Farmakoterapi pada Kelompok

Khusus

Fathiyah Safithri
Laboratorium Farmakologi FK-UMM
2009
 Kelompok Khusus ?
• Neonatus dan Pediatri
• Ibu menyusui
• Ibu hamil
• Usia lanjut
• Penderita gagal ginjal
• Penderita gangguan fungsi hepar
 Dosis yg diresepkan (R/)
Kepatuhan pasien

Dosis yang diminum/diberikan

Faktor FK : Fisiologis
A D M E Patologis
Konsentrasi obat di tempat kerja Genetik
Usia
Faktor FD : Interaksi
fungsional reseptor

EFEK / RESPON PASIEN

Efek samping
terapi toxic
FARMAKOTERAPI pada
PASIEN PEDIATRI
 Pasien Pediatri
• Pediatri : semua pasien < 16 th
• Ada 6 kelompok umur pediatri :
Premature infants :< 36 mgg kehamilan
Full-term infants :36-40 mgg kehamilan
Neonates :4 mgg pertama post-natal
Infants :5-32 mgg post-natal
Children :1-12 tahun
Adolescents :12-16 tahun
Factors Affecting Drug Effects on the Infant

I. Drug Absorption
II. Drug Distribution
III. Drug Metabolism
IV. Drug Excretion
Absorption
- Gastric acid secretion commences soon after birth and
increases gradually over several hours. In preterm infants
it appears slowly. Very acidic at birth with gradual
decrease over the first two years. Drugs affected by
gastric pH should not be administered orally.

- Gastric emptying is prolonged in the first day of life.

Newborn infant: 6-8 hours, Toddlers: 2 hours

- Peristalsis in the neonate is slow. Diarrhea causes

decrease absorption in small intestine.
 Absorption
Skin
• thin dermis and epidermis
• increased tendency to absorb larger amounts of a topical
medication
– could result in unwanted systemic effects
• percutan injection  absorption >
Muscle mass
• small muscle mass with poorly developed peripheral circulation
• decrease the rate of absorption from IM injections
Drug Absorption in the neonate compared to adults.
Drug Oral Absorption
Acetaminophen Decreased
Ampicillin Increased
Diazepam Normal
Digoxin Normal
Penicillin G Increased
Phenobarbital Decreased
Phenytoin Decreased
Sulfonamides Normal
Distribution
• Dipengaruhi oleh : komposisi cairan tubuh, lemak tubuh,
ikatan protein.
• Pd neonatus, 70-75% BB adalah air, pd preterm 85% pd
dewasa 50-60% .
• Pd neonatus total body fat adalah 15%, sdg pada preterm
1%, toddlers 23%, preschooler 8-12%
• 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).
Distribution
Blood-Brain Barrier
• not mature until approximately 2 years of age

• drugs more easily distributed to the brain = toxic

effects
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.
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
Drug Excretion
Urine pH
• more acidic in infants
– pH remains constant the day and night
• older children & adults more basic pH during day
and acidic at night
• results in increased reabsorption of acidic drugs
 Penghitungan dosis
Formula Young (berdasar umur)
dosis anak = umur (th) x dosis dws
umur+12(th)
Formula Clark (berdasar berat badan)
dosis anak = BB (kg) x dosis dws
70 (kg)
Berdasar luas permukaan tubuh
dosis anak = luas permk tbh(m2) x dosis dws
1,73(m2)
FARMAKOTERAPI pada
IBU MENYUSUI
Drug Therapy during Breast Feeding
• Drugs get through breast milk and can effect infant
– All drugs can be detected in milk, but concentrations usually
too low to be of concern (breast feeding is usually safe)
– Little research done on this aspect because of dangers involved in these
studies
• Concentration of drugs differ in milk
– Lipid soluble drugs are in higher concentration
• Generally most drugs are in too low a concentration to be harmful to infant
• Things That Can Minimize Risk:
– Dose after breast feeding
– Take drugs with short ½ life
– Take drugs that are not found in breast milk
– Avoid drugs known to be hazardous
• ASI : terlibat dalam ekskresi bbrp obat
• Obat/bhn kimia yg dikonsumsi ibu dpt mencapai ASI
melalui mekanisme difusi pasif dan diduga akibat ikatan
obat dg protein atau dg permukaan globul lemak ASI
• Obat/bhn kimia tsb dapat memberi efek pd bayi atau
produksi ASI.
• Target : terapi farmakologik pada ibu efektif dan bayi
tidak mendapat efek negatif dari terapi tersebut
 Obat yg Mensupresi Laktasi

• Bromokriptin
• Estradiol
• Kontrasepsi oral dosis besar
• Levodopa
• Antidepresan trazodon
• Piridoksin dosis tinggi
 Prinsip Pemberian Obat untuk
Ibu Menyusui

• Perhatikan apakah terapi obat tsb benar2 diperlukan .

• Pilih obat yg paling aman utk ibu menyusui (yg tdk
diekskresi lewat ASI, wkt paruh pendek, tdk bahaya utk
bayi)
• Jk diperkirakan obat akan berpengaruh pd bayi, perlu
dipertimbangkan pengukuran konsentrasi obat dalam
darah bayi
• Sedpt mungkin ibu minum obat 30-60 mnt setelah
menyusui atau 3-4 jam sblm menyusui berikutnya
Farmakoterapi pada
Ibu Hamil
• 1/3 to ½ of pregnant women take at least one
prescription drug and most take more
– Some used to treat pregnancy side effects
• Nausea
• Pre-eclampsia
• Constipation
– Some medications used to treat chronic disorders
• Hypertension
• Diabetes
• Epilepsy
• Cancer
• Infectious Diseases
– Drugs of abuse
Dua mekanisme yg melindungi janin
dari obat yg berada dlm darah ibu

1) Placenta, berfungsi sbg :

membran semipermeable
tempat metabolisme obat.
2) Hepar : metabolisme obat
 Plasenta

Placental septum
Intervillus space

Chorionic villus

Chorion Endometrial

Umbilical arteries arteries

and veins

Umbilical vein

Amnion
Faktor yang Mempengaruhi Transfer Obat ke Janin

1. Sifat fisikokimia obat

2. Kadar obat yang mencapai fetus
3. Exposure rate.
4. Lama paparan
5. Distribusi jaringan.
6. Tahap perkembangan janin saat
terpapar obat.
7. Interaksi dengan obat lain .
 Sifat Fisikokimia Obat
A. Kelarutan dalam Lemak (lipofilik)
• Obat lipofilik menembus plasenta .
 kecepatan &  obat menembus tgt : BM &
konsentrasi dlm darah ibu)
 Distribusi tgt aliran darah plasenta .
• Obat non lipofilik  cenderung terikat kuat dg
protein plasma.
Contoh : obat lipofilik : thiopental (SC)  BBL apnea
B. Derajat Ionisasi Obat
- Substansi polar / terionisasi  sulit melewati
plasenta
contoh : suksinilkolin, tubokurarin
 Sifat Fisikokimia Obat
C. Ikatan dg protein.
mis. sulfonamides, barbiturates, phenytoin and local
anesthetic agents.
D. Ukuran molekul obat
- BM 250-500  mudah
- BM 500-1000  sulit
- BM >1000  sgt sulit (mis. heparin vs warfarin)
- Sebagian besar obat mempunyai BM 100-500
.
Distribusi : Affinitas Obat thd Jaringan
Tertentu
Tetracycline Teeth
Warfarin
Aminoglycosides Middle ear
Quinine Retina
Chlorpromazine
Diethylstilbestrol Mullerian Duct
Vagina
Corticosteroids Adrenal Gland
Phenytoin
Thyroid Gland
Iodides
Propylthiouracil
 Stages of Fetal Development
• Sensitivity of fetus to drug is dependent upon developmental stage and when drug is given in
relation to the developmental stage
• 3 stages of embryonic development
• Pre-implantation period
• Embryogenic period
• Fetal period
• Most critical time for any organ is when it is growing and forming its structures. Diff. organs
have diff. critical periods, but the time period from day 15 to day 60 of gestation is most critical
- Heart: weeks 3-4
- Ext genitalia: weeks 8-9
- Brain & skeleton: Week 3- end of pregnancy
 Stages of Fetal Development
• During pre-implantation and embryonic stages the
teratogen acts in an all-or-none response, i.e. , the dose is
high enough that the fetus will die, if dose is sublethal
fetus will recover
• Gross malformations produced by exposure to teratogens
during the embryonic period (1st trimester)
• Exposure during the 2nd and 3rd trimesters usually results
in organ dysfunction rather than gross malformations
 Fetal Development
0 5 15 Full term

CNS

Heart

Arms

Eyes

Legs

Teeth

Palate

Ex. genitalia

Ear
Figure 10-1: Effects of
Teratogens at Specific
Stages of Fetal
Development
Moore, 1993.
Farmakokinetik Obat selama kehamilan

Absorbsi
 Awal hamil, sekresi asam lambung  30-40% 
absorbsi obat asam lemah , obat basa lemah 
 Gastric emptying 
 Motilitas GIT  absorbsi obat yg sukar larut
(digoksin) , absorbsi obat yg dimetab di dind usus
(CPZ) 
 Distribusi
 Vol plasma & CES  (50%)  kdr obat dg Vd kecil
(ampicillin) dlm plasma <<
 Albumin serum  20%, glikoprotein  100% (t.u pd
eklampsia)  fraksi bebas obat asam  (diazepam,
fenitoin, as valproat), fraksi bebas obat basa 
 Body fat   Obat lipofilik tersimpan di jar lemak
 durasi obat (slow release).
Eliminasi
 Trimest 2&3, progesteron me  aktivitas enz metab
hepar  kdr obat cpt  (fenitoin, carbamazepin,
fenobarbital)
 Awal hamil, renal blood flow dan GFR  2x 
eliminasi obat yg eksresi lwt ginjal 
 Akhir hamil, renal blood flow dan GFR 
 PENGARUH OBAT PD JANIN

• TOKSIK  gangg fisiologik / biokimiawi janin

 gejala terlihat stl lahir
• TERATOGENIK  malformasi anatomik pd
pertumbuhan organ janin
• LETAL  kematian janin dlm kandungan

TGT SIFAT OBAT & UMUR KEHAMILAN SAAT

TERPAPAR
 PENGARUH BURUK PD JANIN
 Fase Implantasi (<3mgg)  kematian embrio /
abortus
 Fase embrional / organogenesis (4-8 mgg) 
diferensiasi pertumbuhan  malformasi anatomik
(teratogenik)
- gangg fungsional / metabolik permanen
 mis. Ca di kemudian hari
- letal (IUFD/abortus)
- subletal (malformasi pertumb organ, mis fokomelia)
 Fase fetal (trim 2&3)  gangg fisiologik/biokimiawi
 gangg pertumbuhan
mis. Akhir hamil, Analgetik opioid  depresi nfs
neonatus
 Kategori Obat utk Ibu Hamil
A :byk dipakai, pengaruh buruk (-)
mis. Parasetamol, Penisilin, Eritromisin, digoksin, bhn hemopoetik
(Fe, folat), INH
B :sedikit dipakai, pengaruh buruk (-)
B1 : pd hewan kerusakan janin (-).
mis simetidin, dipiridamol
B2 : peneltian pd hewan blm memadai.
Mis ticarsilin, amfoterisin
C :pengaruh buruk (+) reversibel, malformasi (-).
mis fenitoin, analgetik opioid, fenobarbiton, valproat,
karbamazepin
D / X:pengaruh buruk (+) irreversibel, malformasi (+)
mis. Isotreonin, DES
 Fetal Therapy
Therapy 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.
 Teratogenicity
Teratogen. Bahan yg dpt menyebabkan
perkembangan abnormal pada janin.
mis. alcohol (FAS), Thalidomide (phocomelia), DES
(uterine cancer), valproic acid (spina bifida).
 Identification of Teratogens
• Few drugs considered to be teratogenic: hard to prove
– Incidence of congenital anomalies is low
– Animal test may not be applicable
– Prolonged exposure may be necessary
– Teratogenic effects may be delayed
– Behavioral effects are hard to document
– Controlled experiments cannot be done in humans
• To prove a drug is a teratogen:
– Drug must cause a characteristic set of malformations
– It must act only during a specific window of vulnerability (weeks 4
through 7 of gestation)
– Incidence of malformations should increase with increasing dosage
and duration of exposure
• Risk of malformation with most teratogens is only ~10%
– Table 10-1 lists proven teratogenic drugs
 Teratogenicity
Mekanisme Teratogenik
1) Menimbulkan efek pd jaringan ibu
2) Menghambat penyaluran oksigen
3) Perubahan nutrisi selama proses differensiasi.
4) Defisiensi
 Teratogenicity
1) Efek pd jaringan ibu.
Obat memberi efek langsung pd jar. Ibu, sedang efek
sekunder atau efek tdk langsungnya pada janin.
mis Cocaine meningkatkan resiko spontaneous abortions,
placenta previa and premature labor; neonatal cerebral
infarction, abnormal development and decrease school
performance.
2) Menghambat penyaluran oksigen dan nutrisi.
Akibatnya pd janin : iskemia t. u otak shg menyebabkan
kerusakan otak berat bahkan kematian
 Teratogenicity
3) Perubahan penyaluran nutrisi selama differensiasi.
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.
4) Defisiensi.
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.
FARMAKOTERAPI pada
LANJUT USIA
 Mengapa perlu dipelajari ?
 Perubahan farmakokinetik pd usia lanjut
 Perubahan farmakodinamik pd usia lanjut
 Komorbiditas: interaksi obat-penyakit
 Polifarmasi: interaksi antar obat-obat
 Fungsi fisiologis menurun
 Kepatuhan kurang
 Perubahan Farmakokinetik
• Perubahan fisiologis dan fungsi organ menyebabkan
perubahan farmakokinetik
• Perubahan Farmakokinetik meliputi :
– Absorbsi
– Distribusi
– Clearance: eliminasi (ginjal)
metabolisme (hepar)

2004: Cusack, Amer. J of Geriatric Pharmacotherapy

 Perubahan Farmakokinetik pd Lansia

 VOLUME DISTRIBUSI (Vd)

Pada lansia, adanya peningkatan proporsi body fat,
penurunan massa otot dan total body water akan
mengubah Vd
 Body fat ↑ akan meningkatkan Vd obat yang larut
lemak shg t½ mkn panjang, mis. Diazepam,
thiopental, trazadone
 Total body water ↓ akan menurunkan Vd obat yang
larut air shg konsentrasi obat dalam plasma
meningkat, mis. Ethanol, lithium, aminoglycosides,
digoxin
Perubahan Farmakokinetik pd Lansia

 IKATAN DG PROTEIN
 Pada lansia terjadi penurunan kadar albumin akibat
penyakit kronis, mis. Malnutrisi, gangguan fungsi
hepar atau ginjal.
 Akibatnya bioavailabilitas obat yang mengikat protein
akan meningkat karena fraksi obat bebas dalam
plasma meningkat.
 Contoh obat yg mengikat albumin : ceftriaxone,
diazepam, phenytoin, warfarin.
Perubahan Farmakokinetik pd Lansia

 ELIMINASI
 Fungsi ginjal   menurunkan eliminasi obat yg
diekskresi oleh ginjal. Pada lansia terjadi
penurunan renal clearance (Cl) 35-50%
 Cl metabolit aktif yg turun akan meningkatkan efek
terapi dan resiko utk menjadi toksik
 Perlu dilakukan pengurangan dosis dan atau
memperpanjang interval pemberian obat.
Perubahan Farmakokinetik pd Lansia

 METABOLISME
 Pd lansia 65 th, aliran darah hepar  40-45%
dibanding usia 25 th  mempengaruhi first pass
metabolism
 Dan ukuran hepar mengecil
 Metabolisme oksidatif dg sitokrom P450  
clearance obat 
Perubahan Farmakodinamik pd Lansia

• respon reseptor obat dan target organ berubah

 sensitivitas thd obat berubah  ES obat .
• Beberapa efek obat 
mis. Diazepam (sedasi), alkohol, fentanyl,
morphine, dan theophylline
• Beberapa efek obat 
mis. isoproterenol & beta -blockers
 Suboptimal Prescribing
• Polypharmacy
• Underuse of Effective Medications
• Drug-Drug Interactions
• Drug-Disease Interactions
• Inadequate Monitoring
• Inappropriate Dosing
• Inappropriate Duration
• Drugs to Avoid
 FARMAKOTERAPI pada
PENDERITA
GANGGUAN FUNGSI HEPAR &
GINJAL
• Clearance (Cl) : kemampuan tubuh utk
membersihkan darah dari obat per satuan waktu
 Cl hepar : organ metabolisme utama
 Cl ginjal : organ ekskresi utama
 Cl organ2 lain
Eliminasi utama hepar Cl (tubuh total) = Cl (hepar)
Eliminasi utama ginjal Cl (tubuh total) = Cl (ginjal)
 Gangguan fungsi hepar

 Eliminasi
 kemampuan eliminasi obat yg mengalami metab
hepatal  (tgt keparahan penyakit)  perlu penurunan
dosis
 Berapa banyak perlu diturunkan, sulit ditentukan, krn
parameter fungsi hepar yg menunj kemampuan eliminasi
obat tidak ada.

 Dianjurkan mengganti obat dg obat yg eliminasi

utamanya tidak melalui hepar

 Gangguan fungsi hepar

 distribusi obat.
 produksi albumin   fraksi obat bebas pd obat2an
yg terikat dg protein   toksik
 absorbsi.
 first pass effect terganggu  fraksi obat bebas 
 Gangguan fungsi ginjal

• Cl kreatinin = sbg parameter penurunan fs ginjal.

• RF = renal function

RF = Cl kreatinin pasien

Cl kreatinin normal

Dosis obat = RF X dosis lazim

Mis. Amikasin, eliminasi utama oleh ginjal

pe  fs ginjal  t½  pemberian berulang : akumulasi  toksik 
perlu pe  dosis atau menjarangkan interval pemberian
 References:
• Katzung, B.G. (1998) Basic and Clinical Pharmacology. 7th
ed. Appleton and Lange. Stamford, CT.
• Brody, T.M., Larner,J., Minneman, K.P. and Neu, H.C. (1994)
Human Pharmacology: Molecular to Clinical. 2nd ed. Mosby-
Year Book Inc. St. Louis, Missouri.
• Rang, H.P. et al. (1995) Pharmacology . Churchill Livingston.
NY., N.Y.
• Harman, J.G. et al. (1996) Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 9th ed. McGraw Hill.