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GGP

PRESCRIBING PRACTICE
for
SPECIAL GROUPs
ELDERLY /
GERITRIC

PEDIATRIC
SPECIAL Neonate-Infant
GROUPS: & Children.

PREGNANT &
LACTATION
PHARMACOLOGY :
PREGNANCY &
REPRODUCTIVE SYSTEM

SULANTO SALEH-DANU R.,dr., SpFK


Departemen Farmakologi & Terapi
Divisi Farmakologi-Klinik
Fakultas Kedokteran – UGM

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Objectives of the session
After attending this lecture, med-students
are expected to be able to:
1. Explain the importance of studying drug effects
in pregnant women and breast-feeding period;
2. Explain the pharmacokinetics and
pharmacodynamics process in pregnant women
and breast-feeding period;
3. Explain the impact of medicines in pregnant
women, fetal and during breast-feeding period;
4. Explain how to communicate with mothers
about the risks of medicine use during
pregnancy and breast-feeding period.

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Introduction

This session presents the principles of clinical


pharmacology (stressing pharmacokinetik &
pharmacodynamic) in the special context of
pregnant women and/or during breast-feeding.

At present, the special pharmacokinetic factors


operative in these patients are beginning to be
understood, whereas information regarding
pharmacodynamic differences (e.g., receptors
characteristic and responses) is still incomplete.

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REPRODUCTIVE SYSTEM :
FEMALE & MALE

SEX ORGANS
( & URINARY TRACT)

FEMALE ORGANS:
MALE ORGANS :
-Ovariums
-Kidney -Testis
-Tuba falopii
-Ureter -Prostate gland
-Uterus
-Bladder -Seminalis duct
-Portio uteri
-Urethra -Epididymis
-Vagina
-Bladder
-Bladder
-Urethra
-Urethra
-Mammae

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 CONGENITAL
 TRAUMA
 INFEKSI – INFLAMASI
 METABOLISME
 DEGENERATIVE
 MALIGNANCY

TRIMESTER I (0 – 14 weeks)

TRIMESTER II (15 – 28 weeks) PHARMACO-


THERAPIES
TRIMESTER III (29 – 40 weeks
& partus)
LACTATION PERIODE
RISK –
BENEFIT
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PREGNANCY ????

1ST TRIMESTER

PHARMACO-
2ND TRIMESTER KINETIC (PK)
ANATOMIC ?
PHYSIOLOGIC /
PHARMACO-
FUNCTION ?? 3RD TRIMESTER
DYNAMIC (PD)

PARTURIENT

LACTATION

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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
NORMAL blood volume
red blood cells PREGNANCY
WOMAN
iron
white blood cells
platelets
clotting factors
-CARDIOVASCULAR SYSTEM
heart (size, position, rhythms, murmurs)
cardiac output
blood pressure
peripheral resistance
blood flow
-RESPIRATORY SYSTEM
lung volume
lung capacities , etc.
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MATERNAL PHYSIOLOGICAL CHANGES
DURING PREGNANCY (1)

Body system / Physiological Extent of


function changes Change

Cardiovascular Cardiac output  30 – 35 %


system Heart rate  20 %
Stroke volume  10 %
Arterial BP ↔
BLOOD FLOW : uterus  950 % (to 500 ml)
kidneys  60 – 80 %
liver ↔ or 75 % (?)
skin (hands)  600 – 700 %

Haematological Plasma volume  50 %


System Red cell mass  18 – 30 %
Plasma albumin ↓ 30 %
concentration
Serum lipids  66 %

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MATERNAL PHYSIOLOGICAL CHANGES
DURING PREGNANCY (2)

Body system / Physiological Extent of


function changes Change

Respiratory system Tidal volume  40 %


Respiratory rate ↔

GIT system Gastric tone / mobility ↓


Intestinal mobility ↓

Kidney function GFR  50 %

Body composition Water 


Fat 

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Principle:
PHARMACOKINETIK (PK) &
PHARMACODYNAMIC (PD)
IN PREGNANCY

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Trans- Mucosal,
i.v. oral i.m Topical
dermal buccal,
Vag., rectal,
inhalation

ROUTE OF DRUG ADMINISTRATION


Local Local
effect effect

ABSORPTION

PRESYSTEMIC METABOLISM

systemic circulation
DISTRIBUTION

Site of action METABOLISM EXCRETION


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THERAPEUTIC SITE OF UNWANTED SITE OF
ACTION TISSUE RECEPTORS
“RECEPTORS”
ACTION
BOUND FREE
BOUND FREE BOUND FREE

CENTRAL
COMPARTEMENT CLEARANCE
ABSORPTION
DRUG
DOSE [ FREE DRUG ]
LIBERATION EXCRETION

PROT.BOUND METABOLIT

ROUTE of
ADMINSTRATION BIOTRANSFORMATION /
METABOLISM

ROUTE of DRUGs ADMNTRS. and


PRINCIPLES PHARMAKOKINETIK (PK) &
PHARMACODYNAMIC (PD)
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How drugs act in the body ?
Absorption
Drug Distribution
Metabolism
Excretion
PHARMACOKINETIK
Drug concentration in
systemic circulation (blood) PHARMACODYNAMIC

Drug concentration
at site of action

Adverse effect Therapeutic effect


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Drug fate in the body
Other body fluids
Site(s) of action : and tissues
RESPONSE

Free Drug

Absorption Drug-protein

metabolites
Excretion
Free Drug

Distribution

Metabolism
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DRUGS/MEDICINES

PHARMACOKINETIK PHARMACODYNAMIC
A-D-M-E RESPONSE
PREGNANCY
PLACENTA

FOETUS MATERNAL
• THERAPEUTIC EFFECT  THERAPEUTIC EFFECT
• TOXIC EFFECT  TOXIC EFFECT
• TERATOGENIC EFFECT  EFFECT ON PARTURITION
• ABORTION LABOUR  EFFECT IN LACTATION

PUERPERIUM
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PHARMACOKINETIK ( PK )

Absorption CLEARENCE ( CL – L/hour )


Distribution VOLUME of DISTRIBUTION ( Vd)
HALF-LIFE ( t ½ - hours )
Metabolism etc
Excretion
CLINICAL
RESPONSES :
MATERNAL
ANATOMICAL; FETAL
PHYSIOLOGICAL/
FUNCTIONAL
CHANGES PHARMACODYNAMIC ( PD )
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PLACENTA

MOTHER FETUS

CHORION BASAL
LAYER LAYER

20
MATERNAL FETAL

PLACENTAL

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MOTHER PLACENTA FETUS

BOUND BOUND
METABOLIZED

DRUGS UNBOUND UNBOUND EXCRETED into


The Amniotic Fluid

INGESTED by
the Fetus
EXCRETED

FETAL Intestines
TISSUE

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


in the organism of mother and fetus
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MOTHER /
COMPARTMENT-1 MATERNAL

K 1,2 K 2,1

AMNIOTIC FLUID
COMPARTMENT-2 PLACENTA

K 2,3 K 3,2 COMPARTMENT-5


K 3,5
COMPARTMENT-3 UMBILICAL
CORD
K 5,3
K 3,4 K 4,3
K 4,5
COMPARTMENT-4 FETUS
K 5,4

Schematic representation of the drug transfer and elimination


process between mother and fetus (Kuemmerle, 1980) 23
ABSORPTION PROCESSES :

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
 Praesystemic metabolism ( first-pass metabolism )
- most drugs

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OXYGEN

WATER & FETUS


ELECTROL.
CO2
CARBOHYDRATES
LIPIDS
PROTEINS
VITAMINES Water &
urea
HORMONES
MOTHER
PLACENTA
Antibodies
Waste product
(CERTAIN)

DRUGS
HORMONES

INFECTIONS / (Almost all …)


VIRUSES
PLACENTAL TRANSFER OF MEDICINE:

- diffusion
- influence of Physicochemical properties
- influence of pH Differences
- active transport / fascillitated transportation
- influence of uterine-fetal blood flow
- influence of protein binding

PLACENTAL METABOLISM

content enzyms : Cytochrome P 450


Sulfating & N-acetylation enzyms
Glutathione transferase

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PLACENTAL ABSORPTION OF MEDICINE

placenta may be able to retain some substances


(protection function)
Simone,C.; et als 1994.

PLACENTAL ENDOCRINE SECRETION:

 human Chorionic Gonadotropin ( hCG )


 Estrogen
 Progesteron
 human Placenta Lactogen ( hPL ) :
perkembangan payudara dan
metabolisme organik
 inhibin : menghambat feed-back sekresi
Folikel Stimulating Hormon ( FSH )

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Pharmacokinetics:
drug concentrations in plasma over time
Plasma drug concentration
100
Cmax
Minimum Toxic
Concentration

Kel and T1/2 Therapeutic


window

10
AUC
Minimum Effective
Concentration

Tlag Tmax

1 Time
10

12

14

16

18

20

22

24
0

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Multiple dosing?
• Drugs with narrow therapeutic
60
50 range
40
30
20 • Controlled- release
10
0
0 2 4 6 8 10 12
formulation
• Drugs use in the national
programmes

60
50
40
30
20
10
0
0 2 4 6 8 10 12

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1000.00
Theophylline 1x daily
Plasma concentration (ug/mL)

15
100.00

10.001
00 24
24 48 48 72 72 96 96 120 120 144 144
Time (Hours)
Suryawati, 1999
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Approval of copy/generic products

Plasma nifedipine concentration (ng/ml)


180
Generic
160
Brandname
140
120
100
80
60
40
20
0
1 .5

4 .5

7 .5
0

12

15

18

21

24
.5

.5

.5

.5

.5
10

13

16

19

22
Time (hours)

Suryawati & Santoso, 1995


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Drug in pregnancy
Drug in pregnancy:
drug in maternal body system and crossing the
placenta,
drug in embryo/fetus,
drug in labour and lactation

PHARMACOKINETICS :
Most drugs taken in pregnant women can cross the
placenta barrier and will exposed to the developing embryo.
The factors affecting drug transfer across placenta barrier:
1. Lipid solubility, ionization;
2. Molecular size;
3. Protein binding;
4. Metabolism in placenta and fetus.
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1. Lipid solubility
Drug passage across placenta barriers depend on LIPID SOLUBILITY and
DEGREE of DRUG IONIZATION.
Drug: lipophobic ( low ) ------ difficult to cross the placenta barrier;
lipophilic ( high ) -------- tend to diffuse rapidly.

Drug in the body will be ionized. In pregnancy, crossing the placenta


depends this ionization, low ionization more easy crossing the placenta
than highly ionization drugs.

Example: succinylcholine (highly ionization) drug use in Cesarean


surgery crosses the placenta barrier slowly  very low
concentration in the fetus.
salicylate (highly ionization) can crossing the placenta easily,
why?
Because the small amount of salicylate (not ionized) is highly lipid-
soluble.
thiopental, a hypnotic drugs, use for anesthetic, is lipid
soluble,cross the placenta easily and can produce sedation 
apnea in the newborn infant.

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Acids pKa Bases

1 phenazone
Plasma pH 7.4 Plasma pH 1.4
Strong

Lipid
2 Weak
cloxacillin
salicylic acid 3
diazepam
furosemide 4 quinidine
phenylbutazone
warfarin 5
non-ionised [1] non-ionised [1]
6

membran
phenobarbital 7
trimethoprim
sulfadimidine
8
phenytoin
ionised [1000] ionised [0.001]
9 procainamide
nortriptyline
Weak amphetamine
10
sulfanilamide
11
pentamidine
12 Strong

Fig. 2. The distribution of a week acid (e.g. warfarin pKa 5)


between plasma and gastric juice separated by a lipid mem-
brane permeable only to the non-ionised form of a drug. The
Fig. 1. pKa valu es for some representative acidic and basic figures in square brackets refer to the approximate, relativ e
drugs (see also appensix A).
concentrations of drug in arbitrary units (after Brodie [4])

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2. Molecular size

Molecular weight of the drug can influence the rate of


transfer and amount of drug transfers into the fetus.
Drugs with molecular weight of 250 – 500 gr/mol can cross
easily, 500 – 1000 gr/mol more difficult and more than 1000
cross very poorly.
Example : heparin, an anticoagulant, very large
molecule and polar, unable to cross the placenta.

3. Protein binding.

Drug in the distribution : - free.


- protein binding: - high bound
- low bound.
Drug can easily cross the placenta if :
- lipid soluble and not ionized,
- small molecular weight and
- low protein binding. 35
MATERNAL PLACENTA FETAL
Simple diffusion

DRUGS : Fasciliated diffusion


lipophillic
non-ionized
non-polair
molecule size
Active transport
MATERNAL :
GIT motility
pH
Blood flow
Diseases, etc Pinocytosis

Leakage

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PHARMACOKINETIK VARIABLES :
1. ABSORPTION
2. CLEARANCE
3. VOLUME DISTRIBUTTION
4. HALF-LIFE

PHARMACODYNAMIC VARIABLES :

1. MAXIMUM EFFECT
2. SENSITIVITY

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 CLEARENCE
( CL – L/hour or mL/minute )

 The volume of blood clear of drug per unit time

The efficiency of irreversible elimination of


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

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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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 CLEARENCE
( CL – L/hour or mL/minute )

Faktor utama untuk mendeterminasi KONSENTRASI OBAT


CLEARANCE tergantung pada :
dosis
aliran darah pada organ target
fungsi intrinsik pada hepar dan renal.

DISTRIBUSI OBAT tergantung pada PROTEIN BINDING


Faktor2 yang berpengaruh terhadap PROTEIN BINDING :
1. konsentrasi albumin
2. Alpha1-acid glycoprotein concentration
3. Capacity-limited protein binding.

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VOLUME of DISTRIBUTION
( Vd  Litre )

not a real “volume”  parameter relating


the concentration of a drug in the plasma
to the total amount of the drug in the body.

total amount of the drug in body (A)


Vd = plasma drug concentration ( C )

 quick count a loading dose


loading dose = V x target plasma concentration
= 20 L x 10 mg/L
= 200 mg
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Contoh :

Penghitungan loading dose untuk infus theophylline ;

V untuk theophylline rata-rata 0.5 L/kg


( dari 35 L pada 70 kg BB pasien)

untuk mendapatkan efek yang diharapkan diperlukan


konsentrasi plasma sebesar 10 mg/L ( pada titik terendah
dari rentang dosis )
 loading dose = 0.5 L/kg x 10 mg/L = 5 mg/kg.
untuk pasien ini : 70 x 5mg = 350 mg theophylline

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HALF-LIFE
( t ½ - hours )

is the time taken for the amount of drug in the body


( or the plasma concentration ) to fall by half.

t½ = 0.693 x V
CL

1. The Duration of action after single dose


2. 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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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

PLACENTA ;
 FETAL PROTECTION
 FETAL FEEDING
 ENDOCRINE SECRETION

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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 of jaundice baby, by inducing fetal
hepatic enzyme of the foetus.
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3. Predictable Toxic Drug Actions in the Fetus.
Chronic use of medicine can produce adverse
effect after delivery,
– Opioid may produce dependence in
newborn babies, (withdrawal syndrome
in newborn baby).
– Diethylstilbestrol (DES) produced
adenocarcinoma in pubertal 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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New born
normal
Gametes
Blastocyst Embryo Fetus

Functional
Abnormalities

Major
Death structural
Death abnormalities

Death
Sterility

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


gametogenesis and various stages of prenatal development. Strong dymorphogenic agents:
4722
wide arrows; weak agents; narow arrows (after Tuchmann-Duplessis, 1975)
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ORGAN DEVELOPMENT (ORGANOGENESIS)
DURING PREGNANCY

DEV. SPERMIO-/ BLASTO- NEONATAL


ORGANOGENESIS FETOGENESIS ADAPTATION
PHASES OOGENESIS GENESIS

PHARMACO- GONO- BLASTO- FETO- NEONATO-


GENEOUS
PATHIA PATHIA
EMBRYOPATHIA PATHIA PATHIA

SIDE DEATH- SEVERE FUNCTIONAL MALADAPTA-


EFFECT STERILITY DEFORMITIES
DEFORMITIES
ANOMALIES TION
ABORTION

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TIME LINE I I I I I I I II I I I
DAY 0 7 15 I 60 90 120 150 1-6 weeks
of life 
O
6-12 week 4-9 mo.

ORGANOGENESIS
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COMPLETE (generally)
A

B
5 CATAGORIES
DRUG USE IN C
PREGNANCY

X
( detail >> modul TERATOGEN )

(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 trimester
of 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.

52
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 drug
in pregnant women despite potential risks.

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


bleomycin, busulfan, capecitabine,
carbamazepine, carboplatin, etc.

53
CATEGORY X
(contraindicated in pregnancy)

 Studies in animals or humans have demonstrated


fetal 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 pregnant
women clearly outweigh potential benefits.

e.g.: atorvastatin (statin group),


chorionicgonadotropin,
coumarine, diethylstilbestrol,
dihydroergotamine,
estazolam, estradiol, etc.
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CATEGORY X
(contraindicated in pregnancy)

•ACE inhibitors
•Griseofulvin
•Alcohol
•Isotretinoin •Thalidomide
•A-II antagonist
•Lithium •Tabacco smoking
•Androgens
•Methotrexate •Trimethoprim (3rd
•Anticonvulsants
•Misoprostol trmstr)
•(fenitoin; valproic acid;
•NSAIDs (3rd trimester) •Warfarin & other
carbamazepine)
•Opioids (prolonged coumarin anticoagulants
•Benzodiazepins
use)
•Carbasone (amebecide)
•Progestins -----------------
•Chloramphenicol (3rd
•Radioiodine Note:
trimester)
(antithyroid) ACE= angiotensin
•Cyclophosfamide
•Reserpine converting enzyme;
•Diazoside
•Ribavin SSRIs = selective
•Diethylstilbestrol
•Sulfonamide (3rd trimst) serotonin reuptake
•Disulfiram
•SSRIs inhibitors
•Ergotamine
•Tetracyclin (3rd trimest)
•Estrogens

(Rogers,VL; Cox,S.,CMDT,2011) 55
MEDICINE in LABOR / PARTUS

4 FACTORS INFLUENCE THE LABOR:

1. THE PASSAGE (MATERNAL PEL VIS / bone-soft tissues).


2. THE POWERS (Contraction and Forces of the Uterus).
3. THE FETUS (diameters fetal head / weight) .
4. THE MATERNAL PSYCHE.

ABNORMALITIES CAN BE INFLUENCED :


- MEDICATION
- INTERVENTION
(manual / instruments /
DYSTOCIA forces)

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NORMAL LABOR : 1ST STAGE : begin onset labor until
cervix dilatation (10 cm).
Duration : 6-8 hr multipara
8-12 hr primipara.
depends: parity; frequency-intensity-
duration uterine contraction;
the ability of the cervix;
feto-pelvic diameter;
presentation-position of the
fetus.
2ND STAGE : full dilatation of the cervix
to the birth
Duration menutes – 2 hours
(± 20 – 50 mnt), depend : fetal & mother.
3RD STAGE : from the birth of the infant
to delivery of the placenta.
Warning : bleeding post partum !

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MEDICINE-USE in LABOR:
analgetics ( if needed ) :
meperidine; butorphanol;
anesthesia (epidural)
fluids (Ringer laktat; dextrose 5%);
(1ST STAGE)

local anesthesia (pudendal) :


episiotomy (2ND STAGE)

oxytocin (3RD STAGE) /


methylergonovine
PGF2α
58
WARNING
 MEDICINE-USE during
PARTUS !!

MATERNAL : adverse effects;


FETAL : effects to infant
(post partum effects);
Partus : uterine contraction
during parturient
PUERPERIUM: complication
( infection, etc.),
lactation ( INFANT).

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LACTATION /
MEDICINE in
BREAST FEEDING 60
DRUG USE DURING
BREAST-FEEDING / LACTATION
MOTHER LACTATION  TAKE MEDICINE :

 MEDICINE COULD BE SECRETION via BREAST MILK


 MEDICINE COULD BE RESPONSE TO INFANT

DRUG CONCENTRATION IN THE INFANT, DEPENDING :


 DRUGS FACTORs ( pH; lipid soluble; ionization; etc. )
 INFANT RECIEVES THE SAME AMOUNT OF MILK
 INFANT IS NURSED AT CONSTANT TIME INTERVAL

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DRUG USE DURING BREAST-FEEDING
Most drugs administered to lactating women are
detectable in breast milk. The mechanism of drug
transferring the breast milk is not different as
crossing the placenta.

Factors affecting the drugs distribution to breast


milk:

1.Lipid solubility, pH / ionization;


2.Molecular size;
3.Protein binding ( high-bound or low-bound );
4.The rate and extent of maternal metabolism.

62
TISSUE
MOTHER/
MATERNAL
BLOOD

BREAST MILK

ELIMINATION

INFANT BLOOD TISSUE

ELIMINATION

Compartment system for the transfer of medicine


from mother toi nfant via the breast milk (Reinhardt, D., Richter, O., 1985) 63
ADVICE FOR LACTATION MOTHER
WHO TAKE MEDICINE :

MOTHER LACTATION WHO TAKE MEDICINE :


( prevention Adverse Effect to neonates/infant )

 30-60 minute after lactation; or


 3 – 4 before lactation.

64
BEBERAPA CONTOH :
OBAT YANG DAPAT DISEKRESSI MELALUI ASI.

OBAT: EFEK pada INFANT: KETERANGAN:

Ampisillin minimal AE tidaksiginifikan; diarrhe; alergi sensit

Kloramfenikol signifikan dosis rendah menimbulkan :gray baby syndr.


dpt menimbulkan depressi bone marrow
tidak dianjurkan menggunakan saat laktasi

Kanamysin minimal belum ada laporan dampak pada infant

Isoniasid /INH minimal konsentrasi pada ASI equal dengan


konsentrasi pada plasma ibu;
dapat menimbulkan deffisiensi piridoksin.

Penisillin minimal konsentrasi pada ASI rendah

Tetrasiklin moderate pewarnaan gigi yg permanent pada infant


(brown teeth).
Iodine (radioact.) signifikan ikut disekresi ASI ; suppressi thyroid infant
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OBAT: EFEK pada INFANT: KETERANGAN:

Kafein minimal konsentrasi pada ASI rendah

Aspirin minimal dosis standart aman; dosis tinggi konsentrasi


pada ASI cukup signifikan

Klorothiazide minimal tidak ada laporan terjadinya AE

Klorpromazine minimal kadar di ASI tidak significant

Kodein minimal pada bbrp kasus aman.


hati-hati pd ibu: ultra rapid 2D6 metabolizer;
kodein dapat dimetabolisir menjadi morfine.

Diazepam significant terjadi sedasi pada infant; dpt terjadi akumulasi

Ethanol moderate penggunaan berlebih dapat menimbulkan efek


alkohol pada infant

Kontrasepsi oral minimal dosis tinggi dapat menekan laktasi

Fenobarbital moderate dosis hipnotik pada ibu menimbulkan sedasi


pada infant.
66
OBAT: EFEK pada INFANT: KETERANGAN:

Fenitoin moderate dosis tinggi dapat menimbulkan efek fenitoin


pada infant

Prednisone moderate dosis aman utk ibu 5 mg/hari;


hindari penggunaan dosis tinggi ( >15 mg/hari)

Propylthiouracil significant dapat menimbulkan suppressi fungsi thyroid

Theophylline moderate pada ASI konsentrasi cukup tinggi belaum ada


laporan AE.

Heroine significant disekressi melalui ASI, menimbulkan neonatal


narcotic dependence.

(Katzung, BG; eds, 2009)

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DOSAGE FORMULA
FOR INFANT / CHILDREN :

Age ( years)
by AGE ( Young’s rule ) : Dose = adult dose x
Age + 12

by BODY WEIGHT ( Clark’s rule ) :


Weight ( kg )
Dose = Adult dose x
70
OR
Weight ( lb )
Dose = Adult dose x
150

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TABLE BASED :
BODY SURFACE AREA
Weight
Approximate Surface Percent ( % ) of
(kg) (lb Age Area (m²) Adult Dose

3 6.6 Newborn 0.2 12

6 13.2 3 mo. 0.3 18

10 22 1 yr 0.45 28

20 44 5.5 yr 0.8 48

30 66 9 yr 1 60

40 88 12 yr 1.3 78

(Katzung, BG; eds, 2009)


69
BASED : BODY SURFACE AREA

example calculation based on body surface area :

based on TABLE above :

IF ADULT DOSE of MEDICINE = 1 mg/kg;

Dose for infant age 3 months : 18 % x 1 mg = 0.18 mg /kg

body weight the infant 6 kg  total dose / day :


6 x 0.18 mg = 1.08 mg (1.1 mg)

70
CONCLUSION
1. After the thalidomide disaster, studying drugs
effects in pregnancy and during breast-feeding
become important
2. Changing anatomic and physiologic in
pregnancy change the pharmacokinetic and
pharmacodynamic process
3. The impact of drug use in pregnancy can
terminate the gestation, causing fetal
abnormality and harmful breast-feeding
4. The impact and the risks taking the medicine
during pregnancy and breast-feeding should be
discuss with the pregnant patient

71
MEDICINE

SAFE FOR MOTHER


SAFE FOR BABY
SAFE FOR ALL
Wassalmu’alikum wr wb
72