Basic Pharmacology

ENDOCRINE PHARMACOLOGY

GROWTH HORMONE (GH)

• ANABOLIC EFFECTS:
  • Increases amino acid uptake into tissues.
  • Enhances protein synthesis.
• CATABOLIC EFFECTS:
  • Antagonizes insulin after it's been around for some time: impairs glucose uptake and promotes lipolysis.
  • GH can thus be Diabetogenic for people with Diabetes.
    
     

THYROID HORMONE

• Synthesis of Thyroid Hormone: Thyroglobulin is synthesized in the Thyroid follicular cells and secreted into the lumen of the follicles.
  • Iodide is taken into the thyroid follicular cells from the general circulation, and it is transcytosed to the apical membrane.
    • This transport occurs by active Na⁺-Cotransport
  • ORGANIFICATION: The process of iodinating the thyroxines, forming MIT and DIT, and then forming T₃ and T₄.
    • On the outside of the membrane, in the lumen, peroxidase catalyzes the oxidation of iodide and its attachment to Thyroglobulin, forming Mono-iodothyronine (MIT) and di-iodothyronine (DIT).
    • MIT and DIT then join to form T₃ and T₄
    • This process is blocked by the Thionamides
• Biological Effect:
  • Tri-iodothyronine (T₃): Formed by joining MIT + DIT
    • It is far more potent and has the principal biological effects: increase transcription at target cell, and exhibit negative feedback at pituitary.
    • Very little of it (5�g / day) is released from the Thyroid. The rest is made by converting T₄ ------> T₃ in the peripheral blood.
    • T₃ is carried, in part, by TBG in the blood. However, T₄ binds more tightly to TBG than does T₃.
  • Thyroxine (T₄): Formed by joining DIT + DIT
    • It is far less potent than T₃. It has little biological effect in itself and is more of a "pro-hormone."
    • It is released, in quantity, by the Thyroid, where it then binds to TBG in the blood. It is slowly converted to T₃ in the periphery.
    • It binds more tightly to TBG then does T₃.
    • It has a longer half-life, so it sticks around longer than T₃.
• HYPOTHYROIDISM: Myxedema.
  • TYPES:
    • PRIMARY HYPOTHYROIDISM: Deficiency of Thyroxine itself. Goiter is present, due to increased TSH.
      • TSH will be high and T₄ will be low.
      • TRH Test: Give TRH, and TSH will show a hypersensitive response and shoot way up.
    • SECONDARY HYPOTHYROIDISM: No goiter is present.
      • TSH will be low and T₄ will be low.
      • TRH Test: Give TRH, and TSH will remain low and show little or no response.
    • TERTIARY HYPOTHYROIDISM:
      • TSH is low, initially, and T₃ is low.
      • TRH Test: Give TRH, and TSH will show a delayed response before it finally kicks in and increases somewhat.
  • Cretinism: Childhood hypothyroidism, which leads to retarded growth and mental retardation if not treated.
  • CAUSES:
    • Idiopathic
    • Hashimoto's Thyroiditis
    • Treatment of Hyperthyroidism with radio-iodine, ¹³¹I.
  • SYMPTOMS: Weakness, shallow respiration, puffy face, frowsy hair.
• HYPERTHYROIDISM: Thyrotoxicosis.
  • SYMPTOMS: Hypertension, tachycardia, hypermetabolism, irritability
  • Thyroid Storm: Acute hyperthyroid crisis, which can be deadly.
  • CAUSES:
    • Grave's Disease: Auto-immune stimulation of TSH receptors. You do see exophthalmos.
    • Toxic Nodular Goiter: There is no exophthalmos.
  • TREATMENT:
    • Thionamides: Inhibit organification of iodine.
      • Has a delayed effect, because thyroglobulin stores must first be used up before the effect is seen.
    • Ionic Inhibitors: Inhibit uptake of iodine.
    • Surgery
    • Radio-iodine, ¹³¹I: Diffusely kills thyroid cells. Resulting in eventual and inevitable hypothyroidism.
    • Iodide: Temporarily (early on) inhibits proteolysis of thyroglobulin, preventing freeing of thyroxine. Effect wears off. Used to treat Thyroid Storm.
      • Often given in preparation for an operation, as it makes the thyroid gland firm and shrink up.
        
         

ADRENAL HORMONES:

• MINERALOCORTICOID SYNTHESIS: 21beta-Hydroxylase is required for synthesis.
  • Cholesterol ------> Pregnenolone ------> Progesterone
  • Progesterone ------> 11-Deoxycorticosterone (21beta-Dehydroxylase)
  • 11-Deoxycorticosterone ------> Corticosterone ------> Aldosterone
• CORTICOSTEROID SYNTHESIS: 21beta-Hydroxylase, 17alpha-Hydroxylase and 11beta-Hydroxylase are required for synthesis.
  • Cholesterol ------> Pregnenolone
  • Pregnenolone ------> Progesterone ------> 17alpha-Hydroxyprogesterone (21beta-Hydroxylase, 17alpha-Hydroxylase)
  • 17alpha-Hydroxyprogesterone ------> 11-Deoxycortisol
  • 11-Deoxycortisol ------> Cortisol (11beta-Hydroxylase)
• SEX HORMONE PATHWAY:
  • Cholesterol ------> Pregnenolone ------> Dehydroepiandrostenedione (DHEA) ------> Androstenedione ------> Testosterone
  • Testosterone ------> Estradiol (Aromatase)
  • Estrogen <====> Estriol <====> Estradiol <====> Estrone
• 21beta-Hydroxylase Deficiency: You see reduced Cortisol ------> excess ACTH ------> adrenal hyperplasia.
  • You also see a buildup of the metabolic precursors.
    • Buildup of progesterone and 17alpha-hydroxyprogesterone
    • Buildup of Androstenedione ------> lots of androgens hanging around ------> feminine virilization.
  • TREATMENT: Cortisol will relieve the ACTH and the adrenal hyperplasia, and will replace deficient Cortisol. Sometimes you also have to give mineralocorticoid, but usually there is some residual aldosterone activity.
    
     

CORTISOL

• METABOLITES: 17-hydroxycorticosteroids are the metabolic byproducts of Cortisol. They can be measured in the urine, in order to monitor Cortisol levels in the blood.
• REGULATION: Cortisol, ACTH, CRH, negative feedback, etc. etc.
  • CRH: There is a diurnal rhythm of release of CRH, which results elevated levels of Cortisol in the early morning hour.
  • None of the steroids are stored in the adrenals. They are synthesized on demand and released immediately. Lipophilic substances don't easily fit into vesicles!
• INDICATIONS:
  • Adrenal insufficiency (Addison's Disease)
  • Inflammatory, non-infectious processes of all sorts: Arthritis (all types), auto-immune diseases, Asthma, diseases of the eye.
• CONTRAINDICATIONS / ADVERSE EFFECTS:
  • You must taper off the dose of Cortisol slowly, to allow the patient to adjust. If you withdraw the drug quickly, you will see adrenal insufficiency.
    • ADRENAL ATROPHY: Giving exogenous corticosteroids ------> suppressed ACTH ------> adrenal gland atrophy.
  • Don't use with infections.
  • Because of their side-effects (see Effects below), use with caution in case of Diabetes, CV disease, HTN, psychoses, glaucoma, and osteoporosis.
• EFFECTS:
  • ANTI-INFLAMMATORY: Corticosteroids are the most potent anti-inflammatories available.
    • Effects on Protein Synthesis:
      • Cortisol promotes synthesis of proteins called Lipocortins ------> inhibit Phospholipase-A₂ ------> inhibit production of arachidonic ------> inhibit leukotrienes and prostaglandins.
      • Cortisol inhibits the protein-translation of Inducible Cyclooxygenase II (COX-II) ------> inhibit prostaglandins and thromboxanes.
    • Physiologic Effects:
      • Cortisol has a negative effect on lymphocytes, monocytes, and macrophages. It inhibits release of cytokines, IL-1, IL-2, and IL-6, and TNF-alpha.
        • There is feedback inhibition here, too, because these cells normally have a stimulatory effect on the hypothalamus (CRH) and pituitary (ACTH). When these cells are then inhibited by Cortisol, then the extra stimulus is gone.
      • Reduced migration of inflammatory cells to site of injury.
      • Increased susceptibility to infection.
      • Decreased lymphocyte production.
      • Impairment of DTH (Delayed-Type Hypersensitivity) reactions.
  • PERMISSIVE EFFECTS: The presence of glucocorticoids is required for certain events to take place:
    • The actions of catecholamines on smooth muscle (contraction) and on fat cells (lipolysis).
  • TISSUE EFFECTS:
    • Inhibit fibroblasts ------> connective tissue loss and thinning of skin.
    • Negative Ca⁺² balance ------> osteoporosis.
      • Ca⁺² and Vit. D absorption in the intestine is decreased ------> increased PTH ------> Ca⁺² is lost from bones.
    • Negative nitrogen balance
    • Cardiovascular effects: Increased blood pressure, heart-rate, and TPR. Cross-reactivity with Aldosterone leads to increased Na⁺ retention.
    • CNS: Euphoria, psychosis, behavioral changes, lost cognitive function.
    • GI: Increase stomach acid and pepsin production, which can lead to peptic ulcer.
    • Electrolyte balance: Aldosterone cross-reactivity causes higher Na⁺ and lower K⁺. This can lead to hypokalemia, salt retention, and metabolic alkalosis.
  • METABOLIC EFFECTS: Basically, hyperglycemia, plus any other effects that would increase the amount of glucose delivered to the brain.
    • Gluconeogenesis.
    • Insulin release and glycogen deposition. Glucose use is diverted from the periphery and used centrally.
    • Protein catabolism
    • Uptake of fat by fat cells. Deposition of fat occurs in other places (Buffalo hump)
• CUSHING'S DISEASE: Cushing's disease is Secondary Hypercorticism. ACTH is high in Cushing's Disease.
  • Cushing's Syndrome, on the other hand, describes the general cluster of symptoms attributable to adrenal hyperfunction.
  • If ACTH is low and Cortisol is high, then there is probably a steroid producing tumor somewhere, such as in the adrenal gland, or ectopically, in another location. On the other hand, if ACTH levels are high, then it is Cushing's Disease.
  • SYMPTOMS / CHARACTERISTICS:
    • Moon Facies.
    • Redistribution of fat away from extremities toward the center.
    • Buffalo Hump
    • Bruising, poor wound healing, osteoporosis.
    • Increased susceptibility to infection.
    • Hyperglycemia
• ADRENAL INSUFFICIENCY (ADDISON'S DISEASE):
  • SYMPTOMS:
    • Weakness, fatigue
    • Weight loss, anorexia
    • Hypotension
    • Hypoglycemia
    • Hyperpigmentation: ACTH is derived from pre-opiomelanocortin, the same precursor that Melanocyte Stimulating Hormone (MSH).
      • High ACTH can show some cross-reactivity with melanocytes, resulting in hyperpigmentation.
  • ACTH Test: Give ACTH and measure Cortisol levels, to distinguish between primary and secondary adrenal insufficiency.
    • PRIMARY INSUFFICIENCY: Give ACTH ------> Cortisol levels remain low. Also, you should see normal or high ACTH levels to start with.
    • SECONDARY INSUFFICIENCY: Give ACTH ------> Cortisol levels shoot up.
      • Metyrapone Test: Confirmatory test for secondary adrenal insufficiency. Give Metyrapone to inhibit 11beta-Hydroxylase and therefore inhibit Cortisol synthesis. Normally, this blocking of Cortisol synthesis should result in high ACTH levels. If Metyrapone does not yield high ACTH levels, then we know the problem is secondary.