Renal Pharmacology: ADH and RAAS

Renal Pharmacology: ADH and RAAS

Introduction

• Scott Walker, Scott.Walker@newcastle.ac.uk

• Endocrine System, Newcastle University. UK | Malaysia Singapore

Kidney Functions

• Vital functions of the kidney:

  • Selective reabsorption

  • Filtration

  • Regulating BP

Juxtamedullary Nephron Overview

• Ultrafiltration occurs in the glomerulus.

• Key structures:

  • Afferent arteriole

  • Efferent arteriole

  • Glomerulus

  • Proximal convoluted tubule

  • Descending limb of loop of Henle

  • Ascending limb of loop of Henle

  • Distal convoluted tubule

  • Collecting duct

  • Peritubular capillary

  • Bowman’s capsule

Pharmacology of ADH

Pituitary Gland

• Pituitary = ‘Master endocrine gland’

• Hypothalamus = Supreme commander (power behind the master)

Anatomy of the Pituitary Gland

• Posterior Lobe

• Anterior Lobe

• Two distinct parts:

  • Posterior (neurohypophysis): stores & secretes hormones synthesized in hypothalamus (oxytocin, ADH)

  • Anterior (adenohypophysis): synthesizes and secretes hormones in response to hypothalamic regulation (TSH, ACTH, FSH, LH, GH, PL)

Posterior Pituitary

• Consists mainly of neuronal projections (axons) extending from the supraoptic and paraventricular nuclei of the hypothalamus.

• These axons release peptide hormones into the capillaries of the hypophyseal circulation

• Does not produce any hormones, but simply stores and secretes hormones produced in the hypothalamus

• 2 hormones

  • Antidiuretic hormone (ADH, vasopressin)

    • Regulation of renal function

  • Oxytocin

    • Regulation of uterine contraction

  • Both short peptides (9 a.a.)

• These hormones are then stored in neurosecretory vesicles

ADH and Blood Volume/Pressure Regulation

• Low blood volume/pressure (baroreceptor)

• High osmolarity (osmoreceptors)

• Hypothalamus signals Posterior Pituitary to release ADH

• ADH acts on:

  • V1 receptors (GPCR) in blood vessel smooth muscle: Vasoconstriction (maintain blood pressure)

  • V2 receptors (GPCR) in distal tubule: Increased water reabsorption

• Feedback: Blood volume/pressure returns to normal

ADH Release

• Anterior Hypothalamus

• Hypothalamus & Posterior Pituitary

• ADH

Mechanism of Action of ADH

• Increasing water permeability in distal convoluted & collecting duct resulting in concentrated urine

  1. ADH binds to V2 receptors on the basolateral of principal cells

  2. Promotes conversion of ATP to cAMP via adenylate cyclase

  3. Activated Protein Kinase A

  4. Promotes fusion of aquaporin2 into the apical luminal membrane enhancing permeability to $H_2O$

Water Absorption in Late DCT & Collecting Duct

• Ascending Limb of Loop of Henle, DCT & Collecting duct – Impermeable to $H_2O$

• $H_2O$ absorption can occur in Late DCT & Collecting duct in the presence of the peptide hormone – Anti Diuretic Hormone (ADH)

• ADH promotes membrane fusion of AQP2

Stimulants and Depressants of ADH

• ADH Hormone Level Stimulants:

  • Opioids

  • Anti-Depressants (SSRI, TCA)

  • Nicotine

  • MDMA

• ADH Hormone Level Depressant:

  • Alcohol

Syndrome of Inappropriate ADH Secretion (SIADH)

• Excessive ADH secretion leading high urine osmolality, increased total body water – hyponatremia, hypoosmotic blood plasma and hypervolemia.

• Causes

  • Post Operative (Metabolic Response to Trauma and Stress) (30%)

  • Head Trauma (20%)

  • Ectopic ADH production (Tumours) (20%)

  • Drugs

• Treatment – ADH V2 Antagonist (Tolvaptan)

ADH Compensatory Mechanism in SIADH

• Increased Blood Volume

• Kidney

• Decreased Renin

• Decreased Angiotensin 2

• Decreased Mineralocorticoid

• Decreased Sodium Absorption into Blood

• Dilutes Sodium in Blood

• Increasing water permeability Late Distal Convoluted & Collecting Duct

• High Sodium in Urine

• Makes Hyponatremia Worse!!!!!

Diabetes Insipidus

• Non-Functional ADH system - resulting in excessive loss of water.

• Polyuria, polydipsia, hypernatremia & hypotension.

• Neurogenic DI

  • Failure of ADH secretion – lesion of hypothalamus or pituitary.

  • Treatment - Synthetic ADH (Desmopressin)

• Nephrogenic DI

  • Failure of principal cells to respond to ADH (V2 receptor mutation).

  • Treatment Restricted $Na^+$ diet.

Disorders of ADH and Pharmacological Intervention

• To little ADH Treated with V2 agonists Lypressin, Desmopressin

• Excess ADH Treated with V2 antagonist Demeclocylcine, Tolvaptan

Pharmacology of Adrenal Hormone: Aldosterone

Adrenal Gland Anatomy and Hormones

• Capsule

• Medulla: Adrenaline and Noradrenaline

• Adrenal cortex:

  • Zona glomerulosa: Mineralocorticoids (Aldosterone)

  • Zona fasciculata: Glucocorticoids (Cortisol)

  • Zona reticularis: Androgens (DHEA)

Adrenal Steroidogenesis

• Cholesterol

• P450scc

• StAR protein

• Pregnenolone

• 17a-hydroxylase

• Progesterone

• 17-OH pregnenolone

• 3B-HSD

• 17-OH progesterone

• Androstenedione

• Testosterone

Steroid Hormone Receptor Signalling

• Steroid hormone diffuses across the cell membrane and into the cell

• Binding to intracellular receptors induces translocation to nucleus

• Activated receptors bind to specific target gene response elements in DNA

• Modulate transcription of specific genes (synthesis of mRNA)

• mRNA is translated to protein

• Protein exerts its effect on the cell, altering cellular activity

Steroid Hormone Receptor Signalling - Aldosterone

• ↑ $Na$ Reabsorption

• ↑ Apical ENaC

• ↑ Apical K Channels

• ↑ Basolateral $Na/K$ ATPase Pump

• ↑ SGK1 – Activates $Na/K$ ATPase Pump

Mineralocorticoid: Aldosterone

• Regulates $Na^+$ and $K^+$ balance (Water Balance)

• Acts on distal tubules principal cells to increase

  • $Na$ reabsorption (blood)

  • $K^+$ secretion (urine)

• Nuclear Steroid Hormone synthesized by Zona Glomerulosa of the adrenal gland

• Acts on mineralocorticoid receptors (MR) specific to kidney (also colon, bladder sweat glands)

• Nuclear Steroid receptor (regulate DNA transcription)

• Kidney - Distal convoluted tubule (Principal Cell)

Aldosterone – Regulation

• Direct stimulated by low plasma $Na^+$ or high $K^+$ (action on zona glomerulosa cells of adrenal cortex)

• Indirect – Most Important stimulated by angiotensin II

• Renin-Angiotensin-Aldosterone System

Renin-Angiotensin-Aldosterone System and Hypertension

• Liver: Angiotensinogen

• Kidney: Renin (Decrease in renal perfusion (juxtaglomerular apparatus))

• Lungs: Angiotensin I, ACE

• Kidney: Tubular $Na^+$, $Cl^-$ reabsorption and $K^+$ excretion. $H_2O$ retention

• Adrenal gland (cortex):

  • Aldosterone secretion

• Arteriolar vasoconstriction, increase in blood pressure

• Pituitary gland (posterior lobe): ADH secretion

• Collecting duct: $H_2O$ reabsorption

• Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases.

Hyperaldosteronism

• Conn’s Syndrome - Adrenal hyperplasia/tumor of z. glomerulosa

• Primary causes – Adrenal Gland

• Secondary causes – Pathology outside of the adrenals

• Chronic low blood pressure - Congestive heart failure = High Renin = Excess Aldosterone

• Effects

  • Hypertension

  • Hypernatremia

  • Hypokalemia

  • Thirst

  • Odema

  • Heart Arrhythmia

  • Constipation

  • Weakness

  • Headache

  • Fatigue

  • Confusion

  • Chest pain

Hyperaldosteronism Treatment

• Treated with MR antagonist: Spironolactone or Eplerenone

Hypoaldosteronism

• Addison’s disease- Autoimmune disorder – destruction of z. glomerulosa cells

• Primary causes – Adrenal Gland

• Secondary causes – Pathology outside of the adrenals

• Renin Deficiency – Genetic predisposition (certain ethic groups)

• Effects

  • Hypotension

  • Hyponatremia

  • Hyperkalemia

  • Confusion

  • Fatigue

  • Seizure

  • Coma

  • Heart Arrhythmia

  • Constipation

  • Weakness

  • Vascular collapse

  • Dizziness

Hypoaldosteronism Treatment

• Treated with MR agonist: Fludrocortisone

Disorders involving aldosterone

• Hypersecretion of Aldosterone (Conn’s Syndrome) – Adrenal Ademona

  • Treated with MR antagonist: Spironolactone, Eplerenone

• Hyposecretion of Aldosterone (Addison’s) – Autoimmune Disorder

  • Replacement therapy –Fludrocortisone (aldosterone itself not used since short t ½)

Mineralocorticoids and Glucocorticoids - Summary

• Mineralocorticoids:

  • Endogenous Ligand: Aldosterone

  • Receptor: Mineralocorticoid Receptor (MR)

  • Regulated by: $Na^+$ / $K^+$ and Renin/Angiotensin

  • Physiological function - water & electrolyte balance (increases transcription of $Na$ channels and $Na/K$-ATPase)

    • Hyperaldosterone: Conn’s disease Hypertension – MR antagonist Spironolactone

    • Hypoaldosterone: Addison’s disease Hypotension – MR agonist Fludrocortisone

• Glucocorticoids:

  • Endogenous Ligand: Cortisol

  • Receptor: Glucocorticoid Receptor (GR)

  • Regulated by HPA axis (stress, circadian, feedback)

  • Physiological function – Increased metabolism (gluconeogenesis & protein catabolism)

  • Supraphysiological : Anti-inflammatory/ immunosuppressive (Decrease cytokines and inflammatory mediators)

  • Exploited therapeutically: Glucocorticoid agonists – Dexamethasone, Hydrocortisone, Beclomethasone

    • Hypercortisol: Cushing’s syndrome Metabolic dysfunction – Cortisol Synthesis antagonist - Metyrapone

Pharmacology of MR and GR - PCAP

• MR and GR affinity and the importance of 11β-hydroxysteroid dehydrogenase

Mineralocorticoids vs Glucocorticoids

• 2 hormones

  • Aldosterone

  • Cortisol

• 2 receptors

  • MR

  • GR

• 2 effects

  • Mineralocorticoid – Water Balance

  • Glucocorticoid – Metabolic Regulation

• Aldosterone: High affinity for MR : Low affinity for GR

• Cortisol: High affinity for MR : Low affinity for GR

• Problem! At basal circulating plasma levels of cortisol, MR receptors would be expected to be fully saturated/activated by cortisol

MR Receptor Occupancy

• Basal conditions

  • [Cortisol] > [aldosterone]

  • MR fully saturated by Cortisol

  • MR will not respond to a change in aldosterone !!!

11β-hydroxysteroid dehydrogenase (11β-HSD)

• MR are distributed in specialised tissues (kidney/colon/bladder)

• In these areas MR associated with high levels of an enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD)

• 11ß-HSD metabolises/removes cortisol

• Aldosterone is free to act on the MR

Inhibiting Cortisol Metabolism

• Carbenoxolone is used in the treatment of oral and gastric ulcer

• Glycerrhetinic acid

• Inhibits 11 ß-hydroxysteroid dehydrogenase, increasing cortisol levels.

11ß HSD in placenta

• protects foetus from elevation in cortisol from the maternal bloodstream

• Evidence of placenta levels of 11 ß HSD correlates with birth weight

• Evidence of maternal liquorice intake affecting behaviour in childhood

• Unadjusted individual predicted probability of borderline clinically significant (>82nd percentile) oppositional defiant disorder in children 8.1 years of age born in Helsinki, Finland, in 1998 according to level of maternal consumption of glycyrrhiza in liquorice during pregnancy, in standard deviation (SD) units

  • Temper

  • Argue

  • Spiteful

  • Defiant

  • Intolerant

Renal Pharmacology: ADH and RAAS

Introduction

• Scott Walker, Scott.Walker@newcastle.ac.uk

• Endocrine System, Newcastle University. UK | Malaysia Singapore

Kidney Functions

• Vital functions of the kidney:-

  • Selective reabsorption: This process allows the kidneys to reclaim essential substances like glucose, amino acids, and electrolytes from the glomerular filtrate back into the bloodstream, preventing their loss in urine.

  • Filtration: The kidneys filter blood to remove waste products and excess fluids, forming a filtrate that will eventually become urine.

  • Regulating BP: Kidneys play a crucial role in long-term blood pressure regulation through the renin-angiotensin-aldosterone system (RAAS) and by adjusting fluid volume.

Juxtamedullary Nephron Overview

• Ultrafiltration occurs in the glomerulus, where high pressure forces water and small solutes from the blood into Bowman's capsule.

• Key structures:-

  • Afferent arteriole: Carries blood into the glomerulus.

  • Efferent arteriole: Carries blood away from the glomerulus.

  • Glomerulus: A network of capillaries where filtration occurs.

  • Proximal convoluted tubule: Responsible for the reabsorption of glucose, amino acids, ions, and water.

  • Descending limb of loop of Henle: Permeable to water but not to solutes, allowing water to be reabsorbed into the medullary interstitium.

  • Ascending limb of loop of Henle: Impermeable to water but actively transports $Na^+, K^+$ and $Cl^-$ into the medullary interstitium, contributing to the corticomedullary osmotic gradient.

  • Distal convoluted tubule: Involved in further reabsorption of water and electrolytes, regulated by hormones like ADH and aldosterone.

  • Collecting duct: Collects filtrate from multiple nephrons and transports it through the medulla; the final site of water reabsorption.

  • Peritubular capillary: Surrounds the nephron and reabsorbs water and solutes from the interstitial fluid.

  • Bowman’s capsule: Surrounds the glomerulus and collects the filtrate.

Pharmacology of ADH

Pituitary Gland

• Pituitary = ‘Master endocrine gland’ because it secretes hormones that regulate other endocrine glands.

• Hypothalamus = Supreme commander (power behind the master) because it controls the pituitary gland through hormonal and neuronal signals.

Anatomy of the Pituitary Gland

• Posterior Lobe (Neurohypophysis)

• Anterior Lobe (Adenohypophysis)

• Two distinct parts:-

  • Posterior (neurohypophysis): stores & secretes hormones synthesized in hypothalamus (oxytocin, ADH)

  • Anterior (adenohypophysis): synthesizes and secretes hormones in response to hypothalamic regulation (TSH, ACTH, FSH, LH, GH, PL)

    • TSH (Thyroid-Stimulating Hormone): Stimulates thyroid hormone synthesis and secretion.

    • ACTH (Adrenocorticotropic Hormone): Stimulates adrenal cortex to release cortisol.

    • FSH (Follicle-Stimulating Hormone): Regulates reproductive functions in both males and females.

    • LH (Luteinizing Hormone): Controls ovulation in females and testosterone production in males.

    • GH (Growth Hormone): Promotes growth and development.

    • PRL (Prolactin): Stimulates milk production in females.

Posterior Pituitary

• Consists mainly of neuronal projections (axons) extending from the supraoptic and paraventricular nuclei of the hypothalamus.

• These axons release peptide hormones into the capillaries of the hypophyseal circulation

• Does not produce any hormones, but simply stores and secretes hormones produced in the hypothalamus

• 2 hormones-

  • Antidiuretic hormone (ADH, vasopressin)- Regulation of renal function

    • ADH plays a key role in maintaining fluid balance by increasing water reabsorption in the kidneys.

  • Oxytocin- Regulation of uterine contraction

    • Oxytocin is involved in social bonding, reproduction, and childbirth.

  • Both short peptides (9 a.a.)

• These hormones are then stored in neurosecretory vesicles

ADH and Blood Volume/Pressure Regulation

• Low blood volume/pressure (baroreceptor): Baroreceptors detect changes in blood pressure and signal the hypothalamus.

• High osmolarity (osmoreceptors): Osmoreceptors in the hypothalamus detect changes in blood osmolarity.

• Hypothalamus signals Posterior Pituitary to release ADH

• ADH acts on:-

  • V1 receptors (GPCR) in blood vessel smooth muscle: Vasoconstriction (maintain blood pressure)

  • V2 receptors (GPCR) in distal tubule: Increased water reabsorption

    • Increased aquaporin-2 expression and insertion into the apical membrane of principal cells, enhancing water reabsorption.

• Feedback: Blood volume/pressure returns to normal

ADH Release

• Anterior Hypothalamus

• Hypothalamus & Posterior Pituitary

• ADH

Mechanism of Action of ADH

• Increasing water permeability in distal convoluted & collecting duct resulting in concentrated urine

  1. ADH binds to V2 receptors on the basolateral of principal cells

  2. Promotes conversion of ATP to cAMP via adenylate cyclase

  3. Activated Protein Kinase A

  4. Promotes fusion of aquaporin2 into the apical luminal membrane enhancing permeability to $H_2O$

Water Absorption in Late DCT & Collecting Duct

• Ascending Limb of Loop of Henle, DCT & Collecting duct – Impermeable to $H_2O$

• $H_2O$ absorption can occur in Late DCT & Collecting duct in the presence of the peptide hormone – Anti Diuretic Hormone (ADH)

• ADH promotes membrane fusion of AQP2

Stimulants and Depressants of ADH

• ADH Hormone Level Stimulants:-

  • Opioids: Can stimulate ADH release, leading to fluid retention.

  • Anti-Depressants (SSRI, TCA): Some antidepressants can increase ADH secretion as a side effect.

  • Nicotine: Stimulates ADH release, contributing to fluid retention.

  • MDMA: Can cause excessive ADH release, leading to hyponatremia.

• ADH Hormone Level Depressant:-

  • Alcohol: Inhibits ADH release, causing increased urine output and dehydration.

Syndrome of Inappropriate ADH Secretion (SIADH)

• Excessive ADH secretion leading high urine osmolality, increased total body water – hyponatremia, hypoosmotic blood plasma and hypervolemia.

• Causes-

  • Post Operative (Metabolic Response to Trauma and Stress) (30%)

  • Head Trauma (20%)

  • Ectopic ADH production (Tumours) (20%)

  • Drugs

    • Certain medications can induce SIADH by directly stimulating ADH release or enhancing its effects on the kidneys.

• Treatment – ADH V2 Antagonist (Tolvaptan)

ADH Compensatory Mechanism in SIADH

• Increased Blood Volume

• Kidney

• Decreased Renin

• Decreased Angiotensin 2

• Decreased Mineralocorticoid

• Decreased Sodium Absorption into Blood

• Dilutes Sodium in Blood

• Increasing water permeability Late Distal Convoluted & Collecting Duct

• High Sodium in Urine

• Makes Hyponatremia Worse!!!!!

Diabetes Insipidus

• Non-Functional ADH system - resulting in excessive loss of water.

• Polyuria, polydipsia, hypernatremia & hypotension.

• Neurogenic DI- Failure of ADH secretion – lesion of hypothalamus or pituitary.

  • Treatment - Synthetic ADH (Desmopressin)

• Nephrogenic DI- Failure of principal cells to respond to ADH (V2 receptor mutation).

  • Treatment Restricted $Na^+$ diet.

    • A low-sodium diet can help reduce urine output by decreasing the amount of sodium that needs to be excreted.

Disorders of ADH and Pharmacological Intervention

• To little ADH Treated with V2 agonists Lypressin, Desmopressin

• Excess ADH Treated with V2 antagonist Demeclocylcine, Tolvaptan

Pharmacology of Adrenal Hormone: Aldosterone

Adrenal Gland Anatomy and Hormones

• Capsule: Outer protective layer.

• Medulla: Adrenaline and Noradrenaline, which are catecholamines involved in the ‘fight or flight’ response.

• Adrenal cortex:-

  • Zona glomerulosa: Mineralocorticoids (Aldosterone), which regulate $Na^+$ and $K^+$ balance.

  • Zona fasciculata: Glucocorticoids (Cortisol), which regulate glucose metabolism and have anti-inflammatory effects.

  • Zona reticularis: Androgens (DHEA), which are precursors to sex hormones.

Adrenal Steroidogenesis

• Cholesterol: The precursor for all steroid hormones.

• P450scc: An enzyme that converts cholesterol to pregnenolone in the mitochondria.

• StAR protein: Transports cholesterol into the mitochondria for steroid hormone synthesis.

• Pregnenolone: A precursor to all adrenal steroid hormones.

• 17a-hydroxylase: An enzyme involved in the synthesis of cortisol and androgens.

• Progesterone: A precursor to mineralocorticoids and glucocorticoids.

• 17-OH pregnenolone: A precursor to cortisol and androgens.

• 3B-HSD: An enzyme involved in the synthesis of progesterone and androstenedione.

• 17-OH progesterone: A precursor to cortisol.

• Androstenedione: A precursor to testosterone and estrogen.

• Testosterone: A primary male sex hormone.

Steroid Hormone Receptor Signalling

• Steroid hormone diffuses across the cell membrane and into the cell

• Binding to intracellular receptors induces translocation to nucleus

• Activated receptors bind to specific target gene response elements in DNA

• Modulate transcription of specific genes (synthesis of mRNA)

• mRNA is translated to protein

• Protein exerts its effect on the cell, altering cellular activity

Steroid Hormone Receptor Signalling - Aldosterone

• ↑ $Na$ Reabsorption

• ↑ Apical ENaC

• ↑ Apical K Channels

• ↑ Basolateral $Na/K$ ATPase Pump

• ↑ SGK1 – Activates $Na/K$ ATPase Pump

Mineralocorticoid: Aldosterone

• Regulates $Na^+$ and $K^+$ balance (Water Balance)

• Acts on distal tubules principal cells to increase-

  • $Na$ reabsorption (blood)

  • $K^+$ secretion (urine)

    • Aldosterone promotes sodium reabsorption, increasing water retention and blood pressure, while also increasing potassium excretion to maintain electrolyte balance.

• Nuclear Steroid Hormone synthesized by Zona Glomerulosa of the adrenal gland

• Acts on mineralocorticoid receptors (MR) specific to kidney (also colon, bladder sweat glands)

• Nuclear Steroid receptor (regulate DNA transcription)

• Kidney - Distal convoluted tubule (Principal Cell)

Aldosterone – Regulation

• Direct stimulated by low plasma $Na^+$ or high $K^+$ (action on zona glomerulosa cells of adrenal cortex)

• Indirect – Most Important stimulated by angiotensin II

• Renin-Angiotensin-Aldosterone System

Renin-Angiotensin-Aldosterone System and Hypertension

• Liver: Angiotensinogen, a precursor protein.

• Kidney: Renin (Decrease in renal perfusion (juxtaglomerular apparatus))

• Lungs: Angiotensin I, ACE (Angiotensin-Converting Enzyme)

• Kidney: Tubular $Na^+$, $Cl^-$ reabsorption and $K^+$ excretion. $H_2O$ retention

• Adrenal gland (cortex):- Aldosterone secretion

• Arteriolar vasoconstriction, increase in blood pressure

• Pituitary gland (posterior lobe): ADH secretion

• Collecting duct: $H_2O$ reabsorption

• Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases.

Hyperaldosteronism

• Conn’s Syndrome - Adrenal hyperplasia/tumor of z. glomerulosa

• Primary causes – Adrenal Gland

• Secondary causes – Pathology outside of the adrenals

• Chronic low blood pressure - Congestive heart failure = High Renin = Excess Aldosterone

• Effects- Hypertension

  • Hypernatremia

  • Hypokalemia

  • Thirst

  • Odema

  • Heart Arrhythmia

  • Constipation

  • Weakness

  • Headache

  • Fatigue

  • Confusion

  • Chest pain

    • These symptoms arise due to the imbalance in electrolytes and fluid volume caused by excessive aldosterone secretion.

Hyperaldosteronism Treatment

• Treated with MR antagonist: Spironolactone or Eplerenone

Hypoaldosteronism

• Addison’s disease- Autoimmune disorder – destruction of z. glomerulosa cells

• Primary causes – Adrenal Gland

• Secondary causes – Pathology outside of the adrenals

• Renin Deficiency – Genetic predisposition (certain ethic groups)

• Effects- Hypotension

  • Hyponatremia

  • Hyperkalemia

  • Confusion

  • Fatigue

  • Seizure

  • Coma

  • Heart Arrhythmia

  • Constipation

  • Weakness

  • Vascular collapse

  • Dizziness

    • These symptoms result from the deficiency in aldosterone, leading to electrolyte imbalances and decreased fluid volume.

Hypoaldosteronism Treatment

• Treated with MR agonist: Fludrocortisone

Disorders involving aldosterone

• Hypersecretion of Aldosterone (Conn’s Syndrome) – Adrenal Ademona- Treated with MR antagonist: Spironolactone, Eplerenone

• Hyposecretion of Aldosterone (Addison’s) – Autoimmune Disorder- Replacement therapy –Fludrocortisone (aldosterone itself not used since short t ½)

Mineralocorticoids and Glucocorticoids - Summary

• Mineralocorticoids:-

  • Endogenous Ligand: Aldosterone

  • Receptor: Mineralocorticoid Receptor (MR)

  • Regulated by: $Na^+$ / $K^+$ and Renin/Angiotensin

  • Physiological function - water & electrolyte balance (increases transcription of $Na$ channels and $Na/K$-ATPase)

    • Hyperaldosterone: Conn’s disease Hypertension – MR antagonist Spironolactone

    • Hypoaldosterone: Addison’s disease Hypotension – MR agonist Fludrocortisone

• Glucocorticoids:-

  • Endogenous Ligand: Cortisol

  • Receptor: Glucocorticoid Receptor (GR)

  • Regulated by HPA axis (stress, circadian, feedback)

  • Physiological function – Increased metabolism (gluconeogenesis & protein catabolism)

  • Supraphysiological : Anti-inflammatory/ immunosuppressive (Decrease cytokines and inflammatory mediators)

  • Exploited therapeutically: Glucocorticoid agonists – Dexamethasone, Hydrocortisone, Beclomethasone

    • Hypercortisol: Cushing’s syndrome Metabolic dysfunction – Cortisol Synthesis antagonist - Metyrapone

Pharmacology of MR and GR - PCAP

• MR and GR affinity and the importance of 11β-hydroxysteroid dehydrogenase

Mineralocorticoids vs Glucocorticoids

• 2 hormones-

  • Aldosterone

  • Cortisol

• 2 receptors-

  • MR

  • GR

• 2 effects-

  • Mineralocorticoid – Water Balance

  • Glucocorticoid – Metabolic Regulation

• Aldosterone: High affinity for MR : Low affinity for GR

• Cortisol: High affinity for MR : Low affinity for GR

• Problem! At basal circulating plasma levels of cortisol, MR receptors would be expected to be fully saturated/activated by cortisol

MR Receptor Occupancy

• Basal conditions- [Cortisol] > [aldosterone]

  • MR fully saturated by Cortisol

  • MR will not respond to a change in aldosterone !!!

11β-hydroxysteroid dehydrogenase (11β-HSD)

• MR are distributed in specialised tissues (kidney/colon/bladder)

• In these areas MR associated with high levels of an enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD)

• 11ß-HSD metabolises/removes cortisol

• Aldosterone is free to act on the MR

Inhibiting Cortisol Metabolism

• Carbenoxolone is used in the treatment of oral and gastric ulcer

• Glycerrhetinic acid

• Inhibits 11 ß-hydroxysteroid dehydrogenase, increasing cortisol levels.

11ß HSD in placenta

• protects foetus from elevation in cortisol from the maternal bloodstream

• Evidence of placenta levels of 11 ß HSD correlates with birth weight

• Evidence of maternal liquorice intake affecting behaviour in childhood

• Unadjusted individual predicted probability of borderline clinically significant (>82nd percentile) oppositional defiant disorder in children 8.1 years of age born in Helsinki, Finland, in 1998 according to level of maternal consumption of glycyrrhiza in liquorice during pregnancy, in standard deviation (SD) units-

  • Temper

  • Argue

  • Spiteful

  • Defiant

  • Intolerant