L5: Pregnant Women, Neonates, Elderly

Question 1

What is the standard age range that drugs are developed for?

Answer 1

18-60 years old.

Question 2

What are the phases of a clinical trial and what is in each phase?

Answer 2

1. Discovery phase
2. Safety testing in labs
3. Phase 1: small number of healthy volunteers (no preexisting health conditions), usually young adults.
4. Phase 2: Small number of usually young people with the condition we want to treat.
5. Phase 3: Larger number of people to look for long term effects.

Question 3

Why don’t we know how drugs affect pregnant women or neonates?

Answer 3

Because they are not tested on in clinical trials unless the drug is being designed specifically for them.

Question 4

What is the course of action of drug usage if special populations have differences is pharmacokinetics? Pharmacodynamics?

Answer 4

If the problem is due to pharmacokinetics, then the way we administer the drug can be controlled (dosage, frequency, method of administration…)
If the problem is due to pharmacodynamics, then it is not appropriate to use that drug in that circumstance.

Question 5

How does clearance change as we age?

Answer 5

Newborn (term): clearance is very low (lowest)
1 year: clearance is very high (highest)
Puberty: clearance changes (decreases a bit)
Adulthood: Whatever puberty decreased to

Question 6

What are the physiological changes of pregnancy? Explain.

Answer 6

1. Cardiovascular system: decreases in serum albumin (affects ability of drugs to bind protein in blood, changes in VD), increase in cardiac output, compression of vena cava by uterus, increase in plasma volume
2. Renal system: increases in renal blood flow and glomerular filtration rate (might affect clearance rate of drug which affects elimination of drug)
3. Liver: changes in drug metabolizing enzymes (CYP450s) which could affect metabolism of drugs
4. Nausea and vomiting can affect a woman’s ability to take a drug orally.

Question 7

Does AVD vary within the gestation period? Give an example.

Answer 7

Yes.
Ex: for ampicillin, the AVD is almost doubled between 10 and 40 weeks of pregnancy.
For caffeine the AVD way more than doubles.

Question 8

What are the effects on metabolism in pregnant women?

Answer 8

1. Certain CYP450 enzymes in the liver increase their activity. Some decrease in activity, including CYP1A2 (metabolizes caffeine).
2. In terms of gastric emptying, there are changes such as decreased intestinal motility.

Question 9

What enzyme metabolizes caffeine? How does it change during pregnancy?

Answer 9

CYP1A2. Decreased activity during pregnancy.

Question 10

How does CYP1A2 metabolize caffeine?

Answer 10

It removes methyl groups (3) from caffeine via an oxidation reaction, which turns caffeine into reactive metabolites.

Question 11

What is a consequence of a decrease in CYP1A2?

Answer 11

An increase in the half-life of caffeine.

Question 12

Does the uterus and/or placenta protect the fetus against drugs?

Answer 12

No. Most things women consume potentially as drugs do reach the developing baby because of placental transport.

Question 13

What can pass through the placental membrane? And what types of transport mechanisms does it have?

Answer 13

1. Fat soluble, non-ionized, low molecular weight substances are transported more quickly across the membrane.
2. Viruses
   Has the same transport mechanisms found in any membrane.

Question 14

Can the placenta metabolize drugs?

Answer 14

The placenta can metabolize certain drugs and a certain amount of drugs because it has some metabolizing enzymes. Some free drug will reach the fetus without being metabolized.

Question 15

How does the fetus eliminate the drug?

Answer 15

It doesn’t have a way to eliminate the drug on its own so it gives the drug back to the mother where it gets eliminated in the mother’s kidneys and liver.

Question 16

How does a rapidly diffusing drug (small, lipid soluble, non-polar) affect the concentration of drug in the mother and fetus?

Answer 16

At both single and multiple doses, the drug gets into the mothers circulation fairly quickly and the fetus and mother receive almost equal amounts of the drug and excrete it at the same rate.

Question 17

How does a slowly diffusing drug (large, not lipid soluble, polar) affect the concentration of drug in the mother and fetus?

Answer 17

In the mom, the single dose is the same as for rapid diffusion. As she starts to eliminate the drug, the drug is still slowly reaching the fetal compartment and accumulates there. This is because it cannot cross membranes easily.

Question 18

Why do some drugs have a higher concentration in the fetal compartment than in the maternal compartment?

Answer 18

Because of differences in pH between the compartments and because of placental transport.

Question 19

What are the possibilities in regards to a drugs effect on the fetus?

Answer 19

1. No effect
2. Parallel transient effect: same effect on fetus as mother
3. Some drugs can be safe for the mother but cause irreversible structural malformations in the fetus.
4. Could be delayed effects on IQ, neurodevelopment, and reproductive function.
5. Trans-generational effects: can affect the current baby as well as subsequent generations.

Question 20

What determines the affect a drug will have on a fetus?

Answer 20

The stage of gestation when the drug is administered can have different effects on the baby’s development. Depending on what is being developed in that stage, thats what the drug will affect.

Question 21

Can a drug affect the fetus within the period of implantation and dividing zygote?

Answer 21

Yes.

Question 22

What is a consequence of the development of the CNS having a huge window of time?

Answer 22

Drugs can have an effect on CNS development at any time during pregnancy.

Question 23

What is a teratogenic agent?

Answer 23

Medicinal product or other chemical agent that can produce functional defects in fetus after the pregnant woman is exposed.

Question 24

What are the teratogenic agents in humans?

Answer 24

1. Radiation
2. Infections
3. Hormonal and metabolic imbalance
4. Drugs and environmental chemicals
5. Alcohol
6. Retinoids

Question 25

What are 2 examples of infections that could affect the baby?

Answer 25

1. Zika virus: you can get infected by a mosquito bite or by having unprotected sex with a partner who is infected. It causes microencephaly (smaller head) of fetus if mother is infected. No cure.
2. COVID-19: women infected are at increased risk of pre-term birth and poor outcomes such as pregnancy loss.

Question 26

What are 2 examples of hormonal or metabolic imbalances in the mother that could affect the baby?

Answer 26

1. Diabetes

2. Cretinism

Question 27

What’s an example of drugs and environmental chemicals that could affect the baby?

Answer 27

Thalidomide was used to treat symptoms of nausea and vomiting during pregnancy. It can cause either arm or leg defects depending on when the fetus is exposed. Days 27-30 have arm defects and 30-33 is leg defects. There were also issues in neural system development.

Question 28

What is the affect of alcohol during pregnancy on the baby?

Answer 28

Can cause fetal alcohol spectrum disorder (FASD):
Growth retardation
CNS affects (you can see physical effects in brain)
Changes in behaviour
Lower IQ
Facial defects (thin upper lip and smooth philtrum).

Question 29

What is the affect of retinoids during pregnancy on the baby?

Answer 29

Retinoic acids are morphogens (signalling molecules) that put in action different patterns of gene expression to control limb and organ development. If it is messed up with drugs it can have major effects on development.

Question 30

How can you prevent fetal defects? Explain each one.

Answer 30

Using developmental toxicity testing:

1. Epidemiological studies: if you take a drug for a condition you will be monitored to see if any negative effects come up
2. Animal testing: Test on 2 different species of pregnant animals to ensure that it is safe since different species react differently during organogenesis
3. In vitro: testing drug on stem cells, a whole embryo, etc. to see the drugs effects.
4. Include pregnant women in clinical trials
5. Folic acid: can prevent neural tube defects in baby.
6. Vaccination: Rubella is very efficient in preventing defects associated with the Rubella infection (cataracts, heart disease, deafness, etc.)

Question 31

What is recommended if a woman has a slowly or a rapidly developing cancer while pregnant and why?

Answer 31

Women with a fast progressing cancer is recommended to terminate her pregnancy in order to continue treatment. Women with slowly progressing cancer will have to stop treatments during pregnancy. This is because anti cancer drugs target rapidly dividing cells and the developing embryo has many rapidly dividing cells, so these anti-cancer drugs would seriously affect the fetus.

Question 32

What happens to the baby if the mother is taking drugs while breastfeeding?

Answer 32

The chemicals get into the breast milk, especially if they are lipid soluble, non-ionized and small. Most of the time the amount of the drug the baby receives from the breast milk is very low so there wont be that much of an adverse affect. However, toxic chemicals can have an adverse effect. Ex: Persistent organic pollutants (POPS), heroine (can make baby dependent), radioactive iodine (to treat thyroid).

Question 33

What percentage of drugs are approved by the FDA and have indications specifically for paediatric patients?

Answer 33

25%

Question 34

How is absorption different in paediatrics?

Answer 34

1. Drugs easily get across skin due to increased skin permeability.
2. Slow gastric emptying might affect absorption of drug.
3. Gut microbiome is not developed so they are not protected from many substances that would be combatted by gut bacteria.
4. High gastric pH.

Question 35

How is distribution affected in paediatrics?

Answer 35

Babies have higher body water proportions than other ages, they have less body fat. The distribution changes drastically with age because babies develop rapidly.

Question 36

How is elimination affected in paediatrics?

Answer 36

1. A lot of drug metabolizing enzymes are still not fully mature.
2. Kidney and liver function are not fully mature which can lead to prolonged drug effects and accumulation.
3. Glomerular filtration is continually maturing up to 12 years of life.

Question 37

How is metabolism affected in paediatrics?

Answer 37

Changes in the CYP450 enzymes affect metabolism.

Really low for first moth of life and varies even within the first days of life.

Question 38

Why is caffeine used in newborns?

Answer 38

To treat apnea (slowed or stopped breathing) because the half life of caffeine in new born babies is days. Remember caffeine is metabolized by CYP1A2, and this enzyme is decreased in babies so it has a longer half-life.

Question 39

What is the body composition change for an elderly person?

Answer 39

Higher body fat proportion, lower water. The increased body fat can contribute to depots created by fat soluble drugs that can accumulate.

Question 40

What chronic condition are most seniors treating with drugs?

Answer 40

Drugs for regulating blood pressure.

Question 41

Why is the therapeutic window for drugs more narrow in the elderly?

Answer 41

Because drugs may pose more risks in elderly people with multiple chronic diseases compared to a younger people.

Question 42

What changes in an elderly person with respect to pharmacokinetics? Explain

Answer 42

1. Excretion: decrease in glomerular function and renal clearance as we age.
2. Distribution changes for 2 reasons: 1. There will be an increase in deposition of fat soluble drugs because they have higher body fat (drug stays in body for longer). 2. A decrease in the apparent volume of distribution of water soluble drugs but increased concentration of water soluble drugs in the blood because they have lower body water.
3. Metabolism: decrease in CYP450 enzymes due to reduced hepatic mass. Leads to increases half life of drug.

Question 43

How does half life change with age, what does this mean for drug administration?

Answer 43

Half life increases. Elderly take lower doses less frequently because the drug takes longer to be eliminated from the body.

Question 44

What happens to bioavailability in elderly? Explain.

Answer 44

Bioavailability increases because there is a reduction of drug metabolism in the liver (lower first pass) so more of the drug is available to the rest of the body.