Models of intervention and care for psychostimulant users, 2nd edition - monograph series no. 51

Part I: Pathophysiological considerations

Page last updated: April 2004

Pregnancy associated changes in maternal physiology
Stages of foetal development
Prevalence of birth defects
Classification of drug risk in pregnancy

Pregnancy associated changes in maternal physiology

Pregnant women experience a number of physiological changes that can impact on drug pharmacokinetics (see Tabl 19). They have increased cardiac output and renal function. In addition to increased body weight, high hormone levels and fluid retention, pregnant women also exhibit increases in plasma volume. In contrast, there is a decrease in plasma albumin and intestinal motility (Tuchmann-Duplessis, 1977). Because of this, drugs with a high renal clearance may need to have their dosage increased, while drugs with a high hepatic clearance require no dose change (as maternal liver size and hepatic blood flow remain unchanged). In addition, emesis, constipation and iron deficiency are common (Llewellyn-Jones, Abraham & Oats, 1999).

Table 19: Pregnancy associated physiological changes (Chamberlain & Broughton-Pipkin, 1998; Tuchmann-Duplessis, 1977)

Table 19 is presented as a list in this HTML version for accessibility reasons.

Physiological changes during pregnancy:
  • Cardiac output: Increased
  • Renal function: Increased
  • Body weight: Increased
  • Sex hormone levels: Increased
  • Fluid retention: Increased
  • Plasma volume: Increased
  • Plasma albumin: Decreased
  • Intestinal motility: Decreased
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Stages of foetal development

Clinicians use an obstetric calendar for clinical convenience, where day 0 is defined as the date of the last menstrual period. However, when considering potential drug effects on the foetus, it is more accurate to define day 0 as the moment of conception (approximately two weeks prior to the last missed menstrual period).

Pre-implantation

After fertilisation of the ovum, the embryo takes about 10 to 14 days for implantation in the uterus to occur. Prior to implantation, the embryo (or blastocyst) floats freely in endometrial fluid, depending on uterine secretions for nutrition. During pre-implantation, exogenous agents can become toxic to the blastocyst. However, lack of organ formation precludes the development of organ specific foetal anomalies. Slight injuries to the blastocyst can be overcome without harmful sequelae since the cells retain their ability to segment and produce varied cell lines. At this stage, the woman is usually unaware she is pregnant and inadvertent drug ingestion may occur. Provided she has taken the drug before implantation (roughly prior to her expected menstrual period), there will be little danger of malformations.

Teratogenic period

Once the embryo has implanted, it undergoes very rapid and important transformations (Table 20) (Chamberlain & Broughton-Pipkin, 1998; Tuchmann-Duplessis, 1977). Most organ and tissue differentiation takes place between week three (implantation) and week eight. This is the potential teratogenic period when drug exposure, in sufficient doses, has the potential to cause gross and irreversible malformations. Teratogens taken during this period only affect the vulnerable organ or tissue if drug exposure occurs as the organ is being formed. Thus, exposure to thalidomide after week eight (post-conception) has not been associated with adverse effects such as phocomelia.

Table 20: Key organ differentiation in first trimester (Tuchmann-Duplessis, 1977)

Table 20 is presented as text in this HTML version for accessibility reasons.
First trimester - Pre-Implantation
No organ differentiation.

Drug impact on foetus: Minimal
Weeks post conception: </= Week 2
First trimester - Transformation
  • Development of neural groove (from which spinal cord and brain develop). Heart begins to form.
    Drug impact on foetus: Potential for teratogenicity
    Weeks post conception: Week 3

  • Gut differentiates into fore and hind gut. Optic vessels, liver and pancreas form. Limb buds (arms and legs) develop.
    Drug impact on foetus: Potential for teratogenicity
    Weeks post conception: Week 4

  • Eyes and olfactory organs develop. Heart divides into different cavities.
    Drug impact on foetus: Potential for teratogenicity
    Weeks post conception: Week 5

  • Limbs grow and differentiate. Heart structures completely form. Anal membrane ruptures. Bones begin to develop. Sex is determined.
    Drug impact on foetus: Potential for teratogenicity
    Weeks post conception: Weeks 5-8

  • Effects primarily on nutrition and growth.
    Drug impact on foetus: Minimal
    Weeks post conception: Weeks 9-11
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Second trimester
Effects primarily on nutrition and growth.

Drug impact on foetus: Minimal
Weeks post conception: Weeks 12-24
Third trimester
Drug accumulation and associated toxicity reported.

Drug impact on foetus: Foetal toxicity
Weeks post conception: Weeks >/=24

The foetal period

The foetal period begins at the end of week eight. This is a time of relative drug safety as organ differentiation is largely complete. Thus, drugs given during the foetal period do not cause major malformations. However, CNS development continues throughout pregnancy and for some months after birth; the possibility of drugs producing subtle effects on neural development cannot be excluded (American Academy of Pediatrics Committee on Drugs, 2001). In addition, the foetus demands considerable nutrition for normal growth and development to occur. Drugs that decrease the flow of oxygen and nutrients to the foetus (e.g. vasoconstrictors such as amphetamines and nicotine) have the potential to cause intrauterine growth retardation (Zuckerman, Frank, Hingson, Amaro et al., 1989) and should therefore be avoided during mid pregnancy.

Third trimester

In third trimester, the foetus prepares to function independently of its mother. He or she gradually adapts to performing more of its own nutrient and toxin elimination. However, by 26 weeks gestation, the foetal half-life of many drugs is still up to twice that of the mother. Thus, it is not surprising that drug accumulation and potential for foetal toxicity occur in late third trimester. Drugs that are lipophilic or with long half-lives are more likely to cause foetal toxicity. Many psychostimulants fall into this category. The major consequences of psychostimulant accumulation in the foetus are the potential to influence labour and for the development of neonatal withdrawal symptoms postpartum.

Prevalence of birth defects

Approximately 2% of all births in Australia are associated with congenital malformations (National Perinatal Statistics Unit, 2001). Discovery of internal organ anomalies may not be noticed until later life, which may double the prevalence statistic. Whilst most gross abnormalities cannot be attributed to any specific cause, genetic influences and chromosomal abnormalities have been estimated to cause about 20% of these malformations while environmental factors in the uterus (poor maternal nutritional status, poor folate status, diseases such as diabetes or infection) account for about 10%. Drug ingestion is believed to cause an additional 3% of birth defects, although this may be underestimated due to poor recall and reporting of medicine ingestion (Iams & Rayburn, 1982). For a drug to be implicated as a teratogen, it must therefore cause a dose-related, consistent pattern of anomaly, with an incidence higher than the population 2%.

Classification of drug risk in pregnancy

The Australian Drug Evaluation Committee's (ADEC) classification on medicines in pregnancy is internationally recognised (Table 21) (ADEC, 1999). This drug risk classification system is similar to those developed in Sweden and by the Food and Drug Administration in the USA. Despite the thousands of medicines marketed internationally, there are few (less than 25) proven teratogens. In this categorisation of drugs commonly used in Australia, ADEC has included two psychostimulants — dexamphetamine as category B3 and methylphenidate as category B2. It should also be noted that the categorisation of an individual drug, assigned by the manufacturer and listed in their approved product information, might differ from the ADEC categorisation. Top of page

Table 21: ADEC categorisation of drugs in pregnancy (ADEC, 1999)

Table 21 is presented as a list in this HTML version for accessibility reasons.
  • A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.

  • B: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformations or other direct or indirect harmful effects on the human foetus having been observed. As experience of effects of drugs in this category in humans is limited, results of toxicological studies to date (including reproduction studies in animals) are indicated by allocation to one of three subgroups:

    • B1: Studies in animals have not shown evidence of an increased occurrence of foetal damage.
    • B2: Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
    • B3: Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

  • C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

  • D: Drugs which have caused, are suspected to have caused, or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

  • X: Drugs that have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy.

Breast-feeding

Factors influencing the excretion of a psychostimulant into breast milk can be broadly divided into those relating to the mother, the child and to the drug itself. As with all drugs, psychostimulants have a chemical structure that determines their pharmacokinetic parameters and the extent to which they pass into breast milk. For simplicity, the term drug will be used in describing these processes.

Maternal factors

Breast milk content and yield capacity

Breast milk is a suspension of protein and fat dispersed in an aqueous medium containing carbohydrates and inorganic mineral salts. The extent to which psychostimulants diffuse into the milk depends on fat content, which varies during the day, with duration of lactation, frequency of feeding and the volume of milk produced by the mother (Briggs, 2002; Chaplin, Sanders & Smith, 1982; O'Brien, 1974). The ratio of fat to volume of milk tends to be higher toward the end of a feed (hindmilk) compared with the milk available to the infant at the beginning of the feed (foremilk). Larger babies require larger milk volumes (approximately 165 mg/infant kg/day) and therefore may be exposed to higher levels of psychostimulants. If the mother is undernourished or dehydrated, milk supply is likely to decrease.

Milk is separated from maternal plasma by a membrane that allows selective drug movement from plasma to milk and back diffusion. For the most part, drugs pass by simple passive diffusion from a solution of high concentration to that of a lower concentration, until equilibrium is reached or circumstances are changed, such as the mother receiving her next dose (McGuire, Mitchell, Wright & Noordin, 1987; O'Brien, 1974). Active transport may also occur. Top of page

Underlying illness

Milk quality may be dependent on maternal wellbeing. If, for example, a mother using psychostimulants is unable to maintain adequate nutrition, hydration status and rest, this may impact on milk quality and quantity (Wilson, Brown, Cherek, Dailey et al., 1980).

Drug parameters

When the mother takes a drug, a proportion of the dose will peak in her plasma. Generally, peak blood levels for oral, non-sustained release dose forms occur within two hours of administration, whereas smoking or intravenous injection produces peak drug levels within minutes.

As the drug reaches peak levels in the blood, the drug will be distributed into various body compartments, including breast milk. Once equilibrium is reached and the drug peaks in the milk, back diffusion takes place; the drug is cleared rapidly from the milk back into plasma and from there cleared by the body. This process is repeated with each new dose. Drug transfer and accumulation into breast milk depends on various factors (Table 22) (McGuire et al., 1987; O'Brien, 1974).
Table 22: Drug parameters that impact on drug excretion into breast milk
Table 22 is presented as text in this HTML version for accessibility reasons.
Molecular weight
Molecular weight (MW) determines extent of drug passage through membrane pores between plasma and milk. If MW < 200 - passive diffusion and extensive milk excretion are expected to occur.

Psychostimulant examples:
  • Amphetamines (base) = 135.2
  • Amphetamines sulphate = 368.5
  • Methamphetamine HCL = 185.7
  • Cocaine = 303.4
  • MDMA (free base) = 193.2
Lipid solubility
As the drug increases in lipophilicity (less water soluble), passage through the membrane and excretion into the milk increases.

Psychostimulant examples:
  • Methamphetamine (base) - quite fat soluble
  • Methamphetamine sulphate - low fat solubility
Plasma protein binding (ppb)
Extent of drug and plasma protein binding determines the amount excreted into the milk. Only free, unbound drugs can pass membrane, so highly bound drugs are minimally excreted into milk.

Psychostimulant examples:
  • Amphetamine ppb = 20% (low)
  • Methylphenidate ppb = 15% (low)
  • Cocaine ppb = 20%-50%
  • MDMA ppb = 35%
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Ionisation
The membrane separating the milk from plasma favours transfer of drugs in non-ionised (non-dissociated) state. Milk is more acidic than plasma, thus weak bases ionise more in milk than plasma, producing higher milk to plasma (M/P) ratio. Weak acids ionise preferentially in plasma and have a low M/P ratio.

M/P ratio: deceptive parameter for predicting the quantity of the drug excreted into the milk, as it is only measured at the moment in time when the drug peaks in the milk and does not represent the amount retained in the milk over a 24 hour period.

Psychostimulant examples:
  • Amphetamines, cocaine and MDMA are weak bases
  • Amphetamine M/P 2.8-7.5
  • Milk plasma ratios of most illicit psychostimulants have not been determined
Elimination half-life (t1/2)
ie. length of time taken for drug plasma concentrations to drop by half. It takes five half-lives for a therapeutic dose to be eliminated from the body. Short half-life means less potential for drug accumulation in milk.

Psychostimulant examples:
  • Dexamphetamine t1/2 = 16-31 hours
  • Methamphetamine t1/2 = 12-34 hours
  • Cocaine t1/2 = 1.5 hours
  • Benzoylecgonine t1/2 = 5 hours
  • MDMA t1/2 = 9-31 hours
Pharmacological activity
Adverse effects are commonly dose related and may cause unwanted extension of pharmacological activity.
Dose/frequency
Increased daily dose increases the quantity excreted into the milk. Maintaining same daily dose but increasing administration frequency does not increase the quantity excreted into the milk, but can increase amount ingested by infant.

Infant status

Gestational age

The infant's gestational age at birth affects suckling behaviour and duration on each breast, the quantity of milk consumed per feed (130 to 180 ml/infant kg/day) and the interval between feeds (McGuire et al., 1987). The neonate's immature liver enzymes will also decrease drug metabolism and excretion. A premature infant, particularly if of low birth weight, is likely to feed more frequently and for longer, making manipulation of feeds to minimise infant drug exposure through breast milk more difficult. Top of page

Time of feeding in relation to maternal dose

On the presumption that the drug is in an immediate release and not a sustained or controlled release dose form, the amount of drug transferred into the milk of a breast-feeding mother may be limited or reduced by the following strategies (Anderson, 1977; Berlin, 1981; Wilson et al., 1980).

If the drug is taken once daily, it should be taken around the time of the feed to allow the longest period of time to elapse until the next feed. Often, this would be at the time of the last feed at night to allow the maximum time for maternal drug elimination. Controversy exists over whether it is best to take a drug immediately before, during or immediately after the feed; whichever is most practical should be chosen.

If the drug cannot be taken as a single daily dose, feeds and drug consumption need to be timed to allow the maximum possible time from administration to the next feed. Usually, for non-sustained release dosage forms, this is best achieved if the mother takes the dose at the next feed. Ideally, the mother should wait at least one half-life after the peak milk concentration is achieved before feeding again as this will significantly decrease (by about 50%) the amount of drug excreted into the milk (Berlin, 1981). Feeding away from the time of the peak milk concentration will minimise the infant's drug exposure. In practice, other factors, such as chaotic lifestyle, may influence a mother's ability to ensure breast-feeding occurs away from peak drug concentrations. Any clinical recommendations should take these factors into account.