G3 ADME in pregnancy Flashcards
when considering changes in ADME in pregnancy, what 2 contributing factors are looked at?
- maternal physiological changes
- effects of the placental-foetal compartment
what is meant by volume of distribution?
the volume that would contain the total body content of the drug (Q) at a concentration equal to that present in the plasma
what is meant by Cmax?
the maximum drug concentration observed
what is meant by tmax?
time between dosing and the occurrence of Cmax
what does an increase in plasma progesterone level lead 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 action
- we observe an increase in tmax and reduction in Cmax (takes longer for drug to appear in blood because absorption is slower, conc overall stays the same and curve is stretched out which is why Cmax is reduced)
in the first trimester of pregnancy, what event can interfere with absorption of drugs?
- nausea and vomiting
- these is potential for partial or complete ejection of the dosage form
describe changes in different secretions during pregnancy. what do these lead to?
- decrease in gastric acid secretions
- increase in mucus secretions
- leads to an increase in gastric pH (more alkaline - greater extent of ionisation)
- the absorption of weak acids and bases is therefore affected
during pregnancy, what can have reduced absorption?
weak acids
- eg. analgesics and antiemetics
what is the relationship between the extent of ionisation of an electrolyte and pH described by?
the Henderson-Hasselbalch equation
what assumptions does the pH partition hypothesis have?
GIT acts as a lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion (ionisable drugs)
the GI / blood barrier is impermeable to ionised (poorly lipid soluble) forms of drugs
- only the lipid-soluble unionised species will pass across
what environments are acids ionised and unionised in?
acids are unionised in acidic environments
acids are ionised in alkaline environments
why do the maternal cardiovascular and respiratory systems undergo changes in pregnancy?
- to maintain perfusion of the placenta
- to ensure maternal blood is enriched with oxygen and effectively cleared of carbon dioxide
state some changes that occur to the cardiovascular and respiratory systems in pregnancy. what do these changes all favour?
- cardiac output increases
- tidal volume increases
- pulmonary blood flow increases
- the above changes all favour alveolar uptake
during pregnancy, changes occur that favour alveolar uptake. what does this mean? give an example
- absorption via this route is increased
- the rate of induction in the case of volatile anaesthetic drugs (eg. methoxyflurane) has been shown to increase
- this reduces dosing requirements
during pregnancy, cardiac output increases. what are the consequences of this at different stages of pregnancy?
- 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
what happens to plasma volume and body water during pregnancy?
- 50% expansion in plasma volume
- total mean increase in body water is 8L
- 60% of which is distributed to the placenta, foetus and amniotic fluid
- 40% of which is distributed to maternal tissues
what does the increase in body water result in during pregnancy?
- greater volume of distribution for hydrophilic drugs leading to a decrease in Cmax
- essentially, it becomes more dilute because it is the same dose of drug in a greater volume of plasma
which increases faster during pregnancy: the plasma volume or the albumin production?
the plasma volume expands at a greater rate than the increase in albumin production and steroid and placental hormones occupy the binding site
the plasma volume expands at a greater rate than the increase in albumin production and steroid and placental hormones occupy the binding site. what does this result in?
- a decrease in albumin binding capacity
- an increase in unbound / free drug (the pharmacologically active form)
what does an increase in free drug due to albumin binding capacity decrease mean?
- greater quantities of free drug available at target tissue for binding to receptor
- also means more drug available for enzymatic conversion to metabolites, filtration in the kidneys and delivery at other tissues
when must we be particularly mindful of any changes going on in a patient body eg. a pregnant woman?
when a drug’s therapeutic window is small
describe the different things that can happen to a drug in different locations of the body using an image
what happens to the concentration of albumin in the maternal plasma and foetal plasma during pregnancy? what do these 2 changes mean?
- maternal: conc of albumin in plasma decreases gradually
- foetal: conc of albumin in plasma increases gradually
this means that the ratio of foetal to maternal albumin concentration changes through gestation
what are the effects of alterations in protein binding particularly important for? give an example
- important for highly bound drugs
- eg. during the 2nd and 3rd trimesters, the free fraction of phenytoin is significantly increased
what is the main mechanism of drug transport across the placenta? which drugs cross the most readily? state an exception
- simple diffusion
- generally, lipophilic drugs cross the placenta more readily than hydrophilic drugs
- generally, unionised drugs cross the placenta more readily than drugs that are ionised at physiological pH
NOTE: this is not a clear-cut rile, sodium valproate rapidly reaches the foetus
despite not crossing the placenta as readily by simple diffusion, how can ionised and hydrophilic drugs cross the placenta?
by carrier-mediated transport
by means of an image, describe the following methods of transport:
- simple diffusion
- diffusion through hypothesised polar channels
- facilitated diffusion
- active transport
- receptor-mediated endocytosis
- exit into foetal circulation
what kind of drug molecules readily diffuse across the placenta? what is the rate of transport limited by?
- drug molecules which are unionised
- drug molecules with a molecular weight of UP TO 600 Da
- rate of transfer is not limited by diffusivity but instead by the flow of maternal and foetal blood
- this makes transfer referred to as ‘flow-limited’
compare the pHs of foetal and maternal plasma. explain the effects and when they are most significant
- pH of foetal plasma is slightly lower (more acidic) than maternal
- effects of this are marked more with weakly acidic and weakly basic drugs with a pKa close to the plasma pH
- pH is changed at a point that really affects the proportion of ionised and unionised drugs
what is ‘ion trapping’?
- weak bases that are unionised in the maternal plasma can cross the placental barrier
- after entering the foetal plasma, the weak base becomes ionised due to lower pH
- the ionised molecule can now not readily cross the placental barrier back into the maternal blood
describe the transport of xenobiotics across placenta during pregnancy and the effects of this
- in the case of facilitated diffusion, xenobiotics which are structurally similar to endogenous molecules may be transported
- the presence of these xenobiotics therefore may reduce the transport of endogenous molecules needed for growth and development
state transporters present in the placenta
organic cation transporters
organic anion transporters
carnitine transporters
amino acid transporters
serotonin transporters
norepinephrine transporters
folate transporters
how could drugs cross the placenta other than simple diffusion?
if a drug is structurally similar to any of the endogenous molecules that use the transporters in the placenta, it could use one of these transporters instead of simple diffusion
describe the simple physiological based pharmacokinetic model for lactational transfer as an image
what does the lactocyte barrier represent in a lactating breast?
a lipid bilayer
what kinds of molecules are most likely to readily cross the lactocyte barrier in lactational transfer?
- molecules which are non-polar
- molecule which are < 400 Da (small)
how would molecules > 800 Da cross the lactocyte barrier?
- they are unlikely to cross
- unless there is a specific transport mechanism
other than molecules with a large molecular weight, what kind of drugs will not readily cross the lactocyte barrier in lactational transfer?
- drugs which are highly bound to albumin or other transport proteins
- these behave similarly to large molecular weight drugs (do not readily cross)
give an example of a drug that is highly bound and therefore doesn’t cross the lactocyte barrier in lactational transfer. explain why there is a really small concentration of this drug in breastmilk
- warfarin sodium and celecoxib
- really small but clinically irrelevant quantities are found in breastmilk since they are 99% plasma protein bound (this makes them very large so they can’t cross the lipid barrier)
state an example of a molecule that can reach high levels in breastmilk and why
- lithium
- it is very small (6.94 Da)
- displays no protein binding
- both of these traits mean it can reach high levels in breastmilk
generally describe the kinds of drugs that can cross into breastmilk
- the lipid content of milk is high so the more lipid soluble a drug, the more likely high concentrations are observed in milk
- drugs which are likely to cross the BBB often cross into breastmilk
why does it help to know if a drug crosses the BBB for knowing if it will cross into breastmilk?
this info can be used as a soft-marker, data from BBB can be used to estimate if a drug will end up in breastmilk
what is infant exposure to drugs determined by?
concentration in milk (Cmilk)
what is the milk to plasma ratio (M/P) used to describe? what does a higher M/P value indicate?
- the concentration of drug in the breastmilk 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
what is the main use of M/P?
- to give an indication of the mechanism of drug transfer into milk
- eg. if a selection of drugs have a higher M/P ratio than expected based on physiochemical parameters alone, this indicates that an active transport mechanism may be responsible for the transfer (not passive diffusion)
state some drugs with higher M/P ratios than expected that may have an active transport mechanism responsible for their transport into milk, not simple diffusion
nitrofurantoin, M/P = 6
acyclovir, M/P = 4.1
ranitidine, M/P = 6.7 - 23.77
cimetidine, M/P = 5
iodine, M/P = 23
volume for AID (absolute infant dose)
describe when and why you might use either Cmax or Caverage when calculating absolute infant dose
- when calculating AID, using Cmax is likely to lead to an overestimation, therefore Caverage is more clinically useful
- Cmax can be used if you want to be conservative / extra safe (‘worst-case scenario’)
what is the formula for RID (relative infant dose)?
infant* not infact
describe and explain the different values of RID and what they mean
- generally, drugs with an RID of less then 10% are compatible with breastfeeding
- RID is the percent of drug the baby has had through milk compared to the amount the mother has had
- if the baby has more than 10% but the mother needs the drug then the administration may continue (risk-harm benefits must be considered)
what is hepatic metabolism affected by in pregnancy?
increased oestrogen and progesterone
state the hepatic enzymes that have increased activity and quantity during pregnancy and their substrates
- CYP3A4: carbamazepine, midazolam, antiretroviral drugs
- CYP2D6: fluoxetine, nortriptyline
state the hepatic enzymes that have decreased activity and quantity during pregnancy and their substrates
- CYP1A2: caffeine, clozapine, theophylline
- CBR1: doxorubicin, vitamin E
what happens to maternal renal plasma flow and glomerular filtration rate in pregnancy?
- renal plasma flow increases by 25-50%
- glomerular filtration rate increases by 50%
what kind of drugs exhibit enhanced elimination during pregnancy? what does this lead to?
- those which are eliminated primarily unchanged in the urine
- eg. penicillin, digoxin
- leads to lower steady-state drug concentrations
how does drug elimination from the foetus occur?
- 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 foetus
true or false?
the GIT acts as a lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion
true
true or false?
the unionised form of a weak electrolyte drug is generally more soluble in lipids
true
true or false?
the pH partition hypothesis assumes the membrane of the lining of the epithelium to be an aqueous environment
false
true or false?
the ionised form of a weak electrolyte drug will pass more readily into the membrane of the epithelium lining
false
true or false?
the GI / blood barrier is impermeable to the unionised, lipid soluble form of a drug
false
true or false?
from an absorption perspective, it is generally preferential for a weak electrolyte drug to be in the unionised form
true
