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Pharmacokinetics > Block 3 > Flashcards

Block 3 Flashcards

1
Q

What drugs do CYP2D6 metabolize?

A

Antiarrhythmics

Antidepressants

Antipsychotics

BB (not atenolol)

Codeine + Tramadol

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2
Q

What are the PM alleles associated w/ CYP2D6?

A

CYP2D6 * 3,4,5,6

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3
Q

CYP2D6 PM + Codeine, what happens?

A

PM cant form active metabolite (morphine) and cannot experience pain relief

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4
Q

CYP2D6 UM + Codeine, what happens?

A

Increased rate of morphine metabolites and causes respiratory depression; fatal to newborns

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5
Q

CYP2D6 PM + Antipsychotics, what happens?

A

Increased extrapyramidal side effects

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6
Q

CYP2D6 PM + Tamoxifen, what happens?

A

PM cant form metabolites and their treatment outcomes are worse

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7
Q

PM of CYP2D6 are found in what population?

A

Whites and Asians

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8
Q

What drugs do CYP2C9 metabolize

A

Phenytoin

Warfarin

NSAIDs

ARBs

Glipizide and Glyburide

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9
Q

What are the PM alleles associated w/ CYP2C9?

A

CYP2C9 * 2,3,5

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10
Q

Reduced function of CYP2C9 is found in what population?

A
  • 2 and *3 is found in whites, much less prevalent in blacks and asians
  • 5 is found only in blacks
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11
Q

(R or S) - Warfarin is associated with 60-70% of its anticoagulant effect

A

S-warfarin; that is the one metabolized by CYP2C9 and differences w/ genotype impact the dose

R-warfarin is metabolized by CYP3A4 and 1A2

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12
Q

What is the key factor in explaining the variability in warfarin dose?

A

Vitamin K oxidoreductase complex 1 gene (VKORC1)

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13
Q

What variation would put someone in the NM, IM, and PM section for CYP2C9?

A

NM = 1/1

IM = 1/2 or 1/3

PM = 2/2 or 2/3

Side effects are more prevalent in phenytoin with variant alleles

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14
Q

What are the alleles associated with CYP2C19?

A

CYP2C19 *2,3,17

-only *2 and *3 are associated w/ PM

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15
Q

What populations groups are affected by CYP2C19?

A

*2 and *3 occur in whites and asians

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16
Q

CYP2C19 PM + PPI, what happens?

A

Higher concentration, therefore you expect increased % of AE

PPI have a wide safety margin and therefore work better to treat H.pylori infections

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17
Q

What antiplatelet Rx requires CYP2C19?

A

Clopidogrel (pro-drug)

CYP2C19 activates it to its active moiety, therefore PM dont get the effect of the drug

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18
Q

What is the most abundant CYP enzyme in the liver?

A

CYP3A4

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19
Q

CYP3A422
CYP3A41B
Por*28

Which one is associated w/ reduced activity?

A

CYP3A4*22

Other 2 are increased activity

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20
Q

Which variant of CYP3A5 contain partial loss expression compared to CYP3A5*1?

A

*3

Others are 6,8,9,10

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21
Q

Which variant of CYP3A5 require the highest and lowest dose?

A
  • 1/*1 = highest (lowest plasma concentration)

* 3/*3 = lowest dose (highest plasma concentration)

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22
Q

Which population group is affected by CYP3A5?

A

Blacks and whites

Blacks - Most are 1/1 or 1/3

Whites - Most are 3/3

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23
Q

What drug requires CYP3A5?

A

Tacrolimus

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24
Q

Cigarette smoking induces what CYP enzyme?

A

CYP1A2*1F; enhances clearance affected by this substrate

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25
Q

What drugs do CYP1A2 metabolize?

A

Caffeine

Theophylline

Clozapine + Olanzapine

Activates procarcinogens

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26
Q

P-glycoprotein is encoded by what gene?

A

ABCB1 gene

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27
Q

Which haplotype of ABCB1 is normal and which ones are abnormal?

A

Normal - CC (most renal/biliary excretion)

Abnormal - CT (kind of impaired, therefore more drugs enter blood vessel)

-TT (Totally impaired, therefore most of the drug enters blood vessel, most reduced renal/biliary excretion)

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28
Q

Warfarin class?

A

Oral anticoagulant; Vitamin K antagonist

29
Q

Warfarin MOA?

A

Competitively inhibits C1 subunit of VKORC1 and interferes with clotting factors II, VII, IX, X. Also affects protein C + S

30
Q

Warfarin indications?

A

Tx and prevent VTE

Tx and prevent TE associated w/ A.Fib and cardiac valve replacement

Reduce risk of death, MI, amd TE after MI

31
Q

PK info on Warfarin?

A

Racemic mix of R and S enatiomer but the major one is S

Highly protein bound (99%)

32
Q

PD info on Warfarin?

A

Takes 24 - 72 hrs for onset

Takes 2-5 days for duration

Peak effect in 3-4 days

33
Q

What population groups are highly affected by warfarin?

A

Geriatric + Asians

Geriatric - have higher INR response (more sensitive)

Asians - require lower initiation and maintenance dose

34
Q

CI of warfarin?

A

Pregnant (unless you have a mechanical heart valve, Eclampsia, preeclampsia, and threatened abortion

Unsupervised pt w/ high potential for noncompliance

35
Q

AE of warfarin?

A

Major bleed + Skin necrosis

36
Q

What RX/food decreases warfarin effect?

A

Rifampin

Barbiturates

Carbamazepine

Phenytoin

St. John’s Wort

37
Q

What RX/food increases warfarin effect?

A

ABx

Antifungals

Thyroid Rx

Steroids

Lipid drugs

Grapefruit

Amiodarone

38
Q

What are the variants of VKORC1?

A

GG

GA (intermediate warfarin sensitivity)

AA (highly sensitive to warfarin)

39
Q

What are the tablet colors and doses on warfarin?

A

1, 2, 2.5, 3, 4, 5, 6, 7.5, 10

Pink, Lavender, Green, Brown, Blue, Peach, Teal, Yellow, White

Please Let Greg Brown Bring Peaches To Your Wedding

40
Q

How do you calculate INR?

A

Patient’s Prothrombin time / Mean prothrombin normal range

Low = increased clot risk

High = increased bleed risk

Baseline INR ~1

41
Q

INR goal (warfarin) of 2.5 to 3.5 is indicated for who?

A

Mechanical mitral valve replacement and dual aortic with mitral valve replacement

If you see mechanical aortic valve, bioprosthetic, or rheumatic, its goal is 2-3

42
Q

INR goal (warfarin) of 2-3 is indicated for who?

A

Stroke Tx and prevention

VTE

Antiphospholipid syndrome

43
Q

Frequency of INR monitoring

A

Every 2-3 days during initiation and until INR is achieved

Every 1-2 wks when INR is achieve TWICE or when there is dose adjustments

Every 4 wks if INR has been stable for 2 consecutive readings

Every 8-12 wks if INR has been stable for ≥6 months

44
Q

What are the anticoagulation reversal Rx?

A

Vit. K + Kcentra

45
Q

How is Vit. K administered?

A

PO or IV, NEVER IM

46
Q

Anticoagulation reversal and INR <4.5 w/ no bleed, what should you do?

A

Vit. K NOT recommended

Hold and/or reduce warfarin

47
Q

Anticoagulation reversal and INR <10 w/ no bleed, what should you do?

A

Vit. K NOT recommended

Hold AND reduce warfarin

48
Q

Anticoagulation reversal and INR >10, what should you do?

A

Give low dose ORAL vit. K (2.5-5mg)

49
Q

Anticoagulation reversal with MINOR bleed at any INR, what should you do?

A

HOLD warfarin

May give low dose ORAL vit. K (2.5-5mg)

50
Q

Anticoagulation reversal with MAJOR bleed at any INR, what should you do?

A

Give Kcentra instead of plasma

May or may not give Vit. K 5-10mg IV slowly

51
Q

Phenytoin class?

A

Anticonvulsant for tonic-clonic or partial seizures

52
Q

What is the maintenance dose equation for phenytoin?

A

[Vmax * Css] / [S(F) * (Km+Css)]

53
Q

What could increase Vmax and affect phenytoin MD dose calculations?

A

Enzyme induction (phenobarbital or carbamazepine administration)

54
Q

What could decrease Vmax and affect phenytoin MD dose calculations?

A

Hepatic cirrhosis

55
Q

What could increase Km and affect phenytoin MD dose calculations?

A

Competitive inhibition (cimetidine or chloramphenicol administration

56
Q

What could decrease Km and affect phenytoin MD dose calculations?

A

Decreased plasma protein binding by having low serum albumin

57
Q

How do you calculate Vmax and Km for someone on phenytoin w/ normal renal and hepatic function

A

Vmax = 7mg/kg/day

Km = 4micrograms/mL

58
Q

What are the ways to check steady-state of phenytoin?

A

Two levels are drawn a week apart within 10% value

Wait 2-4 wks after dose change then obtain level

59
Q

What routes should be avoided in phenytoin?

A

IM; painful and precipitates in muscle which gives it prolonged absorption

60
Q

What is the max rate of IV phenytoin?

A

Do NOT exceed 50mg/min, it will cause hypotension

61
Q

What is the equivalent rate of fosphenytoin and phenytoin?

A

100mg PE of fosphenytoin = 100mg phenytoin

62
Q

Phenytoin vs Fosphenytoin, which one is water-soluble?

A

Fosphenytoin

63
Q

Phenytoin vs Fosphenytoin, which one has less hypotension issues?

A

Fosphenytoin

64
Q

What is the max rate of IV fosphenytoin?

A

150mg PE/min

65
Q

What is the salt factor in phenytoin?

A

Assume 0.92 unless it is a suspension or chewable tablet, then its 1. 1 because of phenytoin acid form

66
Q

What is the therapeutic unbound phenytoin levels? Total levels?

A

1-2 microgram/mL - unbound only

10-20 microgram/mL - unbound and bound**

**standard monitoring method

67
Q

What are some causes of protein binding changes in pt w/ phenytoin that can cause their unbound fraction to jump to 30-40%?

A

Hypoalbuminemia

Liver or Kidney issue (endogenous)

Certain drugs like warfarin, valproic acid, NSAIDs (exogenous)

68
Q

How do you calculate loading dose of phenytoin?

A

LD = [Css*Vd] / (S)(F)

Vd = 0.65/kg or 1.3/kg if obese

Pharmacokinetics (3 decks)

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