Pharmacogenetics: Pharmacodynamics

what is warfarin used as?

how does it complete this function?

what is the starting dose of Warfarin?

How would you adjust this dose if you have a target INR

oral anticoagulant

inhibits vitamin K preventing the carboxylation/ activation of clotting factors

4-5mg/day

Warfarin has a starting dose of __-__ mg/day, but may need to change to ___-___ mg to target an INR

what is an INR?

Typically 4-5 mg/day 1-10mg/day

International Normaized Ratio meaasures how long it takes for blood to clot

Narrow Therapeutic Index:

Increased/decreased warfarin: Risk of Bleeding

Increased/decreased warfarin: risk of clotting

increased- bleeding

decreased- clotting

Target INR (international normalized ratio) for warfarin?

2-3

which enzyme is warfarin metabolized by?

CYP2C9

Pharmacodynamics of Warfarin:

• Warfarin inhibits Vitamin K _______ _________ and prevents the regeneration of reduced vitamin K

• CYP_______ reduces the availability reduced Vitamin K

• _______ ( _________ carboxylase) that carboxylates clotting factor

  • limited ____ data

the ________, _______, and ________ pathways have relevant SNPs

epoxidase reductase

4F2

GGCX (glutamyl carboxyl)

• SNP

CYP2C9, VKOR, CYP4F2

CYP ______, CYP_______ and _________ pathways have relevant SNPs related to Warfarin

CYP2C9, CYP4F9 , VKOR

Vitamin K Epoxide is reduced by ______ ____ ________ ____________

which is inhibited by ___________ which is metabolized by ___________

Reduced Vitamin K is converted/recycled back into vitamin K epoxide through ________, which activates clotting factors

vitamin k epoxide reductase

warfarin CYP2C9

GGCX (gamma glutamyl carboxylase)

which step actually activates clotting factors?

reduced vitamin K —→ gamma glutamyl carboxylase —→ active clotting factors

warfarin variability is caused by

VKORC1

CYP2C9

weight

age

Does Warfarin (S) or (R) have more pharmacological activity?

which warfarin is specifically inactivated (through hydroxylation) by CYP2C9?

which warfarin is inactivated (through hydroxylation) by MULTIPLE CYPs ?

(S) has higher pharmacologic activity (shes the Shiz)

(S)-warfarin inactivated by CYP2C(

(R) inactivated by multiple

CYP2C29 Varient Alleles:

Which is the wildtype?

Which varient alleles are common in European Ancestery?

Which are common in African Ancestory?

wildtype = *1

european = *2 and 3

african = *5, 6, 8, 11

CYP2C29 Varient Alleles:

Which alleles have decreased activity vs. which has truncated completely inactive protein?

decreased activity = *2, 3, 4, 5, 8, 11

inactivity due to deletion = *6

which variant allele corresponds to the switch of Arg144Cys in the CYP2C9 gene ?

*2

which variant allele corresponds to the switch of Ile359Leu in the CYP2C9 gene ?

*3

3rd is the one w/ a hairy chest (lui)

which variant allele corresponds to the switch of Arg144Asp and Ile359Thr in the CYP2C9 gene ?

*4

which variant allele corresponds to the switch of Asp360Glu in the CYP2C9 gene ?

*5 (5 year olds play w/ elmers glu to make slime)

which variant allele corresponds to the switch of Nucleotide (A818) deletion leading to truncated inactive proteinin the CYP2C9 gene ?

*6

8 and 18 yr old must be stopped (inactivated)

which variant allele corresponds to the switch of Arg150His or Leu in the CYP2C9 gene ?

*8

which variant allele corresponds to the switch of Arg355Trp n the CYP2C9 gene ?

*11

do the CYP2C9 alleles lead to an increassed rate of bleeding or clotting?

bleeding and anticoagulation

would CYP2C9 *1/1 allele patient need higher or lower dose of Warfarin?

higher bc/ normal metabolizing (removal) function of warfarin

which patient would need the highest dose of warfarin?

which patient would need the lowest dose?

*1/1

*1/2

*1/3

*2/2, 2/3, 3/3

highest warfarin dose = *1/1

lowest warfarin dose = lowest metabolism = 2/2, 2/3, 3/3

______ converts vitamin K- epoxide to vitamin K which is the RATE LIMITING STEP OF VITAMIN K RECYLING

VKOR

what is the common variant of the VKOR gene?

Patients with one or two copies of this variant require lower/higher doses of warfarin

c.- 1639 G>A

lower doses bc/ patients already have low vitamin K epoxide reductase

there are some rare ___________ varients that cause warfarin RESISTANCE and necessitate HIGHER warfarin dose

nonsynonymous

which ethnicity has the highest frequency for nonsynonymous mutation of the VKORC1 -1639 G>A (- so PRIOR TO START SITE)

would they need a higher or lower dose of Warfarin

East Asian

Higher bc/ they cause warfarin resistance

Warfarin and CYP4F2:

liver vitamin K oxidase converts vitamin K to _________which removes vitamin K from the cycle

limiting excessive amounts of vitamin K from accumulating

hydroxy-vitamin K1

what is the nonsynonymous variant of CYP4F2?

what does CYP4F2 do regularly?

would you require a higher or lower dose of Warfarin?

CYP4F2*3 (Val433Met)

metabolizes reduced Vitamin K preventing the recycling back into vitamin k epoxidase and lowers the amount of activated clotting factors

HIGHER dose because now there’s even more reduced vitamin K that can be converted into vitamin K epoxidase by gamma glutamyl carboxylase

the varient of CYP4F2*3 (Val433Met) would require one to increase/decrease thier Warfarin dose by ___%

increase dose by 10%

the ALOX gene encodes for which enzyme?

5-lipoxygenase

ALOX encodes for the lipoxygenase enzyme, what does this enzyme do?

lipoxygenase converts arachidonic acid into leukotriene A4

which drug prevents the conversion of arachidonic acid to Leukotriene A4 by inhibiting ALOX5 which encodes for lipoxygenase ?

what does this drug alleviate?

Zileuton (Zyflo)

reduced airway inflammation due to leukotrienes

how do Zileuton and Montelukast work differently to reduce airway inflammation?

zileuton prevent the creation of leukotriene'

Montelukast prevent leukotriene from binding to GPCR and being effective

the wildtype ALOX5 gene contains how many repeats? (94%)

How many repeats are seen within the gene for variants? (6%)

5

4 or 3

why would some patients not be able to treat their airway inflammation using Zileuton?

zileuton only inhibits wildtype ALOX 5 with 5 repeats

useless against ALOX5 with 3 to 4 repeats

would a ALOX5 allele mutation that has 3 or 4 repeats instead of 5 cause higher/ower inflammation than the wildtype allele with 5 repeats?

WOULD NOT CHANGE

just bc/ there is less repeats doesn’t mean the inflammation is any less severe

is cystic fibrosis an autosomal recessive or dominant disease?

autosomal recessive

______ regulates fluid and ion transport which s critical for host defense in the lungs

CFTR

which CFTR mutation causes defects in gating?

G551D

glycine to aspartate (DONT CONFUSE THIS NOT A BUT D) at 533 position

which medication restores gating of CFTR protein in patients with 1 or 2 G551D alleles?

ivacaftor

true/false: the medication that can can treat the G551A mutation of CFTR channel is ivacaftor

FALSE

the mutation is called G551D not A even though the varient allele is aspartate we represent that with a D!

Cancer Pharmacokinetics:

What is the difference between somatic and germline variations in terms of…

• which DNA is mutated?

• which is inherited?

• in cancer what is disregulated altering drug responses ?

• germ cell DNA vs somatic cell DNA

• germline variations are inherited

• germline - dispiosition of chemicals through metabolism altering drug responses

  somatic- protein kinases altering drug response

Cancers caused by Germline Variants alter the disposition of chemicals which affects responses

list some examples of metabolites that are disrupted due to GERMLINE variations (DNA mutation in germ cell) and which drugs they impact:

TPMT —> 6MP

(TPMT innactivates 6MP preventing myelosupression)

UGT1A —> Irinotecan

(SN-38 inactivated by UGT1A, preventing leukopenia, neutropenia, intestinal diarrhea)

CYP2D6 —> Tamoxifen

(tamoxifen activated to endoxifen using CYP2D6 to treat ER+ breast cancer )

Somatic Variants can affect the efficacy of cancer treatment

List some examples of somatic variants that impact cancer treatment and whether or not they increase or decrease their efficacy

T3I5I - DECREASE efficacy of imatinib and desatinib

P95 = DECREASE efficacy of tratuzumab

G719A/C, L858R, L861Q = INCREASE efficacy of getfitnib

EGFR Pathway Summary:

• EGFR is a _______ kinase receptor

• Requires ________ to activate _____/_______ and ______/________

tyrosine

dimerization Ras/MAPK —> PI3K/ ATK

EGFR Targeted Drugs:

Which drugs prevent growth factors from binding to the receptor?

cetuximab and panitumumab

(cetu later — you aint getting to bind today!)

(panit- you aint getting in my pants!)

EGFR Targeted Drugs:

Which drugs prevent dimerization of HER2/ neu with HER1/EGFR?

Which drugs prevent dimerization of HER2/neu with any other HER?

EGFR/ HER1 specifically = pertuzamab

any other HER dimerization = trastuzumab

** for EGFR it is PERTinent bc/ EGFR is main

** for any other dimerization its a trast = trash cant dimerize with no one wants to be near it

Which EGFR medications prevent tyrosine phosphorylation?

These medicators are reffered to as TKI (tyrosine kinase inhibitors)

getfitinib erlotinit imatinib

IMAtinib GETfit ERLOT preventing phosphorylization tacking a big issue

what are the two types of EGFR genetic varient?

which increase efficacy of cancer treatment, and which decrease efficacy?

1. missense mutation + deletion REDUCE sensitivity of tyrosine kinase domain to inhibitors DECREASING the efficacy of tyrosine kinase inhibitors

2. activating mutations keep tyrosine kinase active despite there not being growth factor—> these mutations have INCREASED sensitivity to receptor tyrosine kinase inhibitors (TKI) to bind with easy

What are the 4 ways to pharmacologically block tumors due to EGFR malfunction?

1. inhibit binding of tyrosine kinase receptor (panitumumab, cetuximab)

2. inhibit dimerization (pertuzamab, trastuzumab)

3. inhibit tyrosine phosphorylation (iaminib, getfittinib, erlotinib)

4. prevent MAPK pathway

KRAS:

• what activates KRAS?

• what happens once KRAS is activated?

• which drugs prevent this pathway?

• ligand binding to EGFR activates KRAS

• once KRAS is activated it will bind to GTP and activate MAPK and PI3K/akt signalling

DRUGS THAT PREVENT EGFR BINDING DISRUPT KRAS AS KRAS IS ACTIVATED THROUGH EGFR BINDING TO LIGAND

THESE DRUGS ARE CETUXIMAB (SEE YA LATER) and PANTIUZUMAB (CANT GET IN MY PANTS)

what genetic mutations should you test for in a cancer patient BEFORE prescribing them CETUXIMAB and PANITUZIMAB?

you should test for activating mutations of KRAS and they will be unnafected

KRAS is usually activated by EGFR binding, BUT if KRAS undergoes a mutation that allows it to be activated without EGFR binding then CETUXIMAB and PANTIUZIMAB wont be effective since they prevent the binding of ligands to EGFR

locus of genes that encode for surface proteins on immune cells

what are the two classes that exist for these genes?

HLA

Class 1 and Class 2

HLA are genes that encode for _______ proteins that will direct T cells towards antigens by marking them.

MHC

Major Histocompatibility Complex

what are two different types of hypersensitivity reactions that can occur due to variants in the HLA genes?

Steven Johson’’s Sydrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Steven Johnsons Syndrome:

• Caused by a mutation to which gene?

• Sever skin rash that includes ______ and _______ lesions

• Skin detachment ______% of surface area

• more common in male/female and older than ___ years old

• Is this hypersensitivity reaction more or less severe than Toxic Epidermal Necrolysis (TEN)

mutation to HLA gene

blisters and mucosal lesions

10% of surface area

men older than 30 years old

less sever

Toxic Epidermal Necrolysis (TEN):

• Hypersensitivity reaction that includes ____________, ______, and multiple ORGAN FAILURE

• skin detachment _______% of surface area

• HIGH MORTALITY

• is this hypersensitivity reaction more or less severe compared to Steven Johsons Syndrome

• dehydration, sepsis

• more than 30% diattachment

• more severe than steven johnsons

carbamzepime is indicated for _______ and ______ ________

seizures and nerve pain

when taking carbamazepine, having which variant mutations can lead to Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

HLA-A *3101 in europeans (number lowkey looks european)

HLA-B*1502 in Asians (Han Chinese)

Should you administer Carbamazepine to treat seizures and nerve pain to patients who ar noncarriers of HLA-B*1502?

yes should not be an issue if they are NONCARRIERS

Should you administer Carbamazepine to treat seizures and nerve pain to patients who have the HLA-B*1502 Varient and have never taken Carbamazepine before (Carbamazepine naive)?

NO (YOU DONT KNOW HOW THEY WILL RESPOND SINCE THEY HAVE VARIENT AVOID ALLTOGETHER FIND A DIFFERNT MEDICATION TO PREVENT SJS OR TEN)

Should you administer Carbamazepine to treat seizures and nerve pain to patients who have the HLA-B*1502 Varient and have taken it before for 3 months without experiencing any adverse reactions?

yes, BUT be very cautious as they have the potential to get SJS or TEN

what is Abacavir? what disease state is it used to treat?

Abacavir is a nucleoside reverse trasncriptase inhibitor

treats HIV (prevents RNA—> DNA and proteins from being formed)

5-8% of patients experience Abacavir hypersensitivity that includes

• _________

• _________

• ____ distress

• _______ symptoms (Cough, SOB, sore throat)

when do patients experience these symptoms? what should you do when experiencing these symptoms?

• fever

• rash

• GI

• respiratory

first 6 weeks of therapy — discontinue therapy

Pharmacogenetic research initially pointed to __________as an important allele in the hypersensititvity of Abacavir

Explain how the PREDICT-1 trial provided evidence that mutation ____________ lead to hypersensitivity reactions

HLA-5701

HA-5701

One patient group took Abacavir without checking their genetics for HA-5701 mutation.

Another patient group took Abacavir AFTER screening and getting a negative result for HA-5701.

0% of the group that did not include induvial with the HA-5701 experienced hypersensitivity reactions

this illustrated that HLA-5701 should be monitored before giving Abacavir as therapy however note that it wont ALWAYS cause hypersensitivity reactions

which medication is used to treat malaria and pneumocystis pneumonia?

Primaquine

im a queen i be treating both malaria and pneumocytis pneumonia and advanced AIDS

how does G-6D provide NADPH to prevent hydrogen peroxide toxicity?

this NADPH is then used to power __________ which will convert ______ into ______

what does that product then do to H2O2 ?

• create NADPH by converting glucose 6 phosphate to 6-phosphogluCONATE

• Glutathione reductase (turns GSSG into GSH)

• GSH stimulates glutathione peroxidase to turn H2O2 into H2O (detoxifying H2O2)

which drugs alongside primaquine increase H2O2 levels?

these drugs usually don’t cause hemolytic anemia UNLESS there is a mutation to ______

sulfa drugs

cancer drug rasburicase (Elitek)

fava beans

if there is a mutation in G6D then consider not using these as therapy as you wont be able to get rid of the H2O2 and detoxify it into water

______-______ males/females were treated with primaquine for malaria and exihibited a high incidence of _______ ANEMIA

• Due to an ___-linked dominant/recessive defect among Mediterranean ethnic groups such as ______, _______, ________ (most to least effected)

afro-Caribbean MALES

hemolytic

X linked RECESSIVE

Kurds, Iraqis,Bantu

what are the class 1 HLA genes that encode for Major Histocompatibility Complex?

HLA A, B, C

what are the class 2 HLA genes that encode for Major Histocompatibility Complex?

HLA- DRB

DQA DQB

DPA DPB

5 total