teratogen -ukdw blok 5

8/12/2019 Teratogen -Ukdw Blok 5.

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SULANTO SALEH-DANU R., dr., SpFKDivisi Farmakologi-Klinik

Departemen Farmakologi & Terapi

Fakultas Kedokteran UGM

OBAT-OBATANFETUS( TERATOGENIC)


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TRIAD MATERNAL PLACENTA FOETUS

TRANSFER OBAT DARI MATERNAL KE FOETUS

PHARMACOKINETICPHARMAKODYNAMIC FOETUS

PERIODE ORGANOGENESISTERATOGENIK

PERLINDUNGAN KEMUNGKINAN KEJADIAN TERATOGEN

BEBERAPA CONTOH CACAD CONGENITAL.

BEBERAPA HAL TENTANG

OBATOBATAN & FETUS.


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- GASTROINTESTINAL TRACT :

oral cavity

motility

esophagus and stomach

intestine

liver and gallbladder

-KIDNEY and URINARY TRACT

renal dilatation

renal function

bladder

-HEMATOLOGIC SYSTEM

blood volume

red blood cellsiron

white blood cells

platelets

clotting factors

-CARDIOVASCULAR SYSTEM

heart (size, position, rhythms, murmurs)

cardiac output

blood pressureperipheral resistance

blood flow

-RESPIRATORY SYSTEM

lung volume

lung capacities

-ENDOCRINE SYSTEM,

etc.

NORMALWOMAN

PREGNANCY :

Anatomical &Physiological

changes


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PREGNANCY

1STTRIMESTER

2ndTRIMESTER

3thTRIMESTER

PARTURIENT

CHANGES :

ANATOMIC ??

PHYSIOLOGIC ??

MEDICINES &

SUBSTANCES

OUTSIDEMATERNAL

PHARMACOKINETIC ??

PHARMACODYNAMIC ??


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MOTHER FETUS

Basal Layer ?Chorion Layer ?

TRIAD MATERNAL PLACENTAFOETUS

PLACEN

TA


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OXYGEN

WATER &

ELECTROL.

HORMONES

Antibodies

DRUGS

INFECTIONS /

VIRUSES

CARBOHYDR-

ATES

LIPIDS

PROTEINS

VITAMINES

CO2

Water &

urea

Waste

product

HORMONE

S

(CERTAIN)

(Almost all )

MATERN

AL

PLACENTA

FETUS


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HARMFUL EXOGENOUSINFLUENCES FACTORS :

1. EXCHANGE PHYSIOLOGICAL CONSTITUENTS.2. RADIATION EFFECTS3. MICROORGANISM / VIRUS INFECTION4. CHEMICAL SUBSTANCES :DRUGS SERUMS VACCINES

FOREIGN SUBSTANCES5. ENVIRONMENTAL:

CLIMATE NUTRITION SMOKING ALCOHOLWORK CONDITION SICKNESS SOC-ECON.


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i.v. oral i.m TopicalTrans-

dermal

Mucosal,

buccal,

Vag., rectal,

inhalation

Localeffect

Localeffect

A B S O R P T I O N

PRESYSTEMIC METABOLISM

systemic circulation

DISTRIBUTION

Site of action METABOLISM EXCRETION


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Drug fate in the body

Absorption

Site(s) of action

Other body fluids

and tissues

ExcretionDrug-protein

Free Drug

Free Drug

Metabolism

metabolites

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How drugs act in the body ?

Drug

Drug concentration in

systemic circulation (blood)

Drug concentration

at site of action

Adverse effect Therapeutic effect

Absorption

Distribution

Metabolism

ExcretionPHARMACOKINETIK

PHARMACODYNAMIC

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FARMAKA

DRUGS/MEDICINES

PREGNANCY

FETUS MATERNAL

THERAPEUTIC EFFECT

TOXIC EFFECT

TERATOGENIC EFFECT

THERAPEUTIC EFFECT

TOXIC EFFECT

EFFECT ON PARTURITION

PLACENTA

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MATERNALPLACENTA FETUS

DRUGS

BOUND

UNBOUND UNBOUND

BOUND

EXCRETED

TISSUE

METABOLIZED

EXCRETED intoThe Amniotic Fluid

INGESTED by

the Fetus

FETAL Intestines

Model of interaction between A-D-M-E of drugs and metabolites

in the organism of mother and fetus


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FACTORS MODULATING THE PASSAGE OF DRUGS

ACROSS THE PLACENTA MEMBRANE :

1. LIPID SOLUBILITY2. MOLECULAR SIZE AND SHAPE

3. DEGREE OF IONIZATION

4. PLACENTAL BLOOD FLOW

5. STAGE OF DEVELOPMENT OF PLACENTA

6. PLACENTAL METABOLISM OF DRUGS


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Simple diffusion

Fasciliated diffusion

Active transport

Pinocytosis

Leakage

DRUGS :

lipophillic

non-ionized

non-polair

molecule size

MATERNAL :

GIT motility

pH

Blood flow

Diseases, etc

PLACENTA FETALMATERNAL

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ABSORPTION PROCESSES IN PLACENTA:

Passive diffusion down a concentration gradient

- most drugs

Cell membrane and fat-solubility of drugs

- most drugs

Active transport - few drugs

Disintegration and dissolution of tablets- many drugs

Presystemic metabolism ( first-pass metabolism )

- most drugs

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PLACENTA;

FETAL PROTECTION

FETAL FEEDING

ENDOCRINE SECRETION


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AbsorptionDistribution

Metabolism

Excretion

PHARMACOKINETIK

CLEARENCE ( CL L/hou r )

VOLUME of DISTRIBUTION ( Vd)

HALF-LIFE ( t - hou rs )


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PHARMACOKINETIK IN PREGNANCY :

DRUGS ABSORTION :

process : transfer by crossing cell membrane

construction from LIPID

lipophilic ?non-ionized ?

non polair ?

molecule size ?

crossing

cell membrane

PREGNANCY gaster pH ?intestinal motility ?

Intestinal lumen emptying ?

hepatic blood flow ?


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CLEARENCE( CL L /hour o r mL/m inute )

The eff ic iency of irreversible el iminat iono f

a drug from the body

-The excretion unchanged drug into urine

-Gut contents

-Expired air

-Sweat , etc

-The metabolic conversion of the drug

different chemical compound

The volum e of blood clear of drug per uni t t ime


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CLEARENCE

PARAMETER THAT DETERMINES THE MAINTENANCE DOSE RATE

REQUIRED TO ACHIEVE A TARGET PLASMA CONCENTRATION

AT STEADY STATE

elimination rate (mg/hour) = clearance (CL) (L/hour) x

plasma drug concentration (C) mg/L

elimination rate (mg/hour) = maintenance dose rate (DR) (mg/hour)

maintenance dose rate (DR) = clearance (CL) L/hour x

steady state drug concentration ( Css ) mg/L

DR dose (mg)CL = or CL (L/hour) =

Css AUC ( mg.hour/L )

note : AUC = Area Under the Curve


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VOLUME of DISTRIBUTION

( Vd L itre )

not a real volume parameter relat ing

the concentrat ion o f a drug in the plasma

to the total amount of the drug in the body.

tota l amount of the drug in body (A)

plasma drug concentrat ion ( C )

quick c ount a loading dose

loading dose = V x target plasma concentration

= 20 L x 10 mg/L

= 200 mg

Vd =


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HALF-LIFE

( t - hours )

is the t ime taken for the amount of dru g in the body

( or the plasma concentrat ion ) to fall by half .

0.693 x V

CLt =

1. The Duration of action after single dose2. The require to reach steady state with chronic dosing

3. The dosing frequency required to avoid too large fluctuations

plasma concentration during the dosing interval


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Pharmacokinetics:drug concentrations in plasma over time

1

10

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Minimum EffectiveConcentration

Minimum ToxicConcentration

Plasma drug concentration

Time

Tmax

Cmax

AUC

Tlag

Keland T1/2 Therapeuticwindow


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Pharmacodynamics

1. Drug action in maternal body system.

Drug effects in pregnant women:- Reproductive tissues, e.g. breast, uterus, etc., are

altered the change of endocrine system according to the

stage of pregnancy;

- Other maternal organs (heart, lung, kidneys, CNS,intestine, etc.) not changed, same as the effect in non

pregnant condition.

2. Drug action in the Fetus.

Some medicine give in perinatal via maternal:- Phenobarbital when given near term, can reduce the

incidence ofjaundice baby, by inducing fetal hepatic

enzymeof the foetus.

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3. Predictable Toxic Drug Actions in the Fetus.Chronic use of medicine can produce adverse effect

after delivery, Opioidmay produce dependence in newborn babies,

(withdrawal syndrome in newborn baby).

Diethylstilbestrol (DES)produced adenocarcinoma inpubertal ages of the baby (delay reaction).

4. TERATOGENIC Drug Action.Even a single intrauterine drug exposure to a drug can

affect the fetal structure, e.g. Thalidomide ---->phocomelia.

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TERATOGEN --> to be TERATOGENIC :

substance or process should :

1. result in characteristic set of malformations,

indicating selectivity for certain target organs.

2. effects at a particular stage of fetal

development (during limited time periode of

organogenesis.

3. shows dose dependent incidence.

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New born

normal

Functional

abnormalities

Major

structuralabnormalities

Gametes Blastocyst Embryo Fetus

Fig. 4. Schematic representation of the influence of dysmorphogenic factors on

gametogenesis and various stages of prenatal development. Strongdymorphogenic agents:

wide arrows; weakagents; narow arrows(after Tuchmann-Duplessis, 1975)

Sterility

Death

Death

Death

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DANGER ZONE


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Fig.7. The stages critical for thehuman fetus. (Notethat the

developmental ages given arepostconceptionages which for

clinical purposes need to be translated intopostmenstrual

ages, ordinarily by adding 2 weeks) After Tuchmann-

Duplessis (1975).

Fig.5. The critical stages of development of the main

structures of thehuman embryo. (Notethat the

development ages given arepostconceptionages which

for clinical purposes need to be translated into

postmenstrualages, ordinarily by adding 2 weeks). AfterTuchmann-Duplessis (1975).

Days

Months

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TERATOGENIC EFFECT:

-Teratogen: a substance that lead to the birth ofmalformed baby.

The mechanism is poorly understood, possibly

multifactorial causes, may by oxygen passing ortissue nutrient for the fetus, or shown to have

important differentiation-directing in normal tissue

like vitamin A analog ( isotretinoin, etretinate ) --

powerful teratogen, or deficiency of criticalsubstance such as folic acid.

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PATHOGENESIS

( manifestation of abnormal Excessive or reduce cell interactions

development created by Fail cell interactions

above mechanism ) Reduce biosynthesisImpeded morphogenetic movement

Mechanical disruption of tissues

COMMON PATHWAYS Too few cells or cell products to

affect localized morphogenesis or

functional maturation.

Other imbalances in growth and

differentiation.

FINAL DEFECTS Death

(final manifestation of abnormal Malformation.

Development) Growth retardation


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ADVERSE EFFECTS OF FETOTOXIC EXPOSURESTAGE DEVELOPMENT

WEEK since

Ovulation Potential ADVERSE EFFECTS

1 Abortion

2-7 Fetal wastage; Structural malformations; Carcinogenesis

Intrauterine growth retardation (severe)

3 Ectopia cordis;Omphalocele; Ectomelia; Sympodia

4 Omphalocele; Ectomelia;Tracheoesophageal fistula;

Hemivertebra

5 Tracheoesophageal fistula; Hemivertebra; Nuclear cataract;

Microphtahalmia; Facial cleft; Carpal of pedal ablation

6 Microphthalmia; carpal or pedal ablation; Cleft lip; Agnathia

Lenticular cataract; Congenital heart disease; Gross

cardiac septal and/or aortic anomalies

(to be continue.)


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DRUGSWITH :SIGNIFICANT TERATOGENIC / ADVERSE EFFECTS ON FETUS

DRUG TRIMESTER EFFECT

ACE inhibitors All, espec 2nd& 3rd Renal damage

Aminopterin First Multiple gross anomalies

Amphetamines All Susp.abnomal development pattern.

decrease school performance

Androgens 2nd& 3rd Masculinization of female fetus

Antidepressants 3rd

Neonatal withdrawal symptoms havetricyclic been reported in few cases

clomopramine, desipramine, imipramin

Barbiturates All Chronic use -> neonatal dependence

Busulfan All Various congenital-malformations; LBW

Carbamazepine First Neural tube defects (eg spina bifida)Chlorpropamide All Prolonged sympt.neonatal hypoglycaemic.

Clomipramine 3rd Neonatal lethargic, hypotonia, cyanosis,

hypothermia

Cocaine All Increased risk of spontaneous abortion,

abruptio placentae, premature labor,

neonatal cerebral infarction, abnrml.dev,etc

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Cyclophosphamide First Various congenital malformations

Cytarabine First & 2nd Various congenital malformations

Diazepam All Chronic use -> neonatal dependenceDiethylstilbesterol All Vaginal adenosis, clear cell vag. Adeno Ca

Ethanol All Risk of fetal alcohol syndr. and alc-related

neurodevelopmental defects.

Etetrinate All High risk of multiple congenital malform.

Heroine All Chonic use -> neonatal dependence

Iodide All Congenital goiter, hypothyroidism

Isotretinoin All Extremely high risk of CNSs, face, ear &

other malformations

Lithium First Ebsteins anomaly

Methadone All Chronic use -> neonatal dependence

Methotrexate First Multiple congenital malformations

Methylthiouracil All Hypothyroidism

Metronidazol First May be mutagenic (animal study;

no effidence for mutagenic/teratogenic

in humans)

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Misoprostol First Mbius sequence

Mycophenolate First Mayor malformations of the face,

mofertil limbs, and other organs.

Organic solvent First Multiple malformations

Penicillamine First Cutis laxa, other congenital malformations

Phencyclidine All Abnormal neurologic examination, poor

suck reflex and feeding

Phenytoin All Fetal hydantoin syndromePropylthiouracil All Congenital goiter

Smoking (consti- All Intrauterine growth retardation, prematurity,

tuents of tobacco sudden infant death syndrome, perinatal

smoke) complication.

Streptomycin All 8thNerve cranialis toxicity

Tamoxifen All Increased risk of spontaneous abortion or

fetal damage

Tetracycline All Discoloration and defects of and altered

bone growth

Thalidomide All Phocomelia (shortened/absent

of long bones of the limbs) and many

internal malformations .

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Trimethadione All Multiple congenital anomalies

Valproic acid All Neural tube defects, cardiac and limbsmalformations

Warfarin First Hypoplastic nasal bridge, chondrodysplasia.

Second CNS malformations.

Third Risk of bleeding. Discontinue use 1 monthbefore delivery

( Koren, G., Special aspects of Perinatal & Pediatric Pharmacology;

In Basic & Clinical Pharmacology, ed: Katzung, BG etals; 12thEd. 2012,

Lange McGraw Hill Medical )

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MATERNAL INFECTIONSAFFECTING THE FETUS/NEWBORN

MATERNAL INFECTION EFECTS ON FETUS/NEWBORN

VIRAL INFECTIONS :.Rubella Malformations, bleeding, hepatosplenomegaly,

pneumonitis, hepatitis, encephalitis

Cytomegalovirus (CMV) Microcephaly, chorioretinitis, deafness, mental

retardation.

Herpes simplex Generalized herpes, encephalitis, death.

Mumps Fetal death, endocardial fibroelastosis (?),

malformations (?)Chicken pox shingles Chicken pox or shingles, increase abortions and

stillbirths.

Smallpox Smallpox, increased abortions and stillbirths

Poliomyelitis Spinal or bulbar poliomyelitis

Hepatitis Hepatitis

BACTERIAL-PROTOZOAN INFECTS.:

Tuberculosis Congenital tuberculosis

Pyelonephritis Prematour labor

Gonorrhea Ophthalmitis

Toxoplasmosis Microcephajy, chorioretinitis, jaundice

Malaria Low Birth Weight (LBW), perinatal mortality (?),


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BEBERAPA BENTUK2

ANOMALI CONGENITAL


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5 CATAGORIES

DRUG USE IN

PREGNANCY

A

B

C

D

X

(US-FDA; TGA-Australia)

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CATEGORY A

Adequate and well-controlled studies have failed to

demonstrate a risk to the fetus in the first trimesterof pregnancy (and there is no evidence of risk in later

trimesters)

e.g.: almost of medicine

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.

e.g.: loperamide, amoxycillin trihydrate, sulbactam+ampisillin, etc

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CATEGORY C

Animal reproduction studies have shown an

adverse effect on the fetus and there are no adequate

and well-controlled studies in humans, but potential

benefits may warrant use of the drug in pregnant

woman despite potential risks.

e. g. : salbutamol, theophyllin, aminophylline, neviparine (antiviral),

ciprofloxacine, clarithromycin, allopurinol, dipyridamole, etc.

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CATEGORY D

There is positive evidence of human fetal risk

based on adverse reaction data from investigational

or marketing experience or studies in human,

but potential benefits may warrant use of the drugin pregnant women despite potential risks.

e. g. : amikacin, amiodarone, amobarbital, atenolol,

bleomycin, busulfan, capecitabine,

carbamazepine, carboplatin, etc.

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CATEGORY X


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CATEGORY X(contraindicated in pregnancy)

Studies in animals or humans have demonstratedfetal abnormalities and/or there is positive evidence

of human fetal risk based on adverse reaction data

from investigational or marketing experience and

the risks involved in use of the drug in pregnantwomen clearly outweigh potential benefits.

e.g.: atorvastatin (statin group),

chorionicgonadotropin,

coumarine, diethylstilbestrol,

dihydroergotamine,

estazolam, estradiol, etc.

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MEDICINE /DRUGS

CHEMICAL & FOREIGN SUBSTANCES

1ST TRIMESTER : ANATOMICAL ANOMALY

2ND TRIMESTER : ANATOMICAL & PHYSIOLOGICAL ANOMALY

3RD TRIMESTER : PHYSIOLOGICAL ANOMALY & PARTURIENT

RESUME :


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teratogen -ukdw blok 5

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