Pituitary Agents PDF

**Pituitary Agents** a. Identify drugs useful to treat acromegaly, their MOA and ADRs i. Pegvisomant (**Somavert**): GH Antagonist (GHA) **MOA** Binds to GH receptors in liver and inhibits IGF. Does not inhibit GH production, but block the physiologic effects of GH on the target tissue...

**Pituitary Agents** a. Identify drugs useful to treat acromegaly, their MOA and ADRs i. Pegvisomant (**Somavert**): GH Antagonist (GHA) **MOA** Binds to GH receptors in liver and inhibits IGF. Does not inhibit GH production, but block the physiologic effects of GH on the target tissues ---------- ------------------------------------------------------------------------------------------------------------------------------------------------ **ADRs** [Hepatoxicity], [↑ LFT], nausea, diarrhea, pain at injection site ii. Somatostatin Analogues (SSA) 1. Octreotide 2. Lanreotide **MOA** Inhibit GH and IGF1 ---------- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- **ADRs** Nausea, flatulence, gallstone, bradycardia, deficient in vitamin B12, chest pain, hyperglycemia in T2DM, severe hypoglycemia in T1DM, malaise, fever, [diarrhea/abdominal discomfort] (happen in 75%, but the episodes decrease after 10-14 days) iii. Dopamine Agonist (DA) 3. Bromocriptine (**Parlodel**) 4. Cabergoline **MOA** ↓ GH, ↓ IGF, ↓ PRL ---------- --------------------------------------------------------------------------------------------------------- **ADRs** Bromocriptine: [nausea], HA, [orthostatic hypotension], fatigue, abdominal pain a. [Dopamine]: drug of choice to treat micro- or macro-prolactinemia b. Useful in patients with pituitary tumor that secretes excess PRL and/or GH, or resistant to bromocriptine. It is a long-acting drug (t1/2 is 65hr) and have high selectivity c. [Use of DA]: hyperprolactinemia, Parkinson's disease, and acromegaly b. Identify relationship between DA, GH, prolactin, and acromegaly iv. Acromegaly is the abnormal growth of the hands, feet, and face due to the increased production of GH and IGF-1 during adulthood. Acromegaly is treated with DA along with GH antagonist and somatostatin analogs. v. Prolactin is a structure like GH. Prolactin is not regulated by negative feedback. The overproduction of prolactin is due to adenoma or the impaired transport of DA, which can cause a ↓ of estrogen. vi. DA inhibits the secretion of prolactin, which is why it is the drug of choice to treat micro- or macro- prolactinemia vii. DA, also known as stimulators of GH secretion in healthy subjects, acts as a suppressor of GH secretion in patients with acromegaly and has been used for medical therapy of acromegaly as well as prolactinoma. c. Identify MOA, ADRs, DDI of recombinant human growth factor viii. **Somatropin** +-----------------------------------+-----------------------------------+ | **MOA** | Acts to mimic and restore the | | | actions of endogenous growth | | | hormone of stimulating linear | | | bone growth, increasing bone | | | mass, increasing muscle and | | | reduced fat mass and regulating | | | blood glucose and lipid levels. | | | Somatropin mediates its effects | | | by both directly by somatropin | | | and indirectly by insulin-like | | | growth factor-1 (IGF-1). It binds | | | to the human GHR; upon binding of | | | growth hormone, GHR dimerizes and | | | interacts with Janus Kinase 2 | | | (JAK2). | +===================================+===================================+ | **ADRs** | Usually tolerated well, | | | [intracranial HTN]: | | | vision, HA, nausea, edema, | | | hypothyroidism, pancreatitis, | | | gynecomastia, myalgia, fluid | | | imbalance, pain at injection, ↑ | | | ALT and AST | +-----------------------------------+-----------------------------------+ | **DDI** | [Glucocorticoid may inhibit GH | | | effect]. [GH may | | | induce insulin resistance in DM | | | or cause | | | hyperglycemia] | +-----------------------------------+-----------------------------------+ | **Use** | Treat growth failure in | | | pediatric due to inadequate | | | endogenous GH secretion | | | | | | treat GH deficiency in adults | | | due to deficiency of GH or other | | | hormones (hypopituitarism), or | | | due to lean body wasting | +-----------------------------------+-----------------------------------+ d. Identify MOA, use of oxytocin and Atoxiban ix. Oxytocin **MOA** Act through G protein → to contract the uterus to induce labor. Contract mammary gland to cause "milk let down". E induce oxytocin receptor synthesis --------- ------------------------------------------------------------------------------------------------------------------------------------------------------- **Use** Induce labor x. **Atoxiban** (Oxytocin Antagonist) **MOA** Prevent uterine contraction and prevent preterm labor --------- ------------------------------------------------------- **Use** Prevent premature labor e. Identify drugs that can induce hyper-PRL xi. Antipsychotic (don't d/c psychoactive drugs), DA Antagonist, Metoclopramide, Tricyclic Antidepressant, MAOI, SSRI, H2 Blocker, Verapamil, Methyldopa f. Identify ADRs of glucocorticosteroids xii. If use oral for more than 2 weeks, can cause systemic ADRs to occur xiii. Need to taper off gradually before discontinuation, to prevent undesirable effects +-----------------------------------+-----------------------------------+ | **ADRs** | 1. **[Adrenal | | | Suppression]** | | | | | | a. If dose is reduced too | | | fast, symptoms of disease | | | may reappear and | | | intensify | | | | | | b. If take 2-12 month for | | | HPA axis to return to | | | normal, and cortisol | | | level may not return to | | | normal for another 6-9 | | | months | | | | | | 2. **[Hyperglycemia] | | | ** | | | | | | c. Causing lipolysis → free | | | fatty acids formation | | | | | | d. Stimulate gluconeogenesis | | | in the liver. ↑ serum | | | glucose, inhibit reuptake | | | of glucose by muscle | | | | | | 3. **[Hypertension and | | | hypokalemia]** | | | | | | e. ↑ Na+ and water | | | retention, ↑ secretion of | | | K+ | | | | | | f. Also ↑ vasopressin | | | release → ↓ ability to | | | excrete water load → HTN | | | | | | 4. **[Increased risk of | | | infection | | | (16-18%)]** | | | | | | g. Normal glucocorticoid | | | level is needed to | | | maintain glucose levels | | | to provide energy for the | | | body to fight stress due | | | to trauma or infection | | | | | | h. Cortisol cause ↓ | | | lymphocytes → ↓ body | | | ability to fight | | | infection | | | | | | 5. **[Osteoporosis]* | | | * | | | | | | i. Glucocorticoids alter | | | bone mineral homeostasis: | | | by antagonizing Vit | | | D-stimulated Ca2+ | | | transport, by stimulating | | | renal Ca2+ excretion (↓ | | | reabsorption osteoclast, | | | and by blocking bone | | | formation (↓ osteoblast | | | precursor) | | | | | | 6. **[Catabolic | | | effect]** | | | | | | j. Glucocorticoids causing ↑ | | | protein synthesis in | | | liver, but causing ↑ in | | | protein breakdown in | | | muscle, fat, and skin | | | | | | i. Myopathy (weakness of | | | proximal limb | | | muscles) | | | | | | ii. Excessive protein | | | catabolism and | | | protein wasting | | | | | | iii. Bruising, thinning | | | of skin | | | | | | 7. **[Behavioral changes: | | | depression, insomnia, | | | psychosis, | | | hypomania]** | | | | | | k. Direct effect on the | | | brain (neurosteroids). | | | Effect mood, neuron → | | | excitability behavior | | | | | | l. Withdrawal of | | | glucocorticoids causing | | | depression, hypomania | | | | | | 8. **[Peptic | | | ulcer]** | | | | | | m. Stimulates over | | | production of gastric | | | acid and pepsin in | | | stomach → exacerbate | | | ulcer | | | | | | n. Suppress local immune | | | response against H. | | | pylori, so H. pylori | | | become active | | | | | | 9. **[Weight gain]** | | | | | | o. Stimulate lipolysis → ↑ | | | fatty acid, ↑ fat | | | deposition | | | | | | p. ↑ serum glucose, inhibit | | | reuptake of glucose by | | | muscle. ↑ appetite | | | | | | 10. **[Glaucoma, | | | cataracts]** | | | | | | q. Intraocular pressure of | | | the eye | | | | | | 11. **[Iatrogenic Cushing | | | Syndrome]** | | | | | | r. Fat distribution in back | | | (buffalo), neck, face | | | (moon face). Metabolic | | | changes can become | | | serious: myopathy, | | | diversion of a.a to | | | glucose production, | | | hyperglycemia, | | | osteoporosis, and others | | | | | | 12. **[Growth Retardation | | | ]** | | | | | | s. During skeletal growth | | | phase, activity of | | | osteoblast predominates. | | | Glucocorticoids decrease | | | osteoblast precursors | | | | | | t. Natural glucocorticoids | | | have less growth | | | suppressing potency than | | | synthetic, even at the | | | "at equivalent doses" | +-----------------------------------+-----------------------------------+ g. State MOA, drug classes, ADRs, and DDI of drugs to treat Cushing Syndrome xiv. Aminoglutethimide (**Cytadren**) **MOA** Inhibit cholesterol desmolase (1^st^ step in synthesis of cholesterol) it can inhibit aromatase, but no specific ---------- ------------------------------------------------------------------------------------------------------------------ **ADRs** [Sedation], nausea, skin rash, [anorexia] (administer Q 6 hr) **DDI** ↓ warfarin effect, ↑ efficacy and less ADRs when used with metyrapone (use lesser dose of aminoglutethimide) xv. Metyrapone (**Metopirone**) **MOA** Inhibit the last step of cholesterol synthesis. Steroidogenesis inhibitor ---------- -------------------------------------------------------------------------------------------------------------------- **ADRs** [Nausea], [sedation], hypertension, hirsutism, acne (↑ androgen), salt and water retention **DDI** n/a xvi. Ketoconazole (**Nizoral**) **MOA** Steroidogenesis inhibitor (at very high dose) ---------- ------------------------------------------------------------------------------------------------------------------------- **ADRs** [↓ T, ↓ libido], ↑ hepatic enzyme, [gynecomastia], [nausea], [vomiting] **DDI** Many serious interaction xvii. Osilodrostat (**Isturisa**) **MOA** Inhibitor of 11-beta-hydroxylase enzyme which is crucial for the cortisol biosynthesis (steroidogenesis inhibitor) ---------- ------------------------------------------------------------------------------------------------------------------------------- **ADRs** [Adrenal insufficiency], [fatigue], [nausea], [headache], [edema] **DDI** [CYP3A4 inducer and inhibitor], [CYP2D6 inducer] xviii. Mifepristone (**Korlym**, **Mifeprex**) **MOA** Anti-progesterone, but also work as glucocorticoid receptors antagonist (potential agent to block excessive glucocorticoids) ---------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------- **ADRs** Vomiting, diarrhea, pain, excessive vaginal bleeding, [abdominal] [and uterine cramping], [nausea], [hypokalemia] **DDI** n/a xix. Cyproheptadine (**Periactin**) **MOA** Central neuromodulators that works to ↓ ACTH release ---------- ------------------------------------------------------ **ADRs** Sedation, hyperphagia, anti-cholinergic **DDI** n/a xx. Mitotane (**Lysodren**) **MOA** Adrenocytotoxic, ↓ cortisol production → adrenal inhibition without causing cellular destruction. Selectively attacks adrenal cortex cells/[cytotoxic] (significant harm to patient if handled improperly) ---------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ **ADRs** Lethargy, rash, [CNS depression], [nausea], [vomiting] **DDI** n/a h. Identify MOA, and use and ADRs of spironolactone xxi. Spironolactone **MOA** Block mineralocorticoid receptors (MR) → prevent formation of aldosterone-induced proteins (AIPs) → indirectly ↓ Na+ channel permeability → ↓ Na+ reabsorption, ↑ K+ retention, inhibit aldosterone action ---------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ **Use** Cushing syndrome (for symptomatic relief of HTN and hypokalemia), aldosteronism (inhibit aldosterone biosynthesis in adrenal gland, ↓ HTN), diagnosis tool to detect aldosteronism, treatment of hirsutism in women, Heart Failure **ADRs** [Hyperkalemia], [metabolic acidosis], [gynecomastia], GI discomfort, fatigue, menstrual irregular, hypotension i. Identify drugs useful to treat Addison and how to take the drugs xxii. Corticosteroids to mimic endogenous level: hydrocortisone, cortisone, or prednisone. Lowest dose to prevent ADRs 5. [Agent of Choice]: hydrocortisone 15-20 mg PO at a.m. and 10 mg PO at 4:00-5:00 p.m. Administration should mimic endogenous cortisol production. Majority of total daily dose (67&) given in a.m., remainder (33%) given in p.m. xxiii. Mineralocorticoids to prevent hyperkalemia: fludrocortisone 6. [Agent of Choice]: fludrocortisone acetate 50-200 mcg/day 7. Do not consume \> 3-4 gm of sodium per day xxiv. ↑ energy and libido: DHEA supplementation, use 25-50 mg/day 8. Optional use for improvement in energy level and libido in females