Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood.

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Principles of Drug Biodisposition in the Neonate

Drugs ingested by a lactating mother would be expected to appear in human milk to some extent and be ingested by a breast-feeding infant. Drugs pass from maternal plasma into milk by passive diffusion and are distributed within the aqueous, protein and lipid phases of milk. Distribution into milk will be affected by physiochemical characteristics of the drug: acid-base characteristics, relative protein binding in plasma and milk, and lipid solubility, as well as milk composition.

Drugs in human milk. Clinical pharmacokinetic considerations.

Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone. The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The β-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 L/kg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/ml. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 ng/ml for norethisterone and 0.8 to 4.5 ng/ml for levonorgestrel. All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin. Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug. The oral contraceptive steroids are involved in drug interactions of clinical significance. While the effect of contraceptive steroids on other drugs is small and unlikely to be of clinical significance, failure of contraception often occurs if enzyme-inducing agents such as rifampkin, phenobarbitone or carbamazepine are coadministered. Oral antibiotics do not seem to cause a significant loss of contraception in the large majority of women. Vitamin C will enhance the effect of contraceptive steroids by competing for sulphate conjugation in the gut wall, thus leading to increased bioavailability of ethinyloestradiol.

Clinical pharmacokinetics of oral contraceptive steroids.

The most widely used longterm injectable female contraceptive is depot medroxyprogesterone acetate. Its advantages as a contraceptive its history of use its present legal status in Australia and its mode of action are discussed. The major concern is that involving interpretation of animal toxicology data related to various carcinogenic side effects of the drug. Of the great amount of human data so far gathered none has shown any evidence of human risk with medroxyprogesterone acetate. There is continuing controversy regarding the size duration and type of studies which must be undertaken in order to exclude all hint of risk. A thorough review of the literature from studies with medroxyprogesterone acetate is presented. Injectable contraceptives do seem to cause a greater amount of menstrual disorders including amenorrhea than other types of contraception. They can however be used during lactation without effect of the lactating factor. Studies must be undertaken to assess whether they do carry risks to the baby through the milk. Few metabolic changes have been confirmed. The relationship which has been shown to exist either negative or positive between medroxyprogesterone acetate and cervical breast endometrial or liver cancer is discussed in detail.

A comprehensive review of injectable contraception with special emphasis on depot medroxyprogesterone acetate.

Objective To examine weight changes in a large cohort of obese and nonobese adolescent girls initiating depot medroxyprogesterone acetate (DMPA), an oral contraceptive (OC), or no hormonal contraceptive method (control). Design, Setting, and Participants Prospective study of 450 adolescent girls, aged 12 to 18 years, who attended 4 urban health clinics and selected DMPA, OC, or control. Data collection occurred at baseline and at 6, 12, and 18 months; consisted of structured interview and measurement of height and weight; and occurred from April 19, 2000, through September 26, 2003. Main Outcome Measure Weight was examined as mean change over 18 months and actual weight at each study visit. On the basis of preliminary analyses, we stratified the sample according to baseline obesity status (nonobese, body mass index [calculated as weight in kilograms divided by the square of height in meters] Results Adolescent girls who were obese at initiation of DMPA gained significantly more weight than did obese girls starting OC or control ( P P P  = .006) between length of time receiving DMPA and weight gain was evident for obese subjects. Conclusions Over 18 months, DMPA use was associated with increasing rates of weight gain in obese subjects. The potential contribution to severe obesity in this population is concerning.

https://jamanetwork.com/journals/jamapediatrics/articlepdf/204332/poa50070_40_45.pdf

K. Shrimanker

Papers

Blood levels of medroxyprogesterone acetate after multiple injections of DepoProvera or CycloProvera.

Transfer of contraceptive steroids in milk of women using long-acting gestagens.

Rate of metabolism of norethisterone in women from different populations