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Final Flashcards

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1
Q

In pharmacodynamics, is the change in drug effect usually proportional to the change in drug dose or concentration?

A

No
-Drug concentrations often must reach certain threshold to exert pharmacologic effect, but provide diminishing returns at higher concentrations (toxicity)

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2
Q

Narrow therapeutic index drugs

A

Drugs in which small changes in dose may lead to therapeutic failure or toxicities.
Little separation between therapeutic and toxic doses
Subject to therapeutic drug monitoring based on PK/PD parameters.

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3
Q

Intersubject variability in narrow therapeutic index drugs

A

Low to moderate

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4
Q

Narrow therapeutic index drugs examples

A

Digoxin, warfarin, lithium, phenytoin, TAC/CSA, theophylline, most anti-infectives (aminoglycosides and Vanc)

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5
Q

Minimum inhibitory concentration (MIC)

A

Lowest antimicrobial concentration that prevents visible growth of a standard inoculum of organism after 24 hours of incubation under standard conditions.

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6
Q

Antibiotics with time dependent killing

A

Penicillins, cephalosporins, carbapenems, vanc, oxazolidinones, macrolides

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7
Q

Which Abx with time-dependent killing should you optimize time above MIC (time >MIC)

A

Penicillin
Cephalosporin
Carbapenem

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8
Q

Which Abx with time-dependent killing should you optimize AUC over MIC ratio?

A

Vanc
Oxazolidinones
Macrolides

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9
Q

Optimizing time over MIC (T>MIC)

A

Extending duration of infusion (continuous infusions) decreases peak concentrations, but extends time over MIC
In a continuous infusion T>MIC is about 100%

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10
Q

Area under the curve

A

Measure of the extent of exposure to a drug, taking into account clearance from the body.

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11
Q

Which antibiotics have concentration dependent killing?

A

Aminoglycosides
Lipopeptides
Lipoglycopeptides
FQs

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12
Q

Which antibiotics with concentration dependent killing should you optimize the peak/MIC ratio?

A

Aminoglycosides

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13
Q

Which antibiotics with concentration dependent killing should you optimize the AUC/MIC?

A

Lipoglycopeptides
Lipopeptides
FQs

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14
Q

PK parameters of vancomycin

A 
Abs- IV- complete; oral-poor
Vd- 0.7L/kg
Metabolism: >90% unchanged
Elimination: >90% urine
Protein binding- 55% protein bound
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15
Q

Serum concentration monitoring for Vanc

A

Trough concentrations:
10-15mcg/mL for UTI, skin/soft tissue infections
15-20mcg/mL for other infections
AUC/MIC >400

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16
Q

Vanc dosing loading dose

A

20-35mg/kg as a single dose (max 3000mg)
Consider in critically ill patients, patients receiving renal replacement therapy
Rapidly achieves targeted vanc concentration but does NOT lead to faster time to steady state.
Doses are based on ACTUAL body weight.

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17
Q

Renal replacement and the PK of vancomycin

A

Renal failure- reduced elimination of vanc
Hemodialysis- generally give a loading dose and maintenance dose after dialysis.
CRRT- give vanc every 12-24 hours

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18
Q

Limitations of the Ryback Nomogram for Vanc dosing

A

Only for adults with weight 50kg-110kg
Only for CrCl 40-110mL/min
Not validated in unstable conditions

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19
Q

AUC monitoring of Vanc

A

AUC/MIC is a PK/PD parameter that predicts clinical cure rate for severe MSSA and MRSA infections.
AUC/MIC >400 is the best way to ensure positive clinical outcomes
AUC/MIC <600 reduces toxicities

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20
Q

Aminoglycosides PK parameters

A

Abs- complete IV/IM
Distribution- highly hydrophilic, minimal penetration to CSF and ocular tissues
Metabolism/elimination- Primary unchanged, Eliminated in urine
Protein binding <30%

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21
Q

Aminoglycosides conventional dosing

A

Only used for synergistic dosing with beta-lactam in endocarditis.
1mg/kg IV Q 8 hrs
Goal peak: 3-5mg/L
Goal trough: <1mg/L

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22
Q

Aminoglycosides extended dosing interval

A 
Most patients with serious gram negative infections are treated this way
Gentamicin/tobramycin: 5-7mg/kg IV Q24 H
Peak: 15-30mg/dL
Goal trough <0.5mg/L
Drug free interval of 4-10 hours
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23
Q

Advantages of extended interval dosing

A

Optimization of PD parameters (Cmax/MIC)
QD dosing
Comparable cure rates
SImilar AE

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24
Q

Disease states affecting the PK/PD of aminoglycosides

A

Obesity
Renal dysfunction
Hemodialysis

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25
Monitoring conventional dosing of aminoglycosides
Serum peak and trough concentrations at steady state (typically around 4-5 dose) Peak: drawn 30-60 minutes after completion of aminoglycoside infusion (goal 3-5) Trough- drawn 30 minutes prior to the next dose (goal <1)
26
Age and warfarin
Increasing age has been associated with an increase response to the effects of warfarin. People need lower doses of warfarin as they age.
27
Gender and warfarin
Men need higher warfarin doses than women
28
Weight and warfarin
Weight effects warfarin requirements in men. | Increasing BW= increasing warfarin dose
29
Warfarin drug interactions
``` Amiodarone Quinolones Macrolides Metronidazole Bactrim Azole antifungals ```
30
Comorbidities that affect warfarin
HF Thyroid disorder Liver disease Diarrhea
31
You need _____ warfarin in hyperthyroidism?
Less
32
What are the factors that affect warfarin requirements?
Age, sex, DDI, diet, weight, smoking, alcohol, comorbidities, genetics
33
Affect on warfarin: Acute exacerbation of HF
Decreases the metabolism of warfarin due to congestion in the liver
34
Thyroid disease affects.....
Metabolism of clotting factors | One of the main AE of amiodarone is hyperthyroidism
35
Pharmacogenomics and warfarin dose
Genetics, age, and BW account for up to 50% of variability in daily dosing requirements
36
Genotype
Particular genetic pattern seen in the DNA of an individual
37
Polymorphism
A difference in DNA sequence among individuals, groups, or populations Can differ in a single nucleotide (SNP)
38
Wild type
The form of the gene that occurs most frequently
39
SNPs affecting warfarin
CYP4F2 GGCX CALU
40
CYP4F2 SNP affect on warfarin
Metabolizes vitamin K and takes it out of the cycle. More sensitive to warfarin A vitamin K oxidase
41
GGCX SNP affect on warfarin
involves a carboxylation of Vitamin K dependent proteins
42
CALU SNP affect on warfarin
A calcium binding protein that binds GGCX and inhibits the Vitamin K cycle A single SNP associated with higher warfarin doses in AA and egyptians
43
Warfarin metabolism
CYP2C9
44
CYP2C9 polymorphisms in warfarin
CYP2C9*1- wild type CYP2c9*2= leads to reduced enzymatic activity, less ability to metabolize S-warfarin, more sensitive to warfarin. Prolongs t1/2. CYP2C9*3- can be homozygous or heterozygous. Results in a reduction in enzyme activity
45
What do CYP2C9 SNPs mean?
Patient will require lower warfarin doses (most pronounced in *3 homozygous patients) Pt will take longer to reach SS Higher risk of bleeding, higher INR
46
VKORC1 SNPs
Occur in promoter region of gene Grouped into haplotypes (H) H1 and H2= group A- require lower warfarin doses H7, H8, and H9= group B- require higher warfarin doses
47
VKORC1 SNPs what does it mean?
Patients with the group A haplocyte have less enzyme present and group B have more. The require lower and higher doses of warfarin respectively.
48
Should you genotype test for warfarin dosing?
Conflicting evidence supports, but is likely not cost effective It may be considered
49
Which polymorphism results in approx. 80% reduction in CYP2C9 activity?
CYP2C9 *3/3
50
What SNP is associated with higher warfarin requirements?
VKORC1 B haplotype
51
DOAC DDI
CYP3A4 and/or Pgp inducers decrease serum DOAC levels and increase thrombotic risk CYP3A4 and/or Pgp inhibitors increase serum DOAC levels and increase bleeding risk
52
Which DOAC do you use in the presence of an inducer?
None, avoid all DOACs
53
Which DOAC to avoid in the presence of a Pgp inhibitor?
Dabigatran and Edoxaban
54
Which DOAC to avoid in the presence of Pgp and strong CYP3A4 inhibitors?
Apixaban, Rivaroxaban
55
Monitoring of dabigatran
aPTT
56
Monitoring of apixaban, rivaroxaban, edoxaban
Anti-Xa levels
57
When do you monitor DOACs?
``` Patient undergoing urgent surgical procedures CKD dialysis Drug interactions Severely obese patients Assessment of pt adherence ```
58
Which DOAC has the greatest renal elimination?
Dabigatran
59
Which clotting assay is best to measure exposure to apixaban?
Anti-Xa
60
Which clotting assay is best to measure exposure to dabigatran?
Ptt
61
What are the substrates for rivaroxaban?
Pgp and 3A4
62
Factors influencing PK of heparin
``` Age Gender Body weight Thromboembolic disease Smoking Hepatic function Renal function ```
63
AT is a 52 year old who is admitted to the hospital for acute DVT. She weighs 152 pounds and all labs are normal. What is appropriate dose of heparin at 25000units/250mL
5600 at 13ml/hr
64
When do you check PTT for UFH
6 hours
65
What is the therapeutic anti-Xa peak level for enoxaparin 80mg SQ Q12H? Pt weighs 172 pounds
0.5-1units/mL
66
Drug therapy options for cancer treatment?
Chemotherapy Immunotherapy Targeted therapy Other
67
What is one of the big toxicities we see with chemotherapy?
Because it targets rapidly dividing cells, it destroys cells in the GI tract. Diarrhea is common.
68
Classic chemotherapy
Cell cycle dependent- schedule dependent | Cell cycle independent- concentration dependent
69
Are cancer cells different than healthy cells?
Yes | They have driver mutations that cause uncontrolled cell growth
70
What do we target in anticancer therapy?
The pathways, not necessarily the direct mutation
71
The higher the dose you give, the ______ the cell kill
Higher until the point where there is no more benefit
PK
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