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
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)`
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
4
Q
Causes of Sedation in the ICU
A
- pain
- mechanical ventilation
- hypoxia
- hypotension
- delirium
- withdrawal (EtOH, drugs)
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
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
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
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
9
Q
Risk Factors for VTE
A
- immobility
- trauma, orthopedic surgery, vascular catheters, sepsis
- cancer, obesity
- prior VTE
10
Q
Risk Factors for Ulcers
A
- shock, coagulopathy, chronic liver disease
- mechanical ventilation
- neurotrauma, burn injury, extracorporeal life support
- NSAIDs, anticoagulants, antiplatelet
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
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
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
14
Q
4 Ways to Regulate Acid
A
1) Buffering
2) Renal Regulation
3) Ventilatory Regulation
4) Hepatic Regulation
15
Q
What are the 3 types of buffers?
A
1) Bicarbonate
2) Phosphate
3) Protein
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
17
Q
Normal pH
A
7.35-7.45
18
Q
Normal HCO3-
A
24 mEq/L
19
Q
Normal PaCO2
A
40 mmHg
20
Q
Normal SaO2
A
> 95%
21
Q
Types of Metabolic Acidosis
A
Non-Anion Gap
Anion Gap
22
Q
Cause of Non-Anion Gap Metabolic Acidosis
A
- diarrhea/pancreatic fistula
- renal loss
- acid administration
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
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`
25
Types of Metabolic Alkalosis
Saline Responsive (urinary Cl < 10-20 mEq/L)
Saline Resistant (urinary Cl > 20 mEq/L)
26
Cause of Saline Responsive Metabolic Alkalosis
- diuretics
- vomiting/NG suction
- exogenous HCO3- administration or blood transfusions
27
Cause of Saline Resistant Metabolic Alkalosis
- increased mineralocorticoid activity
- hypokalemia
- renal tubular chloride wasting (Bartter's Syndrome)
28
Treatment of Metabolic Alkalosis
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
Cause of Respiratory Acidosis
- 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
Treatment of Respiratory Acidosis
mechanical ventilation + O2
- caution O2 in COPD
31
Cause of Respiratory Alkalosis
- central stimulation --> anxiety, pain, trauma, injury
- peripheral stimulation --> hypoxia, hypotension, CHF
- pulmonary edema, PE, pneumonia
- salicylate toxicity
- mechanical ventilation
32
Treatment of Respiratory Alkalosis
mechanical ventilation + sedation +/- NMBA
33
Chemotherapeutic Drug Resistance
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
Enzymes in Hormone Therapy
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
Anti-Cancer Effects of Corticosteroids
- pediatric acute lymphoblastic leukemia
- multiple myeloma
- lymphomas
36
Steroidal Aromatase Inhibitor
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
fms-like kinase 3 (FLT3)
- 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
Bcr-Abl (Philadelphia Chromsome)
- 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
EML4-ALK
- ALK is normally a transmembrane receptor tyrosine kinase
- when ALK becomes inappropriately fused to ELM4, it becomes cytoplasmic and constitutively active
40
BRAF mutation
- BRAF V600 activates downstream MEK and ERK pathways leading to increased cell proliferation and survival
41
Bruton's Tyrosine Kinase (BTK)
- BTK is important in normal B cell activity and tumor growth
42
Chlorambucil
- 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
Cyclophosphamide
- 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
Mitomycin C
- 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
Cisplatin
- 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
Irinotecan, Topotecan
- 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
Doxorubicin
- 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
Etoposide
- 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
Bleomycin
- 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
Vincristine
- 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
Eribulin
- MOA: binds to the end of microtubules & prevents elongation
LOWER RATE OF NEUROTOXICITY
- Resistance:
** increased Pgp & MRP efflux transporters
52
Paclitaxel --> bound to albumin
-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
Ixabepilone
- 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
5-Fluorouracil
- 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
Cytarabine (Ara-C)
- 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
6-Mercaptopurine (6-MP)
- MOA: inhibits multiple enzymes in the purine biosynthesis pathway
- Resistance: loss of HGPRT activating enzyme
- Drug Interaction:
** TPMT
** allopurinol
57
Methotrexate (MTX)
- 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
Cell Cycle of Agents
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
What two drugs can cause local tissue damage via extravasation?
Doxorubicin & Vincristine
60
Which drug is not an intercalator and is not sensitive to glutathione?
Etoposide
61
Which drug is not a PgP substrate?
Ixabepilone
62
Normal WBC
4.8-10.8 x 10^3
63
Severely Low WBC
< 0.5 x 10^3
64
Normal Platelet
140-440 x 10^3
65
Transfusion Required Platelet
< 10 x 10^3
66
Normal RBC
4.8-6.2 x 10^12
67
Workup Required RBC
Hb < 11 g/dL OR > 2 g/dL drop from baseline
68
Do not use EPA if:
- the patient is receiving myelosuppressive chemotherapy with curative intent
- the patient is receiving non-myelosuppressive chemotherapy
- the patient is not receiving chemotherapy
69
Consider use of EPA if:
- Cancer + CKD
- the patient is receiving palliative chemotherapy
- unknown cause
PHRM 864
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