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PHRM 864 > Final Exam > Flashcards

Final Exam Flashcards

1
Q

Risk Factors for Malnutrition

A
  • underweight: 20% below IBW
  • involuntary weight loss of 10% within 6 months
  • NPO 7-10 days
  • gut malfunction
  • mechanical ventilation
  • increased metabolic needs: burn, trauma
  • alcohol/substance abuse
  • HIV/Aids/Cancer/Metabolic
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2
Q

Indications for PN

A
  • anticipated prolonged NPO > 7 days
  • small bowel or colonic ileus
  • small bowel resection
  • malabsorptive state
  • retractable vomiting/diarrhea
  • entercutanous fistula
  • inflammatory bowel disease
  • hyperemesis gravidum
  • bone marrow suppression (mucositis)`
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3
Q

Risk Factors for Refeeding Syndrome

A
  • rapid feeding
  • low BMI (< 16-18.5)
  • excessive weight loss
  • insufficient calories
  • low K, Phos, Mg
  • alcoholism, anorexia, marasmus
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4
Q

Causes of Sedation in the ICU

A
  • pain
  • mechanical ventilation
  • hypoxia
  • hypotension
  • delirium
  • withdrawal (EtOH, drugs)
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5
Q

Lorazepam (Ativan)

A
  • MOA: binds to the allosteric regulatory site of the GABAA receptor that increases the FREQUENCY of Cl- channel
  • Routes: IV, IM, PO
    ** IV contains propylene glycol that can cause lactic acidosis or nephrotoxicity at high doses or prolonged infusions –> MONITOR OSMOL GAP
  • Side effects:
    ** respiratory depression
    ** hypotension, tachycardia
    ** withdrawal (seizures) –> taper
    ** delirium
    ** delayed sedation –> advanced age, prolonged infusion
  • Properties:
    ** anxiolysis
    ** anticonvulsants
    ** amnesia
    ** sedation
  • Metabolism: glucuronidation (less accumulation)
  • Pearls:
    ** long t1/2
    ** prolonged duration of action –> least lipid soluble slowly crossing the BBB
    ** tolerance
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6
Q

Midazolam (Versed)

A
  • MOA: binds to the allosteric regulatory site of the GABAA receptor that increases the FREQUENCY of the Cl- channel
  • Routes: IV only
  • Side effects:
    ** respiratory depression
    ** hypotension, tachycardia
    ** withdrawal (seizures) –> taper
    ** delirium
    ** delayed sedation –> advanced age, prolonged infusion, hepatic/renal insufficiency
  • Properties:
    ** anxiolysis
    ** anticonvulsant
    ** amnesia
    ** sedation
  • Metabolism: hepatically cleared via CYP3A4
    ** prolonged t1/2 life in elderly, hepatic impairment, and drug interactions
  • Pearls:
    ** short t1/2
    ** rapid onset –> lipid soluble crossing BBB quickly
    ** after 48 hours, t1/2 becomes unpredictable especially in renal impairment due to the accumulation of metabolites
    ** tolerance
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7
Q

Propofol (Diprivan)

A
  • MOA: binds to multiple sites on receptors that cause interrupted neuronal signaling leading to global CNS depression
  • Routes: IV only
  • Formulations:
    ** Diprivan: contains EDTA that can cause electrolyte imbalances –> drug holiday after 7 days
    ** Sodium Metabisulfite: allergic reactions in asthmatic patients
  • Side effects:
    ** Hypertriglyceridemia –> Check every 48 hours
    ** Pain with an infusion
    ** hypotension, bradycardia
    ** withdrawal –> taper
    ** Propofol Infusion Syndrome –> metabolic acidosis, hypotension, arrhythmia, bradycardia, lipidemia, rhabdomyolysis
  • PK:
    ** high Vd
    ** highly protein bound
    ** hepatically metabolized into no active metabolites
  • Pearls:
    ** 1.1 kcal/mL –> take into account with nutrients
    ** rapid onset & rapid offset
    ** DO NOT HANG > 12 HOURS –> risk of infection
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8
Q

Dexmed (Precedex)

A
  • MOA: selective alpha-2-agonist within CNS inhibiting norepinephrine release
  • Routes: IV only
    ** avoid loading the dose
    ** most likely give a higher dose and longer duration than what guidelines state
  • Side effects:
    ** Increased BP with rapid administration
    ** hypotension, bradycardia –> AVOID IN HEMODYNAMICALLY UNSTABLE
  • Properties:
    ** anxiolysis
    ** analgesia-sparing effects
    ** LIGHT SEDATION –> easily arousable
  • PK:
    ** high Vd
    ** highly protein bound
    ** hepatically metabolized and excreted in urine as glucuronide –> decrease 40-70% in hepatic impairment
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9
Q

Risk Factors for VTE

A
  • immobility
  • trauma, orthopedic surgery, vascular catheters, sepsis
  • cancer, obesity
  • prior VTE
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10
Q

Risk Factors for Ulcers

A
  • shock, coagulopathy, chronic liver disease
  • mechanical ventilation
  • neurotrauma, burn injury, extracorporeal life support
  • NSAIDs, anticoagulants, antiplatelet
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11
Q

Acidemia

A

Cardiovascular
- decreased cardiac output
** impaired contractility
** increased pulmonary vascular resistance
- arrhythmias

Metabolic
- insulin resistance
- inhibits anaerobic glycolysis
- hyperkalemia

CNS
- coma

Respiratory
- hyperventilation

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12
Q

Alkalemia

A

Cardiovascular
- decreased coronary blood flow
** arteriolar constriction
- arrhythmias

Metabolic
- stimulates anaerobic glycolysis
- hypokalemia, hypomagnesemia

CNS
- decreased cerebral blood flow
- seizures

Respiratory
- hypoventilation

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13
Q

Acid Generation

A

1) Diet

2) Aerobic Metabolism of Glucose

3) Nonvolatile Acid Formation
** anaerobic metabolism: lactic/pyruvic acid
** TG metabolism: acetoacetic/B-OH butyric acid
** Cysteine/methionine metabolism: sulfuric/phosphoric acid

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14
Q

4 Ways to Regulate Acid

A

1) Buffering

2) Renal Regulation

3) Ventilatory Regulation

4) Hepatic Regulation

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15
Q

What are the 3 types of buffers?

A

1) Bicarbonate

2) Phosphate

3) Protein

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16
Q

What 2 ways renally can we regulate acid?

A

1) bicarbonate reabsorption in the proximal tubule

2) bicarbonate generation or H+ excretion in the distal tubule
** ammonium excretion
** titratable acidity

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17
Q

Normal pH

A

7.35-7.45

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18
Q

Normal HCO3-

A

24 mEq/L

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19
Q

Normal PaCO2

A

40 mmHg

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20
Q

Normal SaO2

A

> 95%

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21
Q

Types of Metabolic Acidosis

A

Non-Anion Gap

Anion Gap

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22
Q

Cause of Non-Anion Gap Metabolic Acidosis

A
  • diarrhea/pancreatic fistula
  • renal loss
  • acid administration
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23
Q

Cause of Anion Gap Metabolic Acidosis

A

M: methanol intoxication
U: uremia
D: diabetic ketoacidosis
P: poison/propylene glycol ingestion
I: intoxication/infection
L: lactic acidosis
E: ethylene glycol
S: salicylate toxicity/sepsis

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24
Q

Treatment of Metabolic Acidosis

A

Bicarbonate

0.5 L/kg (IBW) x (12 - actual bicarb) –> only give 1/3 to 1/2 of dose first`

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25
Q

Types of Metabolic Alkalosis

A

Saline Responsive (urinary Cl < 10-20 mEq/L)

Saline Resistant (urinary Cl > 20 mEq/L)

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26
Q

Cause of Saline Responsive Metabolic Alkalosis

A
  • diuretics
  • vomiting/NG suction
  • exogenous HCO3- administration or blood transfusions
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27
Q

Cause of Saline Resistant Metabolic Alkalosis

A
  • increased mineralocorticoid activity
  • hypokalemia
  • renal tubular chloride wasting (Bartter’s Syndrome)
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28
Q

Treatment of Metabolic Alkalosis

A

Saline Responsive:
- 1st line: NS +/- potassium supplement
- Other: CA-I, HCl acid

Saline Resistant:
- decrease the dose of mineralocorticoid or change the agent
- potassium supplement or potassium-sparing diuretic (spironolactone)
- fluids

29
Q

Cause of Respiratory Acidosis

A
  • airway obstruction –> foreign body, asthma, aspiration
  • decreased stimulation from CNS –> trauma, CNS infection, overdose, sleep apnea
  • cardiopulmonary decline –> cardiac arrest, PE
  • neuromuscular defects –> ALS, Gillian-barre
  • mechanical ventilation
30
Q

Treatment of Respiratory Acidosis

A

mechanical ventilation + O2
- caution O2 in COPD

31
Q

Cause of Respiratory Alkalosis

A
  • central stimulation –> anxiety, pain, trauma, injury
  • peripheral stimulation –> hypoxia, hypotension, CHF
  • pulmonary edema, PE, pneumonia
  • salicylate toxicity
  • mechanical ventilation
32
Q

Treatment of Respiratory Alkalosis

A

mechanical ventilation + sedation +/- NMBA

33
Q

Chemotherapeutic Drug Resistance

A

1) Altered drug metabolism
- increased efflux transporters (PgP, MRP)
- decreased influx transporters and membrane permeability
- decrease activation of prodrug
- increased detoxification via CYP450

2) Changes in drug target/function
- increased expression of drug target through gene amplification
- emergence of mutant target
- cells rewire pathway to bypass the need for drug target

3) Physiological changes
- refuge of cancer cells in drug-protected sites (BBB)
- massive stromalization to decrease penetration
- change of state

34
Q

Enzymes in Hormone Therapy

A

Pregnenolone –> 17 alpha hydroxylase –> 17 alpha hydroxy pregnenolone

17 alpha hydroxy pregnenolone –> 17,20 lyase –> DHEA

Testosterone –> 5 alpha reductase –> DHT

Testosterone –> Aromatase (CYP19) –> Estradiol

Androstenedione –> Aromatase (CYP19) –> Estrone

35
Q

Anti-Cancer Effects of Corticosteroids

A
  • pediatric acute lymphoblastic leukemia
  • multiple myeloma
  • lymphomas
36
Q

Steroidal Aromatase Inhibitor

A

Exemestane
- MOA: structurally similar to androstenedione acting as a false substrate that aromatase converts to reactive intermediate that irreversibly inhibits at the active site

  • Treatment: breast cancer in postmenopausal
  • Side effects:
  • hot flashes
  • peripheral edema and weight gain
  • increased cholesterol levels
37
Q

fms-like kinase 3 (FLT3)

A
  • 30% of acute myeloid leukemia

What? FLT3 ligand is a cytokine receptor important for hematopoietic cell survival

Types of Mutations
- internal tandem duplication (ITD): increased dimerization of kinase

Types of Inhibitors
- 1st gen: broad
- 2nd gen: specific
- type 2: ITD

38
Q

Bcr-Abl (Philadelphia Chromsome)

A
  • 95% of chronic myeloid leukemia
  • formed by joining the 5’ portion of the Bcr gene (chromosome 22) with the 3’ portion of the Abl gene (chromosome 9) forming a chimeric Bcr-Abl
39
Q

EML4-ALK

A
  • ALK is normally a transmembrane receptor tyrosine kinase
  • when ALK becomes inappropriately fused to ELM4, it becomes cytoplasmic and constitutively active
40
Q

BRAF mutation

A
  • BRAF V600 activates downstream MEK and ERK pathways leading to increased cell proliferation and survival
41
Q

Bruton’s Tyrosine Kinase (BTK)

A
  • BTK is important in normal B cell activity and tumor growth
42
Q

Chlorambucil

A
  • MOA: electrophile intermediate alkylates nucleophile preventing DNA replication & transcription via cross-links
  • Strategy to reduce reactivity & increase selectivity? –> decreasing nucleophilicity of nitrogen by adding aryl groups
    ** pulls the electron density from the nitrogen through resonance to decrease how reactive the electrophile is
  • Side effects:
    ** myelosuppression
    ** N/V/D
    ** secondary malignancy
  • Resistance
    ** increase concentration of glutathione
    ** increase expression of glutathione S-transferase
    ** upregulate DNA repair enzymes
43
Q

Cyclophosphamide

A
  • MOA: electrophile intermediate alkylates nucleophile preventing DNA replication & transcription via cross-links
  • Strategy to reduce reactivity & increase selectivity? –> prodrug strategy
    ** cyclophosphamide –> phosphoramide mustard + acrolein
    ** phosphoramide mustard is the active metabolite that cross-links the DNA –> highly polar and short t1/2 life
    ** phosphoramide mustard is inactivated by aldehyde dehydrogenase (ALDH) –> high levels of ALDH in bone marrow reduce myelosuppression
    ** acrolein accumulates in the urine causing bladder mucosa damage –> MESNA is the treatment
  • Side effects:
    ** minimal myelosuppression
    ** hemorrhagic cystitis
  • Resistance:
    ** increase concentration of glutathione
    ** increase expression of glutathione S-transferase
    ** upregulate DNA repair enzymes
44
Q

Mitomycin C

A
  • MOA: electrophile intermediate alkylates nucleophile preventing DNA replication & transcription via cross-links –> BIFUNCTIONAL CROSS-LINKS
  • Side effects:
    ** myelosuppression
  • Resistance:
    ** increase concentration of glutathione
    ** increase expression of glutathione S-transferase
    ** upregulate DNA repair enzymes
45
Q

Cisplatin

A
  • MOA: requires reverse hydrolysis in aqueous solution
    ** equilibrium favors cisplatin in plasma with high Cl- concentrations
    ** equilibrium favors aquo form inside the cell with low Cl- concentrations
    ** aquo form is the electrophile that reacts with nucleophiles on DNA base pairs to form a INTRASTRAND cross-link by binding at the guanine N7 and adenine N7 sites
  • Side effects:
    ** nephrotoxicity
    ** peripheral neuropathy
    ** ototoxicity
    ** N/V
    ** minimal myelosuppression
  • Resistance:
    ** increase concentration of glutathione
    ** increase expression of glutathione S-transferase
    ** upregulate DNA repair enzymes
46
Q

Irinotecan, Topotecan

A
  • MOA: binds to Topo I through intercalation and forms a ternary complex that blocks DNA relegation
  • Cell Cycle: S-phase
  • Drug Interaction: UGT1A1
    ** causes toxicity from SN-38 accumulation
  • Resistance:
    ** increased expression of glutathione S-transferase
    ** increased PgP and MRP efflux transporters
47
Q

Doxorubicin

A
  • MOA: binds to Topo II through intercalation and blocks DNA relegation AND produces free radicals
  • Cell Cycle: non cell cycle specific
  • Toxicity: Cardiotoxicity
    ** EDTA can chelate iron-catalyzed free radical formation through Dexrazoxane
    ** local tissue damage via extravasation
  • Resistance:
    ** increased expression of glutathione S-transferase
    ** increased PgP and MRP efflux transporters
48
Q

Etoposide

A
  • MOA: binds to Topo II and blocks DNA relegation

NO INTERCALATION
NOT SENSITIVE TO GLUTATHIONE

  • Cell Cycle: G2 phase
  • Resistance:
    ** increased PgP and MRP efflux transporters
49
Q

Bleomycin

A
  • MOA: thiazole intercalates DNA and imidazole produces free radicals leading to single-strand and double-stranded DNA breaks
  • Cycle Cycle: G2/M phase
  • Toxicity: Pulmonary toxicity
    ** enzyme that inactivates is low in skin and lungs
50
Q

Vincristine

A
  • MOA: binds to tubulin to inhibit microtubule assembly (polymerization) –> mitotic arrest
  • Toxicity:
    ** peripheral neuropathy
    ** local tissue damage via extravasation
  • Resistance:
    ** increased PgP or MRP efflux transporters
51
Q

Eribulin

A
  • MOA: binds to the end of microtubules & prevents elongation

LOWER RATE OF NEUROTOXICITY

  • Resistance:
    ** increased Pgp & MRP efflux transporters
52
Q

Paclitaxel –> bound to albumin

A

-MOA:
1) promotes assembly of a stable bundle that decreases free tubulin
2) stabilization blocks depolymerization & segregation

  • Toxicity:
    ** myelosuppression
    ** some peripheral neuropathy
  • Resistance:
    **increased PgP & MRP efflux transporters
53
Q

Ixabepilone

A
  • MOA:
    1) promotes assembly of a stable bundle that decreases free tubulin
    2) stabilization blocks depolymerization & segregation
  • Toxicity:
    ** myelosuppression
    ** some peripheral neuropathy

NOT A PgP SUBSTRATE

54
Q

5-Fluorouracil

A
  • MOA:
  • Normal: in the presence of tetrahydrofolate, dUMP binds to the active site of thymidylate synthase forming a ternary complex to allow for an exchange of H+ for methyl-creating TMP
  • 5-FU: in the presence of tetrahydrofolate, FdUMP binds to the active site of thymidylate synthase forming a ternary complex that cannot allow fluorine to exchange for methyl-stopping TMP production
  • Drug Rescue: thymidine
  • Drug Synergy: leucovorin –> stable cofactor converted to tetrahydrofolate inside cells
  • Resistance:
    ** upregulate thymidylate synthase
    ** downregulate enzyme that converts 5-FU to FdUMP
  • Toxicity:
    ** polymorphism in dihydropyridine dehydrogenase that metabolizes 5-FU
55
Q

Cytarabine (Ara-C)

A
  • MOA: converted to Ara-CTP intracellularly where it competitively inhibits DNA polymerase and incorporates into DNA to further inhibition
  • Pearl: cytidine deaminase converts Ara-CTP into non-toxic uracil arabinoside
    ** low levels of cytidine deaminase in CNS –> highly toxic
  • Drug Synergy: tetrahydrouridine –> cytidine deaminase inhibitor
  • Resistance:
    ** upregulate cytidine deaminase
    ** downregulate activating enzymes
    ** downregulate drug importers
56
Q

6-Mercaptopurine (6-MP)

A
  • MOA: inhibits multiple enzymes in the purine biosynthesis pathway
  • Resistance: loss of HGPRT activating enzyme
  • Drug Interaction:
    ** TPMT
    ** allopurinol
57
Q

Methotrexate (MTX)

A
  • MOA:
  • Normal: FH2 enters the folate pool where it’s reduced by dihydrofolate reductase into FH4 (tetrahydrofolate)
  • MTX: inhibits dihydrofolate reductase inhibiting TMP synthesis
  • Drug Rescue: leucovorin –> stable cofactor converted to tetrahydrofolate inside cells
  • Resistance:
    ** upregulate dihydrofolate reductase
    ** mutation of dihydrofolate reductase
    ** decrease polyglutamation decreasing MTX accumulation
58
Q

Cell Cycle of Agents

A

5-FU: S phase

Cytarabine: S phase

6-MP: S phase

MTX: S phase

Chlorambucil: cell cycle non-specific

Cyclophosphamide: cell cycle non-specific

Mitomycin C: cell cycle non-specific

Cisplatin: cell cycle non-specific

Irinotecan, Topotecan: S phase

Doxorubicin: cell cycle non-specific

Etoposide: G2 phase

Bleomycin: G2/M phase

Vincristine: M phase

Eribulin: M phase

Paclitaxel: M phase

Ixabepilone: M phase

59
Q

What two drugs can cause local tissue damage via extravasation?

A

Doxorubicin & Vincristine

60
Q

Which drug is not an intercalator and is not sensitive to glutathione?

A

Etoposide

61
Q

Which drug is not a PgP substrate?

A

Ixabepilone

62
Q

Normal WBC

A

4.8-10.8 x 10^3

63
Q

Severely Low WBC

A

< 0.5 x 10^3

64
Q

Normal Platelet

A

140-440 x 10^3

65
Q

Transfusion Required Platelet

A

< 10 x 10^3

66
Q

Normal RBC

A

4.8-6.2 x 10^12

67
Q

Workup Required RBC

A

Hb < 11 g/dL OR > 2 g/dL drop from baseline

68
Q

Do not use EPA if:

A
  • the patient is receiving myelosuppressive chemotherapy with curative intent
  • the patient is receiving non-myelosuppressive chemotherapy
  • the patient is not receiving chemotherapy
69
Q

Consider use of EPA if:

A
  • Cancer + CKD
  • the patient is receiving palliative chemotherapy
  • unknown cause

PHRM 864 (4 decks)

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