5. endocrine pathopharmacology

insufficient synthesis: ↓ Raw Materials, secretory cells dysfunction

feedback system failure: inadequate or excessive synthesis

inactive hormones: ↑ or ↓ Hormonal Degradation, ↑ or ↓ Free Hormone Concentration

delivery dysfunction: inadequate blood supply or carrier proteins, ectopic hormone production

cell receptor disorders: ↓ Receptor Population, Altered Affinity or Functions Anti-Receptor Antibodies

intracellular disorders: Defective Signalling Cascade (2nd messenger), Altered Enzymatic Function, Altered Nuclear Regulation or Protein Synthesis

posterior pituitary alteration

excessive ADH secretion

• ↑ Water Reabsorption

• ↑ ECF Volume

• Hyponatremia (↓ sodium) + Hypoosmolarity (↓ electrolytes)

Sx depend on hyponatremia severity

140-130 mEq/L : Thirst & Fatigue; NO Edema

130-120 mEq/L : Severe GI distress

< 115mEq/L : Confusion & Seizures

Pulmonary Disorders : Pneumonia; Asthma; Cystic Fibrosis

CNS Disorders : Meningitis; Encephalitis; Intracranial Hemorrhage

Surgeries : Procedural Fluid Alterations

Tumors : Ectopic Secretions

Therapeutic Drugs : Antidepressants; Antibiotics; NSAIDs

Renal Mutation : Mutation of Tubular V2R (ADH binds to V2R so hypersensitive or hyperactive has same Sx of SIADH)

Insufficient ADH (water not absorbed at kidneys):

• ↑Diuresis → Polyuria & Polydipsia (↑drinking)

• Hypernatremia + Hyperosmolarity

neurogenic : most common, lesion to hypothalamus or posterior pituitary (brain tumor, head trauma)

renal: genetic or acquired ADH insensitivity (renal pathologies, drug nephrotoxicity)

dipsogenic: excessive fluid intake -> ADH resistance (increased fluid ingestion)

hypopituitarism: hypothalamus dysfunction, surgical removal or destruction of pituitary gland

hyperpituitarism: hypothalamic or pituitary adenomas (tumours)

Insufficient ACTH

• ≈ Cortisol insufficiency

• Fatigue; Hypoglycemia; Hypotension; ↓ Diuresis

Insufficient TSH

• ≈ T3/T4insufficiency

• ↓BMR; ↓Libido; Cold Intolerance

Insufficient GH

• ≈ Mutation of GHRH gene or GH Insensitivity

Kids: Growth Failure

Adults: Osteoporosis; ↓ Muscle Strength

not all hormones equally

excessive prolactin secretion

• Pituitary Adenoma → Prolactinoma

Manifestations Females

Galactorrhea (spontaneous lactation)

Abnormal Menses

↓ Estrogen: Hirsutism & Osteoporosis

Males

hypogonadism

erectile dysfunction

excessive GH secretion

- Pituitary Adenoma → Acromegaly

manifestations:

adults

• ↑ GH & IGF-1• Visceromegaly & Connective Tissue Growth (areas that can still grow as an adult)

Children• ↑ GH & IGF-1 → Bone Growth = Gigantism (risk of death

Overall

↑ Risk of Heart Diseases; T2DM & Cancer

Overall ↓ Life Expectancy

V2R agonists: vaso + desmopressin

Effect: ↑ Water RetentionSafety: Desmopressin > Vasopressin

Vasopressin has strong vasoconstriction effect

1) V2R Antagonists (Ex.: Conivaptan)

2) Loop Diuretics + 3% Hypertonic saline (increases Na+ in system to restore osmolarity)

Pediatric GH Deficiency : Initiate as early as possible (Before epiphyseal closure!!) Continue until satisfactory height or lack of response

Pediatric Non-GH Deficiency Short Stature : Must be 2.25 Standard Deviation below sex & age-adjusted mean height

Prader-Willi Syndrome Associated Short Stature : Only if GH DeficiencyContraindicated in PWS patients with obese BMI → ↑ Risk of Fatality

Adult GH Deficiency: Replacement: ↑ spine density & lean body mass/↓ adipose tissue

Drawbacks: ↑ Systolic BP & Blood Glucose

veryyyyyy costly

↑ Blood Glucose → Adjust Insulin Dosage

GH Antibodies Neutralization → Switch to IGF-1 Analog

Glucocorticoid Replacement Inhibit GH Effects

1) Surgical Excision of Pituitary2) Irradiation of Pituitary3) Drug Therapy

Drug Therapy is usually last resort → Long & Expensive

Somatostatin Analogs (ex.: Octreotide)

Most effective option for GH ↓

Objective = Normalize GH & IGF-1 Levels

GI Distress = Most common Adverse Effects

prevents release

GH Receptor Antagonist (ex.: Pegvisomant)Most effective option for Acromegaly

Objective = Normalize GH & IGF-1 Levels

GI Distress = Most common Adverse Effects

Some risk of Hepatotoxicity → Monitor

blocks action

hyperthyroidism: increased BMR, thin hair, tachycardia, weight loss, diarrhea, enlarged thyroid

hypothyroidism: decreased BMR, loss of hair, puffy face, bradycardia, constipation, cold, edema of extremities

Graves’ Disease

Multinodular Goitre

Follicular Adenoma

Thyroid Medication

once you notice elevated TH and suppressed TSH

-> radioactive iodine uptake scan

IF low uptake = thyroiditis, exogenous thyroid hormone

IF normal uptake = graves, toxic adenoma, toxic goitre

autoimmune disorder: abnormal antibodies that behave like hormone TSH - binds + tells to release more

Prevalence : 50-80% of Thyrotoxicosis

Mechanism

• Type-II Hypersensitivity Reaction• Thyroid-Stimulating Immunoglobulins• Gland Hyperplasia + T3/T4 Synthesis

Manifestations• Toxic Goitre• Exophthalmos (≈ 50%, bulging of eyes)• Pretibial Myxedema/Graves Dermopathy

abnormal growth of some nodules

Mechanism

Gland Hyperplasia due to ↑ TSH

Follicular cells continue secreting excess T3/T4 after response = Toxic Nodules

Manifestations

• Nodular Goitre• No Exophtalmos or Pretibial Myxedema

• ↑ Risk of Thyroid Cancer

Drastic ↑ in T3/T4

Cause: Acute Stress

Risk: Undiagnosed or mistreated hyperthyroidism

Manifestations:

• Hyperthermia • Tachycardia• Delirium

Hashimoto Disease (Autoimmune)

Surgery/Radiotherapy

Congenital

Iodine Deficiency (very rare)

look at slide

Myxedema

• Edema• Tongue Thickening → Slurred Speech

Cretinism

Hypo-TH at birth or childhood

Mental + Physical Retardation

Hashimotos thyroiditis

dry + thining hair, heavy menstrual period

joint + muscle pain, enlarged thyroid

hyperparathyroidism

hypoparathyroidism

PTH has crucial role in regulating CA2+ serum levels

1◦ • ↑PTH+ Hypercalcemia

• Ex.: PT Gland Tumors: more cells = ↑PTH = hypercalcemia

2◦ Hyperparathyroidism

• ↑PTH+ Hypocalcemia (Sx of hypo-PTH)

• Ex.: Chronic Kidney Disease: ↓ vit D = ↓ Ca2+ absorption = hypocalcemia

3◦ Hyperparathyroidism

• ↑PTH + Hypercalcemia

• Autonomous PT Gland: keep secreting PTH even if levels of Ca2+ are high

Mostly Asymptomatic

Can affect Kidneys, Muscles, GI, CNS

↑ Risk Cardiovascular disease

↑ Risk Kidney Stones

• ↓ PTH + Hypocalcemia• Damage or Removal of PT Glands → Ex.:Radiotherapy /Surgery

remember it is a decrease in Ca2+

muscle spams

convulsions

tetany

respiratory failure

hyperphospatemia: ↓ Vitamin D Metabolism, ↓ Ca2+ Absorption

hypercalcemia: mild = mostly asymptomatic, severe = ↑ Risk Kidney Stones & Dysrhythmias

hypocalcemia: Muscular Effects: Spasms, Convulsions, Severe cases = Respiratory failure

Adult Hypothyroidism

Lifelong Hormone ReplacementT4 Alone ≥ T3/T4 Combination

Adequate Replacement eliminates all Symptoms

Infantile Hypothyroidism

Initiate Replacement ASAPWithin Days of Birth: Normal Development

3-4 Weeks Delay: Some permanent disabilities Assessment after 3 years: determine if permanent therapy necessary

Grave’s Disease

1 - Surgical Thyroidectomy + Replacement

2 - Thyroid Destruction via Radioactive Iodine

3) Anti-thyroid Drug to ↓ Synthesis

Best Option for Adults = #2Best option for Younger Patients = #3For Exophthalmos: Surgery or Glucocorticoids

Beta-Blocker = Adjunct Therapy (Quick Action!)

artificial form of thyroid hormone T4

General Information

• Should be taken on empty stomach in the am• Rapidly converted into T3 by \ body• 99.9% protein-bound → T1/2 = 7 Days → Therapeutic Delay

• Indication: All forms of Hypothyroidism• Therapeutic Doses = Very Few Adverse Effects• Toxic Doses = Hyperthyroidism Symptoms

• Biggest Drawback: Several Known Drug Interactions Ex.: Warfarin; Catecholamine; GI Drugs

Compensate Deficiency PreciselyUse Clinical Symptoms + Lab Tests to adjust dosage TSH levels 6-8 weeks post-initiation = Best Test Symptomatic Relief ≠ Cure

Nursing Consideration: Brand Equivalence

Several brands/generic formulations

Debate over the equivalence & interchangeability

Recommendations:

1) Maintain Patients on same product when possible

2) If Switch: Retest TSH Serum at 6 weeks & adjust

artificial form of thyroid hormone T3 (remember T4 is precursor of T3)

Short Action & ↑ CostOnly better if require speedy onset Ex.: Myxedema Coma

antithyroid drugs: ↓ Thyroid Hormone Synthesis

they target iodides, which is best thing to target because they are only there

methimazole and propylthiouracil (PTU)

Half-Life long enough for 1-day dosing

Very Lipid-Soluble → Placenta X-ing

Graves’ Disease

Radiation Therapy Adjunct

Thyroidectomy Preparation

Thyrotoxic Crisis Prophylaxis

Avoid during 1st Trimester & Breast-Feeding

Monitor for Agranulocytosis (↓ WBC)

Hypothyroidism

preferred all the time

Short Half-Life → 2-3x/day

Poor Placental X-ing

When PTU ˃ Methimazole:

Thyroid Storm1st Trimester Pregnancy

Methimazole Intolerance

Severe Hepatotoxicity

↑ Risk in Infants

Agranulocytosis

Action: Partial destruction of thyroid tissue

• Damage to Thyroid Only iodine only in

• Delayed Hypothyroidism thyroid

Long Half-Life → Delayed therapeutic effect Maximal Efficacy ≈ 2 months

Indicated for:

• Adults with Hyperthyroidism Inappropriate Candidates

• Young Children / Pregnancy & lactation ↳ carcinogenic + Lerarogenic mutations

↳more yus forkids to accumulate

Other Usages

• Smaller Doses → Thyroid Function Diagnostic

• Higher Doses → Thyroid Cancer

Advantages:

Low Cost No Surgery;

No Risk of DeathNo Effect on other Tissues

Disadvantages:

Delayed Effect Onset

Delayed Hypothyroidism (≈ 90% of patients)

endocrine disorder w/elevated cortisol levels

results from pituitary adenoma -> excess ACTH (hormone)

ACTH stimulates cells in adrenal cortex of kidneys, which releases cortisol

lipid soluble hormones -> glucocorticoids -> not soluble in water, only 5% are free -> gets filtered in kidneys and dumped into urine

free cortisol is part of circadian rhythm

- levels peak in the morning "get up + go"

- levels drop in the evening

in stress, cortisol:

- increases gluconeogenesis: synthesis of new glucose

- increases proteolysis: breakdown of protein

- increases lipolysis: breakdown of fat

maintains blood pressure

- increases sensitivity of peripheral blood vessel to catecholamines (Api + NE)

receptors in brain

- may influence mood + memory

dampens inflammatory + immune response

- decreased production + release of inflammatory mediators -> prostaglandins + interleukins

- inhibiting t-lymphocytes

levels of free cortisol have to stay in normal range -> negative feedback

cortisol levels are constantly higher than normal

- severe muscle, bone + skin breakdown

- elevated glucose levels -> high insulin levels -> targets adipocytes in centre of body -> activates lipoprotein lipase (obesity)

- hypertension

1. amplify effect of catecholamines on blood vessels

2. cortisol cross-related w/mineralocorticoid receptors

- inhibit gonadotropin releasing hormone - messing up ovarian + testicular function

- dampens inflammatory response - more susceptible to infections

- impair normal brain function

exogenous - medication (steroids) to treat autoimmune + inflammatory disorders

-> similar to cortisol, mimics action on tissue = negative feedback

endogenous

- pituitary adenoma (benign): cushing disease

- ectopic sources of ACTH - small cell lung cancer -> coming from somewhere else

- tumor of adrenal gland - adenoma (benign) or carcinoma (malignant): cells divide abnormally + secret excess cortisol (suppress CRH + ACTH production)

full moon shaped face

buffalo hump

truncal obesity

easy bruising

abnormal striae

fractures - osteoporosis

hyperglycemia (diabetes, hypertension...)

measuring free cortisol: 24 hour urine, blood or saliva test late at night

dexamethason suppression test

- low does - suppresses ACTH production

- should cause decreased cortisol levels

- if positive determine cause of endogenous production

ACTH plasma level checked

- low ACTH: adrenal adenomas + carcinomas

- high ACTH: cushing disease + ectopic ACTH production

imagining

exogenous meds -> drug gradually decreased - avoid withdrawal - adrenal crisis

pituitary adenoma -> surgical excision

adrenal steroid inhibitors -> ketoconazole + metyrapone

Sleep Disorders

Diabetes

Weight Gain

Hypertension

Osteoporosis

Immunosuppression

Dysmenorrhea/PCOS

opposite of cushing's

Insufficient Adrenal Stimulation (↓ ACTH)

ORInsufficient Cortisol Synthesis or Secretion

Common Cause

Autoimmune destruction of adrenal cortex

• Adrenal Atrophy• ↓ Cortisol or Aldosterone or Both

Main Manifestations

GI distress → Nausea; Vomiting; Diarrhea

Hypoglycemia → Fatigue, Weakness, Confusion

Severe Hypotension → Vascular Collapse & Shock

aldosterone helps kidney reabsorb water

1◦ Hyperaldosteronism

Adrenal Cortex Tumor

Hypertension + ↑ Na+ Reabsorption

Hypokalemia → Metabolic Alkalosis; Neuromuscular Defects; Polyuria

2◦ Hyperaldosteronism

Extra-Adrenal Stimulus (ex.:↑Renin/AngII)

Adrenal Medulla Tumor

↑ Epinephrine & Norepinephrine

Main Manifestations• ↑ SNS Activity → Hypertension & Tachycardia• ↑ Cerebral Blood Flow → Severe Headache• Exercise or Tyrosine-Containing Food → Hypertensive Crisis

↑ Risk of Rupture → Severe Hemorrhage

cortisone - short acting - 8-12hr - 0.8

hydrocortisone - short acting - 8-12hr - 1

prednisone - intermediate acting - 18-36 - 4

dexamethasone - long acting - 36-54 - 20-30

• Choice of GCC:

• Biologic half-life = Time to leave body tissues• More representative than plasma half-life for GCC

• Avoid GCC with high mineralocorticoid (fluid retention) potency

• Administration

Multiple routes: Oral, parenteral, topical, inhalational, etc.

Admin in the morning (before 9AM) = Optimal

• Dosage Guidelines

Individualised via trial & error

High-dose prolonged therapy only if 1) Life-threatening or 2) Potential for permanent disability

• Alternate-day therapy = Intermediate-acting GCC every other day

Advantages: ↓ Adrenal Suppression + Growth delay & Overall toxicity

Drawback: Symptoms flare-up on the non-dosing day

Systemic Lupus Erythematosus (SLE)

Short-term high-dose GCC Best Sx management strategy

Graft-versus Host Disease

Prevention of Graft Rejection

Initiated at surgery Continued indefinitely

Preterm Respiratory Distress Syndrome

GCC necessary for fetal lung maturation

Beta or Dexamethasone injections for prevention

Hormonal Replacement Therapy

Cushing’s Syndrome

Primary Hyperaldosteronism

strategy:

Adrenal Adenoma: Surgical Removal + Hormonal Replacement

Bilateral Adrenal Hyperplasia: Aldosterone Antagonists (ex.: Spironolactone)

Addison’s Disease:

Hormonal Replacement (ex.: Hydrocortisone)

Secondary & Tertiary Adrenal insufficiency:

Glucocorticoid Replacement Only

Mineralocorticoid levels are usually ok!

Acute Adrenal Crisis:

Rapid Replacement of: Fluid + Salt + Glucocorticoids

Ex.: Hydrocortisone IV Bolus → Saline + Dextrose IV Infusion

Congenital Adrenal Hyperplasia:

Genetic Enzyme Deficiency → ↓ Glucocorticoid → ↑↑ ACTH Release

Exogenous Hydrocortisone → ↓ ACTH → Stabilise Symptoms

Intensity mostly dependent on therapy duration / Only a little by dose size

Hyperglycemia

Diabetic symptoms exacerbation

Infections

↑ new infection risk ↑ latent reactivation

Adrenal Insufficiency

HPA-axis shutdown

Osteoporosis

↑ Osteoclast activity

Psychological Effects

Insomnia/AnxietyMood Alterations/Depression Hallucinations/DeliriumEffects depend on dosage and duration

Management

Strict and Long Withdrawal Schedule Must ↑ GCC dosage during times of stress

Other Important Toxicities

Peptic Ulcers (Prostaglandin Inhbition)

Growth impairments (Children)

Fluid/Electrolyte Imbalances Cataracts/Glaucoma

NSAIDsPregnancy and Breast-Feeding

Hypokalemia

Potassium-Loss Promoting Rx Ex.: Digoxin, Diuretics

Contraindications

Live virus vaccines & systemic fungal infections

vaccines: reduced efficacy