Phamacology in pregnancy& paediatrics

Pediatric and Perinatal Pharmacology

www.freelivedoctor.com

Pregnancy causes one of the most striking changes in physiology of any normal condition that appears in the human body. Changes in the woman’s body are related to several factors including hormonal influences, the growth of the fetus and her own adaptation to all the changes that are occurring.

Pregnancy


– Increased water retention (7-9Lt).– Increased extracellular volume (4-6Lt).– Increased cardiac output.– Decrease colloidal osmotic pressure.– Progressive increase of renin thru pregnancy.– Increase levels of aldosterone.– Decrease peripheral vascular resistance.– Gastric acid secretion high in 1° and 2nd Trimesters.– Decrease gastric emptying.– Increased absorption.– Increased intestinal transit times.

– Increase body fat.

Changes during pregnancy


– Dilutional decrease in serum albumin levels. More free drug.

– Decrease concentration of total plasma proteins. More free drug.

– Progesterone stimulates hepatic enzyme systems. Increase clearance and shorter half-life.

– Greater fat and glycogen storage in the liver.

– Increased CO2 gradient between mother and fetus.

– Renal blood flow and GFR increase early in pregnancy and decrease in late pregnancy.

Changes during pregnancy (con’t)


To cross the placenta

vs

not to cross the placenta

GOAL:


Drug Therapy in Pregnancy

PHARMACOKINETICS

Factors Affecting Drug Transfer to the Fetus

I. Physicochemical properties of the drug.

II. Amount of drug reaching the fetus.

III. Exposure rate.

IV. Duration of exposure.

V. Tissue distribution.

VI. Developmental stage.

VII. Co-exposure w/other drugs. www.freelivedoctor.com

I. Physicochemical Properties of the Drug

A. Lipid solubility

B. Degree of ionization

C. Protein binding

D. Molecular size

E. Placental and fetal drug metabolism

F. Placental transport



A. Lipid Solubility• Lipophilic drugs tend to cross the placenta readily

at rates dependent on their molecular weight, charge characteristics, and concentration in the maternal blood.

• Drugs with low lipid solubility tend to be highly bound to plasma protein.

• Their distribution is affected by placental blood flow.

i.e. thiopental, nicotine, salicylate


I. Physicochemical Properties of the DrugB. Degree of Drug Ionization

- In the blood a weak acid or weak base distributes to all compartments of the body differently, forming an equilibrium between charged and uncharged forms of the drug in each compartment.

- Polar substances cross the placenta more slowly than drugs that are ionized at physiologic pH.

- Impermeability of the placenta to ionized/polar compounds is relative rather than absolute.

i.e. succinylcholine and tubocurarine (ionized, cross slowly) vs salicylate (small amts of the non-ionized drug cross rapidly because they are highly lipid soluble).



C. Protein binding.- Affected by lipophilicity and ionization state

of drug => lipophilic compounds (anesthetic gases) are not greatly affected by protein binding.

- Low affinity of fetal proteins.- The protein content in fetal plasma increases

with gestational age.- Fetal albumin levels usually exceed maternal

levels at birth.i.e. sulfonamides, barbiturates, phenytoin and local

anesthetic agents.www.freelivedoctor.com

Two mechanisms protect the fetus from drugs in the maternal circulation:

1) The placenta, which serves as a semipermeable membrane and as a site of drug metabolism.

2) Liver metabolism of the drug.


Placenta - The placenta is a living tissue that synthesizes a number of peptides, enzymes and hormones. It actively transports molecules to the fetus and carries away wastes. It serves as an effective immunologic barrier and is also a site of metabolism of some drugs.


The Placenta

Umbilical arteries

Umbilical vein

Chorionic villus

Placental septum

Endometrial

arteries

and veins

Intervillus space

Chorion

Amnionwww.freelivedoctor.com

The Maternal-Fetal Unit

Maternal transfer• Antibodies• Drugs• Hormones• Nutrients• Oxygen• Pathogens• Vitamins• Viruses• Water

Fetal Transfer• Urea• Carbon dioxide• Other catabolites



D. Molecular Size- Depending on M.W. drugs cross the placenta

readily (250-500), with difficulty (500-1000), or poorly (>1000).

- The great majority of drugs have molecular weights between 100 and 500.

i.e. heparin vs warfarin.



E. Placental and Fetal Drug Metabolism- 40-60% of umbilical venous blood flow enters the

fetal liver.- The fetal liver contains the adult complement of

enzymes, however, at term, the activity of these enzymes is only about half those in the adult.

- Liver enzymes in the fetus are poorly inducible.- Drug metabolites may be pharmacologically active

and able to cause adverse effects in the fetus.- Several different aromatic oxidation reactions can

occur in the placenta (e.g. hydroxylation, N- dealkylation, demethylation).www.freelivedoctor.com


F. Placental Transport1. Simple Diffusion. gases.

2. Facilitated Diffusion. glucose.

3. Active Transport. e.a.a. and water soluble vitamins.

4. Pinocytosis. Complex proteins, antibodies, small amounts of fat and viruses.

5. Leakage. Fetal cells exfoliate into the maternal circulation.


II. Amount of Drug Reaching the Fetus

- Determined by the degree of plasma permeability to the drug and the drug’s physicochemical properties, as well as to the maternal absorption, distribution and biotransformation of the drug.


III. Exposure Rate

- Determined by the degree of plasma permeability to the drug and the drug’s physicochemical properties, as well as to the fetal absorption, distribution and biotransformation of the drug.


IV. Duration of Exposure

- Determined by the degree of placental permeability to the drug and the drug’s physicochemical properties. It will also depend on the maternal absorption, distribution, biotransformation and clearance of the drug as well as the fetal absorption, distribution, biotransformation and clearance of the drug .

Because the fetus clearance is via the kidney (urine) and the urine goes to the amniotic fluid, the fetus might take in the drug again.www.freelivedoctor.com

V. Tissue Distribution

- Drugs may be stored in tissues differently.

- Drugs are removed from circulation and stored in bone, teeth, hair and adipose tissue.

- Lipid soluble drugs are stored in adipose tissue, which increases during pregnancy, with a resulting prolonged effect of the drug (slow release).


VI. Developmental Stage

• The fetus is most vulnerable during the first trimester.

From conception (0) to 14 days.

Little morphologic differentiation.

From 15 to 60 days after conception.

Time of organogenesis. Fetus is most vulnerable.


Fetal Development

CNS

Heart

Eyes

Legs

Arms

0 5 15

Teeth

Palate

Ex. genitalia

Ear

Full term


Drug Affinity for Specific Tissues

TetracyclineWarfarinAminoglycosidesQuinineChlorpromazineDiethylstilbestrol

CorticosteroidsPhenytoinIodidesPropylthiouracil

Teeth

Middle ear

Retina

Mullerian DuctVagina

Adrenal Gland

Thyroid Gland


Factors Affecting Placental Transfer of Drugs

• Lipid solubility. • Nonionized substances.• Molecular weight < 600• Low protein binding.• High maternal-fetal

gradient.• Increased placental

blood flow.• Increased fetal acidity.• Larger surface area.

• Increased diffusion distance.

• High molecular charge.• High molecular weight.• Drug bound to maternal

RBCs or plasma protein.• Drug altered or bound

by placental enzymes.• Decreased maternal

blood flow.• Drugs highly

metabolized by mother.www.freelivedoctor.com

Drug Therapy in Pregnancy

PHARMACODYNAMICS

Factors Affecting Drug Actions in the Fetus:

I. Maternal factors.

II. Fetal Therapy.

III. Drug Toxicity.

IV. Teratogenicity


I. Maternal Factors1) Reproductive tissues are altered by pregnancy

(breast, uterus, etc).

2) Drug effects in other tissues are not significant. (except: for a decreased GI motility, delayed gastric emptying).

3) Other physiologic changes do occur => increased plasma volume, increased cardiac output, increased renal blood flow.

i.e. cardiac glycosides may be used for CHF due to increase work load. Insulin may be needed for pregnancy-induced diabetes. www.freelivedoctor.com

II. Fetal TherapyTherapy directed to the fetus.

Corticosteroids. Stimulate fetal lung maturation when preterm birth is expected.

Phenobarbital. Given during the last trimester, close to term, induces fetal liver enzymes responsible for the glucoronidation of bilirubin, reducing the incidence of jaundice.

Antiarrhythmic drugs. For the treatment of fetal arrythmias.


III. Drug Toxicity

- Many drugs of abuse cross the placenta.

- Chronic use of opioids by the mother may produce dependence in the fetus and newborn and withdrawal.

- Whatever is toxic to the mother will probably be toxic to the fetus.


IV. Teratogenicity

A. Teratogen

B. Teratogenic Mechanisms

C. Teratogenic Risk


IV. Teratogenicity

I. Teratogen. Substance capable of causing abnormal development or function by interfering with fetal development.

- A single intrauterine exposure to the drug can affect the fetal structures undergoing rapid development at the time of exposure.

- Characteristic set of malformations.- Exert its effects at a particular time in fetal

development.- Show a dose-dependent incidence.

i.e. alcohol (FAS), Thalidomide (phocomelia), DES (uterine cancer), valproic acid (spina bifida).www.freelivedoctor.com

Drugs that cause severe adverse effectsACE Inhibitors

Aminopterin

Amphetamines

Androgens

TCAs

BARBs

Busulfan

Carbamazepine

Chlorpropamide

Clomipramine

Cocaine

Cyclophosphamide

Cytarabine

Diazepam

DES

Ethanol

Etretinate

Heroin

Iodide

Isotretinoin

Lithium

Methadone

Methotrexate

Methylthiouracil

Metronidazole

Organic solvents

Misoprostol

Penicillamine

Phencyclidine

Phenytoin

Propylthiouracil

Streptoycin

Tamoxifen

Tetracycline

Thalidomide

Trimethadione

Valproic acid

Warfarinwww.freelivedoctor.com

IV. Teratogenicity

B. Teratogenic Mechanisms:1) Effects on maternal tissues.

2) Delivery of oxygen and nutrients.

3) Alterations during differentiation.

4) Deficiencies.


IV. Teratogenicity

1) Effects on maternal tissues.Drugs may have a direct effect on maternal

tissues with secondary or indirect effects in the fetus.

e.g. Cocaine increases the risk for spontaneous abortions, placenta previa and permature labor; neonatal cerebral infarction, abnormal development and decrease school performance.


IV. Teratogenicity

2) Delivery of oxygen.

Interference of oxygen delivery to the fetus may cause ischemia to tissues specially to brain, and cause severe damage or even death.


IV. Teratogenicity

3) Food and Nutrient alterations during differentiation.

Interference with nutrient delivery may cause anemia and poor growth.

Alterations of certain factors such as vitamins or minerals may be teratogenic.

e.g. Vitamin A (Retinol) has important differentiation-directing actions in normal tissues. Excessive amounts may cause birth defects, bone abnormalities and liver damage.

Excess niacin may cause ocular abnormalities.www.freelivedoctor.com

IV. Teratogenicity

4) Deficiencies.Alterations of certain factors such as vitamins or

minerals may be teratogenic.

e.g. Folic acid causes neural tube defects, supplementation reduces the incidence of spina bifida.


IV. Teratogenicity

C. Teratogenic Risk• It is recommended that all pregnant women

be counseled with regard to taking

medications during pregnancy. • In reality, the risk of a neonatal abnormality

in the absence of any known teratogen is

less than 3%. • Up till know about 30 compounds have

been identified to be teratogenic.www.freelivedoctor.com

Drug Therapy in Infants

PHARMACODYNAMICS

Factors Affecting Drug Effects on the Infant:

I. Drug Absorption

II. Drug Distribution

III. Drug Metabolism

IV. Drug Excretion



I. Drug Absorption• Absorption in infants and children follows the same

rules as in adults.• Factors affecting absorption are determined by the

physiologic status of the infant or child and are influenced by:

1.) Blood flow at the site of administration.

2.) Gastrointestinal function.



Drug Absorption in

Drug

Acetaminophen

Ampicillin

Diazepam

Digoxin

Penicillin G

Phenobarbital

Phenytoin

Sulfonamides

the neonate compared to adults.

Oral Absorption

Decreased

Increased

Normal

Normal

Increased

Decreased

Decreased

Normalwww.freelivedoctor.com


1.) Blood flow at the site of administration.- Physiological conditions that might affect blood flow are:

cardiovascular shock, vasoconstriction (sympathomimetic agents), and heart failure.

- Diminished muscle mass in i/ch may reduce blood flow causing irregular and unpredicatble absorption. Drug will concentrate in the muscle and if perfusion suddenly increases, drug may reach toxic concentrations.

e.g. cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.

2.) Gastrointestinal function.www.freelivedoctor.com

Drug Therapy in Infants2.) Gastrointestinal function.Significant changes occur in the neonate shortly after birth. • Gastric acid secretion commences soon after birth and

increases gradually over several hours. In preterm infants it appears slowly. Drugs affected by gastric pH should not be administered orally.

• Gastric emptying is prolonged in the first day of life. Thus, drugs absorbed through GI may be more completely absorbed than anticipated.

• Peristalsis in the neonate is slow. If drugs are absorbed in the small intestine, their effect may be delayed. Diarrhea causes decrease absorption in small intestine.



II. Drug Distribution• As body composition changes with development so

does the distribution volume of drugs.• In the neonate, 70-75% of body weight is water vs

85% in preterm vs 50-60% in the adult.• Most neonates will experience diuresis in the first 24-

48hrs of life.• In neonate 40% of body weight is extracellular water

vs 20% in the adult.• In the neonate total body fat is 15% vs 1% in preterm.



II. Drug DistributionBinding to Plasma protein• Protein binding of drugs is reduced in the neonate.

Therefore, concentration of free drug in plasma is increased => increased effect or increase toxicity.

• Drugs (e.g. sulfonamide antibiotics) that displace bilirubin from albumin may cause kernicterus. Conversely, bilirubin may also displace protein-bound drugs (e.g. phenytoin).


Drug Therapy in InfantsIII. Drug Metabolism• Metabolism of most drugs occurs in the liver. • The metabolizing activity of cytochrome P450-

dependent mixed-function oxidases is reduced in neonates (50-70% of adult values).

• Glucoronide formation doesn’t occur until the 3th -4rd years of life. Thus, in the neonate, drugs have slow clearance rates and prolonged half-lives.

• If the mother was taking phenobarbital, neonatal liver enzymes could have been induced. The ability of the neonate to metabolize certain drugs would be greater than expected and the effect could be less.www.freelivedoctor.com

Biotransformation of Benzodiazepines

From Katzung, 1998www.freelivedoctor.com


IV. Drug Excretion• Glomerular filtration is much lower (30-40% of adult) in

neonates for the first few days of life. Within a week glomerular filtration and plasma flow increase by 50% and reach adult values within 6-12 months. Drugs that depend on renal flow are eliminated very slowly in the first few weeks of life (penicilins, aminoglycoside antibiotics, digoxin)

Ampicillin

< 7 days old=> 50-100 mg/Kg/d , 2d at 12 hr intervals.

> 7 days old => 100-200 mg/Kg/d, 3d at 8 hr intervals.



Dosage Forms and Compliance:

To ease administration and compliance, drug manufacturers prepare drugs as:

a) Elixirs. Alcoholic solutions in which the drug molecules are dissolved and evenly distributed.

b) Suspensions. Contain undissolved particles of drug which must be distributed throughout the vehicle by shaking to prevent uneven drug dispensing. www.freelivedoctor.com

Drug Therapy in InfantsCompliance may be difficult to achieve in pediatric

medicine and may prove a challenge when taking into account:

• measuring errors• spills• spitting

A calibrated medicine spoon should be recommended.

Parents should be told to repeat dosage or not after spitting or whether to wake up the child every 6 hr dose day or night. Possible drug-drug interactions with ODC medications should be discussed.www.freelivedoctor.com


NO ASSUMPTIONS SHOULD BE MADE ABOUT WHAT THE

PARENT MAY OR MAY NOT DO.



Drugs ContraindicatedAmphetamine

Bromocryptine

Cocaine

Cyclophosphamide

Cyclosporine

Doxorubicin

during Lactation:Ergotamine

Heroin

Lithium

Marijuana

Methotrexate

Nicotine

Phenindione


FDA Drug CategoriesCategory A. Controlled Studies have not demonstrated

fetal risk.Category B. Studies in animals have not demonstrated fetal

risk.Category C. Studies in women or animals are not available.Category D. There is positive evidence of human risk.

However, the benefits of use in pregnancy may be acceptable in spite of this risk.

Category X. Studies or experience in humans or animals has demonstrated fetal risk. The risk far outweighs any potential benefit. The drug is contraindicated in pregnant women or women who may become pregnant.


Documents

Phamacology in pregnancy& paediatrics