The kidney filters the extracellular fluid volume across the renal glomeruli an average of 12 times a day, and the renal nephrons precisely regulate the fluid volume of the body and its electrolyte content via processes of secretion and reabsorption. Disease states such as hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis may disrupt this balance. Diuretics increase the rate of urine flow and Na+ excretion and are used to adjust the volume or composition of body fluids in these disorders. Precise regulation of body fluid osmolality is also essential. It is controlled by a finely tuned homeostatic mechanism that operates by adjusting both the rate of water intake and the rate of solute-free water excretion by the kidneys—that is, water balance. Abnormalities in this homeostatic system can result from genetic diseases, acquired diseases, or drugs and may cause serious and potentially life-threatening deviations in plasma osmolality.
Part I of this chapter first describes renal physiology, then introduces diuretics with regard to mechanism and site of action, effects on urinary composition, and effects on renal hemodynamics, and then integrates diuretic pharmacology with a discussion of mechanisms of edema formation and the role of diuretics in clinical medicine. Specific therapeutic applications of diuretics are presented in Chapters 32 (hypertension) and 33 (heart failure). Part II of this chapter describes the vasopressin system that regulates water homeostasis and plasma osmolality and factors that perturb those mechanisms and examines pharmacological approaches for treating disorders of water balance.
Abbreviations
ACTH: corticotropin (previously adrenocorticotropic hormone)
ADH: antidiuretic hormone
AIP: aldosterone-induced protein
Ang: angiotensin (e.g., AngII and AngIII)
ANP: atrial natriuretic peptide
ATL: ascending thin limb
AVP: arginine vasopressin
BNP: brain natriuretic peptide
cGMP: cyclic guanosine monophosphate
CHF: congestive heart failure
CKD: chronic kidney disease
CNGC: cyclic nucleotide-gated cation channel
CNP: C-type natriuretic peptide
CNT: connecting tubule
COX: cyclooxygenase
DAG: diacyglycerol
DCT: distal convoluted tubule
DDAVP: 1-deamino-8-D-AVP (desmopressin)
DI: diabetes insipidus
DTL: descending thin limb
ECFV: extracellular fluid volume
ENaC: epithelial Na+ channel
ENCC1 or TSC: the absorptive Na+-Cl− symporter
ENCC2, NKCC2, or BSC1: the absorptive Na+-K+-2Cl− symporter
ENCC3, NKCC1, or BSC2: the secretory Na+-K+-2Cl− symporter
GFR: glomerular filtration rate
GPCR: G protein-coupled receptor
IMCD: inner medullary collecting duct
IP3: inositol trisphosphate
LOX: lipoxygenase
MR: mineralocorticoid receptor
NP: natriuretic peptide
NPR: natriuretic peptide receptor (e.g., NPRA, B, or C)
NSAID: nonsteroidal anti-inflammatory drug
OAT: organic anion transporter
PG: prostaglandin
PK: protein kinase (e.g., PKA, PKB, PKG)
PL: phospholipase (e.g., PLC, PLD)
PTH: parathyroid hormone
PVN: paraventricular nucleus
RAS: renin-angiotensin system
RBF: renal blood flow
SGLT2: sodium-glucose cotransporter type 2
SIADH: syndrome of inappropriate secretion of ADH
SON: supraoptic nucleus
TAL: thick ascending limb
TGF: tubuloglomerular feedback
VP: vasopressin
VRUT: vasopressin-regulated urea transporter
vWD: von Willebrand disease