Pharmacology - Endocrine Flashcards
Describe: Acromegaly
- Caused by excess production of growth hormone
- Most commonly affects middle-aged
- Can result in premature death
- Due to slow onset it is frequently incorrectly diagnosed
- Most common symptoms are abnormal growth of hands & feet.
Describe: Acromegaly Treatment
Aim is to reduce Growth Hormone production:
- Surgical removal of tumour, difficult due to tumour’s position within brain
- Drug therapy:
Ooctreotide & Lanreotide (somatostatin analogues, somatostatin receptor ligands SRLs)
Opegvisomant (growth hormone receptor antagonist)
Obromocriptine (dopamine agonist)
- Radiation therapy
Results of Deficit of Growth Hormone
Deficit:
- Dwarfism may be:
- general anterior pituitary dysfunction -
- specific GH deficit
- normal GH but hereditary somatomedin deficit
- Accelerated aging if loss of growth hormone occurs after adolescence
- decreased protein synthesis
Results of Excess of Growth Hormone
Excess GH
*Gigantism - early life pituitary tumour
*Acromegaly- pituitary tumour after adolescence
Dopamine agonists treat prolactinoma
Prolactin inhibiting factor (PIF) is dopamine
Dopamine acts at D2 receptors in the pituitary gland to inhibit prolactin release
Cabergoline and bromocriptine are dopamine agonists that inhibit prolactin production and can reduce the size of a prolactinoma
**Antipsychotics that are D2 receptor antagonists can cause hyperprolactinaemia
Hypopituitarism
- Rare - results from a deficiency in one or more pituitary hormones
- Panhypopituitarism – a deficiency in all anterior pituitary hormones
Multiple causes (acquired more often than congenital); tumours most common
+ traumatic, infective, vascular, autoimmune, functional (anorexia nervosa; starvation) - Symptoms mirror those of a primary deficiency in hormone secretion by the target endocrine gland
+ for example, primary and secondary hypothyroidism
+ if the deficiency is mild the patient may be asymptomatic - Managed by replacement therapy with the appropriate hormone(s)
+ e.g. recombinant GH (pituitary dwarfism); levothyroxine (2o hypothyroidism)
Describe: Hypelactinoma
Hyperlactinoma - too much prolactinoma in the blood
Benign pituitary tumours (adenomas) are the most common cause
Prolactin is the ‘milk hormone’
Common presentation:
Galactorrhoea - milky secretion from the breasts (male & female)
Amenorrhoea – females absence of periods
Hypogonadism – diminished production of sex hormones, diminished function of gonads in males & females
Erectile dysfunction - males
Vision loss, due to compression of the optic chiasm, is a common comorbidity
Explain the release and control of Growth Hormones
Hypothalamus release tropic factors into local circulation, & modified neurosecretory cells which release hormones enter the pituitary gland posterior,
The pituitary gland anterior releases primary hormones (such as prolactin & growth hormones), and trophic factors.
The GHRH (Growth Hormone Releasing hormone) stimulates the pituitary to release the GH (Growth Hormone), which is stopped by Somatostatin, a GH inhibitor.
TRH (Thyrotropin-releasing hormone) acts on the pituitary gland anterior, releasing TSH (Thyroid stimulating hormone), which acts on the Thyroid, causing the release of T3 (tri-iodothyroxine) & T4 (Thyroxine), both stimulate metabolic rate and growth, by acting at nuclear receptors to regulate gene transcription.
Describe both Hypersecretion & Hyposecretion, and the hormone whose activity results in these conditions.
Hypersecretion – too much hormones, resulting from an adenoma, a benign tumour
Hyposecretion – hormones are made against the hormone releasers, resulting from autoimmune disease.
GHRH activity results in these conditions.
The hypothalamic-pituitary axis
Hypothalamus releases TRH, causing the pituitary to release TRH onto the Thyroid, which releases T3 & T4, resulting in action within tissues. The negative feedback loop results in balance, loss of the feedback results in an unbalanced & diminished axis.
Thyroid hormone synthesis by follicle cells
TSH stimulates the Thyroid to synthesize Thyroid hormones, by stimulating iodide uptake into the cells by the transport protein Pendrin into the Follicle Lumen where TPO and TO enzymes catalyse addition of tyrosyl residues in Thyroglobulin.
When Thyroid hormones are needed the Thyroglobulin are Phagocytosed back into the cell and de-iodinated for more hormone synthesis.
Drugs act here to reduce the TPO action, limiting synthesis of Thyroid hormones.
Describe Hypothyroidism
Hypothyroidism – most common is autoimmune disease where antithyroid antibodies are made, stopping Thyroid hormone production.
A version called Hashimoto’s thyroiditis results in an enlarged thyroid gland.
Women may also get postpartum thyroiditis, but will typically recover.
May also occur from iodine deficiency.
Treated with lifelong hormone replacement.
Clinical signs & symptoms of hypothyroidism
Tiredness
Weight Gain
Cold intolerance
Goitre (large thyroid glands)
Dry thin hair
Dry skin
Mental Slowness
Slow heart rate
Slow-relaxing reflexes
Describe Hyperthyroidism (thyrotoxicosis)
Grave’s disease – autoimmune disease where antibodies act like TSH, meaning Thyroid hormones are released continuously, but can be caused by an inflammatory process or drug action.
Treated by antithyroid drugs, surgery or radiation.
Clinical features of hyperthyroidism (thyrotoxicosis) symptoms and signs
Weight Loss
Increase appetite
Tremor
Heat intolerance
Hyperkinesis
Overexcitable heart
Grave’s disease may result in bulging eyes
Hyperthyroidism treatment - 3
Treatment options:
1. Antithyroid drugs (e.g., Carbimazole): BetaBs may be coadministered for faster symptomatic relief.
2. Radioiodine: Only used for patients who have been made euthyroid first. It is contraindicated in pregnancy & breastfeeding.
3. Surgery: Reserved for patients who are euthyroid prior to the procedure.
Grave’s disease diagnosis
Graves’ disease is diagnosed with a low serum TSH & elevated T3 or T4 levels. TSH receptor antibodies are often present in cases, while thyroid peroxidase (TPO) & thyroglobulin antibodies are commonly found.
Q: What is Primary Hyperaldosteronism (Conn’s Syndrome)?
A condition caused by adrenal adenomas (benign tumours) producing excess aldosterone, leading to excessive sodium reabsorption and high blood pressure.
Q: What is the treatment for Primary Hyperaldosteronism (Conn’s Syndrome)?
A: Surgery to remove the adenoma or the use of aldosterone antagonists
Q: What is Hypoadrenalism (Addison’s Disease)?
A: A condition typically caused by autoimmune destruction of the adrenal glands, leading to insufficient production of cortisol and aldosterone.
Q: What is the treatment for Hypoadrenalism (Addison’s Disease)?
A: Hormone replacement therapy.
Q: What is Hypercortisolism (Cushing’s Syndrome)?
A: A condition caused by either endogenous (overactive adrenal glands or excess ACTH) or exogenous (glucocorticoid therapy for other conditions) factors, leading to excess cortisol production.
Q: What is the treatment for Hypercortisolism (Cushing’s Syndrome)?
A: Withdrawal of glucocorticoids or the use of cortisol synthesis inhibitors.
Q: Where is the adrenal gland located?
A: The adrenal gland is a triangular structure located on top of the kidneys.
Q: What are the two main parts of the adrenal gland?
A: The adrenal gland consists of an outer cortex and an inner medulla.
Q: What are the different zones of the adrenal cortex responsible for?
A: The cortex is zoned, with different areas responsible for synthesizing specific steroid hormones.
Q: Where is aldosterone primarily produced in the adrenal gland?
A: Aldosterone, a mineralocorticoid, is primarily produced in the outermost zone of the cortex, called the glomerulosa.
Q: Which hormone is produced in other cortical zones of the adrenal gland?
A: Glucocorticoids, like cortisol, are produced in other cortical zones.
Q: How can disorders affecting the adrenal cortex impact hormone production?
A: Disorders affecting different parts of the cortex can impact the synthesis of specific hormones, leading to various dysfunctions depending on the hormone involved.
Synthesis of aldosterone -
- Cholesterol
- to pregnenolone
- to progesterone
- to deoxycortone
- finally aldosterone.
Aldosterone - MoA
Aldosterone: primary mineralocorticoid that promotes reabsorption of sodium in the kidneys. As sodium is reabsorbed, water follows by osmosis, increasing blood volume, & raising blood pressure. Aldosterone acts by binding to mineralocorticoid receptors (MR), which are mainly found in the kidney, colon, & bladder—the organs responsible for regulating sodium.
The synthesis & secretion of aldosterone - renin system
The synthesis & secretion of aldosterone are controlled by the renin-angiotensin system. Increased sodium reabsorption is also linked to the secretion of potassium (K+) & hydrogen ions (H+). In circulation, most aldosterone is bound to proteins, and the receptor is part of the nuclear receptor superfamily (NR3C2).
Minerlocorticoids & glucocorticoid receptors - 5
- Steroid hormones like corticosterone (glucocorticoid) & aldosterone (mineralocorticoid) bind to nuclear receptors. 2. These lipophilic molecules pass bind to receptors attached to chaperone proteins.
- Upon binding, the hormone-receptor complex loses the chaperones & forms a dimer.
- This liganded dimer then translocates to the nucleus, where it binds to specific DNA sequences, called glucocorticoid receptor recognition elements.
- This binding either increases or decreases gene transcription depending on the required cellular outcome.
Aldosterone secretion: renin-angiotensin system - 8
The release of aldosterone is controlled by the renin-angiotensin system. Here’s the sequence:
1. BP drops (e.g., from bleeding).
2. Sympathetic nervous system activity increases & the Bowman’s capsule in the kidney detects the BP drop
3. This triggers the release of renin from the kidney.
4. Renin converts angiotensinogen (from the liver) to angiotensin I.
5. Angiotensin I is converted to angiotensin II in the lungs.
6. Angiotensin II acts as a vasoconstrictor, narrowing blood vessels to increase BP.
7. Angiotensin II also stimulates the release of aldosterone from the adrenal glands.
8. Aldosterone acts on the kidneys to promote sodium reabsorption, which increases blood volume & raises BP.
Clinical uses of aldosterone antagonists
Aldosterone antagonists, like spironolactone, are used to treat primary hyperaldosteronism and resistant hypertension.It competitively blocks aldosterone receptors but also affects sex hormone receptors, leading to possible side effects.
Clinical uses of exogenous antagonists
Exogenous mineralocorticoids like fludrocortisone are used in replacement therapy for conditions like Addison’s disease where both mineralocorticoid (aldosterone) & glucocorticoid (cortisol) need to be replaced. Fludrocortisone increases sodium reabsorption in the kidney’s distal tubules, while also promoting the efflux of potassium & hydrogen ions.
Spironolactone - 3
- Spironolactone is an aldosterone antagonist used to treat primary hyperaldosteronism (AKA Conn’s syndrome).
- Primary symptom of this condition is hypertension
- Spironolactone is a prodrug, which is converted into canrenone, with a half-life of 24 hours.
Primary Hyperaldosteronism (Conn’s Syndrome): - 7
- hypertension cases, but still poses significant risks like stroke, heart disease, & kidney failure.
- Diagnosis: high plasma aldosterone-to-renin ratio & plasma aldosterone levels that aren’t suppressed by saline infusion.
- Symptoms: low serum potassium (leading to muscle weakness) & increased urinary potassium.
Treatment:
5.Tissue growth: Aldosterone antagonist (spironolactone) for bilateral hyperplasia. - Unilateral, aldosterone-secreting adenoma:
- Surgical removal (usually laparoscopic/keyhole surgery) for unilateral adenoma.
Cortisol & Glucocorticoid Receptors: - 3
- Cortisol (main glucocorticoid)
- Synthesis & secretion regulated by ACTH (adrenocorticotropic hormone) from the pituitary, which stimulates cell overgrowth in the adrenal cortex.
- Synthetic glucocorticoids work by binding to nuclear receptors & regulating gene transcription, distinguishing them from more localized mineralocorticoid receptors.
Glucocorticoids - Treatment & Excessive use
- Treatment: rheumatoid arthritis, psoriasis, & eczema, where their immune-suppressive effects are beneficial.
- Excessive use: can casue disruptions in glucose regulation & lipid homeostasis, contributing to obesity & hyperglycemia.
Glucorcorticoid regulation - 3
- Increased ACTH indicates primary hyposecretion of glucocorticoids, where insufficient cortisol prevents negative feedback on ACTH production, leading to elevated levels.
- Decreased ACTH causes secondary adrenal insufficiency (low cortisol production due to insufficient ACTH release).
- Pituitary tumour can cause excess ACTH release, leading to excess glucocorticoids
Negative feedback in the HPA axis
The HPA axis involves CRH from hypothalamus triggering pituitary to release ACTH, which stimulates cortisol production by the adrenal glands. Cortisol then provides negative feedback to both the pituitary and hypothalamus to regulate the system.
Addison’s Disease (Primary Adrenal Insufficiency):
- 5
- Caused by autoimmune diseases
- Symptoms: Chronic fatigue, loss of appetite, generalized weakness, hypotension.
- Pathophysiology: Reduced production of adrenal steroids
- Diagnosis: Increased ACTH levels due to lack of cortisol feedback, leading to hyperpigmentation of the skin & vitiligo.
- Secondary features: Increased melanocyte-stimulating hormone (MSH) due to ACTH excess causes skin changes.
