Pharmacokinetics in Pregnancy
Factors which contributes to transient uteroplacental hypoperfusion (blood /drugs).
1. uterine contractions (decrease transfer and clearance of drugs to the placenta) 2. cord compression 3. supine position of the mother
How does maternal changes during pregnancy affect the absorption of drugs?
. 1.-.Nausea& vomiting (impair GI absorption) 2.-Decreased esophageal peristalsis & intestinal transit may increase absorption in small intestine may increase absorption of hydrophilic drugs (cross GI epithelia slowly) 3.-No change in absorption of lipophilic drugs 4.-Decreased gastric emptying reported in labor May be secondary to the use of opiates By 20 weeks --tidal volume increased by 40% --residual volume decreased by 20% By term --alveolar ventilation increased by 70% This causes increase uptake of inhaled drugs. a. Skin perfusion and skin hydration are both increased ( transdermal and subcutaneous absorption is more rapid) b. Enhanced perfusion to muscles (IM absorption of drugs is more rapid)
Describe the drug pathway within the placenta?
1 Nutrients and some drugs pass through the syncythiotrophoblasts on a normal basis . As pregnancy progresses the distance between the maternal and fetal blood decreases due to thinning of the syncytiotrophpblast and connective tissue and capillaries increase in size and number of capillaries in the villi. Thus more drugs passes to the fetus 2.Most drugs cross the placenta by simple diffusion, some are transported by facilitated diffusion,active transport( most common method is pinocytosis)
How does maternal changes during pregnancy affect the metabolism of drugs?
1.-Metabolism in liver influenced by increased steroidal hormones, estrogen & progesterone (second trimester) 2.-Leading to slower metabolism of some drugs (caffeine) and faster metabolism of others 3.-Hepatic blood flow is not changed to a large degree, so first-pass effects are not significantly different. 4.-First pass effect: drug metabolism that occurs as a drug passes through the intestinal lumen, portal vein, and liver prior to getting to the target organ. 5.-Thus, the availability of drugs for metabolism may be decreased due to: -lower plasma concentration -fairly stable blood supply
How does maternal changes during pregnancy affect the Pharmacokinetics of drugs?
1-Absorption--:decreased gastric motility -increases the oral bioavailability of slowly absorbed drugs by prolonging transit time. Increased cardiac output and increased peripheral blood flow may increase the rate of absorption from the stomach and small intestines. Cardiovascular and integumentary changes may led to more rapid absorption of drugs delivered via transdermal, intranasal , intravascular, epidural, and subcutaneous routes. 2- Distribution--: For many drugs the volume of distribution is increased due to increased plasma volume , blood volume , cardiac output , total body water and body mass. 3- Metabolism--: Some drugs are metabolized in their first pass through the liver are cleared rapidly because their clearance are dependent on the hepatic blood flow. Drugs with low first pass clearance (theophylline, caffeine) has lower elimination rate and tends to increase in pregnancy with increase half life. 4. Elimination --: Most drugs are excreted in the kidneys thus the increased GFR in pregnancy facilitates more rapid elimination. Because of the increased GFR and shorter half life, some drug dosage (digoxin, atenolol, penicillins, cephaosporins etc.) may have to be increased during pregnancy. The 3rd trimester has the highest GFR.
Describe the drug pathway within the fetal unit.
1. Concentration gradients between the maternal and fetal blood affects the rate of diffusion as does a slight difference in maternal and fetal pH. Due to pH gradient, weak basic unionized drugs such as opiates, can concentrate into the fetal more acidic compartment because the drug is now more ionized and trapped-ION TRAPPING. 2. Prior to skin keratinization at 20 weeks, amniotic fluid acts as extracellular fluid with drugs diffusing readily across the fetal skin. 3. As development continues, skin permeability decreases significantly, and drugs that enter the fetus must be excreted rather than simply diffused into the amniotic fluid. .4. Drugs that enter the fetal circulation in the umbilical vein can either be metabolized in the liver via the first-pass effect or shunted across the ductus venosus directly to the heart and general circulation.
How does solubility affect transfer?
1. Drugs that are more lipophilic cross the placenta more readily than drugs that are hydrophilic, as the placenta is lipoid in characteristic. 2. A non-ionized state also facilitates transfer.
What does the size of the drug mean?
1. Most drugs have a small molecular weight usually less than 500 daltons(Da), so they are easily transferred across the placenta. 2. Drugs with a molecular weight greater than 500 Da transfer incompletely. 3. Those like insulin and heparin which have MW of greater than 1000Da, transfer poorly into the placenta ( Don't assume large molecular weights can't pass (heparin, erythromycin) simply more difficult & usually through pinocytosis engulfing of molecule & active transport across membrane.
How is drug transfer across the placental membranes facilitated?
1. by varous characteristics of the drug, its: size (molecular weight), lipid solubility,plasma protein binding, and acid vs basic properties.
How does maternal changes during pregnancy affect the distribution of drugs?
1.-more serum albumin is produced but lower albumin concentration due to intravascular volume expansion 2.-less albumin binding 3.-more "free" drug available at lower plasma concentration 4.-binding varies inversely with pregnancy ( as pregnancy increases albumin decreases) 5.-Plasma levels of steroid hormones suchas estradiol and progesterone increasein the later half of pregnancy. 6.-These steroids compete for protein-binding sites on albumin and other plasma proteins. 7.-Steroid hormones may also displace drugs already bound to plasma proteins. ■ 8.-Overall effect is more free drug, which is unbounded and metabolically active. 9. fetal albumin concentration in plasma increases throughout pregnancy and is 20% higher than maternal concentration at term 10. drugs that are highly bound to albumin can concentrate in the fetus at term (Valium, Demerol)
Describe the drug pathway within the maternal unit of the pregnant woman
1.Site of absorption depends on route of administration (p.o., i.m.,i.v., topical or inhaled). Drugs are carried in the blood, either bound to plasma proteins or as a free drug. Protein bound drugs are stored. Free drug is the active component that can interact with target cells. 2. Biotransformation takes place mostly in the liver, but also inthe lungs, the intestinal mucosa and the kidneys. The drug is converted into water soluble compounds. Most drugs are metabolized in the liver before elimination but some are excreted directly by the kidneys.
Which are some of the most common prescription medication used in pregnancy?
Antidepressants, antixiolytics, antiasthmatics, antibiotics,Non-steriodal anti-inflammatory drugs (NSAIDs), oral contraceptives,Rho (D) immunoglobulin.
What is biotransformation?
Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body. Biotransformation is vital to survival in that it transforms absorbed nutrients (food, oxygen, etc.) into substances required for normal body functions. For some pharmaceuticals, it is a metabolite that is therapeutic and not the absorbed drug.
What pathological factors affect uteroplacental blood flow and drug transfer?
a. inflammation b. hypoxia c. vascular degeneration d. partial placental separation
How does maternal changes during pregnancy affect the half -life of drugs
Most drugs are excreted in the kidneys thus the increased GFR in pregnancy facilitates more rapid elimination. Because of the increased GFR and shorter half life, some drug dosage (digoxin, atenolol, penicillins, cephaosporins etc.) may have to be increased during pregnancy. The 3rd trimester has the highest GFR.
What happens in the 3rd trimester that causes increased drug transfer ?
increased unbound drug available for transport • increased uteroplacental blood flow (500mL/min) • increased placental surface area • decreased thickness of semipermeable lipid membranes between placental capillaries • greater physical disruption of placental membranes • more acidic fetal circulation to "trap" basic drugs