K-19 Obat-obat dalam Masa Kehamilan.ppt

7/29/2019 K-19 Obat-obat dalam Masa Kehamilan.ppt

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Aznan Lelo- Datten Bangun

Departemen Farmakologi & Terapeutik

FK USU

2012


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Awareness of physiology of pregnancy

How pregnancy alters pharmacokinetics

Placental transfer Teratology

Drugs utilised in pregnancy

Points to ponder:


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Pregnancy poses important problems.

Most drugs will diffuse passively acrossplacenta, and some are transported actively,

so the potential benefit of a drug to motherhas to be considered in relation to thepotential risk to the fetus.

As a general rule, all drugs should be avoided

in pregnancy unless theres a compellingreason for their use.

Some drugs have been definitely linked tofetal abnormalities .

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Only half of all pregnancies are planned

Many women need medications forpregnancy induced conditions (e.g.

= Morning Sickness),= chronic conditions (e.g. Epilepsy),

intercurrent conditions (Allergies)

Women work with chemicals, exposed to

radiation and use illicit drugs During embryogenesis-drugs &chemicals

may adversely affect development


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A) Anxiety of birth defects:

Leads women not to take medications duringpregnancy& lactation.

Leads pharmaceutical companies not todevelop drugs for pregnant &lactatingwomen.

B) Women are not treated appropriately evenafter first trimester, or for life threateningconditions


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Sebagian besar dari obat-obat yang diminumoleh ibu hamil dapat melewati plasenta dan

dapat masuk ke tubuh janin

Efek farmakologi

Efek teratogenik


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Critical factors affecting placental drug transferand drug effects on fetus :

1. Physicochemical properties of the drug

2. The rate at which the drug cross the placenta

3. The amount of drug reaching the fetus

4. The duration of the exposure to the drug

5. Distribution characteristic in different fetal

tissues6. The stage of placental and fetal development

at the time of exposure

7. The effects of drugs used in combination


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in plasma volume in cardiac output in renal blood flow and GFR Induction of liver enzyme pathways

in plasma protein content Delayed gastric emptying


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volume of distribution plasma concentration excretion renal excretion hepatic metabolism


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Golden rule is that every drug crosses the

placenta and under normal circumstances

most drugs equilibrate between maternal

and fetal compartments. The only exception is heparin, which

because of its large molecular weight and

polarity, does not cross


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1. Liphophilic drugs :

- tends to diffuse readily across the placenta

- enter the fetal circulation

Thiopental (used during caesarean section) :

cross the placenta immediately can produce sedation or apnea in the newborn infant


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2. Highly ionized drugs :

- cross the placenta slowly achieve lowconcentration in the fetus

Succinylcholine or tubocurarine


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3. Polar compound, but high-maternal-fetalconcentration gradient cross the placenta

Salicylate


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Drugs with mol. weight :- 250-500 cross the placenta easily- 500-1000 : more difficulty- > 1000 : poorly

Heparin :

- very large and polar unable to cross the placenta- safe to the fetus

- used the placental transporter

Warfarin : - smaller than heparin

- teratogenic

- should be avoided


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Ex. P-glycoprotein transporter pumps drugs backto the maternal circulation

Including :

- anti-cancer drugs (vinblastin, doxorubicin)- digoxin


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Some drugs like sulfonamides, barbiturates,phenytoin, local anaesthetics exhibit greaterprotein binding in maternal plasma than in

fetal plasma because of lower bindingaffinity of fetal proteins


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1. Placenta :

- semipermeable barrier

- site of metabolism

- baru sempurna setelah 4 bulan kehamilan

2. Drugs enter the fetal circulation

enter the livermetabolism


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A. Maternal Drug Actions- The effects of drugs on reproductive tissues ofthe pregnant woman sometimes are altered byendocrine environment appropriate for the

stage of the pregnancy.- Drug effects on other system tissue (heart,lungs, kidneys, CNS) are not changedsignificantly, though sometimes cardiac outputor renal blood flow maybe altered

Ex. diureticsinsulin for pregnancy induced diabetic


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B. Therapeutic Drug Actions in The Fetus- Drugs are given to the mother with the fetusas the target of the drug

Examples:

corticosteroids to stimulate fetal lungmaturation when preterm birth is expected.

phenobarbital to reduce the incidence of

jaundice


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C. Predictable Toxic Drug Actions in The Fetus

- chronic used of opioid by mothers drugdependence in the fetus and new born

- ACE-I used by the mothers renal damage inthe fetus

- diethylstilbesterol adenocarcinoma


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Teratos = monster

Teratogen : substance that leads to the birth

of malformed baby Teratogen :

* result in a characteristic set ofmalformation

* exerts its effect at a particular stage offetal development (organogenesis)

* show a dose-dependence incidence

Pharmacodynamics


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Dose

Frequency

Length of exposure

Stage of pregnancy upon exposure

The properties of the drugs

Note: The Thalidomide babies (phocomelias) in early1960.


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Major congenital anomalies Functional & minor anomaliesEmbryoDeath

Highly sensitive period Less sensitive period

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TA, ASD, and VSD

Amelia/Meromelia

Cleft lip

CNS

TEETH

EARS

PALATE

GENITALIA

Early development Main embryonic period (weeks) Fetal period (weeks)

EYES

Masculinsation

Neural tube defects Mental retardation

HEART

LIMBS

UPPER LIP

Low-set malformed ears and deafness

Microphthalmia, cataracts,glaucoma

Enamel hypoplasia

Cleft palate

Common site(s) of action


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Drugs 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


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Thalidomide is a tranquiliser,

sedative & immunosuppressant

Critical exposure window 24 to 36 days post fertilisation

Defects : amelia - no limbs

micromelia - short limbs cardiac defects

haemangiomas

defects of urinary tract

defects of digestive tract


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The intra-uterine period between 2 weeks 3 monthsis when the most serious abnormalities of fetaldevelopment can be caused by drugs.Its during this period that the major organs are beingformed.

In animal studies, even one dose of a drug administeredat the critical time has been shown to have a majoreffect. The mechanisms of damage are notyetknown, but the molecular basis of differentiation ofembryonic cells is an intense area of basic researchand is likely to provide new insights in the near

future. Ampicillin and Cephalosporins are considered one of

the safest drugs which can be used during pregnancy.

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During T2 & T3 of pregnancy, adverse effects onfetus of drugs administered to the mother aregenerally an exaggeration of the effects seen in theadult. Exceptions to this rule are the damage to

tissues which are still developing e.g. teeth &bones by Tetracycline, and the impairment of braindevelopment by Coumarin anticoagulant.

Particular care must be taken with drugs givenshortly before delivery. Analgesics, e.g.Meperidine (Pethidine), and tranquillizers e.g.(Benzodiazepines) may severely impair neonatalrespiration. In addition, the newborn lacks manyenzymes necessary for the efficient metabolism of

drugs. 30


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K-19 Obat-obat dalam Masa Kehamilan.ppt

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