Endocrine System

Disorders and Drugs

 Definititions
• Endocrine: secretes into blood
• Exocrine: secretes into epithelial surfaces
• Hormone: product secreted by endocrine
gland
– Autocrine: affects cell that secreted it
– Paracrine: affects nearby cells
 Endocrine Organs
• Hypothalamus • Pancreatic Islets
• Pituitary • Ovaries
• Pineal • Testes
• Thyroid
• Other
• Parathyroid
– Heart
• Thymus
– Kidneys
• Adrenals
– Endothelium
 Mechanisms of Hormonal Control
• Rhythms of Release
– Diurnal, Pulsatile-cyclical, Substrate level
• Feedback systems: +,-
• Act only on cells with appropriate
receptors—alter cell action/metabolism
• Elimination: kidneys excrete or liver
metabolizes
• Under control of nervous system, but in
turn influence nervous system
 Hormone Structural Classes
• Water Soluble
– Peptides
– Glycoproteins
– Polypeptides
– Amines
• Lipid soluble
– Steroids (cholesterol derivatives)
– Arachidonic derivatives
 Hormone Transport
• Targets
– Autocrine – affect cell that released hormone
– Paracrine – affect nearby cells
– Endocrine – affect distant cells
• Transport
– Water soluble travel unbound
– Lipid soluble are mostly bound to carrier
proteins
 Hormonal Mechanisms of Action
• Receptors:
– Location: Surface (membrane), Internal
– Affinity
• Activation effects
– Change membrane permeability by affecting
existing channel proteins
– Activate existing proteins via second
messenger
– Stimulate synthesis of new proteins
 Thyroid
• Two thyroid hormones
– T4 (thyroxine), T3
– Must have iodine to synthesize
• Effects
– Stimulation of energy use (Na/K pump)
• ↑O2 use, higher body temp
– Stimulation of heart
• ↑HR, ↑contraction
– Promotion of growth and development
• Maturation of nervous and muscle tissue
 Fate of Thyroid Hormones
• Fate of thyroid hormones
– More T4 released than T3
– T4 is converted to T3 by enzymes in
peripheral tissues
– 99.5% of both are bound to plasma proteins
• Hepatic metabolism
• Half-life
– T3: 1.5 days
– T4: 7 days
 Regulation of Thyroid Hormone
• Hypothalamus – TRH
• Stimulates:
• Anterior Pituitary – TSH
• Stimulates:
• Thyroid: T3, T4
• Inhibits:
• Anterior -TSH
 Influence of Iodine
• Not enough iodine
– Thyroid enlarges: goiter
– Increases ability to absorb iodine
– Compensation may be enough to keep T4, T3
at normal levels
• Too much iodine
– Thyroid decreases iodine uptake
– Decreased T4, T3 release
 Hypothyroidism
• Mild adult: hypothyroidism
• Sever adult: myxedema
• Infancy: cretinism
 Adult Hypothyroidism
• Etiology
– Thyroid malfunction
• Chronic autoimmune thyroiditis (Hashimoto’s dz)
• Insufficient Iodine
• Surgical removal or radioactive iodine tx
• Insufficient TSH or TRH
• Clinical Manifestations
– Face: pale, puffy, expressionless
– Skin: cold and dry
– Hair Brittle, alopecia
– Heart rate, Body temperature
– Lethargy, depression, fatigue, cold intolerance
 Hypothyroidism
• Laboratory monitoring
– TSH
– T4
– T3
• Treatment
– T4 replacement
• Levothyroxine (T4)
• Levothyroxine plus liothyronine (T3)
 Hypothyroid in Infants
• Mental retardation
• Large protruding tongue, potbelly, dwarfish
posture
• Abnormal development of:
– Nervous system
– Bones, teeth,
– Muscles
• Early treatment (2-3 days): normal
• Delayed tx: (2-3 months): physical normal,
but mental damage is done
 Maternal Hypothyroidism
• Can cause decreased IQ and other neuro
problems
• Fetal thyroid gland is fully functional by
second trimester
• First trimester is critical
• Screening for all pregnant women
 Hyperthyroidism
• Two forms:
– Grave’s Disease: exophthalmos
– Plummer’s Disease (toxic nodular goiter)
• Thyrotoxicosis
– Heart: Tachy, dysrhythmias, angina
– Rapid thought, speech
– Nervousness, insomnia
– Muscle weakness and/or atrophy
– Increased appetite, weight loss
 Grave’s Disease
• 6 times more likely in women; ages 20 –
40
• Thyroid stimulating immunoglobulins
• Treatment
– Surgical removal of thyroid tissue
– Destruction of thyroid tissue with radioactive
iodine
– Suppression of thyroid hormone synthesis
– Adjunct treatment: propanolol and iodine
 Hyperthyroid
• Toxic nodular Goiter: thyroid adenoma
– Same treatment as grave’s Disease
• Thyrotoxic Crisis (Thyroid storm)
– Manifestations:
• Hyperthermia
• Severe tachycardia
• Profound weaknes
• Unconsciousness, coma, heart failure
– Etiology: overdose or excess endogenous
production
 Thyroid Function Tests
• TSH
– More sensitive
– Can help to distinguish primary problems from
secondary
• T4, Free T4
• T3
 Levothyroxine
• Synthroid, Levothroid, Levoxyl
• Pharmacokinetics
– Absorbed in GI tract
– Converted to T3 in blood and tissues
– Half-life
• Takes four weeks to reach steady state
• Convenient daily dosing
• Adverse effects
– Thyrotoxicosis
 Levothyroxine Interactions
• Drugs that reduce levothyroxine:
– Cholestyramine, Colestipol, Calcium,
Sucralfate, Aluminum antacids, Iron suppl.
• Drugs that help break down levothyroxine
– Phenytoin, carbamazepine, rifampin,
sertaline, phenobarbital
• Levothyroxine potentiates:
– Warfarin
– Catecholamines (epinephrine, et al.)
 Levothryoxine
• Almost always PO
• May be given IV if necessary
• Evaluation
– TSH and T4 levels
– Symptoms
• Duration of Therapy
– LIFELONG!!!
 Hyperthyroid Medications
• Propylthiouracil (PTU) & Methimazole
– Inhibits thyroxine production
• Radioactive Iodine-131
– Taken up by thyroid where it decays and
destroys thyroid cells
– Half-life 8 days
– Reduction is gradual: effects begin at 2-3
weeks and increase up to 2-3 months
– 66% of patients cured by one dose
 Radioactive Iodine
• Benefits:
– Cheap
– No surgery or recovery
– Death unlikely
– Only thyroid is affected
• Drawbacks
– Delayed effects
– Delayed hypothyroidism (10% in first year)
 Pituitary
• Growth Hormone (GH)
– Too much: gigantism, acromegaly
• Surgical removal or medical suppression
– Too little: dwarfism: treat with GH
• Two forms: somatotropin and somatrem
• Adverse effects:
– Hyperglycemia
– Hypothyroidism
– Antibody development
– Are impaired by glucocorticoids
 Pituitary
• Prolactin Excess:
– Etiology
• Pituitary adenoma
• Hypothalamic injury
• Drugs,
• Idiopathic
– Manifestations
• Women, amenorrhea, galactorrhea, infertility
• Men: decreased libido and potency, galactorrhea
• Delayed puberty
 Antiduretic Hormone
• AKA Vasopressin or AVP (argenine
vasopressin)
• Actions
– ↑ water reabsorption in renal collecting ducts
– Vasoconstriction of vascular smooth muscle
and GI tract smooth muscle
• Not enough: Diabetes insipidus
• Too much: SIADH
 Adrenal Glands
• Cortex: secretes steroids generally called
corticosteroids:
– Mineralocorticoids
– Glucocorticoids
– Androgens (male sex hormones)
• Medulla
– Nervous tissue
– Secretes epinephrine and norepinephrine
 Glucocorticoids
• Several produced
– Cortisol is main one (amount and effect)
• Physiologic effects
– Low levels
• Pharmocologic effects
– High levels
 Glucocorticoids
• Physiological effects
– Carbohydrate metabolism
• Gluconeogenesis
• Reduction of peripheral glucose use
• Promotion of glycogen formation
– Protein catabolism
– Fat catabolism
– Cardiovascular: membrane permeability, RBC
counts, ↑polys, lymphs and monos
 Glucocorticoids
• Physiologic effects cont
– Skeletal muscle – maintain perfusion
– CNS: affect excitability
• Too little: depression, lethargy, irritability
• Too much: excitation, euphoria
– Stress: in combination with epinephrine,
ensure that glucose and blood supply is
adequate
– Respiratory in neonates: stimulates
maturation of lung
 Regulation of Glucocorticoids
• Hypothalamus: CRF
• Stimulates Anterior Pituitary: ACTH
• Stimulates Adrenal Cortex: Synthesize and
release glucocorticoids
• Glucorticoids suppress hypothalamus and
pituitary release of CRF and ACTH
• Two modes of stimulation
– Circadian rhythm
– Stress
 Other Cortical Steroids
• Mineralocorticoids
– Most important is aldosterone
– Controlled by RAAS
• Adrenal androgens
– Men: not much effect, testosterone from
testes is greater
– Women: testosterone is metabolized from
androgens. Causes axillary & pubic hair and
maintains libido
 Glucorticoid Disorders
• Glucocorticoid excess: Cushing’s Syndrome
– Etiology
• Excess ACTH (Cushing’s Disease)
• Hypersecretion by adrenal adenoma or carcinoma
• Large doses of exogenous glucocorticoids
– Manifestation
• Obesity, hyperlgycemia, glycosuria, hypertension,
F&E imbalances, osteoporosis, muscle weakness,
hirsutism, increased infections
• Weakened skin, striae
• Fat redistribution: belly, moon face, buffalo hump
 Glucorticoid Disorders
• Glucocorticoid deficit: Addison’s Disease
– Manifestations
• Weakness, emaciation, hypglycemia,
hyperpigmentation, F&E imbalances
– Treatment
• Glucocorticoid replacement
• Acute adrenal Insufficiency (Adrenal Crisis)
– Adrenal failure, pituitary failure, sudden d/c of
exogenous glucocorticioids
– Hypotension, dehydration, weakness, lethargy,
NVD, shock, death
 Glucocorticoid Therapy
• Hydrocortisone: artificial cortisol
– Has both gluco- and mineralocorticoid
properties
– IV or IM
• Cortisone converts to hydrocortisone in
body
– PO or IM
• Inhibitors of corticosteroid synthesis
– Ketoconazole
– Aminoglutethimide
 Glucocorticoids used for non-
Endocrine purposes
• Pharmacologic Actions
– Anti-inflammatory and Immune effects
• Inhibit prostaglandin, leukotriene, and histamine
synthesis
• Suppress infiltration of phagocytes
• Suppress proliferation of lymphocytes
– Effects on Metabolism and Electrolytes
• Glucose levels rise
• Protein synthesis suppressed
• Fat deposits mobilized
• Fewer electrolyte effects, but can inhibit calcium
absorption
 Therapeutic Uses
• Rheumatoid Arthritis
• SLE
• Inflammatory Bowel Disease (IBD)
• Miscellaneous Inflammatory D/Os
• Allergic conditions (not acute anaphylaxis)
• Asthma
• Dermatologic disorders
• Neoplams
• Transplant rejection
• Preterm infant
 Glucorticoids Adverse Effects
• Adrenal insufficiency
• Osteoporosis: long term therapy
• Infection
• Glucose intolerance
• Myopathy
• F&E disturbance
• Growth retardation
• Psychological disturbances
 Glucorticoids Adverse Effects
• Cataracts and Glaucoma
• Peptic Ulcer Disease
• Iatrogenic Cushing’s Disease
• Ischemic Necrosis – especially caution
with ETOH
 Agents
• Short Acting Anti-inflammat
– Cortisone, Hydrocortisone 1
• Intermediate Acting
– Prednisone 4
– Prednisolone 4
– Methylprednisolone 5
– Triamcinolone 5
• Long acting
– Betamethasone 20-30
– Dexamethasone 20-30