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Flashcards in Drugs Deck (81)
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1
Q

Acetazolamide Mechanism

A

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.

2
Q

Acetazolamide MOA

A

Oral pill

3
Q

Acetazolamide Net Effects

A

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

4
Q

Acetazolamide Clinical Use

A

o Weak diuretic
o Increase pH of urine to treat Cysteinurea
o Reduce glaucoma inner ocular pressure

5
Q

Acetazolamide Adverse Effects

A

o Metabolic acidosis – increased excretion of HCO3

o Acute K+ deficiency

6
Q

Mannitol or Glucose in Excess Mechanism

A

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

7
Q

Mannitol or Glucose in Excess MOA

A

IV injection (1-5g solution)

8
Q

Mannitol or Glucose in Excess Net Effects

A

o Large increases in urine volume (water excretion)

o Minor increases in NaCl and other ion excretion

9
Q

Mannitol or Glucose in Excess Clinical Use

A

o Reduce intraocular or intracranial pressure

o Treatment of dialysis disequilibrium syndrome (cerebral edema following dialysis)

10
Q

Mannitol or Glucose in Excess Adverse Effects

A

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

11
Q

Furosemide

A

Loop Diuretic

Sulfa Drug

12
Q

Furosemide Mechansim

A

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’

13
Q

Furosemide MOA

A

IV, IM, or Oral (fast onset and short-half life)

14
Q

Furosemide Net effects

A

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

15
Q

Furosemide Clinical Uses

A

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)

16
Q

Furosemide Adverse Effects

A

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

17
Q

Furosemide Drug interactions

A

o Lithium, indomethacin, probenecid, warfarin

18
Q

Bumetanide

A

Loop Diuretic
Sulfa Drug

  • 40x more potent than furosemide
  • Doesn’t cross react with Warfarin
19
Q

Torsemide

A

Loop Diuretic
Sulfa Drug
• Longer lasting loop diuretic; also lowers BP

20
Q

Ethacrynic acid

A

Loop Diuretic
Phenoxyacetic acid derivative
• Loop diuretic used in patients with sulfa allergy; gout is major & ototoxicity is minor side effect

21
Q

Hydrochlorothiazide

A

Class I Thiazide Diuretic

Sulfa Drug

22
Q

Chlorthalidone

A

Class I Thiazide Diuretic

Sulfa Drug

23
Q

Quinothazone

A

Class I Thiazide Diuretic

Sulfa Drug

24
Q

Metolazone

A

Class II Thiazide Diuretic
Sulfa Drug
• More potent version of Class I
• Can be used with patients having GFR between 30-60mL/min

25
Q

Indapamide

A

Class II Thiazide Diuretic
Sulfa Drug
• More potent version of Class I
• Can be used with patients having GFR between 30-60mL/min

26
Q

Thiazide Mechanism

A

inhibits NaCl-symporter in the early part of DCT

27
Q

Thiazide MOA

A

Oral pill

28
Q

Thiazide Net Effects

A

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++

29
Q

Thiazide Clinical Uses

A

o Edema reduction
o Hypercalciurea reduction/osteoporosis treatment
o Anti-hypertensive; can be added to drug regimens
o Treating Nephrogenic Diabetes insipidus

30
Q

Thiazide Adverse Effects

A

o Sulfa allergy
o Hyponatremia, Hypokalemia, metabolic acidosis
o Hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia

31
Q

Spirolactone

A
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
32
Q

Eplenerone

A
Aldosterone Antagonist (K-sparing)
o Lower incidence of gynecomastia
33
Q

Aldosterone Antagonist Mechanism

A

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

34
Q

Aldosterone Antagonist MOA

A

Oral pill

35
Q

Aldosterone Antagonist Net Effects

A

o Increased Na+ excretion

o Decreased K+/H+ excretion from decreased delivery of Na+ to distal nephron tubule epithelial cells

36
Q

Aldosterone Antagonist Clinical Uses

A
o Diuretic (often combined with thiazide diuretic to offset K+)
o Aids in CHF and cirrhosis treatment
37
Q

Aldosterone Antagonist Adverse Effects

A
o Hyperkalemia (reduced K+ secretion/excretion)
o Gynecomastia (mostly with spironolactone)
38
Q

Amiloride

A

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

39
Q

Triamterene

A

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

40
Q

Arginine Vasopressin (AVP, ADH, Anti-Diuretic Hormone, Vasopressin)

A

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

41
Q

Vasopressin 1 Receptor (V1)

A
  • Type q GPCR
  • Found in smooth muscle
  • Vasopressin binding causes Gq-PLC-IP3 pathway, mobilizing Ca++ to vasoconstrict
42
Q

Vasopressin 2 Receptor (V2)

A
  • 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
43
Q

GPCR Mechanisms (Gs, Gi, Gq)

A

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

44
Q

Desmopressin (DDAVP)

A
  • 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)
45
Q

Tolvaptan

A

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
46
Q

Conivaptan

A

• Essentially the same drug, but less selective than Tolvaptan for V2R

47
Q

Terlipressin

A

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

48
Q

Diabetes Insipitus

A

• 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

49
Q

Syndrome of Inappropriate Secretion of ADH (SIADH)

A

• 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+

50
Q

Temsirolimus

A
  • Rapamycin “-limus”
  • Prodrug to sirolimus
  • Given as weekly IV injections
51
Q

Everolimus

A
  • Rapamycin “-limus”

* Given as a daily pill

52
Q

Rapamycin drugs Mechanism

A

• 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

53
Q

Rapamycin drugs Mode of Resistance

A
  • Resistance likely through a secondary mTOR pathway via mTOR2
  • mTOR2 was not known when these drugs were first made
54
Q

Rapamycin drugs Adverse Effects

A
  • CYP 3A4 substrate (worry of drug-drug interactions)
  • Maculopapular rash, mucositis, anemia, fatigue
  • Pulmonary infiltrates develop in a small amount of patients
55
Q

Axitinib

A
  • Tyrosine Kinase inhibitor (“-nib”)
  • Blocks: PDGFR, VEGF
  • Oral administration
56
Q

Sunitinib

A
  • 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.
57
Q

Sorafenib

A
  • Tyrosine Kinase inhibitor (“-nib”)
  • Blocks: PDGFR, VEGF
  • Oral administration
  • Steven Johnson syndrome
  • QT prolongation
  • Hepatic failure
58
Q

Pazopanib

A
  • Tyrosine Kinase inhibitor (“-nib”)
  • Blocks: PDGFR, VEGF, EGFR
  • Oral administration
  • QT prolongation
59
Q

Tyrosine Kinase inhibitor mechanism

A

• Bind to highly conserved ATP binding site of tyrosine kinases, blocking activity

60
Q

Tyrosine Kinase inhibitor Adverse effects

A
  • CYP3A4 substrate
  • Worry of activity on other tyrosine kinases because it works on preserved
  • BBW of hepatic failure
61
Q

Bevacizumab

A

• Monoclonal antibody VEGF inhibitor, which blocks VEGF signaling, thus cel growth

62
Q

Bevacizumab Special Considerations

A
  • 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
63
Q

Bevacizumab BBWs

A
  • 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!
64
Q

Interferon-a 2b

A
  • Immunotherapy agent
  • Off label use for ccRCC; typically an anti-viral for Hep. B&C
  • Administered SC x3 daily
65
Q

Interferon-a 2b Mechanism

A

o Binds to cell surface IFNAR1/IFNAR2 receptors
o Stimulates JAK/STAT pathway
o Produces anti-viral, anti-tumor, and anti-proliferation gene products

66
Q

Interferon-a 2b Adverse Effects

A

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

67
Q

Interleukin-2(proleukin)/Aldesleukin

A
  • 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
68
Q

Interleukin-2(proleukin)/Aldesleukin adverse effects

A

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

69
Q

Carboplatin

A
  • 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
70
Q

Cyclophsphamide

A
  • 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
71
Q

Ifosphamide

A
  • 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
72
Q

Doxorubicin

A
  • Common pediatric renal cancer drug
  • Topo II inhibitor/DNA intercalation/free radical generation to produce damage
  • Myelosuppression
73
Q

Dactinomycin

A

• Common pediatric renal cancer drug
• Intercalation/DNA dependent
RNA synthesis inhibition
• Product of a mold

74
Q

Etoposide

A
  • Common pediatric renal cancer drug
  • Topo II inhibitor
  • Myelosuppression
75
Q

Vincristine

A
  • 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)
76
Q

Definitive Cure for Renal Cancer

A
  • Surgical resection (solid tumors)

* Drugs can be used to aid in treatment or as first-line when surgery isn’t an option

77
Q

Typical treatment regimens for childhood renal cancer

A
Some combination of...
•  Vincristine
• Dactinomycin
• Doxorubicin
• Cyclophosphamide
• Etoposide
• Radiation
78
Q

Recurrent clear cell carcinoma in children typical treatments

A
  • Cyclophosphamide/ Carboplatin

* Ifosphamide/Carboplatin/etoposide (ICE)

79
Q

Treatment for childhood Rhabdoid/Neuepithelial tumor

A

No good treatment currently

80
Q

Adult ccRCC pathogenesis

A

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

81
Q

Mechanism of Hypertension induction with VEGF inhibitory drugs

A
  • Normally VEGF will stimulate NO production, so blockage causes vasoconstriction
  • Can be acute; must be treated with some anti-hypotensive medication