Endocrine Drugs Pharmacological Review

Endocrine Physiology and Hormonal Feedback Loops

• Mechanism of Hormone Regulation:

  • Endocrine hormones operate via negative feedback loops ($-$ feedback loop).

• Thyroid Diagnostic Parameters:

  • Hyperthyroidism: Characterized by decreased Thyroid-Stimulating Hormone ($\downarrow \text{TSH}$) and increased Total Thyroxine ($\uparrow \text{TT4}$).

  • Hypothyroidism: Characterized by increased Thyroid-Stimulating Hormone ($\uparrow \text{TSH}$) and decreased Total Thyroxine ($\downarrow \text{TT4}$).

• Pathophysiology of Diabetes Mellitus:

  • Type 1 Diabetes Mellitus ($\text{T1DM}$): Characterized by pancreatic dysfunction where the pancreas does not function properly; traditionally referred to as juvenile-onset diabetes.

  • Type 2 Diabetes Mellitus ($\text{T2DM}$): Characterized by functional pancreatic beta cells accompanied by peripheral insulin resistance; traditionally referred to as adult-onset diabetes.

• General Principles of Oral Hypoglycemic Pharmacotherapy:

  • A substantial variety of oral hypoglycemic agents exists.

  • Essential study focus must be dedicated to identifying serious side effects, contraindications, and specific mechanisms of action.

Oral Antidiabetic Medications

• Sulfonylureas:

  • Drug Class Representative: Glipizide.

  • Approved Indication: Type 2 Diabetes Mellitus ($\text{T2DM}$) ONLY.

  • Mechanism of Action: Stimulates pancreatic beta cells to secrete endogenous insulin.

  • Administration Guidelines: Administer orally $30\,\text{min}$ prior to meals.

  • Adverse Effects & Clinical Risks: Hypoglycemia. Risk is significantly increased in patients presenting with renal or hepatic impairment.

• Meglitinides:

  • Drug Class Representative: Repaglinide.

  • Mechanism of Action: Stimulates pancreatic beta cells to secrete endogenous insulin (same mechanism as sulfonylureas).

  • Pharmacokinetics: Reaches peak plasma concentration in $1\text{--}2\,\text{hr}$.

  • Administration Guidelines: Administer $3\times \text{day}$, $30\,\text{min}$ prior to meals. Patients must skip the dose if a meal is skipped.

  • Adverse Effects: Hypoglycemia.

• Biguanides:

  • Drug Class Representative: Metformin.

  • Mechanism of Action: Lowers blood glucose levels through $3$ distinct physiological pathways.

  • Adverse Effects: Fatigue and gastrointestinal (GI) upset.

  • Black Box Warning & Adverse Events: Monitor closely for lactic acidosis.

  • Perioperative / Diagnostic Warnings: Withhold medication for $48\,\text{hours}$ prior to and $48\,\text{hours}$ following procedures requiring iodinated contrast dye.

• Thiazolidinediones (TZDs):

  • Drug Class Representative: Pioglitazone.

  • Approved Indication: Type 2 Diabetes Mellitus ($\text{T2DM}$).

  • Absolute Contraindications: Heart Failure ($\text{HF}$).

  • Adverse Effects & Monitoring: Causes fluid retention. Perform daily weight measurements to monitor fluid status.

• Alpha-Glucosidase Inhibitors:

  • Drug Class Representative: Acarbose.

  • Mechanism of Action: Decreases intestinal carbohydrate absorption.

  • Administration Guidelines: Administer $3\times \text{day}$ with meals, specifically taken with the very first bite of food.

  • Adverse Effects & Monitoring: Hepatotoxic. Monitor liver enzyme levels closely and instruct patients to report jaundice immediately.

• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors:

  • Drug Class Representative: Sitagliptin.

  • Mechanism of Action: Increases endogenous insulin release.

  • Drug Interactions: May increase serum digoxin levels ($\uparrow \text{digoxin}$).

  • Contraindications & Co-administration Warnings: Cannot be co-administered with beta blockers, salicylates, Monoamine Oxidase Inhibitors (MAOIs), or Selective Serotonin Reuptake Inhibitors (SSRIs).

• Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors:

  • Drug Class Representative: Empagliflozin.

  • Mechanism Requirements: Understand exact renal mechanism of glucose excretion.

  • Clinical Monitoring: Monitor baseline and ongoing kidney function.

  • Contraindications: Contraindicated in patients with kidney disease, advanced renal dysfunction, or those undergoing dialysis.

• Dopamine Receptor Agonists:

  • Drug Class Representative: Bromocriptine.

  • Therapeutic Role: Used strictly as an adjunct therapy; not to be administered as a standalone monotherapy.

  • Adverse Effects & Monitoring: Monitor for dizziness, drowsiness, and hypotension. Psychosis represents a rare adverse effect.

Parenteral Antidiabetic Therapies and Insulin Management

• General Principles of Insulin Therapy:

  • Mechanism of Action: Directly stimulates cellular uptake of glucose across peripheral tissues.

  • Route of Administration: Standard route is Subcutaneous ($\text{SubQ}$). Regular insulin is the specific formulation approved for Intravenous ($\text{IV}$) administration.

  • Required Knowledge: Memorize onset, peak, and duration for every standard insulin formulation.

  • Key Definitions & Indications: Postprandial refers to the period after eating. Rapid-acting insulins are administered relative to meals. Regular insulin given IV is indicated for Diabetic Ketoacidosis ($\text{DKA}$).

  • Dual-Insulin Mixing Protocol:

  1. Inject air into the NPH (cloudy) insulin vial equal to the dose.

  2. Inject air into the Regular (clear) insulin vial equal to the dose.

  3. Draw up the desired dose from the Regular (clear) insulin vial first.

  4. Draw up the desired dose from the NPH (cloudy) insulin vial second (Clear to Cloudy order).

  • Injection Site Management: Systematically rotate SubQ injection sites to prevent lipodystrophy.

• Management of Hypoglycemia:

  • Conscious Patient Protocol:

  • Immediately administer $15\,\text{g}$ of fast-acting oral carbohydrates/sugar.

  • Follow up oral sugar administration with a complex protein source.

  • Unconscious Patient Protocol:

  • Administer parenteral hyperglycemic agents (e.g., Glucagon) via Intravenous ($\text{IV}$), Intramuscular ($\text{IM}$), or Subcutaneous ($\text{SubQ}$) routes.

  • Once the patient regains consciousness and is fully awake, administer oral carbohydrates.

Non-Insulin Injectable Agents

• Amylin Mimetics:

  • Drug Class Representative: Pramlintide.

  • Mechanism of Action: Synthetic analogue that mimics endogenous amylin to slow gastric emptying.

  • Administration Guidelines: Administer Subcutaneously ($\text{SubQ}$) prior to major meals containing at least $30\,\text{g}$ of carbohydrates.

  • Adverse Effects: Severe risk of hypoglycemia.

• Incretin Mimetics (GLP-1 Receptor Agonists):

  • Drug Class Representative: Exenatide.

  • Mechanism of Action: Slows gastric emptying.

  • Adverse Effects & Patient Education: Associated with acute pancreatitis. Instruct patients to report abdominal pain symptoms immediately.

Thyroid and Antithyroid Pharmacotherapy

• Thyroid Hormone Replacement:

  • Drug Class Representative: Levothyroxine.

  • Approved Indication: Hypothyroidism.

  • Toxicity & Overdose: Excessive dosing results in signs and symptoms of hyperthyroidism.

  • Administration Guidelines: Requires lifelong, daily treatment. Take on an empty stomach $30\text{--}60\,\text{min}$ prior to eating breakfast.

• Antithyroid Agents:

  • Drug Class Representatives: Propylthiouracil (PTU) and Methimazole.

  • Approved Indication: Hyperthyroidism.

  • Mechanism & Over-treatment: Decreases thyroid hormone synthesis across every cell. Excessive suppression yields signs and symptoms of hypothyroidism.

  • Severe Adverse Effects: Risk of agranulocytosis and severe hepatotoxicity.

  • Diagnostic Monitoring: Monitor Complete Blood Count ($\text{CBC}$) and liver function panel labs.

  • Patient Education: Instruct patients to immediately report fever or sore throat (early signs of agranulocytosis), as well as dark urine or jaundice (signs of hepatotoxicity).

  • Contraindications: Contraindicated in patients with pre-existing immunosuppression or liver dysfunction.

• Radiopharmaceuticals & Iodine Therapy:

  • Therapeutic Agent: Radioactive Iodine / Iodine compounds.

  • Therapeutic Onset: Requires $2\text{--}3\,\text{months}$ to achieve full clinical effect.

  • Adverse Effects & Monitoring: Monitor blood labs for bone marrow suppression and observe for signs of radiation sickness.

Anterior and Posterior Pituitary Hormones

• Growth Hormone Replacement (Anterior Pituitary):

  • Drug Class Representative: Somatropin.

  • Mechanism of Action: Mediated by Insulin-like Growth Factor 1 ($\text{IGF-1}$) to promote somatic growth.

  • Administration Guidelines: Administer Subcutaneously ($\text{SubQ}$). Must be administered strictly prior to epiphyseal plate closure.

  • Adverse Effects: Hyperglycemia.

• Antidiuretic Hormone Replacement (Posterior Pituitary):

  • Drug Class Representatives: Vasopressin and Desmopressin.

  • Approved Indication: Diabetes Insipidus ($\text{DI}$).

  • Adverse Effects & Contraindications: Causes severe water intoxication. Avoid administration in patients with renal failure.

Adrenal Cortex Hormones

• Glucocorticoids:

  • Drug Class Representatives: Hydrocortisone, Prednisone, Dexamethasone.

  • Therapeutic Indications: Hydrocortisone is used for hormone replacement in adrenal insufficiency. Hypercortisolemia is categorized as Cushing's syndrome (know signs and symptoms of Cushing's).

  • Abrupt Withdrawal Warning: Stopping therapy abruptly precipitates a life-threatening Adrenal Crisis!

  • Long-Term ($\text{LT}$) Administration Risks: Chronic usage leads to hyperglycemia, osteoporosis, and immunosuppression.

• Mineralocorticoids:

  • Drug Class Representative: Fludrocortisone.

  • Mechanism of Action: Directly replaces endogenous aldosterone.

  • Adverse Effects & Clinical Monitoring: Monitor closely for signs of fluid overload and hypokalemia.