L16 Renal pharmacology ADH and RAAS

what does the posterior pituitary do (neurohypophysis)

stores and secretes hormones synthesised in the hypothalamus (oxytocin, ADH)

what does the anterior pituitary do (adenohypophysis)

synthesises and secretes hormones in response to hypothalamic regulation (TSH, ACTH, FSH, LH, GH, PL)

what does the posterior pituitary consist of

neuronal projections (axons) extending from the supraoptic and paraventricular nuclei of the hypothalamus

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

the posterior pituitary doesnt produce any hormones, but simply stores and secretes…

hormones produced in the hypothalamus

what hormones does the posterior pituitary secrete

Antidiuretic hormone (ADH, vasopressin)

• regulation of renal function

Oxytocin

• regulation of uterine contraction (both short peptides (9.a.a)

stored in neurosecretory vesicles

posterior pituitary secretes ADH in response to low blood volume/pressure (baroreceptor)

• ADH binds to blood vessel smooth muscle V1 GPCR to initiate vasoconstriction (maintains blood pressure)

• negative feedback loop

posterior pituitary secretes ADH in response to high osmolarity (osmoreceptors) in the hypothalamus

ADH binds to distil tubule V2 receptors on the GPCR which increase water reabsorption to maintain blood volume/pressure

• negative feedback loop

anterior pituitary in the hypothalamus signals posterior pituitary to secrete ADH from

paraventricular nucleus cells

• ADH along an axon past axon terminals and into the capillary and out into the veins

mechanism of action of ADH

• ADH binds to V2 receptors on the basolateral of principle cells

• this promotes conversion of ATP to cAMP via adenylate cyclase

• PKA is activated and promotes fusion of aquaporin 2 into the apical luminal membrane, enhancing permeability to H20

• This increases water permeability in the distal convoluted tubule and the collecting duct which results in concentrated urine

the ascending limb of the loop of henle, DCT and collecting duct is impermeable to…

H20

H20 absorption can occur in the late DCT and collecting duct in the presence of the peptide hormone…

ADH

ADH promotes membrane fusion of

Aquaporin 2

• concentrating urine (anti-diuresis)

ADH hormone level stimulants

• opioids

• anti-depressants

• nicotine

• MDMA

ADH hormone level depressant

alcohol

syndrome of inappropriate ADH secretion (SIADH)

excessive ADH secretion leads to high urine osmolatity which increases total body water

• hyponatremia

• hypoosmotic blood plasma

• hypervolemia

what are the causes of inappropriate ADH secretion (SIADH)

• post operative trauma and stress (metabolic) 30%

• head trauma (20%)

• ectopic ADH production (tumours) (20%)

• drugs

what is treamtent for inappropriate ADH secretion (SIADH)

ADH V2 Antagonist

• Tolvaptan

describe inappropriate ADH secretion (SIADH) syndrome

increasing ADH increases water permeability of the late distal convoluted tubule and the collecting duct which increases blood volume

• increased blood volume dilutes sodium in the blood so a compensatory mechanism in the kidney decreases renin which decreases angiotensin 2 which decreases mineralocorticoids and decreases sodium absorption into the blood

• this means a high concentration of sodium is in the urine that makes hyponatremia worse

describe diabetes insipidus

non-functional ADH system resulting in excessive water loss

• polyuria, polydipsia, hypernatremia, hypotension

describe neurogenic diabetes insipidus

failure of ADH secretion-lesion of hypothalamus or pituitary

treatment for neurogenic diabetes insipidus

synthetic ADH (Desmopressin)

describe nephrogenic diabetes insipidus

failure of principal cells to respond to ADH (V2 receptor mutation)

what is the treatment for diabetes insipidus

restricted Na+ diet

what is too little ADH treated with

V2 agonists

• lypressin

• desmopressin

excess ADH treatment

• V2 antagonist

• demeclocylcine

• tolvaptan

adrenal gland adrenal cortex anatomy zona glomerulosa

mineralocorticoids (aldosterone)

adrenal gland adrenal cortex anatomy zona fasciculata

glucocorticoids (cortisol)

adrenal gland adrenal cortex anatomy zona reticularis

androgens (DHEA)

adrenal gland anatomy medulla

AD and NAD

adrenal steroidogenesis

cholesterol forms pregnenolone which forms progesterone which forms deoxycorticosterone which forms corticosterone which forms 18-OH corticosterone which forms aldosterone (mineralocorticoid)

describe steroid hormone receptor signalling

• steroids diffuse across the cell membrane and into the cell

• binding to intracellular receptors induces translocation to the nucleus

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

• modulates transcription of specific genes (synthesis of mRNA)

• mRNA is translated to the protein

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

what does aldosterone regulate

Na+ and K+ balance (water balance)

• acts on distal tubules principle cells to increase Na reabsorption (blood)

• increases K+ secretion (urine)

aldosterone is a nuclear steroid hormone synthesized by

zona glomerulosa of the adrenal gland

aldosterone acts on mineralocorticoid receptors specific to the

kidney

• also colon, bladder, sweat glands

nuclear steroid receptor

regulates DNA transcription

direct aldosterone regulation

stimulated by a low plasma Na+ or a high K+ (action on zona glomerulosa cells of the adrenal cortex)

indirect aldosterone regulation

stimulated by angiotensin II

what are the primary causes of hyperaldosteronism

adrenal gland

• Conn’s syndrome- adrenal hyperplasia/tumour of z.glomerulosa

what are the secondary causes of hyperaldosteronism

pathology outside of the adrenals

• chronic low blood pressure- congestive heart faillure= high renin =excess aldosterone

increasing aldosterone causes decreased Na+ secretion into the urine

this causes Hypernatremia (thirst, odema) that causes hypertension (headache, fatigue)

increasing aldosterone increases K+ secretion into the urine

this causes Hypokalemia (heart arrhythmia, constipation)

what is hyperaldosteronism treated with

Mineralocorticoid Receptor antagonist

• spironolactone

• eplerenone

primary causes of hypoaldosteronism

adrenal gland- Addison’s disease -autoimmune disorder- destruction of z.glomerulosa cells

secondary causes of hypoaldosteronism

pathology outside of the adrenals

• renin deficiency -genetic predisposition (certain ethnic groups)

decreasing aldosterone increases Na+ secretion into urine

this causes hyponatremia (confusion, fatigue) which causes hypotension (vascular collapse, dizziness)

decreased aldosterone causes decreased K+ secretion into urine which causes

hyperkalemia (heart arrhythmias, constipation)

hypoaldosteronism is treated with

a mineralocorticoid agonist

• fludrocortisone

what is hypersecretion of aldosterone (Conn’s syndrome) treated with

MR antagonist: spironolactone, eplerenone

what is hyposecretion of Aldosterone (Addison’s) treated with

replacement therapy

• fludrocortisone (aldosterone itself isnt used due to a short half life)

mineralocorticoid summary

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)

Main Disorders

Hyperaldosterone: Conn’s disease

Hypertension – MR antagonist Spironolactone

Hypoaldosterone: Addison’s disease

Hypotension – MR agonist Fludrocortisone

glucocorticoids summary

Endogenous Ligand: Cortisol

Receptor: Glucocorticoid Receptor (GR)

Regulated by HPA axis (stress, circadian, feedback)

Physiological function – Increased metabolism

(gluconeogenis & protein catabolism)

Supraphysiological : Anti-inflammatory/

immunosuppressive

(Decrease cytokines and inflammatory mediators)

Exploited therapeutically: Glucocorticoid agonists –

Dexamethasone, Hydrocortisone, Beclomethasone

Main Disorders

Hypercortisol: Cushing’s syndrome

Metabolic dysfunction – Cortisol Synthesis

antagonist - Metyrapone

aldosterone has high affinity for MR but

low affinity for GR

cortisol has high affinity for MR but

low affinity for GR

at basal circulating plasma levels of cortisol, MR receptors are

fully saturated by cortisol

basal conditions: cortisol conc is higher than aldosterone

• MR is fully saturated by Cortisol

• MR will not respond to a change in aldosterone

in specialised tissues, MR is associated with high levels of

11beta-hydroxysteroid dehydrogenase enzyme (11beta-HSD)

• 11beta-HSD metabolises/removes cortisol

carbenoxolone (glycerrhetinic acid from liquorice) is used in the treatment of

oral and gastric ulcer

liquorice in pregnancy has side effects (glycerrhetinic acid/glycyrrhiza)

11beta HSD in the placenta protects the foetus from elevation in cortisol from the maternal bloodstream

• baby weight

• mental cognition- oppositional defiant disorder