G3. ADME in pregnancy Flashcards
when considering ADME for pregnancy, what are the two main contributing facors?
-Maternal physiological changes.
-Effects of the placental-foetal compartment.
Vd, Cmax and Tmax definitions?
ONE NOTE (done before)
How does an increase in progesterone levels affect absorption via oral route?
Increase in plasma progesterone level leads to a reduction in intestinal mobility -> 30 – 50 % increase in gastric and intestinal emptying time. This is particularly relevant when we require rapid onset of drug action1. We observe an increase in Tmax and reduction in Cmax.
How does the occurrence of vomiting affect absorption via oral route?
The occurrence of nausea and vomiting; this is particularly prevalent during the first trimester. There is potential for partial or complete ejection of the dosage form.
How does a decrease in gastric acid secretions (by circa. 40 %), and an increase in mucus secretions affect absorption via the oral route?
There is a decrease in gastric acid secretions (by circa. 40 %), and an increase in mucus secretions. This leads to an increase in gastric pH1. The absorption of weak acids and bases is thus affected…
Reduction in absorption of weak acids, for example, analgesics and anti-emetics.
Describe the Henderson-Hasselbalch equation
Relationship between extent of ionisation of an electrolyte and pH is described by the Henderson-Hasselbalch equation
pH partition hypothesis has what following assumptions?
- GI tract acts as a lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion.
- The GI/blood barrier is impermeable to ionised (poorly lipid soluble) forms of drugs - only the lipid soluble unionised species will pass across.
How does the maternal cardiovascular and respiratory system change during pregnancy?
-changes to maintain perfusion of the placenta and ensure maternal blood is enriched with oxygen and effectively cleared of CO2. Thus, during pregnancy:
Cardiac output increases.
Tidal volume increases.
Increased pulmonary blood flow.
-All of these factors favour alveolar uptake
How do the changes in the maternal cardiovascular and respiratory system affect absorption of drug via inhalation route?
The rate of induction in the case of volatile anaesthetic drugs such as methoxyflurane has been demonstrated to increase, reducing dosing requirements
As a consequence of increased cardiac output:
-By the end of the first trimester, renal blood flow increases by 50 %.
-At full term, uterine blood flow peaks at 36 – 42 L/h
An increase in body fat leads to an increase in volume…
-There is a 50 % expansion in plasma volume. Total mean increase in body water is 8L, 60 % of which is distributed to the placenta, fetus and amniotic fluid, 40 % of which is distributed to maternal tissues.
-This increase in water results in a greater volume of distribution (Vd) for hydrophilic drugs, leading to a decrease in Cmax.
The plasma volume expands at a greater rate than the increase in albumin production…
therefore steroid and placental hormones occupy the binding site. This results in a decrease in albumin binding capacity and increase in unbound or ‘free’ drug. Note: Unbound or ‘free’ drug is the pharmacologically active form. This might lead us to expect an increase in drug effect, but free drug is available for biotransformation. Also, this effect does not occur in isolation.
Increase in ‘free’ drug since albumin binding capacity has decreased means…
-greater quantities of ‘free’ drug available at target tissue for binding to receptor (R).
-It also means more drug available for enzymatic conversion to metabolites, filtration in the kidneys, and delivery at other tissues.
ONE NOTE
Concentration of albumin in foetal plasma?
-The concentration of albumin in the maternal plasma decreases gradually during pregnancy. The concentration of albumin in the foetal plasma increases gradually. This means that the ratio of foetal to maternal albumin concentration changes throughout gestation.
-The affects of alterations in protein binding are particularly important for highly bound drugs. For example, during the second and third trimesters of pregnancy, the free fraction of phenytoin is significantly increased1
PLacenta transfer?
ONE NOTE
Describe placenta transfer (distribution)?
-The main mechanism of drug transport across the placenta is simple diffusion. In general, lipophilic drugs cross the placenta more readily than hydrophilic drugs.
-Non-ionised drugs cross the placenta more readily than drugs which are ionised at physiological pH.
-Note: This is not a clear-cut ‘rule’. Sodium valproate rapidly reaches the foetus.
-Ionised and polar drug molecules may cross the placenta by carrier mediated transport1
ONE NOTE
How do drug molecules which are unionised and have a molecular weight of up to 600 Da diffuse across placenta?
diffuse readily across the placenta and the rate of transfer is not limited by diffusivity, but instead by the flow of maternal and foetal blood. Transfer across the placenta in this case is referred to as ‘flow-limited’1.
The pH of fetal plasma is slightly lower (more acidic) than that of maternal plasma, what are effects?
The effects of this are more marked with weakly acidic and weakly basic drugs with a pKa that is close to the plasma pH.
Weak bases which are unionised in the maternal plasma- placental transfer?
Weak bases which are unionised in the maternal plasma are able to cross the placental barrier. After entering the foetal plasma, the weak base becomes ionised as a consequence of lower pH. The ionised molecule does not readily cross the placental barrier. This is known as ‘ion trapping’.
ONE NOTE
Describe xenobiotics
In the case of facilitated diffusion, xenobiotics which are structurally similar to endogenous molecules may be transported1. It is worth noting, that the presence of these xenobiotics therefore may reduce the transport of endogenous molecules needed for growth and development.
Transporters present in the placenta?
-Organic cation transporters
-Organic anion transporters
-Carnitine transporters
-Amino acid transporters
-Serotonin transporters
-Norepinephrine transporters
-Folate transporters2.
Distribution- lactational transfer?
ONE NOTE
Lactocyte barrier?
represents a lipid bilayer
which molecules are likely and not likely to cross the lactocyte barrier?
-Molecules which are non-polar and < 400 Da are most likely to readily cross.
-Molecules > 800 Da are not likely to cross in the absence of a specific transport mechanism.
Lactational transfer with drugs which are highly bound to albumin or other transport proteins?
behave similarly to large MW drugs i.e. do not readily cross. Examples include warfarin sodium and celecoxib which are small but clinically irrelevant quantities are found in milk since they are 99 % plasma protein bound. Conversely, lithium (6.94 Da) which displays no protein binding can reach high levels in breast milk.
The lipid content of milk is high therefore…
-the more lipid soluble a drug, the more likely high concentrations are observed in milk.
-Drugs which are likely to cross the blood-brain barrier often cross into milk
Infant exposure to drugs is determined by?
the concentration in the milk (Cmilk).
The concentration of drug in the breast milk to the maternal plasma is described by?
the milk to plasma ratio (M/P). Drugs that easily pass through the barrier into the breast milk have high M/P values.
The main use of M/P?
-The main use of M/P is to give an indication of the mechanism of drug transfer into milk. For example, a selection of drugs have a higher M/P ratio than expected based on physiochemical parameters alone, indicating that an active transport mechanism may be responsible for the transfer.
-These drugs are nitrofurantoin (M/P = 6),13 acyclovir (M/P = 4.1),14 ranitidine (M/P = 6.7 to 23.77),15 cimetidine (M/P = 5),16 and iodine (M/P = 23).
Absolute Infant Dose (AID) equation?
AID = (Cmax or Caverage) x volume of milk ingested in a day
-Where Cmax and Caverage are the maximum and average concentration in milk, respectively.
-When calculating AID, using Cmax is likely to lead to an overestimation, thus Caverage is more clinically useful.
ONE NOTE
Relative Infant Dose (RID) equation?
𝑅𝐼𝐷(%)=(𝐼𝑛𝑓𝑎𝑐𝑡 𝑑𝑜𝑠𝑒 (𝑚𝑔 𝑘𝑔−1𝑑𝑎𝑦−1) / (𝑀𝑎𝑡𝑒𝑟𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔 𝑘𝑔−1𝑑𝑎𝑦−1 ) 𝑥 100
-Infant dose in mg/kg/day can be calculated by dividing AID by the infant weight.
-Generally, drugs with an RID of less than 10 % are compatible with breast feeding.
ONE NOTE
How does increased oestrogen and progesterone in pregnancy affect metabolism of drugs?
-The activity and quantity of some enzymes is increased during pregnancy, for example:
CYP3A4 (substrates include carbamazepine, midazolam, and anti-retroviral drugs)
CYP2D6 (substates include fluoxetine and nortriptyline)1.
-The activity of some enzymes is decreased:
CYP1A2 (substrates include caffeine, clozapine, and theophylline)
CBR1 (substrates include doxorubicin and vitamin E)2.
-Enzymatic processes such as phase I and phase II metabolism have been documented in the foetal liver at 7 – 8 weeks. However, their activity is very low and effects are marginal
Describe elimination in pregancy
-Maternal renal plasma flow increases by 25 to 50 %.
-Maternal glomerular filtration rate increases by 50 %.
-Drugs which are eliminated primarily unchanged in the urine, e.g. penicillin and digoxin, exhibit enhanced elimination. This leads to lower steady-state drug concentrations.
-Drug elimination from the foetus occurs mostly by diffusion back into the maternal compartment. -Larger quantities of drugs and metabolites in the amniotic fluid later in pregnancy demonstrates kidney maturation in the foetus1.
