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

• absorption – well absorbed orally

• distribution– bound to plasma proteins– albumin, SBG, others

clinical pharmacology

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

CBD

PV

HV STO

About 40-60 % of estrogen removedin 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

Pregnancy 3rd gen Ist gen Non-users

AR(per100000womenyears)

60 30 15 5

RR 12 6 3 1

% ofwomenfree of VTE

99.94 99.97 99.985 99.995

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%