Renal/Uro pharm Flashcards
Diuretic
Any substance that increases urine volume
- Inhibitors of renal ion transporters
- Decreases the reabsorption of sodium at different sites of the nephron
- Increase in urine flow is secondary to increase in sodium excretion
- Kidneys adjust the excretion of sodium and water to maintain extracellular fluid (ECF)
- In pathophysiologic states, this balance is altered
Used for:
- Diseases causing edema: CHF, Cirrhosis, nephrotic syndrome, renal failure
- HTN
- Nephrolithiasis
- Hypercalcemia (loop diuretics)
- Diabetes insipidus
Natriuretic
Any substance increasing renal sodium excretion (same function as diuretci)
Acetazolamide
Carbonic anhydrase inhibitor
Site of action: proximal tubule
MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases–> soon increase Na reabsorption (thus reversing diuresis)
Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH–> increase minute ventilation–> decrease symptoms)
- Glaucoma (decreases rate of aqueous humor formation–> decreased IOP)
AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia–> hepatic encephalopathy)
Dichlorphenamide
Carbonic anhydrase inhibitor
Site of action: proximal tubule
MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases–> soon increase Na reabsorption (thus reversing diuresis)
Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH–> increase minute ventilation–> decrease symptoms)
- Glaucoma- topical use (decreases rate of aqueous humor formation–> decreased IOP)
AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia–> hepatic encephalopathy)
Methazolamide
Carbonic anhydrase inhibitor
Site of action: proximal tubule
MOA:
- Inhibits carbonic anhydrase
- Decreases sodium bicarbonate reabsorption
- Cause bicarbonate diuresis (up to 85%) that may lead to metabolic acidosis
- Over time (several days), effectiveness decreases–> soon increase Na reabsorption (thus reversing diuresis)
Use: metabolic alkalosis (alkalinizes urine)
- Induces hyperchloremic metabolic acidosis after excessive use of other diuretics
- Prophylax acute mountain sickness (decreases CSF formation, pH–> increase minute ventilation–> decrease symptoms)
- Glaucoma (decreases rate of aqueous humor formation–> decreased IOP)
AEs:
- Metabolic acidosis
- Phosphaturia, hypercalciuria (can cause calcium stone formation)
- Potassium wasting
- Toxicity: drowsiness/fatigue (CNS carbonic anhydrase inhibition), parasthesis, avoid in liver disease (increases ammonia–> hepatic encephalopathy)
Furosemide
Loop diuretic
Site of action: cortical and medullary TAL of loop of Henle
MOA: inhibits Na+-K+-2Cl- transporter
Clinical:
- Rapid onset of action (first line in pulmonary edema)
- Stimulates prostaglandin synthesis in lung, kidneys (NSAIDs–> decreased prostaglandins–> decreased diuresis)
- CHF (decrease ECF volume)
- Excretion of: K+, Mg+2 and Ca+2 (Ca reabsorbed later in DCT, but can be used in hypercalcemia)
- Blocks reabsorption of bromide, fluoride, iodide (poisoning)
- Used 2nd line or with thiazide diuretics for HTN
- Edema of nephrotic syndrome (refractory to other diuretics)
Side effects:
- hypokalemia, hypomagnesemia
- hyperuricemia (gouty attack)
- hypochloremic metabolic alkalosis (increased excretion of H+)
- Dose-related irreversible hearing loss (alters membranous labyrinth in inner ear)
- Cross-reactivity with sulfonamide allergy
- Dehydration
- Increased LDL, triglycerides, decreased HDL
Bumetanide
Loop diuretic
Torsemide
Loop diuretic
Ethacrynic acid
Loop diuretic
Hydrochlorothiazide
Thiazide diuretics
Site of action: distal convoluted tubule
MOA: inhibits luminal co-transport of Na, Cl
- Contraction of ECF volume–> decrease in CO–> decrease peripheral vascular resistance
Clinical use:
- Augment production of vasodilatory prostaglandins (NSAID interaction)
- Use in HTN, mild CHF
- Edema due to liver/renal disease
- Only moderately efficacious in decreasing Na+ reabsorption (most reabsorbed before DCT)
- Increased K, H excretion
- Decreased renal Ca+2 excretion (good with urinary stone treatment)
Conditions:
- Nephrogenic DI: paradoxical decrease in urine output
AEs:
- Avoid in low GFR
- “Ceiling diuretics”: increasing dose does not promote further diuresis
- hypokalemia, hypomagnesemia
- hyperuricemia (gouty attack)
- hypochloremic metabolic alkalosis
- Sulfa allergy interaction: photosensitivity, generalized dermatitis (rare)
- Hyperglycemia (impair pancreatic insulin release, tissue utilization of glucose)
- Hyperlipidemia
Chlorothalidone
Thiazide diuretics
Metolazone
Thiazide diuretics
Spironolactone, eplerenone
Potassium-sparing diuretic
MOA: competitive antagonist of aldosterone receptors on collecting tubule (Na-H exchanger)
SIte of action:
- Cortical collecting tubule
Clinical:
- Most effective in primary/secondary hyperaldosteronism (Conn syndrome) - prevents binding of aldosterone to its receptor
- Secondary hyperaldosteronism seen in: CHF, hepatic cirrhosis, nephrotic syndrome
- Ascites
- HTN
- Loop/thiazide-induced hypokalemia
AEs:
- Hyperkalemia (if not on another diuretic)
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)–> can’t excrete H+
- Endocrine abnormalities: gynecomastia, hirsutism, impotence, benign prostatic hyperplasia, menstrual irregularities
Triamterene, amiloride
Postassium-sparing diuretic
MOA: interferes with Na+ influx thru epithelial Na ion channels in luminal membrane (Na-H exchanger in collecting duct)
- K+ secretion coupled with Na+ entry (therefore spare K+ secretion by blocking Na entry)
Clinical use:
- HTN
- Loop/thiazide-induced hypokalemia
AEs:
- Hyperkalemia (if not on another diuretic)
- Hyperchloremic metabolic acidosis= blocks collecting duct Na-H exchange (aldosterone receptor)–> can’t excrete H+
Eplerenone
Spironolactone with greater selectivity to mineralocorticoid receptor
- Less activity on androgen, progesterone receptors (decreased side effects)
- Blocks fibrosis/inflammation caused by aldosterone–> slows albuminuria in diabetes
Mannitol
Osmotic diuretic
Not reabsorbed, causing water to be retained initially, then diuresis
Site of action:
- Proximal tubule: decreased Na reabsorption by osmotic gradient–> increased urine volume
- Descending loop of Henle: increased medullary blood flow, inhibit reabsorption of water
- Collecting duct: opposes action of ADH
Clinical:
- Prevents acute renal failure after severe trauma, complicated surgical procedures (hemolysis, rhabdomyolysis)
- Toxin excretion
- Reduces intracranial, intraocular pressure–> fluid (not Na) leaves cells
- Does not increase Na excretion (only water)
- Must be given IV (only effects colon if given orally)
AEs:
- Rapidly distributes to ECF–> extracts water from cells
- Causes acute increase in ECF/hyponatremia (can’t use in CHF, pulmonary edema)
- N/V, headache
- Severe dehydration, hypernatremia
- Hyperkalemia
Conivaptan
Antidiuretic hormone antagonist
MOA: inhibits effects of ADH
Site of action: collecting duct
Clinical use:
- Hypervolemic, euvolemic hyponatremia not corrected by fluid restriction
- SIADH (with failure of water restriction)
- CHF, cirrhosis (diminished circulating blood volume)–> increased ADH
- Conivaptan= IV
AEs:
- Severe hypernatremia
- Too rapid correction can cause seizures/death
Tolvaptan
Antidiuretic hormone antagonist
Can be administered PO
Edema and diuretics
NaCl reabsorption too high in many disease states leading to:
- Water retention
- increased blood volume
- Expansion of ECF compartment
CHF and diuretics
Diuretic of choice: Loop diuretic
CO continues to deteriorate–> kidney retains sodium, water
- Water leaks from vasculature–> interstitial–> pulmonary edema
Diuretics:
- Improve exercise tolerance, quality of life
- Reduce fluid retention symptoms
- Reduce hospitalizations
Do not:
- alter disease progression
Clinical:
- Change in body weight is sensitive marker of fluid retention due to CHF
Kidney disease and diuretics
Cause retention of sodium, water
- Milder renal insufficiency, diuretics beneficial
- Need larger doses as GFR declines (risk hearing loss)
- Continuous infusion dosing best
Does not:
- reverse clinical disease, help with renal function
- minimally beneficial in severe insufficiency
- avoid acetazolamide (worsening acidosis) and potassium-sparing diuretics (hyperkalemia)
Diuretic resistance in renal failure
- Excessive sodium intake
- Inadequate diuretic dose
- Reduced oral bioavailability (double dose IV to oral)
- Nephrotic syndrome: glomerulus allows plasma protein loss–> decreased osmotic pressure and increased aldosterone–> edema/Na/water retention
- Reduced renal blood flow:
- NSAIDs, ACE-I, Vasodilators
- Hypotension (Intravascular volume expansion, vasopressors)
- Intravascular depletion (volume expansion) - Heart failure
- Nephrotic adaptation
- Cirrhosis (tx: paracentesis)
- Acute tubular necrosis
- Some patients with resistance respond to continuous infusions
Cirrhosis and diuretics
Liver disease–> obstructed portal blood flow–> increased portal pressure
- Decreased plasma protein synthesis–> decreased oncotic pressure
- Both cause fluid to leave portal vascular system–> collects in abdomen
Mechanism for Na retention:
- diminished renal perfusion
- Diminished plasma volume (+ ascites)
- Diminished oncotic pressure (low albumin)
- Primary sodium retention (elevated aldosterone)
HTN and diuretics
Thiazide= first line
Enhance other anti-hypertensives
Nephrolithiasis and diuretics
Thiazide diuretics: enhance calcium reabsorption (decrease urinary calcium concentration)
2/3 kidney stones have calcium phosphate or oxalate crystals (hypercalcuria)
Drug treatments for BPH
- Alpha antagonists (-zosin)
- Old= terazosin, dexazosin (need to be titrated to avoid hypotension)
- Newer formulas target Alpha-1 receptors
- Decreased risk of postural hypotension - 5-alpha reductase inhibitors
- May take 6-12 months for maximal effect
Alpha-1 antagonists: AEs
- Postural hypotension (dizziness)
- Nasal congestion
- Headache
- Asthenia (weakness)
- Abnormal (retrograde) ejaculation)
- Erectile dysfunction (can cause or improve)
- Avoid with planned cataract surgery (Floppy Iris Syndrome)
5-alpha reductase inhibitors
Testosterone converted to 5-DHT in prostate by 5-alpha reductase
- 5DHT contributes to BPH
- Blocking 5-alpha reductase–> decreased DHT–> decreased BPH
Type 2= seen primarily in genitals vs Type 1 (liver and skin)
Finasteride
Inhibits Type II 5-AR
Side effects:
- Decreased libido
- Ejaculatory disorder
- Erectile dysfunction
- Breast tenderness
- Gynecomastia
Dutasteride
Inhibits Type I and II 5-AR
Side effects:
- Decreased libido
- Ejaculatory disorder
- Erectile dysfunction
- Breast tenderness
- Gynecomastia
Comparison of 5-alpha reductase inhibitors vs alpha-1 blockers
5-AR inhibitors:
- Symptom improvement from ~6 months
- increased flow from 1 month
- Effects on symptoms and flow demonstrated to 10 yr
- Reduce prostate volume
- Reduce the risk of AUR (acute urinary retention)
- Reduce the risk of surgery
- Decrease PSA (< 1 month
Alpha-1 blockers;
- increased flow from < 1 month
- Effect on symptoms and flow > 12 months not well established
- Do not reduce prostate volume
- Do not prevent AUR and surgery (Delay??)
Treatment of Erectile Dysfunction
Phosphodiesterase-5 inhibitors:
- Prevent break down of cGMP
Lifestyle modifications:
- Smoking cessation
- Limit/avoid EtOH
- Diet
- Exercise
Medication-induced
- Anti-HTN
- SSRIs
- Hormonal agents
- H2-receptor antagonists
Oral PDE5 inhibitors
Sildenafil
Tadalafil
Vardenafil
AEs:
- Contraindicated with nitrates
- Can potentiate vasodilation and hypotension associated with NO
- Several early deaths in elderly men with concomittant heart disease on nitrates - Caution in vascular disease, coronary disease, vascular risk factors (cardiac eval)
- Any recent MI, arrhytmias, obstructive hypertrophic cardiomyopathy
Second-line therapy for ED
- MUSE: Medicated uretheral suppository for erection
- Administers local alprostadil (PGE-1) to enhance erection
- Useful in non-responsive patients or patients on nitrates
* * PGE-1= stimulates adenylyl cyclase–> increased cGMP - Intracavernosal injection (PDE-inhibitors: alprostadil, papaverine)
- More reliable, instant predictable erection
- Fewer AEs, contraindications
* Phentolamine= alpha-blocker
Muscarinic receptors in bladder
Normal contraction mediated by activation of muscarinic receptors in detrusor muscles (Ach binding):
- M3 receptor= primary mediator of bladder contraction
- M2= more prevalent
Fesoterodine
Derofenisine
Tolteradine
Solifenacin
MOA:
- Antimuscarinic action
- Inhibits binding of acetylcholine to cholinergic receptor and suppresses bladder contractions - Antispasmodic
- Allows detrusor smooth-muscle relaxation to control overactive bladder and urge urinary incontinence
Effects on Urinary Bladder= Motor and sensory
- Increase bladder capacity
- Reduce urinary frequency
- Diminsh urinary incontinence episodes resulting from involuntary bladder contractions
AEs:
- Dry mouth
- Headache
- Constipation
- Diarrhea
- Pain
- Dyspepsia
Oxybutynin
Tertiary amine, antimuscarinic agent
HIgher rates of AEs than tropsium
Tropsium
Quarternary amine
Less likely to cross BBB- better for use in older patients with concern of interfering with cognitive function
Mirabegron
Beta-3 adrenergic agonist
- Relaxes bladder detrusor muscle
Testosterone replacement
ROA: Oral androgens not used in US - Difficulty with achieving consistent levels - Hepatotoxicity Injectable agents Transdermal/topical agents Buccal preparations Long acting implants
Used to treat symptoms of hypogonadism:
- ED, low libido, depression, fatigue, anemia
Diagnosis both clinical and serological
- Should have endocrine eval before T replacement
- Need to be careful in prostate cancer
