Medical Pharmacology Chapter 26:  Renal Pharmacology

• Mechanism by which lithium compounds may cause a syndrome like diabetes insipidus

• Introduction

  • Vasopressin: regulates water conservation.

  • Synonymous terms: vasopressin: arginine vasopressin (AVP): antidiuretic hormone (ADH)

• Similar peptide: oxytocin-- common vasopressin and oxytocin receptor antagonists

  • Binds to myoepithelial cells in the mammary gland (milk ejection) and on uterine smooth muscle cells (uterine contraction)

• The antidiuretic system consists of:

  • CNS component (vasopressin synthesis, transport, storage, release)

    • Supraoptic nucleus (SON)

    • Paraventricular nucleus (PVN)

  • Renal collecting duct system

    • Epithelial cells -- increased water permeability in response to vasopressin.

• Increased plasma osmolality: increased vasopressin release

• Factors affecting/modifying vasopressin release

  • Hypovolemia

  • Hypotension

  • Hypoxia

  • Drugs

  • Pain

  • Nausea

  • Certain endogenous hormones

• Regulation of vasopressin secretion

  •  Osmotic Stimulation of Vasopressin Release

    • CNS structures: osmoreceptive complex

      1.  Osmosensitive: magnocellular neurons (SON, PVN)

      2.  Subfornical organ (SFO) project to SON/PVN

      3.  Organum vasculosum of the lamina terminalis (OVLT) project during clearing directly to SON/PVN

  •  Hypovolemic/hypotension stimulation of Vasopressin Release:

    •  Baroreceptors:

      •  Blood volume (filling pressures) sensed by baroreceptors in:

        •  Left atrium

        •  Left ventricle

        •  Pulmonary veins

      •  Arterial blood pressure: baroreceptors  located in carotid sinus and aorta

      •  Nerve impulses from baroreceptors are carried:

        • By the vagus and glossopharyngeal nerves to the nucleus of the solitary tract

        • To the α₁-noradrenergic cells in the caudal ventrolateral medulla

        • To the SON and PVN

• Hormonal Effects

  • Vasopressin release: stimulation

    • Acetylcholine (nicotinic)

    • Glutamine

    • Histamine (H₁)

    • Dopamine (D₁ & D₁)

    • Neuropeptide Y

    • Prostaglandins

    • Aspartate

    • Cholecystokinin

    • Substance P

    • Vasoactive intestinal peptide

    • Angiotensin II

  • Vasopressin release: inhibition:

    • Atrial natriuretic peptide

    • γ-aminobutyric acid (GABA)

    • Opioids (dynorphin)

  • Drug Effects

    • Vasopressin Release: Stimulation

      • Vincristine (Oncovin)

      • Nicotine

      • Morphine (high doses)

      • Cyclophosphamide

      • Tricyclic antidepressants

      • Epinephrine

      • Lithium (inhibits renal effects of vasopressin; enhances vasopressin release)

    • Vasopressin Release: Inhibition

      • Ethanol

      • Glucocorticoids

      • Haloperidol (Haldol)

      • Promethazine (Pherergan)

      • Phenytoin (Dilantin)

      • Morphine (low dose)

      • Fluphenazine (Prolixin)

      • Oxilorphan

      • Carbamazepine (Tegretol)(renal effects -- anti-diuresis; inhibits vasopressin secretion (central effect)

      • Lithium Effects:

        • Inhibits antidiuretic effect of vasopressin

          • Lithium is used widely for management of bipolar disorder (manic- depressive).

          • Lithium uptake by the sodium channel in the collecting duct, causes lithium-induced nephrogenic diabetes insipidus.

          • Lithium polyuria: normally reversible

          • Mechanism of action:

            • Reduces V₂ receptor-mediated adenyl cyclase stimulation

        •  Often, the antibiotic demeclocycline (Declomycin) reduces the antidiuretic effects of vasopressin (possibly because of reduced cyclic AMP)