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Neonatus dan Pediatri Ibu menyusui Ibu hamil Usia lanjut Penderita gagal ginjal Penderita gangguan fungsi hepar
terapi
toxic
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
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 Drug Acetaminophen Ampicillin Diazepam Digoxin Penicillin G Phenobarbital Phenytoin Sulfonamides
the neonate compared to adults. Oral Absorption Decreased Increased Normal Normal Increased Decreased Decreased 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 doesnt 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)
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
1/3 to 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
Intervillus space Chorionic villus Chorion
Umbilical arteries Endometrial arteries and veins Placental septum
sulit melewati
Fetal Development
0 5 15 CNS Heart Arms Eyes Legs Teeth Palate Ex. genitalia Ear Full term
Figure 10-1: Effects of Teratogens at Specific Stages of Fetal D evel opm ent Moore, 1993.
k Distribusi Vol plasma & CES o (50%) kdr obat dg Vd kecil (ampicillin) dlm plasma << Albumin serum q 20%, glikoprotein o 100% (t.u pd eklampsia) fraksi bebas obat asam o (diazepam, fenitoin, as valproat), fraksi bebas obat basa q Body fat o Obat lipofilik tersimpan di jar lemak o durasi obat o(slow release).
k Eliminasi
Trimest 2&3, progesteron me o aktivitas enz metab hepar kdr obat cpt q (fenitoin, carbamazepin, fenobarbital) Awal hamil, renal blood flow dan GFR o 2x eliminasi obat yg eksresi lwt ginjal o Akhir hamil, renal blood flow dan GFR q
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
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 differentiationdirecting 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.
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
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 t 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
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.
ELIMINASI
Fungsi ginjal q 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.
METABOLISME
Pd lansia 65 th, aliran darah hepar q 40-45% dibanding usia 25 th mempengaruhi first pass metabolism Dan ukuran hepar mengecil Metabolisme oksidatif dg sitokrom P450 q clearance obat q
Perubahan Farmakodinamik pd Lansia respon reseptor obat dan target organ berubah sensitivitas thd obat berubah ES obat o. Beberapa efek obat o mis. Diazepam (sedasi), alkohol, fentanyl, morphine, dan theophylline Beberapa efek obat q 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
Clearance (Cl) : kemampuan tubuh utk membersihkan darah dari obat per satuan waktu
k Cl hepar : organ metabolisme utama k Cl ginjal : organ ekskresi utama k Cl organ2 lain Eliminasi utama hepar Cl (tubuh total) = Cl (hepar) Eliminasi utama ginjal Cl (tubuh total) = Cl (ginjal)
Dosis obat = RF X dosis lazim Mis. Amikasin, eliminasi utama oleh ginjal pe q fs ginjal t o pemberian berulang : akumulasi toksik perlu pe q 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. MosbyYear 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.