Block 2 - Diuretic Pharm Flashcards
How are diuretics classified?
- Site of action (loop)
- Efficacy (high-ceiling)
- Chemical structure (thiazide)
- Similarity of action with other diuretics (thiazide-like)
- Effects on K+ excretion (K+ sparing)
What is a nephron?
Single epithelium lined by a single layer of cells which can generically be referred to as tubular epithelial cells
Describe the efficacy of diuretics working in the PCT?
PCT reabsorbs 65% of filtered Na+, however diuretics have limited effect
thick ascending limb has a great re-absorpative capacity -> reabsorbs most of the rejective from the PCT
What is the MOA of CA-I?
NaHCO3 is poorly reabsorbed from the lumen -> needs to be converted to CO2 and H2O by CA that is inhibited by CAI located in the PCT
How does CA-I effect renal system?
CAI decreases NaHCO3 reabsorption by increasing HCO3 excretion -> Increased urine pH -> Metabolic acidosis
How does CA-I effect extra-renal system?
CA increases HCO3 in aqueous humor-> CAI decreases aqueous humor formation and intraocular pressure
What are the therapeuti uses of CAIs?
Glaucoma, edema (low efficacy)
What is an example of CAI? Its characteristics?
Diamox (Acetazolamide)
F: 100%
t1/2: 6-9 h
Can cause sulfa-like toxicities due to sulfonamide
What is important about the thick ascending loop of henle (TAL)?
- Site for reabsorption of Na, K, Cl but nearly impermeable to water
- Major site of Ca2+ and Mg2+ reabsorption
Why are loops considered high ceiling?
Highly efficacious diuretics
How much Na+ does TAL reabsorb?
20%
What is the NKCC2 and how do loops affect it?
- NKCC2 carriers mediate reabsorption of Na, K, and 2Cl
- Loops inhibit this carrier
What are the loop diuretics?
- Lasix (Furosemide)
- Demadex (Torsemide)
- Ethacrynic acid
- Bumex (Bumetanide)
PK properties of Lasix?
F ~ 60%
t½ ~ 1.5 h
CL (~65% renal ~35% hepatic)].
PK properties of Demadex
F ~ 80%
t½ ~ 3.5 h
CL (~20% renal ~80% hepatic)].
PK properties of Ethacrynic acid?
F ~ 100%
t½ ~ 1 h
CL (~67% renal ~37% hepatic
PK properties of Bumex?
F ~ 80%
t½ ~ 0.8 h
CL (~62% renal ~38% hepatic)
How do loops cause hyponatremia? Along with other ADRs?
↑ excretion of Na+, K+, Ca2+, Mg2+ with fluid volume depletion, hypokalemia, hypomagnesemia, and hypocalcemia
How do loops cause hyperuricemia?
Decrease uric acid excretion that may result to gout like symptoms
What are some non-renal loop actions?
Direct vascular effects, increasing systemic venous capacitance and decreases left ventricular filing pressure
What loop diuretics have weak CAI activity?
Lasix and Ethacrynic acid
What are loop diuretic indications?
- CHF
- HTN
- Edema of CKD
- Nephrotic syndrome
- Ascites of liver cirrhosis
- Acute pulmonary edema
What are the ADR of loops?
- Fluid and electrolyte imbalance
- Gouty attacks
- Hyperglycemia
- Ototoxicity (hearing impairment/deafness)
How much NaCl is reabsorbed in DCT? Water
10%
Impermeable to water
What is the MOA of thiazides?
NCC (Na/Cl carrier) pumps Na+ and Cl- into DCT and benzothiadiazides inhibits this process located in the DCT
What are the thiazide drugs?
- Hydrochlorothiazide
- Hygroton, Thalitone (Chlorthalidone)
- Chlorothiazide
- indapamide
- Metolazone
PK of hydrochlorothiazide?
F ~ 70%
t½ ~ 2.5 h
cleared renally
PK of chlorthalidone?
F ~ 65%
t½ ~ 47 h
CL (~65% renal, ~ 10% biliary, ~25% unknown pathway
PK of chlorothiazide?
F = 9 – 56%
t½ ~ 1.5 h
cleared renally
PK of indapamide?
F ~ 93%
t½ ~ 14 h
cleared hepatically
PK of metolazone?
F ~ 60%
CL (~80% renal, ~10% hepatic, ~10% biliary
What are some of the pharmacological actions of thiazides and how does that contribute to its ADRs?
- Increased Na+ and Cl- excretion with volume depletion -> hyponatermia, hypochloremia, hypotension
- Increase excretion of K+ -> hypokalemia
- Decreased Ca+ and uric acid excretion -> hypercalcemia and hyperuricemia
- Can cause weak CAI action
What are the indications of thiazides?
- HTN
- Edema with CHF
- Hepatic cirrhosis
- Renal (nephrotic syndrome and chronic renal failure)
What are common ADRs of thiazides?
- Fluid and electrolyte balance
- hypotension
- hypokalemia, hyponatremia, hypochloremia
- metabolic alkalosis
- hypomagnesemia
- hypercalcemia, and hyperuricemia
How much of NaCl is reabsorbed in the CT?
2-5%
What is important about the CT?
- Site where aldosterone exerts a significant influence
- Major site of potassium secretion
What drug class is active in the CT?
K+ sparing
What is the MOA of K+ sparing
Na+ is reabsorbed by epithelial Na+ channels (ENaC) with the loss of K+ and H+
Diuretic inhibits ENaC -> increased Na+ and Cl- excretion
What are potassium sparing drugs?
- Amiloride
- Triamterene
PK of amiloride?
F = 12 - 25%
t½ ~ 9 h
cleared renally
PK of triamterene?
F ~ 50%
t½ ~ 4 h
extensively metabolized to an active metabolite which is cleared hepatically
What is aldosterone antagonists site of action?
CT
What are the aldosterone antagonists?
- Spironolactone (Aldactone, CaroSpir)
- Eplerenone
PK of aldactone?
Some affinity toward progesterone and androgen receptors
F ~ 65%
t½ ~ 1.6 h
cleared hepatically
PK of eplerenone?
Very low affinity for progesterone and androgen receptors
t½ ~ 5 h
cleared hepatically
ADRs of diuretics in the CT? Spironolactone?
Hyperkalemia
Gynecomastia, impotence, menstrual irregularities
In what ways are thiazides administered? Names?
Coadministered with thiazides and loops
Dyazide, Maxzide (Triamterene + HCTZ)
K+ sparing/thiazide
How do loops and thiazide induce hyperuricemia?
- Urate is poorly soluble and is transported across cell membranes
- Diuretics increase rate reabsorption at the PCT and inhibit secretion into tubules by competing with irate for the efflux transporters
According to the highlighted number which drugs correspond to hyper uricemia
- Furosemide, bumetanide
- Furosemide, thiazides
- HCTZ, torasemide
- Torasemide
What is the BBW of loop diuretics?
Potent
High doses may need to profound diuresisw with water and electrolyte depletion
What is the BBW of HCTZ? Counseling points?
- Increased risk of non-melanoma skin cancer
Requires protection of skin from sun and undergo skin cancer screenings
What is are the outcomes of chronic diuretic use?
Sustained deficit in total-body Na+ which is not compatible with life
What is diuretic braking?
Renal compensatory mechanisms try to bring the balance of Na+ excretion with Na+ intake
What is the mechanism of braking?
- Activation of sympathetic nervous system
- Activation of RAAS
- Decreased arterial BP, renal epithelial cell hypertrophy
- Increased renal epithelial transporter expression and alterations in natriuretic hormone (ANP)