Module 11 - PP Endocrine

Endocrine Pharmacology Overview

• The endocrine system, along with the nervous and immune systems, regulates bodily functions.
• Glands secrete hormones that travel to distant sites, or act on adjacent (paracrine), original (autocrine), or internal (intracrine) sites.
• Endocrine hormones regulate physiologic responses, initiate signal transduction by binding membrane receptors.
• Hormones activate cellular 2nd messengers and regulate gene expression.
• Hormone dysfunction can manifest as excess, deficiency, or resistance.
• Key Endocrine Glands: Pituitary, thyroid, pineal, thymus, hypothalamus, pancreas and adrenals

Endocrine System: Hypothalamus-Pituitary Review

• The hypothalamus regulates thirst, hunger, the autonomic nervous system, circadian rhythms, body temperature, blood pressure, breastfeeding, learning, memory, sexual drive, and emotional expression.
• It produces hormones like TRH, CRH, GnRH, GHRH, somatostatin, dopamine, vasopressin, and oxytocin.
• Hypothalamic disorders include genetic conditions like Kallman syndrome and Prader-Willi syndrome, hypothalamic obesity, diabetes insipidus, and SIADH.
• Increased cAMP levels from GPRO activation leads to secretory release of pituitary hormones

Pituitary Gland Hormones

• Anterior pituitary hormones: growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, thyroid-stimulating hormone, and beta-lipotropin.
• Posterior pituitary hormones: arginine vasopressin and oxytocin.
• Growth hormone stimulates tissue growth, cell proliferation, protein synthesis, lipolysis, and retention of sodium and water, stimulated by stress and inhibited by pregnancy.
• Adrenocorticotropic hormone regulates cortisol and androgen secretion, with high levels in the AM and low in the PM.

Hypothalamic-Pituitary-Adrenal Axis

• In Cushing's disease/syndrome, tumors or drugs can cause increased hormone (ACTH) and cortisol levels, leading to weight gain, high blood pressure, and thinning bones.
• Thyroid-stimulating hormone accelerates thyroid hormone formation, stimulated by low T3, T4, and calcitonin.
• High Cortisol inhibits the release, and Stress & SNS stimulation inhibits the release of thyroid-stimulating hormone

Arginine Vasopressin (AVP)

• Arginine Vasopressin is produced in the hypothalamus.
• Stored in secretory granules in the posterior pituitary for release.
• AVP acts to vasoconstriction, water retention, and corticotropin secretion.
• It is stimulated by increased plasma osmolarity, hypovolemia, and HOTN
• It is inhibited by decreased osmolarity, cortisol, hypothermia, and ethanol.
• Treats central diabetes insipidus by reducing water loss due to hypernatremia, neurotrauma, pituitary and hypothalamic surgery, and cerebral malignancy.

Vasopressin and Oxytocin

• V1 receptor activation by vasopressin increases intracellular Ca2+ release, causing vasoconstriction and ACTH release.
• Vasopressin adverse effects include coronary ischemia, dysrhythmias, and increased gastrointestinal peristalsis.
• Oxytocin stimulates uterine smooth muscle contraction for inducing labor and reducing postpartum hemorrhage.
• Oxytocin binds to G protein receptors to release Phophatidyl insitol and Calcium
• High doses of Oxytocin can cause decreases in SBP, DBP, venous return, CO and reflex tachycardia, arrhythmias.
• Neonatal risks are fetal hypoxia, hypercapnia, jaundice, and low Apgar scores

Pancreas & Glucose Regulation

• The pancreas contains alpha, beta, and delta cells that secrete hormones.
• Alpha cells secrete glucagon, which mobilizes glucose and fatty acids, metabolized by the liver.
• Glucagon release is increased by stress and beta agonists, and decreased by hyperglycemia and insulin.
• Beta cells secrete insulin to promote glucose, fatty acid, and amino acid storage and hepatic & renal metabolism.
• Stimuli that increase insulin release are Hyperglycemia, Beta agonists and Acetylcholine
• Stimuli that decrease insulin release: Hypoglycemia, Alpha agonists and Insulin.

Diabetes Mellitus

• Diabetes mellitus affects 11.3% of the US population.
• Type 1 is an autoimmune disorder involving destruction of pancreatic beta cells.
• Type 2 involves pancreatic beta cell dysfunction and insulin resistance.

Insulin Pathophysiology and Effects

• Absent insulin can lead to lipolysis, excess ketones, and low insulin levels.
• Low insulin or resistance results in hyperglycemia and proinflammatory and prothrombotic conditions.
• Physiologic effects of insulin promote glucose uptake and storage and inhibit lipase and protein degradation.
• Insulin increases the activity of glucokinase and the permeability of muscule membranes
• Rapid elimination of insulin is 5-10 min..

Diabetes and Surgical Stress Response

• Surgical stress induces release of epinephrine, glucagon, cortisol, growth hormone, and inflammatory cytokines.
• Risks include insulin resistance, decreased glucose utilization, lipolysis, protein catabolism, and hyperglycemia.
• General anesthesia and surgery type exacerbate this response.
• A1C levels and Glucose levels indicate severity elevated risk
• Macrovascular/microvascular and cardiovascular risks are concerns with neuropathy

Insulin Therapy

• Consists of slow, long-acting and rapid, short-acting insulins.
• Lispro and insulin aspart are short-acting, paralleling physiologic insulin secretion before meals.
• NPH is intermediate-acting, while glargine and detemir are long-acting for basal replacement.
• Regular insulin (Humulin R) addresses abrupt hyperglycemia and ketoacidosis.

Perioperative Insulin Management

• Consider correctional insulin if a patient needs glucose management protocol with typical glucose goals.
• Administered subcutaneously for shorter surgical durations, and anticipate hemodynamic stability.
• Intravenous insulin is used for longer surgical durations involving hemodynamic fluctuations, massive fluid shifts, or critical illness.
• Infusion includes short half-life allowing for rapid dose adjustments
• Hypoglycemia can occur

Oral Diabetes Medications

• Metformin is a first-line biguanide that lowers glucose and improves lipid profiles with rare hypoglycemia.
• Metformin can cause Gl disturbances or VitB12 deficiency and is held because of lactic acidosis risk.
• Sulfonylureas lower BG by inhibiting K+-ATP channels, but carry a high risk of therapy failure and severe hypoglycemia.
• Thiazolidinediones increase insulin sensitivity, but risk edema, weight gain, and liver dysfunction.
• GLP-1 drugs act to increase beta cells.

GLP-1 Agonists

• Increase beta cell insulin secretion and decrease alpha cell glucagon production, increasing satiety.

Thyroid Gland and Hormones

• The thyroid gland is composed of two lobes connected by an isthmus, storing thyroglobulin and thyroid hormones.
• Thyroid hormones (T3 and T4) maintain metabolism for tissue function.
• T3 increases metabolism and oxygen consumption, protein catabolism
• Feedback loop involves hypothalamus, pituitary, and hormones

Pharmacology of the Thyroid

• T3 & T4 are synthesized from tyrosine.
• T3 is more active than T4 and has a shorter half-life.
• Calcitonin is a polypeptide hormone that inhibits osteoclasts and promotes the use of Calcium from plasma.
• Hyperthyroidism is excess TH with Grave's and Hashitoxicosis
• Hypothyroidism prevalence is 11.7% where the gland does not produce enough.
• The first line hypothyroidism management is Levothyroxine

Treatment of Thyroid Conditions

• Levothyroxine is a synthetic thyroxine to be converted to T3 in peripheral tissue.
• Liothyronine is a synthetic isomer more potent than levothyroxine
• Thionamides inhibit thyroid peroxidase to reduce TH synthesis.
• Higher risks exist when the surgical manipulation of the thyroid occurs
• Arrythmias, Ischemia and beta-blockage is required

Adrenal Cortex

• Adrenal cortex secretes hormones like corticosteroids derived from cholesterol.
• Steroid hormones include mineralocorticoids, glucocorticoids, androgens and estrogens.
• Mineralocorticoids (aldosterone) promotes fluid and electrolyte balance by increasing sodium reabsorption.
• Glucocorticoids (cortisol) stimulates storage as glycogen.

Cortisol and HPA Axis

• Cortisol release is episodic, following a sleep-wake cycle and stress-induced.
• Cortisol can cause Excitability and mood changes and can reduce Bone remodeling.
• Synthetic corticosteroids are use to release immune cells and come in diffent dosage.
• Endogenous Cortisol release triggers in the Hypothalamus and pituitary gland.
• Stress/trauma induces -HORMONE release Adrenal -Cortisol.

Adrenal Insufficiency

• Adrenal insufficiency is a condition resulting from insufficient hormone production. Primary causes are Localized adrenal gland problem.
• Exogenous glucocorticoid use is also a cause
• Adrenal glands do not produce sufficient steroid hormones during Addison's disease.
• It can cause LOW blood pressure.

Mechanisms and Considerations of Corticosteroids

• Corticosteroids bind cytoplasmic receptors and regulate DNA transcription.
• Anti-inflammatory and immunosuppressive.
• HPA axis suppression can stem from Steriod dose, duration.
• For Longterm treatment, corticosteroids can cause electrolyte imbalance, metabolic or skeletal change, and CNS dysfunction