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Oral contraceptive prescribing • clinical pharmacology – mechanism of action – ADME • interactions • adverse reactions • benefits and harms what are they • • • • • around since late 1950’s social revolution progestogen /oestrogen variety of components and doses changes over time in both components • oestrogen – ethinyoestradiol – mestranol • progestogen – – – – – – – norethisterone norgestrel Levonorgestrel medroxyprogesterone ethynodiol diacetate gestodene desogestrel doses • monophasic • oestrogen - up to 50g/day • progestogen - up to 1mg/day • biphasic • oestrogen: constant • progestogen: eg 11 days @50, 10 @125 g • triphasic • oestrogen 30/40/30 • progestogen 50/75/125 clinical pharmacology • mechanism of action – inhibit secretion of FSH, LH - inhibit ovulation – additional actions on endometrium tubal motility, cervical mucosa clinical pharmacology • absorption – well absorbed orally • distribution – bound to plasma proteins – albumin, SBG, others metabolism • Oestrogens – first pass clearance • metabolised in liver, conjugated • excreted in the bile - (estradiol vs EE) • enterohepatic circulation • Progestogens – depends on which one - “natural” progestogen extensive first pass metabolism excretion • urinary • remember the bile duct STO HV PV CBD About 40-60 % of estrogen removed in the first pass through the liver HMW conjugates are excreted in bile interactions (1) • antibiotics – impaired absorption (effect on gut enzymes) reduced bacterial sulfatase leading to reduced entero-hepatic recycling – enzyme induction -> increased clearance, lower plasma estrogen concentrations (eg rifampicin, griseofulvin, anticonvulsants, St John’s Wort) interactions (2) • anticonvulsants – Older drugs are enzyme inducers -> increased clearance and reduced concentration and failure (phenytoin, phenobarbitone, primidone, carbamazepine). No effect of sodium valproate – Newer drug have variable effects (no change with gabapentin, lamotrigine, tiagabine, levetiracetam) (induction with topiramate and oxcarbazepine) – try higher dose estrogen pills, double product dosing – valproate less of a problem adverse reactions • estrogen excess – – – – – late cycle breakthrough bleeding menorrhagia/dysmenorrhoea nausea/vomiting fluid retention breast tenderness adverse reactions • progestogen excess – – – – – – amenorrhoea acne/oily skin weight gain mood changes depressed libido breast tenderness other risks • thromboembolic disorder – high dose oestrogen - Inman, dose response relationship – worse with other risk factors (age, smoking) – ?third generation progestogens – differentiating effects on VTE and other cardiovascular disease big picture risks • endometrial cancer – progestogen is protective • ovarian cancer – protective • breast cancer – jury out /data unconvincing • cervical cancer – confounded other benefits • reduction in menstrual flow - may lower incidence of anemia • reduction in dysmenorrhoea • possible reduction in auto-immune thyroid disease, rheumatoid arthritis • some protection against PID risk of nonfatal VTE AR (per 100000 women years) RR Pregnancy 3rd gen Ist gen 60 30 15 Nonusers 5 12 6 3 1 99.97 99.985 99.995 % of 99.94 women free of VTE other issues • • • • compliance gastro. missing pills alternative forms of hormonal contraception balance sheet • benefits – effective contraception – other health benefits – long-term health and social impact • harms – immediate adverse effects – risk of failure – long-term health effects other uses • morning after pill – EE 100mcg + norgestrel 1mg within 72 hours, 2 doses – Failure rate of about 1%
