibitors(acarbose, miglitol):delay digestion & absorption of starch and disaccharides. – Additional agents like pramlintide, exenatide, sitagliptin are also used (incretin-mimics).
Oxytocic Drugs
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Used in cervical ripening and labor induction.
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Include oxytocin, ergometrine, and prostaglandins.
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Cervical ripening is a process of the cervix becoming softer and thinner to facilitate labor induction..
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Oxytocin:
- A neurohypophyseal hormone (octapeptide).
- Its release is stimulated by cervical dilation and suckling.
- Synthetic oxytocin is used clinically.
- Actions on the uterus to contract the uterus, mammary gland (milk let-down), and a weak antidiuretic (water retention) effect
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Ergometrine: – Isolated from fungus-Ergot (Claviceps purpurea). – Mechanism of action not entirely understood -possibly acts on alpha-adrenoceptors and 5-HT receptors. – Effects on the uterus to contract thus reducing bleeding from placental beds and blood vessels as a moderate vasoconstrictor.
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Prostaglandins: – Endogenous prostaglandins include PGF2a, PGE2, and PGI2 (prostacyclin). – Uterus has substantial prostaglandin-synthesizing capacity.
- Actions: implicated in ischaemic necrosis of the endometrium (little vasoconstrictor effect in humans), are vasodilator prostaglandins.
– Used in obstetrics to treat postpartum haemorrhage, late (second trimester) therapeutic abortions, and cervical ripening.
– Unwanted effects include uterine pain, cardiovascular collapse, and phlebitis.
- Actions: implicated in ischaemic necrosis of the endometrium (little vasoconstrictor effect in humans), are vasodilator prostaglandins.
– Used in obstetrics to treat postpartum haemorrhage, late (second trimester) therapeutic abortions, and cervical ripening.
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Tocolytics: – Inhibit uterine contractions to delay labor. – Examples include oxytocin antagonists, beta-2 adrenergic agonists, calcium channel blockers, and NSAIDs.
Other Ovarian Hormones
- Androgens: – Testosterone, androstenedione, and dehydroepiandrosterone. – The normal ovary produces minor amounts of androgens, mostly testosterone. – Important in normal hair growth, female libido and metabolic effects.
- Inhibin and activin: – Inhibin inhibits FSH secretion, while activin increases FSH secretion.
- Relaxin: – Similar to insulin but with slightly different AA sequences.
- Other nonsteroidal substances: – Corticotropin-releasing hormone, follistatin, and prostaglandins. They seem to exert paracrine effects in the ovary.
Contraception
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Methods:
- Barrier (condoms, diaphragm, cervical cap)
- Surgical (tubal ligation, vasectomy)
- Hormonal (oral contraceptives, depot progestogens, injections, transdermal patches, vaginal ring, implants, intrauterine devices (IUDs))
- Natural (rhythm, breastfeeding).
- Combination oral contraceptives (COC):
- Used for contraception, reduction of bleeding disorders , and management of secondary sex characteristics.
– Contains estrogen and progestin.
- Progestin-only pills (POP):
- Used for contraception. – Contains progestin. – Less efficacious than COC and may cause irregular menses.
- Injectable and implantable contraceptives: - Have extended duration of effect, similar to some oral contraceptive preparations.
- Emergency contraceptive : Mifepristone and other prostaglandins are used to terminate early pregnancy.
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