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Transcript
Oral contraceptives:
50 years ago introduction of Enovid
(mestranol and norethynodrel)
Jessica Oesterheld, MD
Vignette
• A 25 year old woman with several prior
depressive episodes has a first hypomanic
episode. You wish to treat her with a mood
stabilizer. She does not wish to become
pregnant and takes oral contraceptives (OC).
What mood stabilizers would you consider?
What should you avoid?
ORAL CONTRACEPTIVES
• In use by more than 1/4th of women
• Introduced 50 years ago as “Enovid”
• Contain an estrogen (17-alpha ethinyl
estradiol, EE) and progestin (PG)
• EE supresses ovulation, PG supresses LH
and limits endometrial hyperplasia, reduce
endometrial carcinoma
ORAL
CONTRACEPTIVES
• Usually 35-50 ug of ethinyl estradiol (EE)
• Low dose OC contain 20ug EE to reduce EE
side effects, headaches and
thrmoboembolic events (Alesse, Mircette
etc)
• Only a few contain mestranol, a pro-drug of
EE (Nelova 1/50, Ortho-Novum 1/50)
Many formulations of
contraceptives
Oral:
– Monophasic- same amount of EE and progestintaken for 21 days
– Biphasic and triphasic: progestin is reduced and
the effects similar to hormonal influences during
natural menstrual cycles
– Continuous daily regimens of ethinyl estradiol (10
and 30 ug) and a progestin-allow withdrawalbleeding periods only 4 times a year (Seasonale,
Seasonique). A yearly no cycling version of
levonorgestrel and EE (Lybrel)
Many formulations of
contraceptives
Transdermal- OrthoEvra
(norelgestromin and ethinyl
estradiol)
Transvaginal- Nuva-Ring (3ketodesogestrel or etonogestrel
and ethinyl estradiol)
Progestin-only
Contraceptives
• the minipill containing norethindrone, norgestrel or
levonorgestrel (POPs)
• a subdermal implant (Implanon)
• intramuscular and subcutaneous preparations of
medroxyprogesterone acetate administered every 3 months
• intrauterine devices that release progesterone and
levonorgestrel.
Non-CYP Drug Interactions from
other metabolic pathways
• Conjugated EEs
– chewed up by gut bactria (Clostria)---> free
EEs and if Rx ampicillin, neomycin-->more
EE conjugates in feces, less EE in plasma
– Unclear interaction - better to be safe than
sorry
• Drugs that compete for sulfation
– in gut wall and raise EE levels (e.g.,
acetaminophen, vitamin C)
Metabolism of
EE/Progestins
• Extremely complicated- 50% reach systemic
circulation
• Major pathway: CYP3A4
• Minor pathway: CYP2C9
• Conjugated by UGT1A1, possibly UGT1A8 and
UGT1A9
• Mestranol is a pro-drug metabolized by CYP2C9
• Progestins metabolized by CYP3A4 including
desogestrel which is a pro-drug (Korhonen et al
2005)
Inactivation of EE
Phase 1
EE
2-OH EE
CYP3A4
Phase 2
conjugation
UGT1A1
Sulfation
CYP-based drug
interactions
1 How other drugs affect
OCs
2 How OCs affect other
drugs
How other drugs affect OCs:
• Drugs that induce CYP3A4/
UGT1A1:
– may lead to increased clearance of EE
and/or progestins and loss of clinical
efficacy.
– drug interactions resulting in spotting,
breakthrough bleeding, or unwanted
pregnancy
How other drugs affect OCs:
CYP 3A4 Inducers
•
•
•
•
•
•
•
Aprepitant-long term
Carbamazepine
Griseofulvin
Nelfinavir
Oxcarbazepine
Phenytoin
Rifabutin/Rifampin
• St Johns wort
Bosentan
Felbamate
Nevirapine
Phenobarbital
Primidone
Ritonavir/
“boosteds”
Topiramate
(200mg/d)
Modafinil
(200mg/d)
What to do for
contraception if must take
a 3A4 inducer?
• Barrier contraception
• Increase OC to 50-100 mg-some support
• Switch to depo medroxyproesterone acetate as a
contraceptive, since it does not seem to be affected
by inducing anticonvulsants
• Remember that induction continues 2-4 weeks after
inducing drug is discontinued
• Phenytoin different----- show you in a minute
How other drugs affect OCs:
CYP 3A4 Inhibitors
(increase OC availability/activity)
Amprenavir
Atorvastatin
Delavirdine
Erythromycin et al
?Fluoxetine
?Gestodene
Indinavir
Ketoconazole
Voriconazole
Atazanavir
Dapsone ? 1984 study
Efavirenz-1 neg study
Fluconazole
?Fluvoxamine
GF Juice
Itraconazole
Nefazodone
Special issue of very low
dose OCs
• Mircette, Asesse, Levlite, Loestrin
– have 20 mcg of EE
• If inhibited by CYP3A4 inhibitors----EE
concentrations increases and shift them to
“high dose EE” ( lead to adverse events e.g.,
breast tenderness, bloating, weight gain)
• Case report with nefazodone
Remember desogestrel OCs
• Apri, Cesia, Cyclessa, Desogen,
Kariva, Mircette, Ortho-Cept, Solia,
Velivet
• Desogestrel is a pro-drug metabolized
via CYP3A4 to become active (has
other pathways)
Remember mestranol
• Pro-drug that is metabolized via
CYP2C9 to EE
• Vulnerable to CYP2C9 inhibitors to not
be converted to active metabolite
• Sulfaphenazole (check the CYP2C9
potent inhibitor list)
How OCs affect other drugs:
CYP and UGT-based DDIs
OCs Effect Other Drugs - Inhibition
OCs are moderate inhibitors of 1A2, 2C19 and mild
inhibitors of 2B6 and 3A4:
Amitriptyline
Caffeine
?Chlordiazepoxide
Clozapine
Diazepam
?Olanzapine
Phenytoin
Prednisolone
Selegiline
Tizanidine
Voriconazole
Bupropion
Carisoprodol
Chlorpromazine
Cyclosporine
Imipramine
Omeprazole
Proguanil (pro-drug)
?Tacrine
Theophylline
OCs Effect Other Drugs Inhibition
• CYP 1A2
– theophylline (30% decrease in clearance), olanzapine, CLZ,
tacrine
• CYP 2C19
– special case of phenytoin, ? proton pump inhibitors
• CYP 3A4
– How potent is it: documented cyclosporine, prednisolone,
<not midazolam>
• 2C19 and 3A4
– imipramine, amitriptyline, diazepam, chlordiazepoxide (via
nordiazepam intermediate)
Phenytoin and OCs
• Remember I said phenytoin will
induce CYP3A4, but OCs increase
levels of phenytoin through CYP2C19
inhibition- thus the strategy of
increasing OC dosage to overcome
phenytoin induction will lead to
phenytoin toxicity
OCs Effect Other Drugs –
Induction of CYP2A6 and some
UGTs
• EE induces CYP2A6- nicotine- woman have
higher rates of lung CA
• Induce UGTs: acetaminophen, clofibrate,
diflunisal, lamotrigine and valproate
• During OC wash out week levels increase 84% for
lamotrigine (Contin et al. 2006; Christensen et al. 2007)
• Consider continuous regimens of OCs, dose reduction of
25% during pill-free weeks or progestin only OCs
Clearance changes in each trimesterpregnancy
(Increase in Clearance-> reduced blood levels)
CYP1A2
1st trim
Dec 33%
2nd trim
Dec 48%
3rd trim
Dec 65%
CYP2C9
No change
No
change
Inc 20%
Dec 50%
Dec 50%
CYP2C19
CYP2D6
Inc 26%
Inc 35%
Inc 48%
CYP3A4
Inc 35-38%
Inc 3538%
Inc 35-38%
(Tracy et al 2005, Anderson 2005, Hebert et al 2008)
Clearance changes in each trimester-pregnancy
(Increase in Clearance-> reduced blood levels)
1st trim
2nd trim 3rd trim
UGT1A1
increased
UGT1A4 Inc 200% Inc
200%
UGT2B7
Inc 300%
NAT2
No
change
No
change
Xanthine No
oxidase change
No
change
Increased
Drug levels decrease in late
pregnancy
• Lamotrigine levels decrease 50% (Brodtkorb & Reimers
2007) : do monthly levels (Harden& Sethi 2008)
• Levetiracetam levels decrease 50% (Westin et al 2008)
• Oxcarbazepine decrease 30-40% (Brodtkorb & Reimers
2007)
• Labetalol decreased (UGT1A1, Jeong et al 2008)
• Others that also may be decreased phenytoin,
phenobarbital (Pennell & Hovinga 2008)
• Carbamazepine may be least affected (Harden& Sethi
2008 )
Medroxyprogesterone and
HIV drugs
• IM medroxyprogesterone but not oral progestins
increased clearance of prednisolone 25% (Tsunoda et
al 1998)
• On nelfinavir, nevirapine, efavirenz HIV regimens no
ovulation, no change CD4+ , minor pk changes in
increasing clearance of nelfinavir and decreased Cx
nevirapine not clinically significant- none for efavirenz
and no changes in medroxyprogesterone (Cohn et al
2007)
• Effects of HIV antiretrovirals on the pharmacokinetics of
hormonal contraceptives.
Medroxyprogesterone and
HIV drugs
• Women on
zidovudine/lamivudine/efavirenz
showed no pk changes in
medroxyprogesterone (Nanda et al
2008)