DRUG USED IN

FOURTH YEAR MBBS

REPRODUCTIVE MODULE

PREGNANCY DEPARTMENT OF
PHARMACOLOGY
PREGNANCY
Whether planned or
unplanned ,
a pleasant or an
unpleasant surprise
always brings concerns
about prescription and
over the counter drugs.
 LEARNING OBJECTIVES
1. Discuss the pharmacokinetics of drug during pregnancy
2. Discuss the pharmacodynamics of drugs during pregnancy
3. Classify Pregnancy risk categories for drugs with specific example for each
category
 PRE ASSESSMENT QUIZ

1. Name Any One Drug That Is Commonly Given In

Pregnancy
TRIMESTER-SPECIFIC RISKS
AND CONSIDERATIONS IN
PREGNANCY
FIRST TRIMESTER: Congenital Malformations (Teratogenesis)

SECOND & THIRD TRIMESTER: Affect Growth & Fetal Development Or Toxic Effects On Fetal Tissues

NEAR TERM : Adverse Effects On Labour Or Neonate After Delivery

PHARMACOKINETICS
Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their pharmacologic and
teratogen effects.

Critical factors affecting placental drug transfer and drug effects on the fetus include the following:

• The physicochemical properties of the drug;

• The rate at which the drug crosses the placenta and the amount of drug reaching the fetus;

• The duration of exposure to the drug;

• Distribution characteristics in different fetal tissues;

•The stage of placental and fetal development at the time of exposure to the drug; and

• The effects of drugs used in combination

 LIPID SOLUBILITY
Drug passage across the placenta depends on lipid solubility and the degree of drug ionization.

1. Lipophilic Drugs:

• Example: Thiopental

• Readily diffuse across the placenta and swiftly enter fetal circulation.

• Clinical Impact: Thiopental, commonly used in cesarean sections, can induce sedation or apnea in the newborn.

2. Ionization and Drug Permeability:

• Highly ionized drugs, like succinylcholine and tubocurarine, cross the placenta slowly.

• Clinical Impact: Low concentrations in the fetus for drugs used in cesarean sections.

• Impermeability of placenta to polar compounds is relative, not absolute.

3. Relative Impermeability:

• Polar Compounds: Generally less permeable.

• Exception: Salicylate, despite being highly ionized, crosses rapidly due to its small lipid-soluble fraction
 MOLECULAR SIZE
Molecular weight significantly impacts the rate and extent of drug transfer across the placenta.

1. Molecular Weight and Placental Transfer Dynamics:

• Molecular Weights (250–500):

Easily cross the placenta based on lipid solubility and ionization.

• Molecular Weights (500–1000):

Cross the placenta with more difficulty.

• Molecular Weights (>1000):

Cross very poorly.

2. Clinical Application: Heparin as Anticoagulant:

• Heparin, a large and polar molecule, doesn't cross the placenta.

• Safe alternative to warfarin in pregnant women needing anticoagulation.

• Unlike warfarin, heparin avoids teratogenic effects during fetal brain development.

.
pH OF THE DRUG:
•Maternal Blood: pH 7.4

•Fetal Blood: pH 7.3

1. Ion Trapping Mechanism:

•Effect on Weakly Basic Drugs: Those with pKa above 7.4 are more ionized in the fetal compartment.

•Consequence: Ion trapping occurs, leading to higher fetal drug levels.

2. Example - Lidocaine:

•Characteristics: Weakly basic drug with pKa above 7.4.

•Scenario: Administered to the mother.

3. Result:

•Fetal Blood Entry: Lidocaine enters fetal blood with a pH of 7.3.

•Ionization Increase: Becomes more ionized in fetal blood.

•Outcome: Ion trapping results in elevated drug levels in the fetal compartment.

4. Consequence:

•Impact on Fetal Health: Ion trapping leads to the entrapment of drugs in the fetal compartment, potentially impacting fetal health.
 PLACENTAL TRANSPORTER: P-
GLYCOPROTEIN (MDR1 GENE)
Function:
• Acts as a transporter pumping certain drugs back into the maternal circulation.

Examples of Pumped Drugs:

• Cancer drugs (e.g., vinblastine, doxorubicin).
• Other agents.

Clinical Implications:
• Reduced fetal concentrations of drugs, impacting treatment efficacy.
1. Viral Protease Inhibitors and HIV Risk:
• P-glycoprotein Substrates:
Viral protease inhibitors are substrates of P-glycoprotein.

• Effect on Fetal Concentrations:

Achieve low fetal concentrations, potentially increasing the risk of vertical HIV transmission.

2. Hypoglycemic Drug Glyburide:

• Concentration Discrepancy:
Glyburide exhibits much lower concentrations in the fetus compared to the mother.

• Role of BCRP and MRP3 Transporters:

Effluxed from the fetal circulation by the BCRP transporter.
Effluxed by the MRP3 transporter in the placental brush border membrane.
 DRUG TRANSFER ACROSS THE
PLACENTA: PROTEIN BINDING
1. AND LIPID SOLUBILITY
Protein Binding:

Influence on Transfer: Degree of plasma protein binding, especially with albumin, affects transfer rates and amounts.
Exception - Lipid-Soluble Compounds: Highly lipid-soluble drugs (e.g., some anesthetic gases) are minimally affected by
protein binding.

2. Lipid Solubility:

Dependence on Placental Blood Flow: Lipid-soluble drugs' transfer and equilibration are more dependent on placental blood
flow.
Rapid Diffusion: Very lipid-soluble drugs diffuse rapidly across placental membranes, making equilibration less dependent
on free drug concentrations becoming equal.

3. Ionization and Poor Lipid Solubility:

Slower Transfer: Poorly lipid-soluble and ionized drugs experience slower transfer.

Potential Impediment: Binding to maternal plasma proteins may impede transfer.

4. Differential Protein Binding:

Maternal vs. Fetal Plasma: Some drugs exhibit greater protein binding in maternal plasma due to lower binding affinity of fetal
proteins.

Examples: Sulfonamides, barbiturates, phenytoin, local anesthetic agents.

5. Case Study: Glyburide (Example):

Maternal Protein Binding: >98.8%.

Impact: Contributes to lower fetal levels compared to maternal concentrations.

PLACENTAL AND FETAL DRUG
METABOLISM
1. Placental Defense:

Semipermeable Barrier:
• Limits drug transfer from maternal to fetal circulation.

Metabolic Hub:
• Conducts aromatic oxidation reactions (e.g., hydroxylation, N-dealkylation, demethylation).
• Example: Pentobarbital undergoes oxidation in the placenta.

Caution:
• Metabolic activity may generate toxic metabolites (e.g., ethanol, benzpyrenes).
• Potential augmentation of toxicity.
2. Fetal Circulation Dynamics:

Umbilical Vein Journey:

• Drugs cross the placenta, entering fetal circulation via the umbilical vein.

Liver Interaction:
• 40–60% of umbilical venous blood enters the fetal liver.
• The remainder directly enters the general fetal circulation.

Liver Metabolism:
• Drugs entering the liver may undergo partial metabolism.
• Possible reduction in drug activity before entering general fetal circulation.

Shunting Mechanism:
• A significant portion of drug in the umbilical artery may be shunted through the placenta, reentering the liver.

Important Note:

Metabolites' Impact:
• Some drug metabolites may be more active than the parent compound.
• Caution is advised due to the potential for adverse effects on the fetus.
 PHARMACODYNAMICS OF
DRUG DURING PREGNANCY
 MATERNAL DRUG ACTIONS
1. Effects on Reproductive Tissues:

•Alteration by Endocrine Environment:

• Effects on reproductive tissues (breast, uterus, etc.) can be influenced by the pregnancy-specific endocrine
environment.
• Adaptations to the stage of pregnancy may modify drug responses.

2. Effects on Other Maternal Tissues:

•Consistency in Non-Reproductive Tissues:

• Effects on non-reproductive tissues (heart, lungs, kidneys, CNS, etc.) remain relatively consistent during pregnancy.
• Physiological changes in cardiac output, renal blood flow, etc., may necessitate specific drugs unique to the pregnant
state.

3. Example Scenarios:
•Cardiac Glycosides and Diuretics:
• May be required for heart failure due to increased cardiac workload during pregnancy.
 THERAPEUTIC DRUG ACTION
IN FETUS
1. Corticosteroids for Fetal Lung Maturation:
•Application: Used when preterm birth is expected.
•Purpose: Aids in stimulating fetal lung maturation.

2. Phenobarbital for Fetal Hepatic Enzymes:

•Induction Near Term:
• Given to pregnant women near term.
•Effect:
• Induces fetal hepatic enzymes responsible for bilirubin glucuronidation.
• Lowers incidence of jaundice in newborns.

3. Historical Uses of Phenobarbital:

4. Antiarrhythmic Drugs for Fetal Cardiac Arrhythmias:

•Examples: Digoxin, flecainide, procainamide, verapamil.

•Efficacy: Demonstrated in case series; controlled studies needed.

5. Zidovudine for HIV Transmission:

•Transmission Reduction: Maternal use decreases HIV transmission to the fetus by two thirds.

•Combination Antiretroviral Therapy: Combinations can almost entirely eliminate fetal infection.
 PREGNANCY RISK
CATEGORIES (CATEGORY A)
•Category A: Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of

pregnancy, and there is no evidence of risk in later trimesters.

•The possibility of fetal harm appears remote. Extremely few drugs exist in this category

Example: Multiple vitamins, levothyroxine, folic acid, liothyronine.

1. Folic acid is commonly recommended during pregnancy to prevent neural tube defects in the developing fetus.

2. Levothyroxine, a medication used to treat hypothyroidism. Maintaining proper thyroid function is crucial during
pregnancy for both maternal and fetal well-being.

3. Prenatal multivitamins are specifically formulated to meet the increased nutritional needs of pregnant
individuals. Adequate intake of certain vitamins and minerals is crucial during pregnancy to support the health of
both the mother and the developing fetus.
PREGNANCY RISK
CATEGORIES (CATEGORY B)
Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and
well-controlled studies in pregnant women.

If there is a clinical need for a drug in this category they are considered safe to use.

Examples: acetaminophen, amoxicillin, metformin, hydrochlorothiazide, cyclobenzaprine, pantoprazole.

Amoxicillin is a commonly prescribed antibiotic, especially for treating bacterial infections. The potential benefits of
treating the infection and preventing its complications may be deemed more significant than any potential risks.

Metformin is often used to manage diabetes, including gestational diabetes in pregnant individuals. Maintaining
adequate glucose control is crucial during pregnancy to prevent complications.. Healthcare providers weigh the
potential benefits of glycemic control against potential risks to both the mother and the developing fetus.
PREGNANCY RISK
CATEGORIES (CATEGORY C)
Category C : Animal studies have shown adverse effects on the fetus, but there are no adequate and well-controlled
studies in humans. The potential benefits may warrant the use of the drug in pregnant women despite potential
risks.These drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Examples: fluoroquinolones, gentamicin, saccharin, aspirin, tramadol, gabapentin, amlodipine, trazodone.

Fluoroquinolones are a class of antibiotics that are effective against a broad spectrum of bacteria. They are commonly
prescribed to treat various bacterial infections, including respiratory, urinary tract, and skin infections.
Fluoroquinolones are generally not the first choice during pregnancy due to concerns about potential adverse effects
on fetal cartilage development.

Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic (pain-relieving), antipyretic (fever-
reducing), and anti-inflammatory properties. Additionally, it is used for its antiplatelet effects to reduce the risk of
cardiovascular events.: Aspirin is generally considered safe in low doses for short durations during pregnancy.
However, in the third trimester, its use is often discouraged due to concerns about potential effects on the fetal
cardiovascular system and prolonged labor.
 PREGNANCY RISK
CATEGORIES (CATEGORY D)
Category D: Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing
experience or studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite
potential risks.

Examples: Tetracycline, ACE inhibitors, most Anti-neoplastics.

Tetracycline are a class of antibiotics with a broad spectrum antibiotic used to treat infections such as respiratory tract
infections, urinary tract infections, and skin infections. Tetracycline are generally contraindicated during pregnancy,
particularly in the second and third trimesters. They may interfere with fetal bone and teeth development, leading to
discoloration and impaired mineralization. Pregnant individuals are advised to avoid tetracyclines, and alternative
antibiotics are often preferred
PREGNANCY RISK
CATEGORIES (CATEGORY X)
Category X: The risk of use of the drug in pregnant women clearly outweighs any possible benefit. The drug is
contraindicated in women who are, or may become pregnant.

Examples: Thalidomide, Oral Contraceptives, Statins, Warfarin, Methotrexate, Finasteride.

Warfarin is an anticoagulant (blood thinner) used to prevent and treat blood clots. It works by inhibiting the synthesis
of certain clotting factors. Warfarin is known to cross the placenta, and its use during pregnancy is associated with an
increased risk of fetal malformations, particularly in the first trimester. Pregnant individuals with conditions
requiring anticoagulation may be switched to alternative medications with a more favorable safety profile during
pregnancy.
POST ASSESSMENT QUIZ
Which FDA pregnancy risk category that signifies animal studies reveal no risk to the
fetus, and there is a lack of sufficient and well-controlled studies in pregnant
women?

A) Category B
B) Category C
C) Category D
D) Category X
 SUMMARY
Pharmacokinetics during Pregnancy:
Maternal physiological changes, such as increased lipid solubility and altered ionization, impact drug
transfer across the placenta, influencing fetal exposure and potential effects.
Pharmacodynamics of Drugs During Pregnancy:
The pharmacodynamics of drugs in pregnancy involve understanding how drugs interact with maternal
and fetal tissues. Key points include:
•Maternal Drug Actions: Drugs may affect reproductive tissues and other maternal organs. Changes in
physiology during pregnancy may alter the response to certain drugs.
•Therapeutic Drug Actions in the Fetus: Fetal therapeutics involves administering drugs to pregnant
women with the fetus as the target. For example, corticosteroids stimulate fetal lung maturation.
•Predictable Toxic Drug Actions in the Fetus: Chronic opioid use by the mother may lead to neonatal
withdrawal syndrome. Certain drugs, like angiotensin-converting enzyme inhibitors, can cause
irreversible fetal renal damage.
•Teratogenic Drug Actions: Some drugs can cause structural abnormalities in the fetus if exposure occurs
during critical developmental periods. Thalidomide is an example, causing limb abnormalities during
specific weeks of gestation.