Block 3 Flashcards
What drugs do CYP2D6 metabolize?
Antiarrhythmics
Antidepressants
Antipsychotics
BB (not atenolol)
Codeine + Tramadol
What are the PM alleles associated w/ CYP2D6?
CYP2D6 * 3,4,5,6
CYP2D6 PM + Codeine, what happens?
PM cant form active metabolite (morphine) and cannot experience pain relief
CYP2D6 UM + Codeine, what happens?
Increased rate of morphine metabolites and causes respiratory depression; fatal to newborns
CYP2D6 PM + Antipsychotics, what happens?
Increased extrapyramidal side effects
CYP2D6 PM + Tamoxifen, what happens?
PM cant form metabolites and their treatment outcomes are worse
PM of CYP2D6 are found in what population?
Whites and Asians
What drugs do CYP2C9 metabolize
Phenytoin
Warfarin
NSAIDs
ARBs
Glipizide and Glyburide
What are the PM alleles associated w/ CYP2C9?
CYP2C9 * 2,3,5
Reduced function of CYP2C9 is found in what population?
- 2 and *3 is found in whites, much less prevalent in blacks and asians
- 5 is found only in blacks
(R or S) - Warfarin is associated with 60-70% of its anticoagulant effect
S-warfarin; that is the one metabolized by CYP2C9 and differences w/ genotype impact the dose
R-warfarin is metabolized by CYP3A4 and 1A2
What is the key factor in explaining the variability in warfarin dose?
Vitamin K oxidoreductase complex 1 gene (VKORC1)
What variation would put someone in the NM, IM, and PM section for CYP2C9?
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
What are the alleles associated with CYP2C19?
CYP2C19 *2,3,17
-only *2 and *3 are associated w/ PM
What populations groups are affected by CYP2C19?
*2 and *3 occur in whites and asians
CYP2C19 PM + PPI, what happens?
Higher concentration, therefore you expect increased % of AE
PPI have a wide safety margin and therefore work better to treat H.pylori infections
What antiplatelet Rx requires CYP2C19?
Clopidogrel (pro-drug)
CYP2C19 activates it to its active moiety, therefore PM dont get the effect of the drug
What is the most abundant CYP enzyme in the liver?
CYP3A4
CYP3A422
CYP3A41B
Por*28
Which one is associated w/ reduced activity?
CYP3A4*22
Other 2 are increased activity
Which variant of CYP3A5 contain partial loss expression compared to CYP3A5*1?
*3
Others are 6,8,9,10
Which variant of CYP3A5 require the highest and lowest dose?
- 1/*1 = highest (lowest plasma concentration)
* 3/*3 = lowest dose (highest plasma concentration)
Which population group is affected by CYP3A5?
Blacks and whites
Blacks - Most are 1/1 or 1/3
Whites - Most are 3/3
What drug requires CYP3A5?
Tacrolimus
Cigarette smoking induces what CYP enzyme?
CYP1A2*1F; enhances clearance affected by this substrate
What drugs do CYP1A2 metabolize?
Caffeine
Theophylline
Clozapine + Olanzapine
Activates procarcinogens
P-glycoprotein is encoded by what gene?
ABCB1 gene
Which haplotype of ABCB1 is normal and which ones are abnormal?
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)
Warfarin class?
Oral anticoagulant; Vitamin K antagonist
Warfarin MOA?
Competitively inhibits C1 subunit of VKORC1 and interferes with clotting factors II, VII, IX, X. Also affects protein C + S
Warfarin indications?
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
PK info on Warfarin?
Racemic mix of R and S enatiomer but the major one is S
Highly protein bound (99%)
PD info on Warfarin?
Takes 24 - 72 hrs for onset
Takes 2-5 days for duration
Peak effect in 3-4 days
What population groups are highly affected by warfarin?
Geriatric + Asians
Geriatric - have higher INR response (more sensitive)
Asians - require lower initiation and maintenance dose
CI of warfarin?
Pregnant (unless you have a mechanical heart valve, Eclampsia, preeclampsia, and threatened abortion
Unsupervised pt w/ high potential for noncompliance
AE of warfarin?
Major bleed + Skin necrosis
What RX/food decreases warfarin effect?
Rifampin
Barbiturates
Carbamazepine
Phenytoin
St. John’s Wort
What RX/food increases warfarin effect?
ABx
Antifungals
Thyroid Rx
Steroids
Lipid drugs
Grapefruit
Amiodarone
What are the variants of VKORC1?
GG
GA (intermediate warfarin sensitivity)
AA (highly sensitive to warfarin)
What are the tablet colors and doses on warfarin?
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
How do you calculate INR?
Patient’s Prothrombin time / Mean prothrombin normal range
Low = increased clot risk
High = increased bleed risk
Baseline INR ~1
INR goal (warfarin) of 2.5 to 3.5 is indicated for who?
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
INR goal (warfarin) of 2-3 is indicated for who?
Stroke Tx and prevention
VTE
Antiphospholipid syndrome
Frequency of INR monitoring
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
What are the anticoagulation reversal Rx?
Vit. K + Kcentra
How is Vit. K administered?
PO or IV, NEVER IM
Anticoagulation reversal and INR <4.5 w/ no bleed, what should you do?
Vit. K NOT recommended
Hold and/or reduce warfarin
Anticoagulation reversal and INR <10 w/ no bleed, what should you do?
Vit. K NOT recommended
Hold AND reduce warfarin
Anticoagulation reversal and INR >10, what should you do?
Give low dose ORAL vit. K (2.5-5mg)
Anticoagulation reversal with MINOR bleed at any INR, what should you do?
HOLD warfarin
May give low dose ORAL vit. K (2.5-5mg)
Anticoagulation reversal with MAJOR bleed at any INR, what should you do?
Give Kcentra instead of plasma
May or may not give Vit. K 5-10mg IV slowly
Phenytoin class?
Anticonvulsant for tonic-clonic or partial seizures
What is the maintenance dose equation for phenytoin?
[Vmax * Css] / [S(F) * (Km+Css)]
What could increase Vmax and affect phenytoin MD dose calculations?
Enzyme induction (phenobarbital or carbamazepine administration)
What could decrease Vmax and affect phenytoin MD dose calculations?
Hepatic cirrhosis
What could increase Km and affect phenytoin MD dose calculations?
Competitive inhibition (cimetidine or chloramphenicol administration
What could decrease Km and affect phenytoin MD dose calculations?
Decreased plasma protein binding by having low serum albumin
How do you calculate Vmax and Km for someone on phenytoin w/ normal renal and hepatic function
Vmax = 7mg/kg/day
Km = 4micrograms/mL
What are the ways to check steady-state of phenytoin?
Two levels are drawn a week apart within 10% value
Wait 2-4 wks after dose change then obtain level
What routes should be avoided in phenytoin?
IM; painful and precipitates in muscle which gives it prolonged absorption
What is the max rate of IV phenytoin?
Do NOT exceed 50mg/min, it will cause hypotension
What is the equivalent rate of fosphenytoin and phenytoin?
100mg PE of fosphenytoin = 100mg phenytoin
Phenytoin vs Fosphenytoin, which one is water-soluble?
Fosphenytoin
Phenytoin vs Fosphenytoin, which one has less hypotension issues?
Fosphenytoin
What is the max rate of IV fosphenytoin?
150mg PE/min
What is the salt factor in phenytoin?
Assume 0.92 unless it is a suspension or chewable tablet, then its 1. 1 because of phenytoin acid form
What is the therapeutic unbound phenytoin levels? Total levels?
1-2 microgram/mL - unbound only
10-20 microgram/mL - unbound and bound**
**standard monitoring method
What are some causes of protein binding changes in pt w/ phenytoin that can cause their unbound fraction to jump to 30-40%?
Hypoalbuminemia
Liver or Kidney issue (endogenous)
Certain drugs like warfarin, valproic acid, NSAIDs (exogenous)
How do you calculate loading dose of phenytoin?
LD = [Css*Vd] / (S)(F)
Vd = 0.65/kg or 1.3/kg if obese
