Acetazolamide Mechanism
Proximal Tubule Carbonic Anhydrase Inhibitor
o Stops the action of CA, diminishing conversion and reabsorption of bicarbonate (HCO3)
o This diminishes the amount of H+ within the proximal tubular epithelial cells, thus diminishing Na/H-antiporter delivery of Na+ to the epithelial cell
o These combined effects increase the amount of NaHCO3/NaCl/water getting past the proximal tubule. The increased solute lowers water reabsorption from a diminished osmotic gradient.
Acetazolamide MOA
Oral pill
Acetazolamide Net Effects
o Increase in urine NaHCO3/NaCl/water delivery to distal nephron
o Increased excretion of NaHCO3/water/potassium
• Most NaCl will be reabsorbed in the thick ascending limb via Na/K-ATPase
• Increased distal nephron Na delivery means more K reabsorption and excretion
o Increased urine pH
Acetazolamide Clinical Use
o Weak diuretic
o Increase pH of urine to treat Cysteinurea
o Reduce glaucoma inner ocular pressure
Acetazolamide Adverse Effects
o Metabolic acidosis – increased excretion of HCO3
o Acute K+ deficiency
Mannitol or Glucose in Excess Mechanism
Proximal Tubule Osmotic Diuretic
o These are simply osmotically active substances that don’t get re-absorbed, so they increase the osmolarity of filtrate
o Minor inhibition of water/Na+ reabsorption in the proximal tubule
o Major inhibition of water/Na+ reabsorption in the Loop of Henle
• Water stays in the descending limb from diminished osmotic gradient
• Ascending limb fluid is more dilute, so less NaCl pumped out via active transport
• Thick ascending limb is affected like the proximal tubule
Mannitol or Glucose in Excess MOA
IV injection (1-5g solution)
Mannitol or Glucose in Excess Net Effects
o Large increases in urine volume (water excretion)
o Minor increases in NaCl and other ion excretion
Mannitol or Glucose in Excess Clinical Use
o Reduce intraocular or intracranial pressure
o Treatment of dialysis disequilibrium syndrome (cerebral edema following dialysis)
Mannitol or Glucose in Excess Adverse Effects
o Volume overload – mannitol may accumulate in the ECF causing increased osmolality; generally indicated by a diminished urine output
o Contraindicated in heart failure – because you could overload the heart even more
Furosemide
Loop Diuretic
Sulfa Drug
Furosemide Mechansim
o Inhibits NK2C (Na-K-2Cl-symporter) in Thick Ascending limb
o Inhibits Macula Densa’s ability to ‘sense’ NaCl
o Stimulates prostaglandin synthesis (Increases total renal bloodflow)
o Maintains GFR via ‘extraction fraction regulation’
Furosemide MOA
IV, IM, or Oral (fast onset and short-half life)
Furosemide Net effects
o Very potent diuretic with copious water and NaCl loss in urine
thick ascending limb; water follows suit with these osmotically active ions
o Increased excretion of Ca/Mg in Thick Ascending Limb
o Increased urinary excretion of K+/H+ in collecting tubule
o Impair ability of kidney to concentrate urine
o Triggers release of PGE2, which increases renal blood flow
Furosemide Clinical Uses
o Edema – allows us to quickly eliminate ECF volume, thus attenuating edema of cardiac, hepatic, or renal origin
• Also useful in diminishing pulmonary edema!
o Hypercalcemia – because of increased Ca++ excretion in urine
o Washout of toxins via increased urine flow
o Protection against renal failure – not sure; perhaps due to increased renal bloodflow from PGE2 release triggered from drug administration
o Can be used to aid in treatment of hypertension with other drugs (reduce blood volume)
Furosemide Adverse Effects
o Hypokalemia – increased K+ excretion from increased distal Na+ delivery
o Metabolic alkalosis – increased h+ excretion from increased distal Na+ delivery
o Elevated BUN, glucose, and uric acid in blood (probably from increased urinary flow)
o Ototoxicity – nobody quite knows why this happens but its fodder for all loop diuretics
o Sialadenitis – swelling of salivary glands; not sure why this happens
o Allergy – lots of people are allergic to sulfa drugs
Furosemide Drug interactions
o Lithium, indomethacin, probenecid, warfarin
Bumetanide
Loop Diuretic
Sulfa Drug
- 40x more potent than furosemide
- Doesn’t cross react with Warfarin
Torsemide
Loop Diuretic
Sulfa Drug
• Longer lasting loop diuretic; also lowers BP
Ethacrynic acid
Loop Diuretic
Phenoxyacetic acid derivative
• Loop diuretic used in patients with sulfa allergy; gout is major & ototoxicity is minor side effect
Hydrochlorothiazide
Class I Thiazide Diuretic
Sulfa Drug
Chlorthalidone
Class I Thiazide Diuretic
Sulfa Drug
Quinothazone
Class I Thiazide Diuretic
Sulfa Drug
Metolazone
Class II Thiazide Diuretic
Sulfa Drug
• More potent version of Class I
• Can be used with patients having GFR between 30-60mL/min
Indapamide
Class II Thiazide Diuretic
Sulfa Drug
• More potent version of Class I
• Can be used with patients having GFR between 30-60mL/min
Thiazide Mechanism
inhibits NaCl-symporter in the early part of DCT
Thiazide MOA
Oral pill
Thiazide Net Effects
o Increased urine flow
o Loss of Na/K/Cl/H+ in urine
o Decreased urinary excretion of Ca++
o Increased urinary excretion of Mg++
Thiazide Clinical Uses
o Edema reduction
o Hypercalciurea reduction/osteoporosis treatment
o Anti-hypertensive; can be added to drug regimens
o Treating Nephrogenic Diabetes insipidus
Thiazide Adverse Effects
o Sulfa allergy
o Hyponatremia, Hypokalemia, metabolic acidosis
o Hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia
Spirolactone
Aldosterone Antagonist (K-sparing) o Can cause Gynecomastia from metabolism to Canrenone, which is an aldosterone receptor antagonist as well as an androgen receptor antagonist
Eplenerone
Aldosterone Antagonist (K-sparing) o Lower incidence of gynecomastia
Aldosterone Antagonist Mechanism
o Bind/inhibit aldosterone channels so it never translocates to the nucleus
o Lack of aldosterone effect results in decrease of Na-epithelial (Enac) channel density; thus resulting in less Na+ reabsorption in the distal nephron
Aldosterone Antagonist MOA
Oral pill
Aldosterone Antagonist Net Effects
o Increased Na+ excretion
o Decreased K+/H+ excretion from decreased delivery of Na+ to distal nephron tubule epithelial cells
Aldosterone Antagonist Clinical Uses
o Diuretic (often combined with thiazide diuretic to offset K+) o Aids in CHF and cirrhosis treatment
Aldosterone Antagonist Adverse Effects
o Hyperkalemia (reduced K+ secretion/excretion) o Gynecomastia (mostly with spironolactone)
Amiloride
ENaC channel Blockers (K-sparing)
• Pretty much the same effect as aldosterone antagonists except they directly block ENaC channels
• Can cause megaloblastic anemia in patients with cirrhosis
Triamterene
ENaC channel Blockers (K-sparing)
• Pretty much the same effect as aldosterone antagonists except they directly block ENaC channels
• Can cause megaloblastic anemia in patients with cirrhosis
Arginine Vasopressin (AVP, ADH, Anti-Diuretic Hormone, Vasopressin)
Vasopressin receptor agonist
• Binds to V1 and V2 GPCRs to increase Water reabsorption and blood pressure
• Endogenous aquaretic synthesized in the paraventricular and supraoptic nuclei of the hypothalamus
• Stored in the posterior pituitary gland for quick release upon increases in plasma osmolarity
• Typically plasma osmolariy > 280 mOsm/Kg triggers release through osmoreceptor signaling
Vasopressin 1 Receptor (V1)
- Type q GPCR
- Found in smooth muscle
- Vasopressin binding causes Gq-PLC-IP3 pathway, mobilizing Ca++ to vasoconstrict
Vasopressin 2 Receptor (V2)
- Type s GPCR
- Found in principle cells of the renal collecting ducts
- Vasopressin binding causes Gs-cAMP/PKA pathway
- PKA phosphorylates Aquaporin-2 (AQP-2) so it insets into membrane to allow for greater water reabsorption
- PKA phosphorylates Urea Transporter-1 (UT1 or VRUT) to increase urea reabsorb.
- Overall can GREATLY increase the concentration of urine
GPCR Mechanisms (Gs, Gi, Gq)
o Gs → Adenylyl cyclase → (ATP → cAMP) → PKA
o Gi inhibits the Gs pathway by downregulating adenylyl cyclase
o Gq → PLC → (Cleaves PIP2 from lipids to DAG/IP3)
• DAG → PKC activation
• IP3 increases calcium in the cell
Desmopressin (DDAVP)
- Synthetic AVP that’s highly selective for V2 receptors over V1
- Nasal, IV, or oral administration
- Used in bleeding disorders to increase Factor VIII and Von Willenbrand Factor in the blood via binding to extra-renal V2 receptors
- Can be used to remedy nocturnal enuresis (bed wetting)
Tolvaptan
Vasopressin 2 Receptor agonist
• Extremely selective antagonist for V2R • Often used in significant hyponatremia that has failed to correct with fluid restriction • IV administration (Hospital settings ONLY; treats acute hyponatremia) • CYP3A4 metabolized • Side Effects: o Hyperglycemia o GI disturbances o Clotting problems
Conivaptan
• Essentially the same drug, but less selective than Tolvaptan for V2R
Terlipressin
Vasopressin 1 Receptor agonist
• IV drug restricted only for post-operative ileus, esophageal varicies, and acute hemorrhagic gastritis
• Constricts GI/vascular smooth muscle to limit bleeding
• Less side effects than using AVP for the same effect
Diabetes Insipitus
• Central origin = inadequate AVP secretion so little AQP-2, thus lots of peeing
o Acquired: damage to the hypothalamus or pituitary gland
o Genetic: chromosome 20 mutation (auto. dominant)
o Treat with desmopressin
• Nephrogenic origin = insufficient kidney response to AVP
o Acquired: obstructive renal disease or drug damage to nephron
o Genetic: X-linked V2 receptor mutation
o Treat with thiazine diuretics
Syndrome of Inappropriate Secretion of ADH (SIADH)
• Excessive ADH production causing excessive water reabsorption
• Drug induced
o Psychotropics (SSRIs, Haloperidol, Tri-cyclic anti-depressants)
o Sulfonylureas (chloropropamide)
o Vinca alkaloids (vincristine/vinblastine)
• Paraneoplastic: small cell lung carcinoma or intracranial neoplasms
• Treatments
o Water restriction
o “Vaptan” treatment if [plasma Na+
Temsirolimus
- Rapamycin “-limus”
- Prodrug to sirolimus
- Given as weekly IV injections
Everolimus
- Rapamycin “-limus”
* Given as a daily pill
Rapamycin drugs Mechanism
• Block mTOR activity to stop cell cycle and promote apoptotsis (critical choke point in proliferative signaling)
o Bind to FKBP12 to inhibit TORC1
o Causes immunosuppression, inhibition of cell-cycle/angiogenesis, promotes apoptosis
Rapamycin drugs Mode of Resistance
- Resistance likely through a secondary mTOR pathway via mTOR2
- mTOR2 was not known when these drugs were first made
Rapamycin drugs Adverse Effects
- CYP 3A4 substrate (worry of drug-drug interactions)
- Maculopapular rash, mucositis, anemia, fatigue
- Pulmonary infiltrates develop in a small amount of patients
Axitinib
- Tyrosine Kinase inhibitor (“-nib”)
- Blocks: PDGFR, VEGF
- Oral administration
Sunitinib
- Tyrosine Kinase inhibitor (“-nib”)
- Blocks: PDGFR, VEGF
- Oral administration
- Hepatic failure
- Steven Johnson syndrome – mucous membrane drug reaction: begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters. Then the top layer of the affected skin dies and sheds.
Sorafenib
- Tyrosine Kinase inhibitor (“-nib”)
- Blocks: PDGFR, VEGF
- Oral administration
- Steven Johnson syndrome
- QT prolongation
- Hepatic failure
Pazopanib
- Tyrosine Kinase inhibitor (“-nib”)
- Blocks: PDGFR, VEGF, EGFR
- Oral administration
- QT prolongation
Tyrosine Kinase inhibitor mechanism
• Bind to highly conserved ATP binding site of tyrosine kinases, blocking activity
Tyrosine Kinase inhibitor Adverse effects
- CYP3A4 substrate
- Worry of activity on other tyrosine kinases because it works on preserved
- BBW of hepatic failure
Bevacizumab
• Monoclonal antibody VEGF inhibitor, which blocks VEGF signaling, thus cel growth
Bevacizumab Special Considerations
- Only available as IV infusion because it’s a peptide
- No CYP3A4 interactions (nice!)
- Best when combined with interferon-a to treat renal cell carcinoma
Bevacizumab BBWs
- Hemorrhage – weakening of blood vessel because of lack of repair
- GI perforation – weakening of GI wall with damage to blood vessels
- Wound healing complications – affects blood vessel formation during repair
- Renal toxicity due to damage to blood vessels in kidney!
Interferon-a 2b
- Immunotherapy agent
- Off label use for ccRCC; typically an anti-viral for Hep. B&C
- Administered SC x3 daily
Interferon-a 2b Mechanism
o Binds to cell surface IFNAR1/IFNAR2 receptors
o Stimulates JAK/STAT pathway
o Produces anti-viral, anti-tumor, and anti-proliferation gene products
Interferon-a 2b Adverse Effects
o Can produce hypertension causing pre-renal damage to the kidney
o Fatigue, fever, flu-like symptoms
o Leukopenia/neutropenia
o Xerostomia (dry mouth)/Dysguesia (altered taste) are less common interesting ones
Interleukin-2(proleukin)/Aldesleukin
- Immunotherapy agent
- Works as a T-cell stimulant essentially placing the body in a controlled septic shock
- Also works via the JAK/STAT pathway like INF-a
- IV administration 3x weekly; typically patients can only tolerate 14 total
Interleukin-2(proleukin)/Aldesleukin adverse effects
Sepsis
• You must administer an antimicrobial alongside this drug to prevent sepsis; your T-cells are non-specifically proliferating so they won’t be able to respond to a bacterial prevention because they won’t be simulated by the bacterium
Capillary leak syndrome
• Increased capillary permeability from septic shock effect can cause this
• Hypotension, low systemic resistance, tachycardia, pulmonary edema, renal toxicity
This is one of the drugs that Dr. Sweatman noted for its direct renal toxicity
Carboplatin
- Common pediatric renal cancer drug
- Intra-strand DNA linkage (very small so only a limited reach chemically)
- Myelosuppresion; infection susceptibility
- Renal damage is important because its actively uptaken via the copper transporter in the kidney and accumulates, causing damage
Cyclophsphamide
- Common pediatric renal cancer drug
- Alkalating agent (inter/intra-strand DNA linkage)
- Myelosuppression
- Hemorrhagic cystitis due to acrolein production (MESNA prophylactic antidote)
- Not directly renotoxic though
Ifosphamide
- Common pediatric renal cancer drug
- Alkalating agent (inter/intra-strand DNA linkage)
- Myelosuppression
- Hemorrhagic cystitis due to acrolein production (MESNA prophylactic antidote)
- Also directly renotoxic via chloroacetaldehyde metabolite production
Doxorubicin
- Common pediatric renal cancer drug
- Topo II inhibitor/DNA intercalation/free radical generation to produce damage
- Myelosuppression
Dactinomycin
• Common pediatric renal cancer drug
• Intercalation/DNA dependent
RNA synthesis inhibition
• Product of a mold
Etoposide
- Common pediatric renal cancer drug
- Topo II inhibitor
- Myelosuppression
Vincristine
- Common pediatric renal cancer drug
- Vinca alkaloid; prevents tubulin polymerization (formation of microtubules) to stop separation of daughter cells
- Neurotoxicity “stocking-glove pattern” (lack of neural delivery)
Definitive Cure for Renal Cancer
- Surgical resection (solid tumors)
* Drugs can be used to aid in treatment or as first-line when surgery isn’t an option
Typical treatment regimens for childhood renal cancer
Some combination of... • Vincristine • Dactinomycin • Doxorubicin • Cyclophosphamide • Etoposide • Radiation
Recurrent clear cell carcinoma in children typical treatments
- Cyclophosphamide/ Carboplatin
* Ifosphamide/Carboplatin/etoposide (ICE)
Treatment for childhood Rhabdoid/Neuepithelial tumor
No good treatment currently
Adult ccRCC pathogenesis
o Major genetic basis is mutation in von Hippel-Lindau gene
o Normal function is to produce pVHL to form pVHL-E3 ligase complex, which ubiquinates HIF for proteasome destruction so it can’t stimulate EPO production to stimulate angiogenesis
o Mutated VHL makes a pVHL that is non-functional so you get HIF running wild and upregulating EPO
• EPO binds to its EPO-receptor which stimulates anti-apoptotic signals, angiogenesis, and inflammation
• HIF stimulates VEGF, PDGF-B, and TGFa to bind to their receptors to stimulate effects
• Genetic predispotision gives “first hit” then subsequent “hits” lead to cancer development
o Treatments go after VEGF, VEGFR, and mTOR as they are the major pathways for HIF induction in cells
Mechanism of Hypertension induction with VEGF inhibitory drugs
- Normally VEGF will stimulate NO production, so blockage causes vasoconstriction
- Can be acute; must be treated with some anti-hypotensive medication