- ER of cells - mainly in liver - gut, lung, skin, kidney

p450 reactions Flashcards by Tim Pulleyn

AUC and steady state concentrations are dependent only on what

the enzymes involved

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phases of liver metabolism

phase 0 - uptake to hepatocyte
phase 1 - oxidation, reduction, hydrolysis
phase 2 - glucuronidation, methylate, acetylate
phase 3 - excrete into blood

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pharmacodynamics definition

what drugs do to the body

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metabolism phase 1 reactions

oxidation
reduction
hydrolysis

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metabolism phase 2 reactions

glucuronide conjugation
methylation
acetylation

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metabolic processes affected my gene mutations

metabolism
transport
PD

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5 functions of P450’s

metabolize drugs
synthesize steroid hormones/bile acid
synthesize prostaglandin, thromboxane, leukotriene
metabolize fat-soluble vitamins
synthesize vitamin D3

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where are P450s

ER of cells
mainly in liver
gut, lung, skin, kidney

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most common P450s

1A2
2C9/2C19
2D6
2E1
3A4

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solute carrier transporters typically go which direction

extracellular to intra (influx transport)

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ATP binding cassette transporters go which direction

efflux

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example of ATP binding cassette transporter

P-glycoprotein

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P-glycoprotein drug importance when deficient

tumor drug resistance

- reduction DOAC effect

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power source of P-gp

ATP

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reversible inhibition

temporary association with CYP

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irreversible inhibition

suicide substrate that covalently binds to enzyme

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types of reversible inhibition

competitive
noncompetitive
uncompetitive

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noncompetitive inhibition

binds to a non-active site, making enzyme not function

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uncompetitive inhibition

binds to enzyme-substrate complex

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degree of inhibition depends on

affinity to enzyme

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strong inhibitor classification

> 5 fold increase in plasma AUC or >80% reduction in clearance

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moderate inhibitor classification

> 2 fold increase in plasma AUC or 50-80% reduction in clearance

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weak inhibitor classification

> 1.25 and <2 fold increase in plasma AUC or 20-50% reduction in clearance

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when does inhibition occur

within 24 hours
can be concentration-dependent
clinical effect may take a couple days

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inducers function

-form more CYP enzymes or transporters via transcription

rifampin induces

``` 2C9 2C19 3A4 P-gp OATP ```

ritonavir induces

3A4 P-gp OATP

how long to see induction effects

3-5 days

things that cause autoinduction

carbamazepine smoke alcohol

strong inducer classification

>80 decrease in AUC

moderate inducer classification

50-80% decrease in AUC

weak inducer classification

20-50% decrease in AUC

examples of prodrugs

cyclophosphamide codeine hydrocodone

1A2 substrates

``` caffeine clozapine duloxetine naproxen theophylline cyclobenzaprine ```

1A2 inhibitors

cimetidine ciprofloxacin fluvoxamine amiodarone

1A2 inducers

charbroil tobacco rifampin

2C9 substrates

``` NSAIDS fluoxetine losartan glipizide phenytoin warfarin ```

2C9 inhibitors

``` amiodarone fluconazole (Strong) isoniazide metronidazole paroxetine Sulfamethoxazole voriconazole ```

2C9 inducers

barbiturates rifampin SJW

2C19 substrates

``` amitriptyline cyclophosphamide clopidogrel diazepam lansoprazole omeprazole phenytoin ```

2C19 inhibitors

``` cimetidine ketoconazole fluoxetine fluvoxamine lansoprazole omeprazole ```

2C19 inducers

efavirenz rifampin ritonavir SJW

2D6 substrates

``` SGA's codein duloxetine metoprolol paroxetine tramadol tamoxifen ```

2D6 inhibitors

``` bupropion (S) cimetidine duloxetine fluoxetine (S) paroxetine (S) quinidine (S) ritonavir (S) methadone ```

2D6 inducers

none, its resistant

2E1 substrates

APAP | acute alcohol

2E1 inhibitors

disulfiram

2E1 inducers

chronical alcohol

3A4 substrates

``` macrolides benzos immune modulators HIV protease inhibs CCB statins DOACs methadone ```

3A4 inhibitors

``` amiodarone nefazodone (S) CCBs grapefruit ketoconazole (S) clarithromycin (S) erythromycin cimetidine ```

3A4 inducers

``` carbamazepine phenobarbital phenytoin rifabutin rifampin SJW ```

P-gp substrates

``` apixaban rivaroxaban dabigatran digoxin losartan ```

P-gp inhibitors

amiodarone diltiazem carvedilol verapamil

P-gp inducer

amiodarone

fluoxetine primarily inhibits

2C19 | 2D6

fluvoxamine inhibits

1A2 2C19 2D6 3A4

paroxetine primarily inhibits

2D6 | 3A4

citalopram inhibits

barely any, very little DDI

2 herbal interactions to know about

SJW induce 3A4 | Dill may inhibit 3A4

high risk drug interactions

- narrow therapeutic window drugs - no alternate elimination pathways - no alternatives - dose adjustments not known

top 4 drug interactions to be aware of

- sildenafil + isosorbide mononitrate (nitrate) - potassium and spironolactone - warfarin and basically anything - tyrosine kinase inhibs + 3A4 inhib/QT drugs/P-gp inhib/PPIs

rate of DDIs increase with

- # of prescribed meds - # of OTC meds - increased age age