Pharmacology of

Infection

Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
HASIL 100 penderita, 423 item obat
11 penderita tanpa obat-obatan
7 penderita dengan terapi tunggal
82 penderita dengan terapi polifarmasi
rata-rata = 4.23 item obat per-
90 penderita
80
70
60
50
40
30
20
10
0
TANPA MONO POLI
 HASIL ...... Golongan obat yang paling banyak
digunakan : antiinfeksi
cairan-ivfd
analgetika
Penggunaan obat GENERIK hampir
sama banyak dengan obat PATEN
160 250
140
200
120
100 150
80
60 100
40
50
20
0 0
ANTIINFEKSI CAIRAN-IVFD ANALGETIKA GENERIK PATEN
Haruskah diresepkan
antibiotika
untuk keadaan ini
 KENAPA ?
Antibiotik obat yang lazim diresepkan
Indonesia tropis kejadian infeksi sangat
tinggi penggunaan antibiotik tinggi
Kesalahan dalam penggunaan dan
pemberiannya.
Pasien akan sering mengalami efek samping
yang tidak diinginkan.
Infeksi Penyakit infeksi
Mikroorganisme
infeksi

Tubuh manusia

Tidak Sakit Karier

sakit
Penyakit infeksi
 KEMOTERAPEUTIK
ANTI-INFEKSI

VIRUS BAKTERI

INFEKSI

PROTOZOA JAMUR
 Beta-lactam
tetracycline sulfonamide

amino-
macrolide INFECTION glikoside

etc. quinolone
fluoro-
quinolone

musculoskeletal pain, fever, BSR, leucocytosis

 PENGGUNAAN ANTIBIOTIK

Terapi Empiris Terapi Profilaksis

Terapi Definitif
PERTIMBANGAN PEMILIHAN
ANTIBIOTIK

Tempat infeksi
Tipe infeksi
Sumber infeksi
Keadaan klinis pasien
Faktor obat / antibiotik
Sensitivitas kuman terhadap antibiotik
Inappropriate Antibiotic Treatment
Appropriate Inappropriate
100 antibiotic treatment antibiotic treatment
*
90
80
Mortality rate (%)

* *
70 p<0.05
60
50 *
*
40
30
20
10
0
Micek Harbarth Garnacho Dhainaut
(n=102) (n=904) (n=406) (n=1690)

Micek et al. Pharmacotherapy 2005;25:2634

 Bacteria by Site of Infection
Mouth Skin/Soft Tissue Bone and Joint
Peptococcus S. aureus S. aureus
Peptostreptococcus S. pyogenes S. epidermidis
Actinomyces S. epidermidis Streptococci
Pasteurella N. gonorrhoeae
Gram-negative rods

Abdomen Urinary Tract Upper Respiratory

E. coli, Proteus E. coli, Proteus S. pneumoniae
Klebsiella Klebsiella H. influenzae
Enterococcus Enterococcus M. catarrhalis
Bacteroides sp. Staph saprophyticus S. pyogenes

Lower Respiratory Lower Respiratory Meningitis

Community Hospital S. pneumoniae
S. pneumoniae K. pneumoniae N. meningitidis
H. influenzae P. aeruginosa H. influenza
K. pneumoniae Enterobacter sp. Group B Strep
Legionella pneumophila Serratia sp. E. coli
Mycoplasma, Chlamydia S. aureus Listeria
 Kasus 1
Laki-laki, dewasa, 42 tahun,
Sesak, batuk, riwayat TBC (+)
Sianose
Tensi 100/65 mmHg, nadi 112 x/min
Pleural effusion (+)

OAT
PLEURAL Ciprofloxacin
PUNCTION Celecoxib
 Kasus 2

Laki-laki, dewasa muda, 27 tahun

benjolan di leher,
berwarna unggu,
sekret nanah seperti susu,
tanpa nyeri tekan,
badan makin kurus
Lymphadenitis tuberculosa
 Perlu ANTIMIKROBA

OBAT Eff. Safe. Suit. Avail Cost Total

Tetra + - - + +++ 5+
siklin
Amok - ++ - + ++ 5+
sisilin
Rifam +++ + +++ + + 9+
pisin
 Kasus 3
Perempuan, lansia, 72 tahun
Batuk-batuk, sesak, demam
Produksi urine sangat sedikit
Dx: Pneumonia + GGK
 Perlu ANTIMIKROBA
Efek samping
??? Contra indication
GGK

OBAT Eff. Safe. Suit. Avail Cost Total

Genta ++ - - + + 4+
misin
Doksi + ++ ++ + ++ 8+
siklin
RATIONAL ANTIMICROBIAL THERAPY

SOP

SENSITIVITY
INFECTION CULTURE
TEST

EDUCATED
ANTIMICROBA GUESS
THERAPY

DOSAGE &
ADM. resistance
intolerable side effect
EVALUATION
high cost
 Manifestation of Infection
Local Inflammation Systemic Inflammation
initial and sometimes fatigue,
final response malaise,
What is observed? anorexia,
wound margins myalgia,
exudates
arthralgia, and
sensations
skin temperature fever
 Signs & Symptoms of Infection
Fever
Increased white blood cell count (WBC)
Redness, warmth, swelling, tenderness
Purulent drainage
menguji kepekaan bakteri patogen secara in vitro
terhadap antimikroba

UJI
KEPEKAAN

mengukur konsentrasi obat yang diperlukan untuk

menghambat perkembangan atau membunuh organisme
tersebut
 Culture and Sensitivity
Culture of infected area is done to determine type of
bacteria responsible for infection
Sites: urine, wound, sputum, throat, blood, etc.
Results show type of bacteria grown
Sensitivity report specifies to which antibiotics the
cultured bacteria are sensitive
Used to guide antibiotic therapy choices
Cultures should be obtained prior to initiation of antibiotic
therapy
 Mortality Rates
Rello et al Appropriate therapy
Inappropriate therapy
Alvarez-Lerma

Ibrahim et al

Luna et al

Garnacho-Montero et al

Valls et al

0 20 40 60 80 100
Mortality (%)
Rello et al. Am J Respir Crit Care Med 1997;156:196200; Alvarez-Lerma. Intensive Care Med 1996;22:387394
Ibrahim et al. Chest 2000;118:146155; Luna et al. Chest 1997;111:676685
Garnacho-Montero et al. Crit Care Med 2003;31:27422751; Valls et al. Chest 2003;123:16151624
 PK problems in critically ill patients
increased distribution volume are observed.
This results in inadequate serum levels of antibiotics.
Since protein binding is frequently reduced in severely ill patients, the
influence of altered binding of highly bound drugs on distribution
volume and drug clearance should be taken into account
The unbound serum concentration of the antibiotic should be above
the MIC for at least 40% to 50% of the dosing interval
concentration-dependent drugs,
a clinical success of approximately 90% response rate was achieved at
the Cmax/MIC ratios of 10 (8 to 12).
the higher the drug concentration, the faster the eradication of
pathogens. High drug levels should be then the goal of therapy.
This approach, however, is not feasible for the fluoroquinolones owing
to dose-limiting CNS toxicity.
the time above the MIC required for maximal -
lactam activity may differ depending on the
pathogen.
 Antibiotic use
Susceptible
Antibiotic
Pathogen
Pathogen
resistant pathogen
Prevent Prevent
transmission infection

Antibiotic
resistance Infection
Optimize Effective
use diagnosis
and treatment
Antibiotic
use
 History of resistance

1941 Penicillin 1960 Methicillin

1943 Streptomycin 1962 Lincomycin
1945 Cephalosporins 1962 Quinolones
1950 Tetracyclines 1970 Penems
1952 Eryrthromycin 1980 Monobactams
1956 Vancomycin 2010 The end of the
antibiotic era?

26
 Selection of Antimicrobial Therapy:
Host Factors
Allergies, age, pregnancy, hepatic and renal function,
concomitant drug therapy, immunocompentence,
and co-morbidities
Site of infection
Must cover common pathogens for specific infectious
diagnosis until culture results return
Must consider temporal relationships
Organisms differ with early vs late onset hospital-acquired
pneumonia
Organisms may reflect selective pressure if antibiotics
previously administered (Antimicrobial history taking is
extremely important!)
 Selection of Antimicrobial Therapy: Drug
Factors
Variable antibiotic tissue penetration
Protected sites: pulmonary secretions, the central nervous system,
eye, prostate, abscess, bone
Drug clearance: many are renally cleared
Exceptions: the macrolides, amphotericin, caspofungin, voriconazole,
clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and the
antistaphylococcal penicillins
Bioavailability
Good absorption for most quinolones, linezolid, cotrimoxazole,
metronidazole, fluconazole, voriconazole, clindamycin, cephalexin,
doxycycline, minocycline
Toxicity profile
Cost truths:
generic cheaper than brand name and oral/enteral cheaper than
parenteral, BUT: antimicrobial costs represent a small fraction of
infection treatment
 Drug Factors for
Selection of Antibiotic
Pharmacokinetics
tissue penetration
Pharmacodynamics
Toxicity
Cost
 Antibiotika yang diresepkan ?
Keluhan Diagnosa Antibiotik
Penyakit Dalam
Mencret Gastroenteritis akut Tetrasiklin
Nyeri perut Dispepsia tipe ulkus Cefotaxim
Penurunan kesadaran ec. syok sepsis ec.
Penurunan kesadaran Cefotaxim
ISK tersangka
Sesak nafas COPD ec. bronchitis kronis Unasyn
Sesak nafas TB paru dengan infeksi sekunder Cefotaxim
Penyakit Anak
Demam Demam Chikungunya Gentamicin & Ampicillin
Sesak nafas Pneumonia + TB tersangka Ampicillin & Kloramfenikol
Kejang Tetanus Eritromisin
Kejang Kejang demam sederhana ec. laryngitis Amoxicillin
Penurunan kesadaran Ensefalitis Ampicillin & Cefotaxim
Bedah
Tidak bisa buang air kecil Blunt abdominal injury + Gross hematuria Cefotaxim
Luka di kaki kiri Open lower third tibia fibula fx. grade III A Cefotaxim
Sakit di pinggang Multiple cystic kidney + pelvis renalis stone Ampicillin
Sakit benjolan inguinal kanan Ca penis Amoxicillin
Tidak buang air besar 2 hari Femoral hernia Cefotaxim
The tree of antibiotics
 The mechanism of action of anti-microbial drugs

Cell wall Nucleic acid

Beta-lactam Levofloxacin
replication

Cell transcription Nucleic acid

membrane 50S Rifampicin
Polymixin B
30S mRNA
protein
translation
Anti-metabolites Protein synthesis
Ethambutol Streptomycin
Isoniazid
PAS
Bacterial Targets for Antibiotics
 Classification of Antibiotics
Bacteriostatic Bactericidal
 What is PK and PD ?
Pharmacokinetics (PK)
is what the body does to a drug.
This includes absorption, distribution,
metabolism, and excretion
Pharmacodynamics (PD)
the biochemical and physiologic effects of the
drug and
its mechanism of action i.e. what the drug does
to the body (or micro-organism in the case of
antibiotics)
 Relationship between PK and PD
Concentration
Pharmacologic
vs time in
or toxicologic
tissue and
effect
other body fluids
Concentration
Dosage vs time in
regimen plasma Concentration
vs time in Antibiotic
Absorption site of effect vs time
Protein binding
Distribution infection
Biotransformation
Excretion

pharmacokinetics pharmacodynamics

Craig WA. Pharmacokinetic/pharmacodynamic parameters:

Rationale for antibacterial dosing of mice and men. Clin Infect Dis. 26:112,1998
Bacterial Targets for Antibiotics
 PK/PD and Antibiotic Efficacy
3 patterns of bacterial killing
Concentration dependent with prolonged persistent
effect
Aminoglycosides, quinolones
Correlated with AUC/MIC , Cmax/MIC
Time dependent with no persistent effect
Betalactams
Correlated with Time above MIC (T>MIC)
Time dependent with moderate to prolonged persistent
effect
Macrolides, azalides, clindamycin, tetracyclines, glycopeptides,
oxazolidinones
Correlated with AUC/MIC
PAE
Craig, 4th ISAAR, Seoul 2003
 AUIC: Pharmacodynamic Modeling

.
Dudley MN. In DiPiro ed. Pharmacotherapy A Pathophysiological Approach 3rd ed. Appleton & Lange.
 Important PK/PD Parameters
concentration dependent

Area under the curve AUC/MIC is the

over MIC ratio of the AUC
concentration
Antibiotic

Cmax to MIC
Cmax/MIC is the
MIC ratio of the peak
concentration
to MIC

Time
 Important PK/PD Parameters
time dependent

8 Drug A Time above MIC

Antibiotic concentration

Proportion of the
6 dosing interval
Drug B
(ug/ml)

when the drug

4
concentration
exceeds
2 MIC
B the MIC
A
0
Time above MIC
Time
 antibiotics can be divided into
3 categories
Goal of PK/PD
Pattern of Activity Antibiotics
Therapy Parameter
Type I
Aminoglycosides
Concentration-dependent
Daptomycin Maximize 24h-AUC/MIC
killing and
Fluoroquinolones concentrations Peak/MIC
Prolonged persistent
Ketolides
effects
Carbapenems
Type II
Cephalosporins Maximize
Time-dependent killing
Erythromycin duration of T>MIC
and
Linezolid exposure
Minimal persistent effects
Penicillins
Type III Azithromycin
Time-dependent killing Clindamycin
Maximize
and Oxazolidinones 24h-AUC/MIC
amount of drug
Moderate to prolonged Tetracyclines
persistent effects. Vancomycin
PD parameters predictive of outcome

Parameter
correlating T>MIC AUC:MIC Cmax:MIC
with efficacy
RepresentativePenicillins Azithromycin Fluoroquinolones
Antimicrobial Cephalosporins Fluoroquinolones Aminoglycosides
Agents Carbapenems Ketolides Metronidazole
Macrolides
Organism kill Time-dependent Concentration- Concentration-
dependent dependent
Therapeutic Optimise Maximize Maximize
goal duration of concentration concentration
exposure exposure exposure
Drusano & Craig. J Chemother ;9:3844,1997
Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S2741,1998
Vesga et al. 37th ICAAC 1997
 Pharmacodynamics of Bacterial Killing
Concentration-dependent (greater bacterial kill at higher concentrations) vs.
Concentration-independent
Once-daily vs. Conventional Three-times Daily Aminoglycoside
Regimens Optimizes Concentration-dependant Effect on
Bacterial Kill

12
Concentration (mg/L)

Once-daily regimen
Conventional
8 (three-times daily regimen)

MIC
0
0 8 16 24
Time (hours)
Nicolau et al. Antimicrob Agents Chemother 39:6505,1995
Relationship between the
maximal peak plasma
level to MIC ratio and the
rate of clinical response
in 236 patients with
Gram-negative bacterial
infection treated with
aminoglycosides
(gentamicin, tobramycin,
or amikacin).
Vertical bars represent SE values.
 Levofloxacin PK/PD correlations
134 hospitalized patients with respiratory tract, skin or complicated urinary tract
infections treated with 500 mg qd for 5-14 days

120
Bacteriologic outcome 100
100
No. of patient

Success
80 Failure

60

40
23
20 4
3 3 1
0
AUC:MIC <25 AUC:MIC 25-100 AUC:MIC >100
Peak:MIC <3 Peak:MIC 3-12 Peak:MIC >12
Bacteriologic
failure rate 43% 11.5% 1%
Preston et al., JAMA 279:125-9,1998
LEVOFLOXACIN
OFLOXACIN
TROVAFLOXACIN
CIPROFLOXACIN
LOMEFLOXACIN
SPARFLOXACIN
NORFLOXACIN
 Meropenem 500 mg administered
as a 3 h infusion extends the time over the MIC vs a 0.5 h
infusion

100
Rapid Infusion (30 min)
Concentration

Extended Infusion (3 h)
(ug/mL)

10

MIC
1

0.1
0 2 4 6 8
Time (h)
Dandekar PK et al. Pharmacotherapy. 23:988-91,2003
 6
Quinolone Serum Concentrations
and MICs for Difficult Organisms

5
Ciprofloxacin
Norfloxacin
Ofloxacin
Lomefloxacin

4
g/ml

2
S. pneumoniae MIC

P. aeruginosa MIC
1

0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hours)
 Major route of elimination
Hepatobiliary Renal
Choloramphenicol Most beta lactams
Doxycycline Aminoglycoside
Moxifloxacin TMP-SMX
Macrolides Carbapenems
Nafcilin Polymyxin
INH Tetracycline
PRZ Vancomycin
Rifampin Most quinolones
Clindamycin Nitrofurantoin
Metronidazole
 Dosing Adjustments in Renal Disease?

Yes No
Almost all cephalosporins and Doxycycline
most other beta-lactams Erythromycin, azithromycin
(penicillins, aztreonam, Linezolid
carbapenems)
Most quinolones Clindamycin
Vancomycin Metronidazole
Cotrimethoxazole Oxacillin, nafcillin, dicloxacillin
Daptomycin Ceftriaxone
Fluconazole Caspofungin
Voriconazole PO
Avoid use altogether Amphotericin b
Tetracycline
Nitrofurantoin (CrCl <40)
Voriconazole IV (CrCl<50)
Aminoglycosides (if possible)
 Adverse Reactions to Antimicrobial
Agents
There are three general types of adverse
reactions to antimicrobial agents:
hypersensitivity reactions (which are not dose
related),
direct drug toxicity (which usually is dose
related and manifests in a single organ or,
occasionally, in several organs), and
microbial superinfection.
 direct drug toxicity
to the kidney are aminoglycosides, polymyxins, and amphotericin B;
azotemia and renal tubular damage may be caused by any of these drugs.
Penicillins, cephalosporins, tetracyclines, and rifampin can cause
hemolytic anemia, thrombocytopenia, and leukopenia that involve an
immune mechanism, but these reactions are uncommon. Neutropenia can
occur during therapy with penicillins, cephalosporins, or vancomycin.
Macrolides and trimethoprim-sulfamethoxazole have been associated
with agranulocytosis.
Trimethoprim can produce anemia, leukopenia, and thrombocytopenia
from folate deficiency; the effect is reversible with folinic acid.
Amphotericin B commonly produces a reversible normocytic
normochromic anemia, probably secondary to injury to the red cell
membrane.
Flucytosine causes bone marrow suppression (leukopenia or
pancytopenia) when its excretion is reduced by renal failure.
Linezolid can also produce myelosuppression; although experience is
limited, bone marrow function usually recovers when the drug is
discontinued.
 Safety Other Antimicrobials (selected)-1
clarithromycin erythromycin
CONTRAINDICATION co- CONTRAINDICATED
administration with interacting drugs- In patients taking terfenadine or astemizole
postmarketing reports of cardiac WARNINGS
arrhythmias prolonged QT in geriatric patients
WARNINGS hepatic dysfunction
re: use in pregnancy pseudomembranous colitis
Pseudomembranous colitis PRECAUTIONS
Drug interactions CYP P450 3A aggravate weakness of patients with myasthenia
ADVERSE REACTIONS: Post-Marketing gravis
Experience Drug interactions
Hepatic effects
QT prolongation & arrhythmias azithromycin
WARNINGS
Rare serious allergic reactions
For outpatient mild severity CAP not for
moderate or severe CAP
pseudomembranous colitis
PRECAUTIONS
macrolides and QT
ADVERSE REACTIONS
liver and biliary adverse reactions
 Safety Other Antimicrobials (selected)-2
Beta-lactams
CONTRAINDICATIONS
Allergy to Cephs/PCNs
WARNINGS
Hypersensitivity to Cephs /
PCNs
Pseudomembranous colitis
Tetracyclines
WARNINGS
Effect on tooth development
pregnancy, children
Pseudomembranous colitis
photosensitivity
Fluoroquinolones
WARNINGS
Peds arthropathy juvenille
animals
CNS disorders
Hypersensitivity reactions
anaphylactic
rash, fever, Eos, jaundice,
hepatic necrosis, fatal outcomes
(rarely reported)
Peripheral neuropathy
Tendon effects
PRECAUTIONS
Effects on QT - arrhythmia
 Duration of
Antibiotic Therapy
Duration of Antibiotic Therapy
Resolution of clinical parameters 27 VAP pts
Mean log CFU/mL White blood cell count x 103/L
7 17
6 16
5 15
4 14
3 13
2 12
1 11
0 10
-1 9
0 3 6 9 12 15 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:13711375
Duration of Antibiotic Therapy
Resolution of clinical parameters 27 VAP pts
Highest temperature (C) PaO2:FiO2 ratio (KPa)
40 50

45

39 40

35

38 30

25

37 20
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:13711375
Kapankah penggunaan ANTIBIOTIK
dikatakan berhasil?
setelah tiga hari terutama dilakukan
pemberian obat berdasarkan tampilan klinis

EVALUASI

parameter laboratoris : hitung

menilai
leukosit, pemeriksaan kultur dan
kegagalan terapi
resistensi
 Successful treatment outcomes
Temperature returns to normal
Symptoms improve
Signs of infection resolve
White blood cell counts normalize
Cultures become negative
 Administration
Schedule at regular intervals to maintain
steady blood levels
Assess allergies prior to administration
Monitor for adverse and therapeutic effects
Drug interactions
Importance of completing full course
IV therapy changing to oral
Patient education
Antibiotic Cyt.P-450 Related Interactions
Inhibits Cyt.P-450:
Anticoagulants oral -- hypoprothromb.>
Erythromycins Carbamazepine toxicity -- >
Cisapride --Ventric. Arrhytmia
Fluconazole Digoxin bl.levels -- >>

Itraconazole Dilantin bl.levels -- <

Terfenadine -- Ventric. Arrhytmia
Ketoconazole Theophylline bl.levels -- >
Valproate bl.levels -- >

Induces Cyt. P-450: Anticoagulants -- hypothrombinaeia <

Rifampicin Chloramphenicol levels -- <

Contraceptives levels -- <
Corticoster. levels -- <
Cyclosporine levels -- <
 Failure of Antimicrobial Therapy

Caused by drug selection

Caused by host factors
Caused by microorganisms
 Mengganti ANTIBIOTIK?

tidak adanya indikasi tidak ada indikasi untuk

lanjutan diberikannya konsentrasi antibiotik di
antibiotik intravena jaringan

Kriteria Klinis
ALIH TERAPI
tidak ada gangguan ANTIBIOTIK bebas demam
pada saluran cerna kurang lebih 2 hari

adanya perubahan leukosit, hitung

jenis dan protein fase akut ke arah
normal
KENDALA PENGGUNAAN ANTIBIOTIK

antibiotik tidak tersedia di tempat

pelayanan kesehatan
yang tersedia hanya antibiotik tertentu
penggunaan tidak tepat
muncul mikroorganisme yang resisten
 Permasalahan:
Profesi dan Pemerintah

Dokter cari mudah

hajar saja dengan antibiotika

cari aman
penyakit seakan-akan sembuh,
dokter seakan-akan pintar/ahli.
cari untung
faktor pemasaran lebih penting
daripada ilmiah-rasional & pasien.

Apotek menutup sebelah mata

Pemerintah tidak peduli / tidak ahli / tidak tahu?
 Problems with Antibiotics
Inappropriate management
Increasing resistance
Side Effects: anaphylaxis, rashes and other
allergic phenomenon, C. difficile colitis, GI
upset and diarrhea
Drug interactions
Return visits for something stronger
 Pertimbangan Penggunaan
ANTIBIOTIK Kombinasi
Terapi spektrum luas pada pasien-pasien
sakit parah
Mengobati infeksi polimikroba
Mengurangi munculnya strain resisten
Mengurangi toksisitas terkait dosis
Mendapatkan peningkatan penghambatan
atau pembunuhan bakteri
 KOMBINASI ANTIBIOTIKA
SINERGIS
Penisilin (amoksisilin) + aminoglikosida (gentamisin)
Amoksisilin + asam klavulanat
Sulfametoksazol + trimethoprim
Kloramfenikol + trisulfa
ANTAGONIS
Penisilin (bakterisid) + tetrasiklin (bakteriostatik)
Penisilin + aminoglikosida
[dalam satu wadah/spuit]
 drug interaction
Synergism
Penicillins Aminoglycosides
Cephalosporins Colistine
Synergism Synergism

Fosfomicin
Antagonism Synergism Additive

Macrolides
Tetracyclines
Chloramphenicols
 KOMBINASI ANTIBIOTIKA
Efek yang
Antimikroba Obat lain
tak diinginkan
Tetrasiklin Kalsium Absorpsi tetrasiklin
ber(-)
Gentamisin OAINS Efek samping
gentamisin ber(+)
Penisilin Probenesid Efek penisilin ber(+)

Sulfonamida NaHCO3 Kejadian kristaluria

ber(-)
 KESIMPULAN
ANTIMIKROBA bukan ANTIPIRETIKA
ANTI-TUSIVA
ANTI-DIARE
ANTI-ANXIETY
ANTIMIKROBA hanya diberikan bila terbukti atau disangka
kuat ada proses INFEKSI (kuman, jamur, virus, protozoa)

ANTIMIKROBA TUNGGAL lebih baik daripada

ANTIMIKROBA KOMBINASI
Waspada terhadap interaksi ANTIMIKROBA dengan
OBAT LAIN
 Principles of antimicrobial treatment
when to give? how much to give?
correct indication the satisfactory dose
what to give? is the multiple amount of MIC at the
the most suitable locus of infection!
1. the most effective one Dosage : age, liver and kidney
2. the less toxic one functions, BW, height, pregnancy
3. (the cheapest) how long to give?
as long as there is no danger of
Ad 1. effective relapse
antimicrobial activity acute infection: min. 5 days
- spectrum = against which species is it severe infection: 8-14 days
effective?
- numerically expressed: MIC, MBC sepsis/endocarditis: 3-4-6 weeks,
the sensitivity of a bacterium can be tbc: 9-12 months
detected in vitro
pharmacokinetic features
resistance
Pharmacology of
analgesic
Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
 Batasan Nyeri
Pengalaman sensoris dan emosional yang
tidak menyenangkan terkait dengan jejas
jaringan yang nyata atau potensial atau yang
dapat digambarkan sebagai suatu kerusakan
jaringan.

The International Association for the Study of Pain

(IASP, 1994), adopted from Merskey.
 Managing Pain: A Few Thoughts

Pain is complex, involving many organ

systems and several pathways
Medications are often very helpful
Medications have limited sites and
mechanisms of action
All analgesics and adjuvant have risks, from
minor to severe
 Obati penyakit yang mendasarinya
Contoh pada kasus reumatologi, beberapa
obat di bawah ini dapat dipakai:
OAINS
Kortikosteroid
Anti-malaria
DMARDs
Biologic agents
Stem cell / bone marrow transplantation
 Pain Management
Goals of Pain Management
Relieve suffering
Subjective patient comfort (pain free)
Inhibiting stress response (stress free)
Increase functional capacity
Improve quality of life

Ways to advocate for Pain Management

Dont use placebos
Promote pain education with all disciplines
 Principles of Medical Ethics
in Pain Management
Pharmaco-therapeutic
Principles approaches
BENEFICENCE : Pain killer (analgesic),
mengutamakan
kepentingan pasien
potent, rapid onset
NON MALEFICENCE : Minimal ADR,
tidak memperburuk not deteriorate other clinical
keadaan pasien problems
JUSTICE : Rational
tidak mendiskriminasikan
pasien, apapun dasarnya
AUTONOMY : Religion, Preference, PRN,
menghormati hak pasien
dalam memutuskan
pharmaco-economics
 Withdrawal rates after 12 weeks of treatment
JJ Deeks et al. BMJ 325:619,2000
patients taking placebo were more likely to withdraw because of lack of improvement in
symptoms than because of adverse events

60 56%
Withdrawal (%)

50

40

30 23%

20

10

0
Placebo Celecoxib Celecoxib Naproxen Diclofenac
200mg 400mg 1000mg 150mg
 Rational prescription (WHO,1995)
Patient receive Appropriate patient
appropriate medicines ( Tepat Pasien )
according to their Appropriate indication
clinical needs ( Tepat Indikasi )
at an appropriate
dosage, Appropriate drug
administration ( Tepat Obat )
& duration Appropriate dosage,
and in a way administration & duration
(Tepat dosis, cara & lama pemberian)
that encourages
the patient compliance Appropriate information
and ( Tepat Information )
at the lowest cost Appropriate cost
to the community ( Tepat biaya )
 Critical approaches
in selecting medicines
Therapeutic Adverse NNH
reaction
NNT
effect GREATEST
Minimal
(> 100) Maximal
SMALLEST

SMALLEST
Maximal
(2-4) Yes ?
Minimal
GREATEST ? No
There are two reasons to withdraw from the treatment either
no efficacy (NNT very high) or
serious adverse reactions (NNH very low).
 Nociceptive VS neuropathic pain

Nociceptive pain Neuropathic pain

Caused by activity in Mixed pain Initiated or caused by
neural pathway in response Caused by a combination primary lesion or
to potentially tissue- of both primary injury or dysfunction in the nervous
damaging stimuli secondary effects system

CRPS
Postoperative ARTHRITIS PHN
pain
Adjuvant
NSAID
Sickle cell crisis Neuropathic LBP
Trigeminal
Mechanical LBP
ANALGESIC neuralgia

Sport / exercise Distal Central post

injuries polyneuropathy stroke pain
(e.g. diabetic)
International Association for the Study of Pain. IASP Pain Terminology.
Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
 Penggunaan OAINS
Nyeri inflamasi akut,
Breakthrough pain
OAINS waktu paruh pendek
Ibuprofen, diclofenac, dan sebagainya
Nyeri inflamatorik kronik
OAINS waktu paruh panjang
Oxicam, COXIB
Pertimbangan Pemilihan OAINS
Isu terkait pengobatan Isu terkait pasien

Efektivitas Keparahan nyeri

Toleransi organ Faktor risiko pada sistim
Keamanan GI, platelet, renal dan
Rejimen dosis cerebro-cardiovascular
Harga system.
Obat-obatan yang
sedang dipakai.
Ko-morbiditas
Pilihan pasien
Kepatuhan
 Principles of Analgesic Prescribing
WHO Analgesic Ladder
Strong opioid
NSAID
adjuvant analgesic
NSAID
adjuvant analgesic
weak opioid
(codeine)
paracetamol
or NSAID
adjuvant analgesic

Pain threshold Pain tolerance

0 1 2 3 4 5 6 7 8 9 10
mild moderate severe
 Hal-hal Umum Seputar OAINS
Berbeda pada kelompok kimiawi.
Berbeda dalam potensi dan farmakokinetik
Mekanisme umum (hambatan cyclooxygenase)
Berbeda selektivitas terhadap COX-1 dan COX-2
Indikasi klinis umum
Analgesik (efek SSP dan periferal) dapat terkait efek yang
tidak melibatkan Prostaglandin (PG).
Antipiretikum (efek SSP)
Anti-inflamasi (terutama melalui hambatan PG)
Dosis efektif analgesik anti-inflamasi antipiretikum
Common analgesic ceiling effect
Choose the PAIN
Opioids
appropriate Alpha-2 agonists

one
Local anesthetics
Opioids
Subst. P,
Alpha-2 agonists
Glu., PG
GABA, 5-HT
Nadr, Ach
CCK, AND,
CGRP, dll

Local anesthetics

BK
PG
TRAUMA
Hist. Local anesthetics
5HT
Anti-inflammatory
Subst. P
drugs
 HYPERALGESIA
Prostaglandin
BBB BBB BBB BBB BBB BBB BBB BBB BBB
INFLAMMATION
MACROPHAGES

TNF-
IL-6 IL-8

IL-1 SYMPATHETIC
NERVE

COX-2 PG BK
POLYMORPHS
FIBROBLASTS

NOCICEPTOR
Ferreira, 1993 ALGESIA
 Mekanisme Kerja OAINS
Mekanisme Ibu- Diclo- Piro- Cele- Etori-
profen fenac xicam coxib coxib
COX-1 ++ + + - -
COX-2 + ++ + ++ +++
COX-3 + +++ ? ? ?
Anti-BK + + + ? ?
K-opener ? + ? ? ?
Tembus + + + ? ?
BBB
 phospholipids

arachidonic acid

COX LOX
COX-2 COX-1
cyclic
endoperoxides 5-HPETE

PGI2
inhibits platelet
TXA2 LTA4
aggregation, stimulates platelet
vasodilator, aggregation,
vasoconstriction LTB4
hyperalgesia chemotaxis

LTC4
PGD2 PGE2 PGF2alfa brochoconstriction
inhibits platelet bronchodilatation LTD4 increase
vasodilator, myometrial contr. vascular
aggregation,
vasodilator hyperalgesia hyperalgesia permeability
LTE4
 COX hypothesized centrally involves
in inflammatory pain

Willoughby DA, et al. COX-1, COX-2, and COX-3 and the future treatment of
chronic inflammatory disease. Lancet 355: 646-8,2000.
 Increase the dose
Celecoxib vs Naproxen vs Placebo
single dose post-surgical dental pain study
Placebo Celecoxib 100 mg

3 Celecoxib 200 mg Naproxen 550 mg

2.5
Pain relief

1.5

0.5

0
O 1 2 3 4 5 6 7 8
Time (hours)
FDA Advisory Committee Meeting, December 1, 1998
Chandrasekharan NV et al. Proc. Natl. Acad. Sci.USA, 99 (21): 13926-31,2002.
 Ringkasan aktivitas analgesik, anti-inflamatorik, dan
antipiretik OAINS (ED50 dalam mg/kg)

Anti-
OAINS Analgesik Antipiretik
inflamatorik
Ketorolac 0.7 2 0.9
Indomethacin 3 4 2.1
Diclofenac 8 7 0.4
Naproxen 13 56 0.5
Ibuprofen 45 10 7
Piroxicam 100 3 1.7
Tenoxicam 100 5 1.7
Aspirin 228 162 18
 Inflammatory mediator
and its actions
Vascular Vaso- Chemo
Mediator Pain
permeability dilatation taxis
Histamine - ++ -
Serotonin - +/- -
Bradykinin +++ +++ -
Prostaglandin + +++ +++
Leukotriene - - +++
 Farmakodinamik analgetika
Obat Analgetik Anti- Anti-piretik Tekan SSP
inflamasi
Paracetamol + - ++ -

Ibuprofen + ++ ++ -

Diclofenac ++ ++ +++ -

Piroxicam +/- +++ ++ -

Coxib + ++ - -

Tramadol + - - ++

Morfin +++ - - ++
 all
Acidic NSAIDs
HYPERALGESIA
Prostaglandin
BBB BBB BBB BBB BBB BBB BBB BBB BBB
INFLAMMATION
MACROPHAGES

TNF-
IL-6 IL-8

IL-1 SYMPATHETIC
NERVE

COX-2 PG BK
POLYMORPHS
FIBROBLASTS

DICLOFENAC all
and NOCICEPTOR
Non-COXIB
Nimesulide
Ferreira, 1993 ALGESIA
number needed to treat (NNT) for at least 50% pain relief over 4-
6 hours in patients with moderate to severe pain, all oral
analgesics except morphine, pethidine and ketorolac
 Analgesic ceiling effect of NSAIDs

OAINS Dosis NNT

50 mg 4.7
50 100 mg 3.7
Percent Responders

Ibuprofen
200 mg 2.7
40
400 mg 2.5
30 600/800 mg 1.7
25 mg 2.6
20
50 mg 2.7

10 Diclofenac 100 mg 1.8

200 mg 4.5
Celecoxib Celecoxib Celecoxib
0 Placebo
2 x 100 2 x 200 2 x 400 400 mg 3.7
Placebo C 2x100 C 2x200 C 2x400
600/800 mg 3.0
Simon et al., 1999
Martini A, et al. Diclofenac increases beta-
endorphin plasma concentrations.
J Int Med Res 1984;12(2):92
activation of K(+) channels by diclofenac as
potent analgesic
the peripheral antinociceptive
effect of diclofenac may result
from the activation of several
types of K(+) channels,
which may cause
Activation of hyperpolarization of peripheral
K channels
terminals of primary afferents.
Ortiz MI, et al. Pharmacological evidence for the activation
of K(+) channels by diclofenac. Eur J Pharmacol.
438(1-2):85-91,2002.
Ortiz MI, et al. The NO-cGMP-K+ channel pathway
participates in the antinociceptive effect of
diclofenac, but not of indomethacin. Pharmacol
Biochem Behav. 76(1):187-95,2003.
Alves DP, et al. Diclofenac-induced peripheral
antinociception is associated with ATP-sensitive K+
channels activation.
Life Sci. 74(20):2577-912004.
 Pelepasan
neurotransmitter
 Kombinasi analgetika
Analgetika Obat lain Efek
Non-COXIB Paracetamol Bertambah
COXIB Paracetamol Tdk nyata
Tramadol Paracetamol Bertambah
Morfin Paracetamol Bertambah
Non-COXIB An-adjuvant Bertambah
COXIB Dextrometorfan Menghambat meta-
Codein bolisme obat lain
Tramadol Anti-konvulsan Penekanan SSP
bertambah
 Multimodal Analgesia
Kombinasi beberapa obat:
Anestesi lokal
Opioids
OAINS
Paracetamol
Alpha-2-agonists
The National Cancer Institute. Pain. www.webmd.com/content/article/5/1680_50742.htm
PRE-SYNAP OPIOIDS POST-SYNAP
1
NMDA
INHIBITION

Glu
ACTIVATION
Subs.P
M1 NK-1
2 PAIN

NAdr 2
CLONIDINE

ACh INHIBITION

GABA GABA

MIDAZOLAME
 NSAID GI
Toxicity

Lowest GI risk
generally
varies
with half-life
of the agent
Shortest half-life

NSAID Diclofenac Naproxen Piroxicam

Dose (mg/d) 100 750 20
Half-life (hr) 1.5 14 50
24 hr fecal blood
loss (mL) 0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med 28(4):436,1998

Prescribing of diclofenac in England (December
2005 to November 2008).
The lines represent the linear regression lines for the proportion of diclofenac
prescribed in England overall before and after November 2007.

Encouraging prescribing trends for NSAIDs

Monday, March 9th, 2009
 Ageing Consideration
do not care .
to the kinetics of drug administered
1600
500 mg tid, 2 hrs
Plasma concentration (mg/L)

1400 1500 mg od, 2 hrs

500 mg tid, 12 hrs
1200 1500 mg od, 12 hrs

1000

800

600

400

200

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

Drug accumulation
3x11x3
Efek terapeutik Efek samping obat
Choose the shortest half-life
 Prinsip Penatalaksanaan Farmakologik

Gunakan dosis dan jadwal pengobatan yang

sederhana dan kurang invasif.
Jadwalkan dosis secara reguler (misal, "by the
clock") untuk mempertahankan kadar obat yang
mampu mencegah berulangnya nyeri. Mintalah
kooperasi pasien dan keluarganya dalam
mencapai tingkat yang efektif.
Tambahkan dosis tambahan p.r.n untuk
breakthrough pain.
Pada geriatri, mulai dengan dosis kecil dan
tingkatkan perlahan (starts low and go slow).
The National Cancer Institute. Pain. www.webmd.com/content/article/5/1680_50742.htm
 Adjuvant Analgesics
Defined as drugs with other indications
that may be analgesic in specific
circumstances
Numerous drugs in diverse classes
Sequential trials are often needed

Multipurpose analgesics
 Adjuvant Analgesics for Neuropathic Pain
Class Examples
Antidepressants amitriptyline, desipramine, nortriptyline,
paroxetine, venlafaxine, citalopram, others
Anticonvulsants gabapentin, phenytoin, carbamazepine,
clonazepam, topiramate, oxcarbazepine, others
Alpha-2 adrenergic agonists tizanidine, clonidine
Local anesthetics mexiletine, tocainide
NMDA receptor dextromethorphan, ketamine, amantadine
Antagonists
Miscellaneous baclofen, calcitonin
Topical lidocaine, lidocaine/prilocaine, capsaicin,
NSAIDs
Steroids prednisone, dexamethasone
Neurotropic Vitamin B1, B6, B12 (+B9 Folic acid)
Adjuvant analgesics
 Nociceptive and neuropathic pain

Nociceptive pain Neuropathic pain

 Medina-Santilln R, Reyes-Garca G, Rocha-Gonzlez HI, Granados-Soto V.
B vitamins increase the analgesic effect of
ketorolac in the formalin test in the rat.
Proc West Pharmacol Soc. 2004;47:95-9.
Ketorolac (0.32-10 mg/kg, po), B-vitamins (56-316 mg/kg), or a
combination of B-vitamins (either 100:100:1 or 100:100:5 proportion of
vitamin B1, B6 and B12, respectively) and ketorolac was administered
orally and the antinociceptive effect was determined.
Ketorolac (ED25 3.5+/-0.7 mg/kg), B-vitamins in a 100:100:1 (ED25
277.1+/-30.2 mg/kg) or 100:100:5 (ED25 157.3+/-13.7 mg/kg) proportion
and fixed-ratio B-vitamins-ketorolac combinations dose-dependently
reduced flinching behavior during second phase of the test.
Theoretical ED25 values for the combination ketorolac-B vitamins
estimated from the isobolograms were 140.3+/-15.1 and 80.4+/-6.8 mg/kg
for 100:100:1 and 100:100:5 proportions, respectively. These values were
significantly higher than experimental ED25 values which were 73.3+/-6.3
and 47.7+/-6.4 mg/kg for 100:100:1 and 100:100:5 proportions,
respectively.
Results indicate that oral ketorolac and B-vitamins can interact
synergistically to reduce inflammatory pain in the formalin test and
suggest the use of those combinations to relief this kind of pain in
humans.
The role of neurotropic vitamin in
alleviating pain
Investigators Year Animal Vitamin Bs
Hanck & Weiser 1985 Rats B12
Wang et al 2005 Rats B1, B6, B12
Song et al 2009 Rats B1
Caram-Salas et al 2006 Rats B1, B6, B12 +
dexametasone
Granados-Soto et al 2004 Rats B12 +
diclofenac
Rocha-Gonzlez et al 2004 Rats B1, B6, B12 +
diclofenac
Medina-Santilln et al 2004 Rats B1, B6, B12 +
ketorolac
 Klemes. Vitamin B-12 in acute
subdeltoid bursitis.
Indust. Med. Land Surg. 1957;26:290-2
40 acute patients received vitamin B-12
1000mcg daily for 7-10days; then 3x weekly
for 2-3wks; then 1-2x weekly for 2-3wks
(depending upon their rate of progress). All
but 2 or 3 improved with rapid relief of pain
and subjective symptoms, sometimes within a
few hours. Complete relief was often noted in
several days.
 Peters TJ, et al. Treatment of alcoholic
polyneuropathy with vitamin B complex: a
randomised controlled trial.
Alcohol Alcohol. 2006;41(6):636-42

McGill's New form. Old form. Placebo

pain B1, B2, B6, B1, B2, B6, (N = 85)
question- B12 + B9 B12 (-) B9
naire (N = 85) (N = 83)
Total pain 8.6 (7.55) 7.5 (6.76) 3.8 (8.18)
score*,
VAS (mm)*, 35.0 34.9 9.5
(18.61) (20.32) (18.65)
*P < 0.001: new formulation versus placebo (Wilcoxon-Rank Sum Test).
*P < 0.001: old formulation versus placebo (Wilcoxon-Rank Sum Test).
 The role of neurotropic vitamin in
alleviating pain
Investigators Years Subject Vitamin Bs
Mazzoni &Valenti 1964 Patients B1
Hieber 1974 Patients B12
Mder 1988 Cervico- B1, B2, B9
brachialgia
Vetter et al 1988 Patients B1, B6, B12 +
diclofenac
Brggemann et al 1990 Patients B1, B6, B12 +
diclofenac
Abbas & Swai 1997 Patients DM B1, B6
Mauro et al 2002 Patients LBP B12
Peters et al 2006 Patients B1, B6, B12, B9
Mibielli et al 2009 Patients B1, B6, B12 +
diclofenac
 Low back pain
Double Blind, 252 Patients (Vetter et al., 1988)
Hari ke 7 Akhir terapi
Sharpness Rhythm Sharpness Rhythm
0

-1

-2
[Hoppe Pain Questionnaire]

-3
Mean Difference

-4

-5

-6

-7

-8

-9

-10 3x Diclofenac vitamins

Neurotropic 3x Diclofenac
increase + B1 + B6 + B12
the production of serotonin and
50 mg/d 50 50 50 0.25 mg/d
noradrenalin, then inhibit the transmission of pain
 Cerebral cortex
Hypothalamus

PAG

DESCENDING
Spinoreticular

PATHWAY
afferents Enkephalin

NRM NRPG

Spinoreticulothalamic
Pain Projection 5-HT NE
Inter- Inter-
ASCENDING
PATHWAY

neuron neuron

- - C fibers
 Mibielli MA, et al.
Diclofenac plus B vitamins versus
diclofenac monotherapy in
lumbago:
the DOLOR study.
Curr Med Res Op 2009;25(11):2589-99
A randomized, double blind controlled study in
parallel groups
Received twice-daily po.
Group DB (50 mg diclofenac, 50 mg B1, 50 mg
B6, 1 mg B12) vs Group D (50 mg diclofenac)
Sufficient pain reduction = VAS < 20 mm
 The number of patients who meet the
confirmative primary study objective
at visit 2 (after 3 days of treatment)
Group DB Group D
(n=187) (n=185)
n % n %
Study withdrawal reasons
Treatment success 87 46.5 55 29.7
Treatment failure 10 5.3 10 5.4
Side effects (AEs) 3 1.6 0

Patients with continued 87 46.5 120 64.9

intervention
Difference in treatment success. X2 = 12.06; p = 0.0005
 Patients response captured between visit 1
and visit 2 to the Visual Analogue Scale (VAS)
60
DB
50
D
% Patients

40

30

20

10

0
< 0 mm 0 - 20 mm 21 - 40 mm 41 - 60 mm > 60 mm

VAS mm
 Farmakologi nyeri campuran
Nyeri campuran = nyeri nosiseptif + nyeri
neuropatik
Terapi nyeri campuran = AINS + Analgetik
adjuvant
Terapi farmaka nyeri campuran yang
terbaik dan
aman adalah
diclofenac + neurotropic vitamin
 Peran vitamin neurotropik pada
terapi nyeri campuran
Pyridoxin atau vitamin B6 diperlukan dalam proses
konversi tryptophan menjadi serotonin, suatu
neurotransmitter yang memodulasi persepsi nyeri,
sehingga bertindak sebagai agonis serotonin.
Selain itu, vitamin neurotropik meningkatkan
keberadaan dan atau efek noradrenalin dan
serotonin yang bertindak sebagai penghambat
transmisi sistem nyeri
Gabungan AINS dan vitamin neurotropik berkhasiat
terhadap nyeri campuran
 Medan PP4GP 2010

KEBANGGAAN INDONESIA UNTUK DUNIA

 Pain Management
Goals of Pain Management
o Relieve suffering
o Increase functional capacity
o Improve quality of life
Ways to advocate for Pain Management
o Dont use placebos
o Promote pain education with all
disciplines
 PAIN
Opioids
Alpha-2 agonists

Local anesthetics
Opioids
Subst. P,
Alpha-2 agonists
Glu., PG
GABA, 5-HT
Nadr, Ach
CCK, AND,
CGRP, dll

Local anesthetics

BK
PG
TRAUMA
Hist. Local anesthetics
5HT
Anti-inflammatory
Subst. P
drugs
 Factors to consider when
choosing therapy
Drug issues Patient issues
Efficacy Pain severity
Tolerability Risk factors: GI,
Safety platelet, renal and
Dosage cerebro-
cardiovascular system.
Cost
Co-prescription.
Co-morbidity.
Compliance.
 Principles of Analgesic Prescribing
WHO Analgesic Ladder
Strong opioid
NSAID
adjuvant analgesic
NSAID
adjuvant analgesic
weak opioid
(codeine)
paracetamol
or NSAID
adjuvant analgesic

Pain threshold Pain tolerance

0 1 2 3 4 5 6 7 8 9 10
mild moderate severe
 Critical approaches
in selecting medicines
Therapeutic Adverse NNH
reaction
NNT
effect GREATEST
Minimal
(> 100) Maximal
SMALLEST

SMALLEST
Maximal
(2-4) Yes ?
Minimal
GREATEST ? No
There are two reasons to withdraw from the treatment either
no efficacy (NNT very high) or
serious adverse reactions (NNH very low).
Drug issues
efficacy
safety
Current view in selecting analgesic and
anti-inflammatory drugs
Efficacy (indication)
Safety (side effect)
Not only GI toxicity
Cardiovascular toxicity
Renal toxicity
Bone healing impairment etc
Pharmacokinetics
Daily cost
Evidence based medicine
number needed to treat (NNT) for at least 50% pain relief
over 4-6 hours in patients with moderate to severe pain,
all oral analgesics except morphine, pethidine and ketorolac
NSAIDs: COX-2 vs COX-1 selectivity
100 6-MNA
Naproxen Paracetamol
COX-2 IC50 (M)

10 Ibuprofen

Meloxicam Nimesulide
1
Rofecoxib
Indomethacin Celecoxib
0.1
Diclofenac

0.01
0.01 0.1 1 10 100
COX-1 IC50 (M)
FitzGerald & Patrono. N Engl J Med 345:433,2001
 all
Acidic NSAIDs
HYPERALGESIA
Prostaglandin
BBB BBB BBB BBB BBB BBB BBB BBB BBB
INFLAMMATION
MACROPHAGES

TNF-
IL-6 IL-8

IL-1 SYMPATHETIC
NERVE

COX-2 PG BK
POLYMORPHS
FIBROBLASTS

DICLOFENAC all
and NOCICEPTOR
Non-COXIB
Nimesulide
Ferreira, 1993 ALGESIA
 synaptic transfer of pain signals in the spinal
cord
peripheral sensory
afferent nerve dorsal root central

PAIN

COX-2
COX-2
inflammation
COX-1
EP1, EP3 DP & EP2
EP4 & IP

PG K-channel opener BK bradykinin

Hyperpolarisation inhibit transmition of pain
PG receptor BK receptor
activation of K(+) channels by diclofenac
as potent analgesic
the peripheral
antinociceptive effect of
diclofenac may result from
the activation of several
types of K(+) channels,
Activation of which may cause
K channels
hyperpolarization of
peripheral terminals of
primary afferents.
Ortiz MI, et al. Pharmacological evidence for the
activation of K(+) channels by diclofenac. Eur J
Pharmacol. 438(1-2):85-91,2002.
Ortiz MI, et al. The NO-cGMP-K+ channel
pathway participates in the antinociceptive effect
of diclofenac, but not of indomethacin. Pharmacol
Biochem Behav. 76(1):187-95,2003.
Alves DP, et al. Diclofenac-induced peripheral
antinociception is associated with ATP-sensitive
K+ channels activation.
Life Sci. 74(20):2577-912004.
Rx Rivals Annual percentage change in
prescriptions dispensed in the U.S.
 Change in phenytoin excipients resulted in
epidemic toxicity
obat yang berdasar uji lab
mempunyai BA/BE yang
sama, ternyata
secara klinis berbeda dan
ditemukan efek samping
[PHENYTOIN]

yang lebih besar

g/mL

WEEKS
Bochner F, et al. Proc Aust Assoc Neurol 1973;9:165-70
 Comparative Bioavailability Study of Two
Different Nimesulide-Containing Preparations
Available on the Italian Market
V. Hutt, J. Waitzinger, F. Macchi Clin Drug Invest 21(5):361-369, 2001

Drug product Percentage of nimesulide dissolved

15 min 30 min
Aulin 89.25 98.45
Nimesulide Dorom 52.43 63.85
 Original vs "Me-Too" prices
Friend or Foe?
Nimesulide Pharmaceutical Co. Price (Rp)/100mg
Original
Aulin Gala 2.950,-
Nimed Schering 2.950,-
Me-Too
Arnid Pharos 2.750,-
Ilusemin Phapros (?)
Ximede Combiphar 3.200,-
Capone ML, et al. Int J Immunopathol Pharmacol. 16(2 Suppl):49-58,2003.

Clinical pharmacology of
selective COX-2 inhibitors
Acidic COX-2 inhibitors
have been hypothesized that this
peculiar chemical feature may lead to
an enhanced concentration in
inflammatory sites
that may translate into
an improved clinical efficacy
 NNH (safety) of celecoxib
for 6 months administration
Type of ADR NNH
Gastrointestinal 210
Cardiovascular 77
Dermal/skin 30
Renal ?
Liver ?
Bone ?
Respiratory tract ???
the absence of evidence is not the evidence of absence
 Hidden issues of NSAIDs
COOH

COX-1 COX-2
Arachidonic acid
Prostaglandines Prostaglandines
PGE2, PGI2, TXA2 PGE2, PGI2, TXA2

TXA2 PGI2
stimulates inhibits COX-2
specific inhibitor
platelet platelet

Gastric
mucosal
hidden
aggregation,
vasoconstriction
aggregation
vasodilation
Inflammation
Inflammation
Pain
Pain
protection

causes GI damage
issues
thrombosis
STROKE
ischemic
MCI
Fever
Fever
Renal function
Boneanti-
formation
Reproduction
inflammatory
Apakah setiap AINS aman bebas dari reaksi
sampingan yang merugikan?
Ototoxic Color blindness

Bronchospam CV events

Hepatotoxic GIUGIB
ADR

Bleeding Nephrotoxic

Allergy Tocolytic

Mekanisme = Mekanisme
efek yang diinginkan efek yg tak diinginkan
 Proposed issues of NSAIDs
COOH

COX-1 COX-2
Arachidonic acid
Prostaglandines Prostaglandines
PGE2, PGI2, TXA2 PGE2, PGI2, TXA2

COX-2
specific inhibitor

Gastric Inflammation
mucosal Pain
protection Fever

causes GI damage anti-

inflammatory
 phospholipids

arachidonic acid

COX LOX
COX-2 COX-1
cyclic
endoperoxides 5-HPETE

PGI2
inhibits platelet
TXA2 LTA4
aggregation, stimulates platelet
vasodilator, aggregation,
vasoconstriction LTB4
hyperalgesia chemotaxis

LTC4
PGD2 PGE2 PGF2alfa brochoconstriction
inhibits platelet bronchoconstriction LTD4 increase
vasodilator, myometrial contr. vascular
aggregation,
vasodilator hyperalgesia hyperalgesia permeability
LTE4
Evolution in arthritis management: focus on COX-2 inhibitors
Carlos Valdes, PharmD, BCPS. Clinical Science Manager. Pharmacia Co.
April 14, 2002
 The 10 leading causes of death
as a percentage of all deaths
in the United States, 1990 and 1996

1990 1996
Pnemonia Heart Diseases
Tuberculosa Cancer
Diarrhea/Enteritis Stroke
Heart Disease Chronic Lung Diseases
Stroke Accidents
Liver Diseases Pneumonia
Injuries Diabetes
Cancer HIV
Senility Suicide
Diphteria Chronic Liver Diseases

0 2 4 6 8 10 12 0 5 10 15 20 25 30 35 40

Source: CDC, National Center for Health Statistics

 WHO Statistical Information System (WHOSIS)
Numbers and rates (per-100.000) of registered deaths
United States of America - 2000

No Cause N Rate
1 CVS 941.524 668.5
2 Malignancy 553.091 393.4
3 Respiratory disease 186.346 132.5
4 Gastrointestinal disease 84.015 58.8
5 Accidents 73.785 55.1
6 Diabetes Mellitus 69.301 49.2
7 Infectious & Parasitic disease 69.007 42.0
8 Skin & Subcutaneous tissue disease 3.753 2.6
9 Drug, medicaments causing adverse 2.059 2.1
effects in therapeutic use

+ Ulcer of stomach and duodenum 4.504 3.2

Incidence rates of major events possibly prevented
or caused by NSAIDs,
as assessed in observational studies among non-
users

Incidence rate
Event per 1,000 patient years
Heart failure 24
Myocardial infarction 14
Upper GI
bleeding/perforation 0.6 1.7
Colorectal cancer 0.4 0.7
Acute renal failure 0.002 0.08
 NSAID induced CHF
Page J, Henry D. Arch Intern Med. 160:777-84,2000
History of NSAID Odds ratio
heart disease use (95% CI; range)
- - 1
+ - 2.1 (1.2.3.3)
- + 1.6 (0.7 3.7)
+ + 10.5 (2.5 44.9)
The risk increases if NSAID administered:
in higher dose and/or with longer half-life
NSAID GI Toxicity generally varies
with half-life of the agent

Henry, et al. BMJ.312:1563,2000

 NSAIDs and faecal blood loss in elderly patients with
osteoarthritis:
is plasma half-life relevant?
Scharf etal Aust N Z J Med 28(4):436-9,1998

NSAID Diclofenac Naproxen Piroxicam

Dose
(mg/d)
100 750 20

Half-life
1.5 14 50
(hr)
24 hr fecal
0.53 +/- 2.76 +/- 1.16 +/-
blood loss
0.21 2.22 0.62
(mL)
 Weighing the Benefits and the Risks: COX
inhibitors
platelet
aggregation
COX-1
inhibitor
fewer heart attack Bleeding

platelet
bleeding
aggregation

Bleeding
more heart attack
COX-2
platelet inhibitor
aggregation

Lelo A, 2000
Incidence of primary gastrointestinal and cardiovascular end
point in CLASS (celecoxib), VIGOR (rofecoxib) and TARGET
(lumiracoxib)

1.8
COXIB
1.6
NSAID
1.4
1.2
1
0.8
0.6
0.4
0.2
0
GI CV GI CV GI CV
CLASS VIGOR TARGET
FDA Hearing 8.2.2001; Schnitzer TJ et al. Farkouh ME et al. Lancet 2004;364:675-84, 665-74.
 Chemical structure of COXIBs and
clinical effects
Wiholm BE. Identification of
O
S
O O
S
O O
S
O sulfonamide-like adverse drug
H2N Me H2N
reactions to celecoxib in the
N N
CF3 O O WHO database.
N
O
Curr Med Res Opin 17(3):210-
6,2001
celecoxib MK-966 valdecoxib
Celebrex
rofecoxib
Schneider F, et al. Fatal allergic
Vioxx
vasculitis associated with
celecoxib. Lancet
O O
S
O 359(9309):852-3,2002
N
Kumar et al. Fatal
Na
O haemorrhagic pulmonary
N
oedema and associated
angioedema after the ingestion
parecoxib sodium
of rofecoxib. Postgrad Med J.
78:439-40,2002
 RESPIRATORY TOXICITY
AA
NSAID

LTs PGs

bronchoconstriction bronchodilatation

NSAID-induced asthma
 R Muoz-Cano, J Bartra, MC Vennera, A Valero, C Picado.
Asthmatic Reaction Induced by Celecoxib in
a Patient With Aspirin-Induced Asthma

It is suggested that COX-2 inhibitors are

an alternative to NSAIDs for patients who
experience cutaneous or respiratory
symptoms after taking these drugs
(intolerance to NSAIDs).
In fact, 20 minutes after taking 100 mg of
celecoxib, she presented severe dyspnea
with a signifi cant fall in lung function.
Celecoxib oral challenge test
Evolution of FEV1 and urinary leukotrienes during
challenges with aspirin (dotted lines) and celecoxib
(continuous lines).
J All Clin Immun 117(1):215-7,2006
 Lack of efficacy discontinuation:
placebo, etoricoxib, and individual NSAIDs.
in studies conducted over 4 to 12 weeks for OA or RA
Where is the data of
etoricoxib 30 mg,
celecoxib 200mg,
diclofenac 150 mg ?

Where is the data of

etoricoxib 90 mg,
etoricoxib 120mg?

Moore et al. Arthritis Research & Therapy 2008 10:R53

 UK & US Market Withdrawal
Year CV Hepato-
Withdrawn Approval
NSAID event toxicity others

1982 Benoxaprofen 82 deaths

1984 indomethacin 40 deaths
SR
1999 Indoprofen 217 adverse
reactions
Acute liver
1998 1997 Bromfenac failure

2004 1999 Rofecoxib 139.000

AMI/SCD/Stroke ??????

1985 Nimesulide 6
2003 Lumiracoxib 2
Pharmaco-politics ?
 NSAID GI
Toxicity

Lowest GI risk
generally
varies
with half-life
of the agent
Shortest half-life

NSAID Diclofenac Naproxen Piroxicam

Dose (mg/d) 100 750 20
Half-life (hr) 1.5 14 50
24 hr fecal blood
loss (mL) 0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med 28(4):436,1998

 NSAID induced CHF
Page J, Henry D. Arch Intern Med. 160:777-84,2000
History of NSAID Odds ratio
heart disease use (95% CI; range)
- - 1
+ - 2.1 (1.2.3.3)
- + 1.6 (0.7 3.7)
+ + 10.5 (2.5 44.9)
The risk increases if NSAID administered:
in higher dose and/or with longer half-life
Patient issues
Risk population
 Principles of Medical Ethics
in Pain Management
Pharmaco-therapeutic
Principles approaches
BENEFICENCE : Pain killer (analgesic),
mengutamakan
kepentingan pasien
potent, rapid onset
NON MALEFICENCE : Minimal ADR,
tidak memperburuk not deteriorate other
keadaan pasien
clinical problems
JUSTICE : Rational
tidak mendiskriminasikan
pasien, apapun dasarnya
AUTONOMY : Religion, Preference, PRN,
menghormati hak pasien
dalam memutuskan
pharmaco-economics
 Number of Risk Factors &
Incidence of Ulcer Complications

NNH 5
20
18
incidence of ulcer (%)

15
NNH 12
10
8
NNH 50
5 NNH 125
2
0.8
0
No Risk Factor 1-2 Factors 3 Factors 4 Factors

Silverstein FE. Ann Intern Med 1995;123:241-9

 Dental pain in risky population
PATIENT PREDICTABLE
GROUP PROBLEMS
Babies& Infants Communication; drug handling
Elderly Coexisting illness; drug handling
Respiratory Resp depression; NSAIDs &
disease asthma
Renal Failure Drug handling; NSAIDs
Pregnant Early closure of ductus arteriosus
women
Ketepatan Sendok Takar 5 (Lima) Milliliter Sediaan
Cair (Syrup) dari berbagai Perusahaan Farmasi
Sake Juli Martina, Aznan Lelo, Dayat S Hidayat (2007)

Perusahaan Jumlah Volume (ml)

Farmasi Sendok terkecil terbesar
Ethica 1 4,2
Kimia Farma 9 5 5
Universal 3 5 5,8
Sanbe Farma 8 5 6
Phapros 2 5,2 5,4
Suggested dosages of some NSAIDs
for postoperative pain management
NSAID Dose Route
Diclofenac 0.7 - 2 mg/kg Rectal, IM
Ibuprofen 5 - 10 mg/kg oral
Flurbiprofen 1 mg/kg oral
Ketorolac 0.3 0.5 mg/kg IM, IV
Ketoprofen 1 2 mg/kg IV
Naproxen 4 - 6 mg/kg oral
Nimesulide 1.5 mg/kg oral
Tenoxicam 0.75 mg/kg IM
Kokki H. Nonsteroidal anti-inflammatory drugs for postoperative pain.
A focus on children. Pediatr Drugs 5(2):103-23,2003
 Anak: 4 tahun & berat badan 15 kg

diclofenac
Dosis per- hari adalah:
(0,7 2) mg/kg x 15 kg =
(10.5 - 30) mg
dosis terbagi 3 kali sehari,
(3.5 10) mg per-kali
ibuprofen
Dosis per- hari adalah:
(5 10) mg/kg x 15 kg =
(75 150) mg
dosis terbagi 3 kali sehari,
(25 50) mg per-kali

R/ Diclofenac mg 5 R/ Ibuprofen mg 50
Saccharum lactis qs Saccharum lactis qs

m f pulv dtd No X m f pulv dtd No X

S 3 dd pulv I S 3 dd pulv I
 CATAFLAM DROPS
(Diclofenac resinate)
Dosis : 1 tetes/ 1 kg BB/ 1 X pemberian
 Analgesia Delivery Methods
Formula Cel Dic Ket Ibu
Topical
Oral
(cap) (tab) (tab/
syr)

Drops
for child
I.M.
I.V.
Suppository

Prescribing of diclofenac in England (December
2005 to November 2008).
The lines represent the linear regression lines for the proportion of diclofenac
prescribed in England overall before and after November 2007.

Encouraging prescribing trends for NSAIDs

Monday, March 9th, 2009
 Medan PP4GP 2010

KEBANGGAAN INDONESIA UNTUK DUNIA

 Ungkapan Nyeri
Aching = nyeri
Stabbing = tertusuk / tikam
Tender = nyeri tekan
Tiring = nyeri melelahkan
Numb = baal
Dull = nyeri tumpul
Crampy = nyeri kram
Throbbing = nyeri seperti
tercekik
Gnawing = nyeri seperti
digigit
Burning = rasa terbakar
Shooting = rasa menyentak
Sharp = nyeri tajam
Exhausting = nyeri
melelahkan
Nagging = perih
Unbearable = tidak
tertahankan
Squeezing = seperti diremas
Pressure = seperti ditekan
Penetrating = rasa
tertembus
Miserable = menyusahkan
Radiating = menjalar
Deep
Pokdisus=Nyeri.
nyeriPenuntun
dalam Praktis Nyeri
Neuropatik, 2007
 Terminologi Seputar Nyeri
Allodynia Neuritis
Analgesia Neurogenic pain
Anesthesia dolorosa Neuropathic pain
Causalgia Neuralgia
Central pain Hypoalgesia
Hypoesthesia Hyperalgesia
Dysesthesia Hyperpathia
Hyperesthesia
Pokdisus Nyeri. Penuntun Praktis Nyeri Neuropatik, 2007
 Terminologi Seputar Nyeri
Allodynia
Nyeri yang disebabkan oleh stimulus secara
normal tidak menimbulkan nyeri
Hyperalgesia
Respon yang berlebihan terhadap stimulus yang
secara normal menimbulkan nyeri.
Hyperpathia
Sindroma dengan nyeri bercirikan reaksi nyeri
abnormal terhadap stimulus, khususnya stimulus
berulang, seperti peninggian batas ambang.

Pokdisus Nyeri. Penuntun Praktis Nyeri Neuropatik, 2007

 Terminologi Seputar Nyeri
Hypoalgesia
berkurangnya respon nyeri terhadap stimulus
yang dalam keadaan normal menimbulkan nyeri
Paresthesia
Sensasi abnormal, yang tidak menyenangkan baik
spontan ataupun dengan pencetus .
Neuralgia
Nyeri pada daerah distribusi saraf.
 Terminologi Seputar Nyeri
Analgesia
Hilangnya respon nyeri terhadap stimulus yang dalam
keadaan normal menimbulkan nyeri.
Anesthesia dolorosa
Nyeri pada area atau regio yang semestinya bersifat
anestetik.
Causalgia
Sindroma yang timbul pada lesi saraf paska trauma
yang ditandai nyeri seperti terbakar, alodinia,
hiperpatia yang menetap, seringkali bercampur
dengan disfungsi vasomotor serta sudomotor dan
kemudian diikuti oleh gangguan trofik.
 Terminologi Seputar Nyeri
Neuritis
Inflamasi pada saraf
Nyeri Neurogenik
Nyeri yang didahului atau disebabkan oleh lesi,
disfungsi, atau gangguan sementara primer pada
SSP atau SST.
Nyeri Neuropathic
Nyeri yang didahului atau disebabkan oleh lesi
atau disfungsi primer sistem saraf.
 Terminologi Seputar Nyeri
Central pain
Nyeri yang didahului atau disebabkan oleh lesi
atau disfungsi primer pada sistem saraf pusat.
Dysesthesia
Sensasi abnormal, yang tidak menyenangkan baik
spontan ataupun dengan pencetus .
Hyperesthesia
Meningkatnya sensitifitas terhadap stimulus, tidak
termasuk di dalamnya sensasi khusus.
 Klasifikasi Nyeri
Nyeri

Nyeri Nosiseptif Nyeri Non-nosiseptif

Nyeri Nyeri Nyeri Nyeri

Somatik Viseral Neuropatik Fungsional

N. Neuropatik N. Neuropatik
Perifer Central
 Acute vs Chronic Pain

Nociceptive Acute

Neuropathic Chronic
--- frequently intractable

Psychogenic
 Acute Pain
Associated with tissue damage or injury.
Recent onset.
Limited duration.
Stimulation of peripheral and central
nociceptors by algogenic substances
(bradykinin, prostoglandin, leukotrienes,
histamines, substance P, excitatory AAs).
 NYERI CAMPURAN

NOSISEPTIF PATOFISILOGIK

NORMAL INFLAMMATORY NEUROPATIK

contoh NYERI CAMPURAN adalah Low Back Pain

 Diagram Skematik Gate Control Theory
Mekanisme Nyeri
Central control system
cognitive evaluation

Motor
mechanism

Long fibers - + Motivational-

+ Trigger affective-sensory
Impulse Substansi
cells in -discriminative-
a
- spinal
gelatinos - + action system
Small fibers cord
a
+ exitation
- inhibition
Pain
perception
Peripheral pain mechanisms
and nociceptor plasticity
Descending SIGNAL TO NOCICEPTORS
Control
fibers CNS

Satellite
Cells

Lymphocytes
Dorsal
Fibroblasts
Hom
neurons
PMN leukocytes
E, G OP

Macrophages
Glia NGF PG
Pain Blood
transmission Vessels CK

H+
NO BK CELL DAMAGE
and
Platelet INFLAMMATION
NE
Autonomic PG
neurons
Mast cells
Peptides
EAA, NT

EFFERENT ACTIONS
Byers and Bonica, 2000
with permission, meliala modification
 Respons Nyeri: Sensitisasi Perifer
Tissue Sympathetic
Inflammation
damage terminals

SENSITIZING SOUP
H+ Histamines Purines LT
Neurotransmitter K+ Cytokines Nerve Growth Factors
BK PG 5-HT Neuropeptides

High threshold nociceptor

Transduction sensitivity

Low threshold nociceptor

Wolf, Chong. Anesth Analg, 1993

 Apakah semua jenis NYERI harus diterapi
dengan AINS?

Nyeri inflamasi Nyeri dada ?

Nyeri kanker Nyeri epigastrik ?
Nyeri rematik Nyeri inpartu ?

Migrain Nyeri neuropatik ?

AINS
Kenapa harus memilih dan menggunakan AINS?
Bukti saintifik AINS sebagai analgetik

Type of evidence Strength and

Intervensi Cancer Other consistency of
patients patients evidence
Parasetamol dan AINS lainnya
Oral Ia Ib A
Oral IIa Ib A
(adjunct to opioid)
Rectal IIb, IIIb B
Parenteral Ia Ib A
 Pain Transmission
Pain

perception
modulation
Descending
modulation Dorsal Horn

Dorsal root ganglion

transmission
Ascending
input

transduction
Spinothalamic
Peripheral
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
 Sudah kenalkah dengan AINS
(anti-inflamasi non-steroid)
Sediaan yang paling banyak digunakan diklinik
Berkhasiat sebagai
anti-inflamsi
antipiretik
analgetik
Mekanisme kerja adalah menghambat aktivitas
cyclo-oxygenase (COX) dengan demikian kadar
prostaglandin berkurang
Kebanyakan AINS menghambat COX-1 dan COX-2
Namun,
kurang bermanfaat untuk nyeri kronis dan nyeri
neuropatik
Keamanan menentukan penghentian pemakaiannya
Terakhir sekali dipasarkan COX-2 selective inhibitor
Lumiracoxib
 phospholipids

arachidonic acid

COX LOX
COX-2 COX-1
cyclic
endoperoxides 5-HPETE

PGI2
inhibits platelet
TXA2 LTA4
aggregation, stimulates platelet
vasodilator, aggregation,
vasoconstriction LTB4
hyperalgesia chemotaxis

LTC4
PGD2 PGE2 PGF2alfa brochoconstriction
inhibits platelet bronchoconstriction LTD4 increase
vasodilator, myometrial contr. vascular
aggregation,
vasodilator hyperalgesia hyperalgesia permeability
LTE4
 AINS sebagai
analgetik dan anti-inflamasi
Mula kerja sebagai:
Analgetika : 1-2 jam
Anti-inflamasi : 2-3 minggu
Khasiat AINS penghambatan selektif COX-2 tidak
lebih superior dibandingkan AINS klasik
Penghambat selektif COX-2 TIDAK sebagai AINS
BARIS PERTAMA
diperuntukan bagi penderita dengan RIWAYAT
atau yang mempunyai RISIKO TINGGI untuk
mengalami PSMBA
Dosis analgetik dosis anti-inflamasi
Which one do we have to
block in imflammatory
pain?
COX-1 or COX-2
to get analgesic effect
 Torres-Lopez JE, et al.
Comparison of the antinociceptive effect of
celecoxib, diclofenac and resveratrol in the formalin
test.
Life Sci. 70(14):1669-76,2002

Purpose: to compare the antinociceptive action of:

selective COX-2 inhibitor (celecoxib),
preferential COX-2 inhibitor (diclofenac), and
selective COX-1 inhibitor (resveratrol)
Method: formalin-induced inflammatory pain in rat.
Results:
Peripheral administration of celecoxib did not produce
antinociception
diclofenac and resveratrol produced a dose-dependent
antinociceptive effect
 Celecoxib vs Naproxen vs Placebo
single dose post-surgical dental pain study
Placebo Celecoxib 100 mg

3 Celecoxib 200 mg Naproxen 550 mg

2.5

2
Pain relief

1.5

0.5

0
O 1 2 3 4 5 6 7 8
Time (hours)
FDA Advisory Committee Meeting, December 1, 1998
 Salo et al. (2003)
A randomized, clinical trial comparing oral celecoxib 200
mg, celecoxib 400 mg, and ibuprofen 600 mg for acute
pain

600 mg 200 mg 400 mg

0 Ibuprofen Celecoxib Celecoxib
-5
VAS (mm) reduction

-10
-15
-20
-25
-30
-35
NSAIDs: COX-2 vs COX-1 selectivity

100 6-MNA
Naproxen Paracetamol
COX-2 IC50 (M)

Ibuprofen
10
Meloxicam Nimesulide
1 Rofecoxib
Indomethacin Celecoxib

0.1
Diclofenac

0.01
0.01 0.1 1 10 100
COX-1 IC50 (M)
FitzGerald & Patrono. N Engl J Med 345:433,2001
 Summary of analgesic, anti-inflammatory and
antipyretic activity of NSAIDs (ED50 in mg/kg)
ketorolac indomethacin diclofenac ketorolac indomethacin diclofenac ketorolac indomethacin diclofenac
naproxen ibuprofen piroxicam naproxen ibuprofen piroxicam naproxen ibuprofen piroxicam
120 60 8
7
100 50
6
80 40
5
60 30 4
3
40 20
2
20 10
1
0 0 0
analgesic anti-inflammatory antipyretic

NSAID Analgesic Anti-inflammatory Antipyretic

ketorolac 0.7 2 0.9
indomethacin 3 4 2.1
diclofenac 8 7 0.4
naproxen 13 56 0.5
ibuprofen 45 10 7
piroxicam 100 3 1.7
tenoxicam 100 5 1.7
aspirin 228 162 18
 Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Ketorolac Piroxicam Ketoprofen
Meloxicam COXIB
Rofecoxib
Nimesulide Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic

Vane JR et al. Annu Rev Pharmacol Toxicol. 38:97-120,1998.

number needed to treat (NNT) for at least 50% pain relief over 4-
6 hours in patients with moderate to severe pain, all oral
analgesics except morphine, pethidine and ketorolac
 Analgesic ceiling effect of NSAIDs
Incidence of Hypertension
as adverse effect of Rofecoxib
50
10
Percent Responders

40
8
30
6

Incidence (%)
20 4

10 2

0 0
Placebo C 2x100 C 2x200 C 2x400 Rofecoxib 12.5 mg Rofecoxib 25.0 mg Rofecoxib 50.0 mg (n=476)
Celecoxib Celecoxib Celecoxib (n=1215) (n=1614)
Placebo
2 x 100 2 x 200 2 x 400

Simon et al., 1999

 WORLD HEALTH ORGANISATION
ANALGESIC LADDER
Strong opioid
NSAID
adjuvant analgesic
NSAID
adjuvant analgesic
weak opioid
(codeine)
paracetamol
or NSAID
adjuvant analgesic

Pain threshold Pain tolerance

0 1 2 3 4 5 6 7 8 9 10
mild moderate severe
 Reuben SS, Buvanendran A, Kroin JS, Steinberg RB.
Postoperative modulation of central nervous system
prostaglandin E2 by cyclooxygenase inhibitors after vascular
surgery.
Anesthesiology. 104(3):411-6,2006.

CSF PGE2 is elevated in patients after lower

extremity vascular surgery.
Post-surgical intravenous administration of
cyclooxygenase 1 inhibitor ketorolac (30 mg), and
cyclooxygenase 2 inhibitor parecoxib (40 mg),
reduces CSF PGE2 concentration and
postoperative pain.
 HYPERALGESIA
Prostaglandin
BBB BBB BBB BBB BBB BBB BBB BBB BBB
INFLAMMATION
MACROPHAGES

TNF-
IL-6 IL-8

IL-1 SYMPATHETIC
NERVE

COX-2 PG BK
POLYMORPHS
FIBROBLASTS

NOCICEPTOR
Ferreira, 1993 ALGESIA
NSAIDs which can penetrate the
blood-brain barrier

NSAID Reference
oxyphenbutazone, Bannwarth B, et al.,
indomethacin, 1989
ketoprofen
diclofenac Zecca L, et al., 1991
nimesulide, Ferrario P & Bianchi M,
hydroxynimesulide 2003
 Dembo G, Park SB, Kharasch ED.
Central nervous system concentrations of
cyclooxygenase-2 inhibitors in humans.
Anesthesiology. 102(2):409-15,2005

Celecoxib Rofecoxib Valdecoxib

Dose (mg) 200 50 40
CSF (ng/ml) 22 57 25 10 4
CSF/Dose 1 : 100 1:1 1:4
non-acidic COX-2-selective should only weakly affect COX-2 related functions
of the CNS, due to slow blood-brain barrier penetration (Brune & Neubert,
2001)
Capone ML, et al. Int J Immunopathol Pharmacol. 16(2 Suppl):49-58,2003.
Clinical pharmacology of
selective COX-2 inhibitors

Acidic COX-2 inhibitors

have been hypothesized that this
peculiar chemical feature may lead to an
enhanced concentration in
inflammatory sites
that may translate into
an improved clinical efficacy
 NSAIDs with ANTICYTOKINE activities
IL-6 production IL-8 production
NSAIDs TNF-
Basal Stimulated Basal Stimulated

Ibuprofen - - -
Indomethacin - -
Piroxicam - - - - -
Diclofenac - -
Nimesulide - -
Celecoxib - - -
Rofecoxib - - - - -
Sanchez et al. J Rheumatol 29(4):772-82,2002
Henrotin YE, et al. Clin Exp Rheumatol. 17(2):151-60,1999
NSAIDs that can attenuate the algesic
action of BK
Acetylsalicylic acid,
Diclofenac,
Etodolac
Indomethacin,
Ketoprofen,
Meloxicam,
Naproxen,
Phenylbutazone,
Piroxicam,
 COX hypothesized centrally involves
in inflammatory pain

Willoughby DA, et al. COX-1, COX-2, and COX-3 and the future treatment of
chronic inflammatory disease. Lancet 355: 646-8,2000.
Chandrasekharan NV et al. Proc. Natl. Acad. Sci.USA, 2002; 99 (21): 13926-31.
 synaptic transfer of pain signals in the spinal
cord
peripheral sensory
afferent nerve dorsal root central

PAIN

COX-2
COX-2
inflammation
COX-1
EP1, EP3 DP & EP2
EP4 & IP

K-channel
PGD(2), PGE(2), opener
PGF(2alpha) and PGI(2) BK bradykinin
Hyperpolarisation inhibit transmition of pain BK receptor
PG receptor
activation of K(+) channels by diclofenac as
potent analgesic
the peripheral antinociceptive
effect of diclofenac may result
from the activation of several
types of K(+) channels,
which may cause
Activation of hyperpolarization of peripheral
K channels
terminals of primary afferents.
Ortiz MI, et al. Pharmacological evidence for the activation
of K(+) channels by diclofenac. Eur J Pharmacol.
438(1-2):85-91,2002.
Ortiz MI, et al. The NO-cGMP-K+ channel pathway
participates in the antinociceptive effect of
diclofenac, but not of indomethacin. Pharmacol
Biochem Behav. 76(1):187-95,2003.
Alves DP, et al. Diclofenac-induced peripheral
antinociception is associated with ATP-sensitive K+
channels activation.
Life Sci. 74(20):2577-912004.
Bone fracture
healing
COX-2 specific
inhibitors
celecoxib and
rofecoxib
delay bone fracture
healing
 Emerging concern of NSAID used

o Elderly ( > 65 years of age)

o Female (pregnant)
o Previous peptic ulcer, gastrointestinal
bleeding, gastric outlet obstruction
o Concomitant disease (CHF or CRF)
o High dose and or long half-life NSAID
o Concurrent NSAID, steroid, potassium-
sparing agent or anticoagulant therapy
o Bleeding disorders
o Allergy (acetosal, sulfonamide)
 blindness dementia

anorexia hearing loss

heart disease dyspnoe

liver impairment renal impairment

cancer constipation

arthralgia weakness

Pharmacological problems in the elderly

 Mana obat ku ?
Ooh ini dia.
Cara menggunakannya
gimana?

Sudah ku gunakan apa

belum?

3x11x3
Therapeutic effect Adverse effect
Avoid the dangerous drug . . . . .
. . . . . . . . . . . choose the safest one
Kurata etal., (1999)
NSAID loxoprofen prescribed by
an orthopedic to treat a patient with lumbago

Risk factors Case

Age Elderly (80 years)
Gender Woman
Concomitant disease
hypertension
(CVS, kidney & liver)
Concomitant ACE-Inhibitor
drugs used imidapril
The grandmother was syncope
What next? due to hyperkalemia, bradycardia
 The use of NSAIDs in the elderly

Self medication Prescription

Fatal toxic
reactions Safe

elderly
Concomitance chronic short t-
diseases use
NSAID + single
NSAIDs NSAID
topical
Concomitance
drugs
Long t-
COX-2 inh.
women
 PAIN
ALZHEIMER
CANCER DISEASE

NSAID
Rp

water increase epigastric

retention Iatrogenic diseases
BP
PUB
pain

Anti-
Rp
diuretic Iatrogenic
Rp
hypertension COST
Rp
misoprostol Rp
antacid

Prescribing Cascade
 COMPARATIVE COSTS for 28 DAYS THERAPY
(in , spent by the General Medical Services on NSAID in 1999)
DICLO 50 mg TDS +
Lansoprazol 15 mg OD
DICLO/MiSO 75 mg BD
NIMESULIDE 200 mg BD
NIMESULIDE 100 mg BD
MELOXICAM 15 mg OD
MELOXICAM 7.5 mg OD
ROFECOXIB 25 mg OD
ROFECOXIB 12.5 mg OD
CELECOXIB 400 mg OD
CELECOXIB 200 mg OD
DICLOFENAC 50 mg TDS
IBUPROFEN 800 mg TDS

0 10 20 30 40 50
 Biaya pengobatan NYERI AKUT
COXIB Name Rp (rupiah)
BSO
BRAND GENERIC Harga/st Biaya/hr
Celebrex Celecoxib Cap 5.570 11.140
100mg 100mg
Celebrex Celecoxib Cap 8.711 17.422
200mg 200mg
Arcoxia Etoricoxib Tab 6.300 6.300
60mg 60mg
Arcoxia Etoricoxib1 Tab 27.000 27.000
120mg 20mg
Prexige Lumiracoxb Tab 5.500 5.500
400mg 400mg
 cara memilih AINS yang rasional
Pastikan untuk mengatasi nyeri inflamasi
AINS yang aman adalah yang memiliki waktu paruh yang
pendek (diclofenac, ibuprofen, lumiracoxib dsb)
Nyeri akut
Bisa per-oral
Tanpa faktor risiko ; diclofenac, ibuprofen
Dengan faktor risiko: lumiracoxib
Tak bisa per-oral:
Tanpa faktor risiko GI : ketorolac injeksi
Dengan faktor risiko GI: parecoxib injeksi
Kekambuhan akut nyeri kronis
Diclofenac oral atau injeksi diikuti dengan diclofenac slow release
Meloxicam injeksi diikuti dengan meloxicam oral
 cara memilih AINS yang rasional
Nyeri kronis
COX-2 selective inhibitor diawali dengan dosis besar dan diikuti
dengan dosis kecil
Hindari kombinasi AINS dengan
steroid dan AINS lainnya, meskipun COX-1 selektif (aspirin, ketorolac)
dengan COX-2 selectif (celecoxib, etoricoxib, lumiracoxib)
Untuk meningkatkan khasiat AINS, dapat digabungkan dengan
Paracetamol (kecuali COX-2 selektif inhibitor) atau analgetik adjuvan,
Awasi interaksi dengan obat-obatan lain (antihipertensi,
antidiabetes, antikoagulan dsb)
 Pediatric
Pharmacology
Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
 Obat-obat yang mempengaruhi pertumbuhan
dan perkembangan anak
Sifat kimia-fisik obat pada anak
Metabolisme bahan berkhasiat :
Memperlambat pertumbuhan dan perkembangan
Mempercepat pertumbuhan dan perkembangan
Obat-obat yang diekskresikan melalui ASI
PERTUMBUHAN
= perubahan ukuran fisik (ANTROPOMETRI) dari waktu
ke waktu, baik dari segi dimensi, proporsi, maupun
komposisi tubuh

PERKEMBANGAN
= perubahan kemampuan anak
dari waktu ke waktu dalam gerakan motorik
kasar/halus, kecerdasan, mental, dan perilaku
 INTRODUCTION

Children are not miniature of an adult

Physiology

Consider Medical History

Pkinetic
Drug
Pdynamic
Desired result

Psychosocial
Sifat kimia-fisik obat pada
anak
 Pharmacokinetic

Drug Absorpsion

Parameter Neonatus Infant Child

Gastric Acid Secretion Reduce Normal Normal
Gastric Emptying time Decrease Increased Increased
Intestinal Motility Reduce Normal Normal
Billiary Function Reduce Normal Normal
Microbial Flora Acquiring Adult Pattern Adult Pattern
 Absorbsi
Dua faktor yang berperan dalam hal absorpsi obat dari saluran
cerna:
pH dan
waktu pengosongan lambung.
pH bayi yang aterm waktu lahir 6 8, dalam 24 jam turun jadi
1- 3
Bayi prematur lebih lambat mengosongkan lambung, sehingga
akan lebih sempurna diserap karena lebih lama kontak dengan
mukosa saluran cerna.
phenobarbital cepat diabsorbsi, sedangkan
diazepam lebih lambat.
Absorpsi melalui kulit bertambah karena belum
berkembangnya epidermis pada bayi yang baru lahir, ini bisa
menimbulkan keracunan pada penggunaan hexachlorophene
yang ditambhkan pada sabun atau bedak salep asamsalisilat,
alkohol,
 Oral Drug Absorption in
Neonate vs. Older Children
Drug Oral Absorption
Acetaminophen Decreased
Ampicillin Increased
Diazepam Normal
Digoxin Normal
Penicillin G Increased
Phenobarbital Decreased
Phenytoin Decreased
Sulfonamides Normal
 Distribusi
Total body water dibanding dengan berat
badan:
Janin 94%
Prematur 85%
Anak-anak 78%
Dewasa 60%

Extracellular fluid volume dibanding dengan berat

badan
Anak prematur 50%
Bayi 4- 6 bulan 35%
1 tahun 25%
Dewasa 19%
 Distribusi
Distribusi volume gentamycine pada dewasa 0,48L/kg, sedang
pada neonati 0,20L/kg.
Pengikatan obat dengan protein plasma lebih sedikit pada bayi,
karena kadar protein plasmanya , kemampuan mengikat
protein lebih sedikit dibanding dewasa, seperti fenobarbital,
salisilat, peniccilin, chloramphenicol.
Jumlah lemak pada bayi lebih sedikit dari dewaa, juga
mempengaruhi efe. k terapi obabat yang larut lipid lebih sdikit
beredar bada balita dibanding dewasa. Volume distribusi
diazepam pada balita berkisar antara 1,4-1-8 L/kg, dewasa
2,2-2,6 L/kg
 Metabolism

Infant Liver Function <<

Children Liver Function N

 Eliminasi
Eliminasi darimetabolit dan obat terutama melalui
ginjal.Proses filtrasi glomerulus, sekresi tubulus dan
reabsorpsi menetukan efeikasi dari eleminasi obat
melalui ginjal Memerlukan satu tahun sejak lahir
fungsi ginjal sampai sepenuhnya berfungsi.
Karena belum sempurna fungsi ginjal,
chloramphenicol bisa terakumulasi daam tubuh.
Newborn GFR < 50 % adult Elimination > Interval >

Elimination

> 6 months GFR > 90 % adult

 DOSAGE CALCULATION
1. Clark's Rule for Infants or Children:
(Weight in pounds x (Adult dose)
150

2. Fried's Rule for Infants and Children up to 1 to 2 Years:

(Age in Months) x (Adult Dose)
150

3. Young's Rule for Children from 1 year to 12 Years:

(Age in Years) x (Adult Dose)
Age + 12
 Obat-obatan memperlambat
pertumbuhan dan perkembangan anak

Fluoroquinolon
Jangan digunakan oleh wanita hamil, juga selama
laktasi, karena dapat masuk ke dalam air susu ibu
dan akan menyebabkan kelainan di tulang, rawan
dan persendian.
Jangan diberikan pada anak-anak di bawah usia 16
tahun, karena dapat menimbulkan penyimpangan
pada tulang.
Fluoxetine
 Examples on long-term adverse effects of
medicines in early infancy and childhood
Target/ Organ Drug Effect
teeth tetracyclines discoloration/ enamel dysplasia
genital tract cyclophosphamide infertility/ovarian failure
immune system tacrolimus lymphoproliferation
diabetes
heart antracyclines cardiotoxicity
alkylating agens heart failure
methylphenidate cardiovascular events like myocard.
infarct
CNS phenobarbital attention and memory dysfunction
glucocorticoides cerebral palsy
methylphenidate stroke
cisplatin hearing loss
kidney furosemide nephrocalcinosis

bone glucocorticoids growth failure

 Melamine
a white crystalline solid.
Use: manufacture of synthetic resins, in leather tanning.
an industrial chemical used to make fertilizer and plastics.
It can cause renal problems such as kidney stones or
acute renal failure if consumed in large doses, but it
was mixed with powdered milk by suppliers or
manufacturers to artificially boost protein levels.
Nearly 13,000 infants in mainland China and Hong Kong were
admitted to hospital with kidney stones and four have died
after consuming melamine-contained powdered milk, Chinese
media reported in mid-September 2008.
Fetal Alcohol Syndrome (FAS)
4,000-12,000 infants per
year in US
Fetal Alcohol Effect (FAE)
milder form but still serious
nervous system effects
Symptoms included facial
deformities, growth
retardation, sever nervous
system effects and reduced
intelligence
Obat-obatan mempercepat pertumbuhan
dan perkembangan anak

Vitamin Bs
Stimulant methylxanthin
Insomnia, fever, convulsion
Hormone estrogen
Tanda sex sekunder perempuan
 Control of GH Secretion
Stimulation of GH secretion
Blood Glucose
Blood Amino Acids, (Arginine, Leucine)
GRH, TRH, ADH, glucagon, dopamine, uncontrolled Diabetes
Drugs-Dopamine agonists
ExerciseStress sleep puberty
Inhibition of GH secretion
SRIF, IGF, hypothyroidism
Increased Blood Glucose
Dopamine antagonists, chlorpromazine
Emotional deprivation in children, Aging
 Obat-obatan yang
diekskresikan melalui ASI
 Obat dan ASI
obat yang dikontra-
indikasikan bagi ibu
menyususi
Amthoptrine ???,
cimetidine,
methimazole,
cycloposphamide,
obat-obat yang thiouracil dll.
terdistribusi ke dalam obat yang diekskresikan
ASI membawa ke dalam ASI
masalah kepada bayi. MSG
 ASI
obat masuk kedalam
ASI secara difusi pasif
karena lipid di plasma
tidak sebanyak yang
terdapat dalam ASI
yang banyaknya 5-15%
triglyceride, sehingga
obat yang telah masuk
ke dalam ASI tak bisa
kembali ke darah ibu
 Kinetik obat ke ASI
KELARUTAN DALAM LEMAK
IKATAN DENGAN PROTEIN PLASMA
WAKTU PARUH
BERAT MOLEKUL

BIOAVILABILITAS
FARMAKOKINETIK
DOSIS DAN FREKWENSI
JALAN MASUK OBAT

TRANSPOR AKTIF MOLEKUL DARI DINDING KAPILER

IBU KE DALAM ALVEOLUS PAYUDARA
DIFUSI TRANSELULAR
DIFUSI PASIF DARI PLASMA IBU KE DALAM ASI

JUMLAH DAN FREKWENSI MINUM ASI

WAKTU PENGOSONGAN LAMBUNG
 Kinetik obat ke ASI
Kemampuan obat masuk kekompartemen susu
tergantung dari beberapa faktor seperti berat
molekul, kelarutan lipid, kelarutan dalam air,
pengikatan dengan protein plasma, pKa obat.
Makin kecil berat molekul makin banyak obat bisa
masuk kedalam ASI, sebaliknya makin besar berat
molekul makin sedikit masuk ke ASI.
Makin banyak obat terikat dengan protein plasma ibu,
makin sedikt obat yang bebas yang bisa masuk
kdalam ASI.
METODE MENGUKUR PAPARAN OBAT
PADA ASI
MILK PLASMA RATIO [ m/p ratio ]

rasio obat pada ASI

dan obat pada plasma
 EFEK ANTIBIOTIK yang merembes ke
ASI DAN BAYI MENYUSUI
NO. JENIS OBAT PENJELASAN
1 AMINOGLIKOSIDA AMAN UNTUK ASI KARENA TRANSFER DAN AVAILABILITAS
YANG RENDAH
2 SEFALOSPORIN DIANGGAP AMAN KARENA TRANSFER KE ASI RENDAH
SEFALOSPORIN GENERASI KETIGA BERPOTENSI LEBIH
TINGGI UNTUK MENGUBAH FLORA NORMAL
3 FLUROKUINOLON HARUS DIHINDARI, SEBAB MENINGKATKAN RESIKO
ARTHROPATHY
4 MAKROLID AMAN WALAUPUN MENGUBAH FLORA NORMAL USUS

5 PENISILIN AMAN

6 TETRASIKLIN DIHINDARI, RESIKO PEWARNAAN PERMANEN PADA GIGI

DAN EFEK SAMPING PERKEMBANGAN TULANG
7 FLUKONAZOL BERPOTENSI BERAKUMULASI TERUTAMA PADA BAYI
PREMATUR
8 KOTRIMOKSAZOL HINDARI PADA BAYI DENGAN HIPERBILIRUBINEMIA DAN
G6PD
9 KLORAMFENIKOL DIHINDARI. MENIMBULKAN GRAY BABY. KEMUNGKINAN
SUPRESI SUMSUM TULANG TETAP ADA
10 ISONIAZID DAPATMENYEBABKAN HEPATOTOKSIK PADA BAYI
 EFEK ANALGETIK yang merembes ke
ASI DAN BAYI MENYUSUI
NO. JENIS OBAT PENJELASAN
1 ASPIRIN HINDARI KARENA KEMUNGKINAN TIMBULNYA REYES
SINDROME
2 KODEIN KONSENTRASI PADA ASI RENDAH

3 INDOMETASIN KONSENTRASI DALAM ASI RENDAH, KONSENTRASI DALAM

PLASMA BAYI SANGAT RENDAH
4 MORFIN BIOAVAILABILITAS ORAL BURUK, KONSENTRASI PADA ASI
RENDAH, DIANGGAP AMAN.
5 IBUPROFEN KADARNYA TIDAK TERDETEKSI PADA BAYI

6 NAPROXEN WAKTU PARUH PANJANG, MUNGKIN TERAKUMULASI PADA

BAYI JIKA DIGUNAKAN DALAM WAKTU LAMA
7 METADON KONSENTRASI PADA ASI RENDAH

8 PIROKSIKAM HINDARI

9 KETOROLAK KONSENTRASI PADA ASI SANGAT RENDAH

10 PARASETAMOL AMAN

11 MEPERIDIN, PETIDIN HINDARI, KARENA MENYEBABKAN GANGGUAN PERILAKU,

SEDASI DISEBABKAN METABOLI WAKTU PARUH PANJANG
12 FENTANIL KONSENTRASI PADA ASI SANGAT RENDAH
 KESIMPULAN
1. hindari penggunaan
antibiotik dan analgetik
serta obat-obatan lainnya
selama masa laktasi jika
memungkinkan
2. ketahui farmakokinetik /
farmakodinamik dari obat
yang diberikan pada ibu
yang menyusui
3. obat-obat yang belum ada
data tentang keamanan
dan efek sampingnya harus
dihindarkan pada masa
laktasi
 3.RUMUS AUSBERGER
Rumus ini lebih tepat, karena diturunkan dari luas
permukaan badan:

Untuk anak 2 12 thn : ( m + 13 ) % dari D

Untuk anak 1- 11 thn : ( 4n + 20 ) % dari D
Untuk anak 12-16 thn : ( 5n + 10 ) % dari D

* m = umur dlm bulan ; n = umur dlm thn

 Tabel umur-bobot badan-dosis:
Bobot
badan Dosis bayi-anak terhadap
Umur (kg) dosis dewasa
Prematur* 1,13 2,5-5%
1,81 4-8%
2,27 5-10%
Bayi baru
lahir 3,18 12,5%
2 bulan 4,54 15%

4 bulan 6,35 20%

12 bulan 9,98 25%
3 tahun 14,97 33%
7 tahun 22,68 50%
10 tahun 29,94 60%
12 tahun 35,52 75%
14 tahun 45,36 80%
Misalnya pada suatu16malam
tahun anak anda panas demam, tidak90%
54,43 ada persediaan obat penurun
panas untuk anak, yang tersedia adalah tablet parasetamol untuk dewasa. Berat badan anak
15 kg, maka cara menentukan dosis anak adalah:
Carilah bobot badan yang terdekat dalam daftar (yang terdekat dengan 15 kg adalah 14,97 kg),
jadi prosentase dosisnya adalah 33% atau sepertiga tablet dewasa.
 CONCLUSION
Several aspects that need attention in childrens drug
administration are physiological development,
pharmacokinetic, pharmacodynamic, desired therapy
result .

Pharmacokinetic and pharmacodynamic affect the drug

dosage, route and frequency of administration, and
duration of treatment .
 CONCLUSION (cont)
Newborn babies need special attention in drug
administration due to their immature physiological
function .

Accurate Dosage calculation is essential in children drug

therapy.
It can be acquired from three formulas : based on body
weight,body surface area, and age .

Several drug administrations are via

oral route, rectal route and parenteral route
 Efek obat terhadap produksi ASI
Obat yang menghambat produksi ASI
Estrogens
Bromocriptine
Ergotamine
Cabergoline
Pseudoephedrine
Testosterone
Progestins (early)

Obat yang merangsang produksi ASI

Prolactin
 Anak
Anak merupakan suatu amanah dari
Allah SWT,
setiap orang tua menginginkan anak-
anaknya tumbuh menjadi anak yang
soleh, cerdas, sehat dan masa depan
yang cerah
Tumbuh kembang anak harus ditangani
dengan seksama
Kecacatan bayi
 Pemaparan bahan aktif yang mempenguruhi
tumbuh kembang anak

Bahan aktif pada ibu hamil dan menyusui

Paparan pada janin
Paparan pada ASI
Bahan aktif yang ditambahkan pada obat-obatan
untuk anak
Bahan aktif yang ditambahkan pada susu tambahan
Bahan aktif yang ada di lingkungan anak
Bahan aktif pada ibu hamil dan
menyusui
Paparan pada janin & Paparan pada ASI

1
Homocysteine
Kadar homocysteine

Kadar homocysteine
meningkat menurut
usia
Kadar homocysteine
berbeda menurut
gender
o Hormon
o Otot
o Gaya hidup
 Kecacatan jiwa yang berkaitan dengan
peningkatan kadar homocysteine
Alcoholism
Age-related memory decline
Alzheimers disease
Autism
Dementia
Depression, severe (especially in women)
Downs syndrome (children low, mothers high)
Epilepsy in children and adults
Mental retardation
Migraine headaches
Parkinsons disease
Schizophrenia
 Homocysteine dan .
Makin tinggi kadar homocysteine makin jelek
rangking di sekolah (Borjel A, dkk.)
Increasing homocysteine levels were strongly associated
with reducing grades (p=0.004).
Makin tinggi kadar homocysteine makin depresi
(Ingvar dkk.)
homocysteine level above 15 mol/L confers a 2 fold risk
for depression.
Makin tinggi kadar homocysteine makin nyata gejala
tanda gila schizopreni (Levine J dkk.)
schizophrenic patients (16.3 M) compared with in
healthy subjects (10.6 M).
 Kecacatan jasmani yang berkaitan dengan
peningkatan kadar homocysteine

Penyakit pembuluh darah otak

Penyakit pembuluh darah jantung
Penyakit pembuluh darah tepi
Trombosis vena dalaman
Dementia/pelupa
Patah tulang (paha/pinggul)
Neurotoxicity (> 14 mol/L)
Sering keguguran
KECACATAN BAYI
 ANEMIA dalam KEHAMILAN
terhadap ibu terhadap janin
o abortus o prematur
o kelahiran prematur o kematian janin
o persalinan lama
o kematian perinatal
o perdarahan
persalinan o cacat bawaan
o shock o cadangan besi
o payah jantung
kurang
 Asam Folat dan
Neural Tube Defects (NTD)

NTD
spina bifida,
anencephaly
Kecacatan bayi yg paling sering
kejadiannya = 1 - 1.5/1000 kelahiran
Asam folat dapat mencegah sampai 70% NTD
(Czeizel & Dudas, 1992)
Homocysteine metabolism
 Bahan aktif yang TIDAK BOLEH ditambahkan
untuk / dikonsumsi IBU
Teratogenic
Thalidomide
Fetal death
NSAID (in particular COXIB) at late semester or in delivery
time
Early closing ductus arteriosus
Mother intoxication
Alcohol
Psychotropic (XTC, cocaine, morphine, etc)
Smoking
 Importance of Micronutrient
Balance During Pregnancy
Examples of important micronutrients during pregnancy:
vitamin A, vitamin D, folic acid, iron, calcium, zinc
Folic acid and iron deficiency are risk factors for preterm birth,
anemia, and infant mortality
Folic acid and iron supplementation are the most widely used
nutritional interventions during pregnancy
Omega-3 fatty acid supplementation ensures appropriate fetal
and neonatal development
Brain growth and central nervous systems (CNS) maturation
Deficiency can be especially dangerous to mother and fetus
Impaired maternal/fetal immunity, vision disturbance, osteoporosis,
hypertension
Stillbirth, birth defects, decreased cognitive development

1. Bartley KA et al. Am J Clin Nutr. 2005;81:1188S-1198S.

2. Holick MF. South Med J. 2005;98:1024-1027.
3. Lips P. Prog Biophys Mol Biol. 2006;92:4-8.
 Importance of Macronutrient Balance
During Pregnancy
Fats, protein, carbohydrates, water
Adequate intake essential to healthy
pregnancy
Excessive intake may cause maternal obesity
and associated morbidity
Hypertension, gestational diabetes
Maternal obesity also linked to birth defects1
NTDs, congenital heart disease, intestinal
malformations

Eating for 2 does NOT mean doubling intake

NTDs=neural tube defects Bartley KA et al. Am J Clin Nutr. 2005;81:1188S-1198S.
 Dose-Response Relationship Between
Folic Acid and Reduced Incidence of NTDs

Increase in Daily Folic Acid Intake (mg)

0
0 0,2 0,4 0,8 1,0 4,0 5,0

-20
Risk reduction (%)

23%

-40 36%

-60 57%

-80
82%
85%

-100
Wald NJ et al. Lancet. 2001;358:2069-2073.
NTDs=neural tube defects Wald NJ. N Engl J Med. 2004;350:101-103.
 The Role of Omega-3 Fatty Acids
Vital to human development and health
Necessary components of cell membranes and tissues
Involved in human reproductive, brain, and visual function
Cannot be synthesized by the body
Maternal fatty acid levels tend to fall
Supplementation during pregnancy is important for maternal health,
fetal development, and early childhood development
Conversion of ALA is minimal and variable
Only 0.2%-15% of ALA is converted
to DHA
DHA is a major fat of CNS, important to brain, heart, eye health, but
the bodys conversion is inefficient
ALA conversion to EPA is better, but still not sufficient to maintain
adequate recommended levels
ALA = alpha-linolenic acid; EPA = eicosapentaenoic acid;
DHA= docosahexaenoic acid Hornstra G. Am J Clin Nutr. 2000;71(suppl):1262S-1269S.
Kris-Etherton PM et al. Arterioscler Thromb Vasc Biol. 2003;23:1-11.
Maternal Omega-3 Supplementation Augments
Childrens Mental Processing

130
Omega-3s (DHA, EPA) Omega-6s

120
K-ABC scores (mean [SD])

109
110 106 106 103 105
102 102
99
100

90

80
Mental Processing Composite Sequential Processing Simultaneous Processing Nonverbal Abilities
P=0.098 P=0.11 P=0.17
P=0.049

Helland M et al. Pediatrics. 2003;111:e39-e44.

Bahan aktif yang ditambahkan pada
obat-obatan untuk anak
2
Sweeteners
Flavors
Dangerous agents
Bahan aktif yang ditambahkan pada obat-
obatan untuk anak
Obat racikan
Saccharum lactis
Obat jadi
Syrup
Flavors
Alkohol
Tablet kunyah
Flavors
Pemanis rasa
Dangerous agents added to medicines
Alcohol, as a solvent
Fluoride
Thimerosal in vaccinations
 Halogenated organic compounds and
child's growth:
a growing public health problem
Halogenated organic compounds (HOCs) such
as
polychlorinated biphenyls (PCBs) and
dichlorodiphenyl dichloroethylene (DDE) may
interfere with normal hormonal function and,
thereby, affect growth and maturation.
two outcomes, easily observed and frequently linked to
HOCs, are birth size and post-natal height and growth.
toxicants were termed endocrine disruptors
Bahan aktif yang ditambahkan pada
susu tambahan
Nutrient
Supplement
Food additives
Bahan aktif yang ditambahkan pada susu
tambahan

Calcium
Vitamin D
EPA dan DHA

Food additives
Excitotoxins MSG
Aspartame
Neurotransmitters: Excitation and Inhibition
 Excitotoxin
Substances that cause an excess of excitatory
neurotransmission in the brain.
If inhibitory neurotransmission is lacking, the excess
excitation may lead to neuronal death.
Neuronal death leads to chronic inflammation in the brain.
Excitotoxins MSG
Aspartame
Eksitotoksisitas proses patologi dimana neuron
menjadi rusak atau mati akibat stimulasi berlebihan
 MSG = monosodium glutamate
It is believed to cause headaches, vomiting,
severe bleeding, loss of consciousness and
convulsions, inflammation to the womb, and
eventually death.
Some items are believed to enter the breast
milk and cause diarrhea and fever in the baby.
Kerusakan otak akibat penggunaan MSG, area putih
pada gambar kanan adalah neuron yang telah mati
 The link between MSG and obesity

Potato chips and others aren't health foods

They're made with
fried fats,
hidden toxic chemicals (acrylamides), and
monosodium glutamate (MSG).
This is basically a recipe for obesity.
How does MSG cause obesity?
Like aspartame, MSG is an excitotoxin, a substance
that overexcites neurons to the point of cell damage
and, eventually, cell death.
 The link between MSG and obesity
Humans lack a blood-brain barrier in the
hypothalamus, which allows excitotoxins to enter the
brain and cause damage
MSG creates a lesion in the hypothalamus that
correlates with abnormal development, including
obesity,
short stature and
sexual reproduction problems
One characteristic of the obesity induced by
excitotoxins is that it doesn't appear to depend on
food intake.
 EPA dan DHA
omega-3 fatty acids
EPA (eicosapentaenoic acid) and
DHA (docosahexaenoic acid)
are important for child growth and development and
associated with a lower risk of heart disease later in
life
ALA's dietary recommendations for children aged 2
years and older stress a diet that primarily relies on
fish, fruits and vegetables, whole grains, low- fat
dairy products, beans and lean meat
Bahan aktif yang ada di
lingkungan anak
4
 Bahan aktif yang ada di lingkungan anak
Di badan
Pewangi yang ada di bedak, pakaian
Di kamar
Semporan pestisida obat nyamuk (organofosfat)
Di rumah
Gas buangan kenderaan bermotor (carbon monoxide)
Makanan yang tidak sehat (MSG)
Obat-obatan
Bahan keperluan lain seperti LEM
Di sekolah
Pewangi aceton (pencyclidin) yang ada pada penghapus, pinsil,
dsb
 Were Surrounded
It is in the air
Coal-fired power plants spew
sulfates, nitrates and mercury
into the airlinked to >20,000
premature deaths each year
10% of women carry mercury
concentrations high enough for
fetal damage
Manufacturing, transportation,
electricity generation and other
human activities are taking its
toll on our health and
environment
 Home Sweet Womb
Even before were born
Mother exposed = Fetus at risk
Average newborn has 200 different
industrial chemicals, pollutants & pesticides
in blood
Carcinogens
Toxic to brain & nervous system
Abnormal development
Urban air pollution linked to chromosomal
abnormalities in infants
 Exposed to the Elements
Environmental metals:
Cadmium, Copper, Cobalt, Nickel, Lead, Mercury, Tin & Chromium
linked to breast cancer
Cadmium & Mercury found in breast milk of nursing mothers
Cause of early puberty and altered mammary gland
development in animals
Fluoride
Fluorinated drinking water linked to Osteosarcoma & Hypothyroidism
Vaccinations
Thimerosal causes autism in children
Radiation
Increased radiation exposure contributed to rising incidence of breast
cancer between 1950 & 1991
 Teratogenic
refers to the capability of a drug to cause fetal
abnormalities when administered to the pregnant
mother
One of the best-known examples of such a drug-
induced birth defect is the Thalidomide disaster.
The drug was prescribed on a wide scale to pregnant
mothers to ease the anxiety associated with it.
The large-scale consumption of the drug resulted in
children born with seal like limbs, often referred to as
phocomelia.
The drug was banned for prescription in 1961.
 Food Additives
MSG (monosodium glutamate)
Aspartame
40% aspartic acid
50% phenylalanine
10% methanol

FDA approves 4 sugar substitutes which have

no CHO:
aspartame, saccharin, acesulfame-K, sucralose
 The link between MSG and obesity

Potato chips and others aren't health foods

They're made with
fried fats,
hidden toxic chemicals (acrylamides), and
monosodium glutamate (MSG).
This is basically a recipe for obesity.
How does MSG cause obesity?
Like aspartame, MSG is an excitotoxin, a substance
that overexcites neurons to the point of cell damage
and, eventually, cell death.
 EPA dan DHA
omega-3 fatty acids
EPA (eicosapentaenoic acid) and
DHA (docosahexaenoic acid)
are important for child growth and development and
associated with a lower risk of heart disease later in
life
AHA's dietary recommendations for children aged 2
years and older stress a diet that primarily relies on
fish, fruits and vegetables, whole grains, low- fat
dairy products, beans and lean meat
 Drug and
pregnancy
Aznan Lelo
Dep. Farmakologi & Terapeutik,
Fakultas Kedokteran
Universitas Sumatera Utara
 major malformations in general population 2 - 3
%
10 % of congenital abnormalities caused by
teratogens
Teratogen
acts during embryonic / fetal development
permanent alteration of form / function
chemicals, viruses, environmental agents, physical
factors, and drugs
 3 Developmental Period
1. Preimplantation period
2 weeks from fertilization to implantation
"all or none" period
large number of cells damage : embryo death
few cells injury : continue normal development
2. Embryonic period
2 - 8 week following conception
organogenesis
critical periods of sensitivity
structural malformations
 3 Developmental Period
3. Fetal period
9 weeks - term
Maturation and functional development
 Food and Drug Administration Categories for Drugs
and Medications
Category A Controlled studies in human: no fetal risk

Category B Animal studies no fetal risks, but no

human studies; or adverse effects in
animals, but not in well-controlled human
studies
Category C no adequate studies, either animal or
human, or adverse fetal effects in animal
studies but no available human data.
Category D evidence of fetal risk, but benefits are
thought to outweigh these risks
Category X Proven fetal risks clearly outweigh any
benefits
 mechanisms of teratogenesis
disruption of folic acid metabolism
essential for normal meiosis and mitosis
neural-tube defects, cardiac defects, cleft lip and
palate
antiseizure : impair folate absorption or act as
antagonists
 mechanisms of teratogenesis
toxic oxidative intermediates
antiseizure : metabolized by microsomes to arene
oxides or epoxides
free oxide radicals have carcinogenic, mutagenic
and other toxic effects
detoxified by cytoplasmic epoxide hydrolase
fetal epoxide hydrolase activity is weak
 Counseling for teratogen exposure

All women have ~ 3% chance of having a

neonate with birth defect
exposure to confirmed teratogen may
increase risk, by only 1 - 2% or at most
double or triple
risk versus benefit
 Drugs or Substances Suspected or Proven to Be
Human Teratogens
ACE inhibitors Kanamycin
Aminopterin Lithium
Androgens Methimazole
A-II antagonists Methotrexate
Busulfan Misoprostol
Carbamazepine Penicillamine
Chlorbiphenyls Phenytoin
Cocaine Radioactive iodine
Coumsarin Streptomycin
Cyclophosphamide Tamoxifen
Danazol Tetracycline
Diethylstilbestrol (DES) Thalidomide
Ethanol Tretinoin
Etretinate Trimethadione
Isotretinoin Valproic acid
 Ethyl alcohol
Fetal Alcohol Syndrome
Behavior disturbances
Brain defects
Cardiac defects
Spinal defects
Craniofacial anomali
Absent or hypoplastic philtrum
Broad upper lip
Flattened nasal bridge
Hypoplastic upper lip vermilion
Micrognathia
Microphthalmia
Short nose
Short palpebral fissures
 Ethyl alcohol

Clinical Characteristics
congenital heart and joint defects
failure to thrive
persistent irritability
Delay growth & development
poor coordination
Comorbid: mental retardation, attention
deficit/hyperactivity disorder, cerebral palsy and
epilepsy
 Ethyl alcohol

highest risk: chronic ingest large quantities

fetal injury can result from 1-2 drink/d
alcohol 0.5 ounce/day: no alcohol-related effects
increase risk of pregnancy complications
 anticonvulsants

Women with epilepsy increase risk of fetal

malformations
most frequent defects: orofacial clefts and
cardiac malformations
Clefts 10 times more frequently than general
population
more prevalent: high serum concentration and
polytherapy
 anticonvulsants
fetal hydantoin syndrome
microcephaly
growth deficiency
developmental delays
mental retardation
dysmorphic craniofacial features
fingernail hypoplasia
cardiac defect
facial clefts
 anticonvulsants
Drug Teratogenesis Affected
Phenytoin Fetal hydantoin syndrome 5-11%

Carbamazepine Fetal hydantoin syndrome; spina 1-2%

bifida
Valproate Neural-tube defects 1-2%

Trimethadione, Craniofacial anomalies, including 70%

paramethadione cleft palate, V-shape eyebrows,
microcephaly, growth deficiency,
mental retardation, speech
disturbance, cardiac defects
 anticonvulsants
Drug Teratogenesis Affected

Phenobarbital Clefts, cardiac anomalies, urinary 10-20%

tract malformations
Lamotrigine Theoreticallowers fetal folate
levels by inhibiting dihydrofolate
reductase
Topiramate Theoreticalhas produced
defects or abnormal pregnancy
outcomes in all animals tested,
even at low or therapeutic doses
 Anticoagulants
Warfarin (Coumadin)
low molecular weight
cross placenta
1/6 of exposed pregnancies: abnormal liveborn
neonate
1/6: abortion or stillbirth
 Anticoagulants
warfarin embryopathy
expose between 6 - 9 week
nasal and midface hypoplasia
stippled vertebral and femoral epiphyses
Inhibit coagulation proteins osteocalcins
dose dependent : >5 mg/d
phenocopy : chondrodysplasia punctata
genetic diseases
defects in osteocalcin
Anticoagulants
 Anticoagulants
fetopathy
second and third trimester
disharmonic growth from hemorrhage and deformation
from scarring
dorsal midline CNS dysplasia; agenesis of the corpus
callosum, Dandy-Walker malformation
midline cerebellar atrophy
ventral midline dysplasia; microphthalmia, optic atrophy,
and blindness
developmental delay / mental retardation
 ACE inhibitors
ACE inhibitor fetopathy
renal papillary and tubular atrophy
impair urinary concentrating ability
prolong fetal hypotension and hypoperfusion
renal ischemia, renal tubular dysgenesis, anuria
Oligohydramnios; pulmonary hypoplasia, limb contractures
Reduced perfusion; growth restriction, limb shortening,
and maldevelopment of calvarium
 Retinoid
Vitamin A
Beta-carotene; precursor of provitamin A
Retinol; preform vitamin A
vitamin A supplements may be safe during
pregnancy
recommend 5000 IU/ day
 Retinoid
Isotretinoin
13-cis-retinoic acid
effective for treatment of cystic acne
26-fold increased malformation rate
1/3 spontaneous aborted
1/3 neonate with major malformation
serum half-life = 12 hours
 Retinoid
Isotretinoin
bilat microtia/anotia, often asymmetrical
Agenesis/stenoses of external ear canal
cleft palate
maldevelopment of facial bones and cranium
conotruncal or outflow tract defects
hydrocephalus
Thymus; aplasia, hypoplasia, or malposition
 Retinoid
Isotretinoin
 Retinoid
Etretinate
treat psoriasis
anomalies similar to isotretinoin
half-life 120 days
women plan future childbearing should not use
etretinate
If etretinate is used, suggest wait at least 2 years
 Retinoid
Tretinoin
all-trans-retinoic acid
Gel; treat acne vulgaris
Oral; antineoplastic therapy for acute
promyelocytic leukemia
topical tretinoin not increase anomalies
 Hormones
external genitalia: bipotential for first 9 wks
9 - 14 wks testis secrete androgen and develops male
perineal phenotype
female phenotype complete by 20 wks
Exposure to exogenous sex hormones
before 7 completed wks no effect on external structures
7 - 12 wks female genital tissue full masculinization
13 - 20 wks partial masculinization or genital ambiguity
 Hormones
Androgens: masculinizing female external genitalia
Testosterones & anabolic steroid: varying degrees of
virilization
progesterone: DMPA; no congenital defects
Danazol: clitorimegaly, fused labia, and urogenital sinus
malformation
Estrogen: most not affect fetal development
 Diethylstilbestrol (DES)

1940 1971 use DES to "support" high-risk

pregnancies
vaginal clear-cell adenocarcinoma
cancer risk increase to 1 per 1000
not dose related
excess cervical eversion (ectropion)
ectopic vaginal glandular epithelium (adenosis)
 Diethylstilbestrol (DES)
1/4 exposed females: cervix or vagina abnormalities
uterine cavity: hypoplastic, T-shaped
cervical collars, hoods, septa, and coxcombs
withered fallopian tubes
Exposed men
normal sexual function and fertility
increased risk for epididymal cysts, microphallus,
cryptorchidism, and testicular hypoplasia
 Antineoplastic agent

Cyclophosphamide
cell death and DNA alterations
Missing/hypoplastic digits on hands and feet
cleft palate
single coronary artery
imperforate anus
fetal growth restriction with microcephaly
 Antineoplastic agent

Methotrexate and Aminopterin

alter folic acid metabolism
growth restriction
failure of calvarial ossification
craniosynostosis
hypoplastic supraorbital ridges
small posteriorly rotated ears
Micrognathia
severe limb abnormalities
 Thalidomide
1956 - 1960 anxiolytic and sedative drug
Treat; erythema nodosum leprosum cutaneous lupus
erythematosus, chronic graft-versus-host disease,
prurigo nodularis, and malignancies
recommend reproductive-aged women taking
thalidomide use 2 highly effective forms of birth
control
20% exposed fetus produce malformations
 Thalidomide

Defects to structures from mesodermal layer

limbs, ears, cardiovascular system, and bowel
relationship between timing of expose and type of
defect
27 - 30 days upper limb phocomelia
30 - 33 days lower limb phocomelia
42 - 43 days gallbladder aplasia
40 - 47 days duodenal atresia
 Tobacco
nicotine, cotinine, cyanide, thiocyanate, carbon
monoxide, cadmium, lead, and hydrocarbons
doubles risk of low birthweight
increase incidence of subfertility, spontaneous
abortion, placenta previa and abruption, and
preterm delivery
 Tobacco
twice risk of combine cleft lip & palate
4 - 7 times risk for cleft palate alone
hydrocephaly, microcephaly
omphalocele, gastroschisis
hand abnormalities
use with vasoconstrictive drugs: fourfold risk
of gastroschisis and small intestinal atresia
 Cocaine
vasoconstrictive and hypertensive effects
Maternal complications
myocardial infarction
arrhythmias
aortic rupture
stroke
seizure
bowel ischemia
sudden death
fourfold risk of placental abruption
 Cocaine
cocaine-related congenital anomalies
skull defects, microcephaly
cutis aplasia
porencephaly
subependymal and periventricular cysts
ileal atresia
cardiac anomalies
visceral infarcts
fourfold risk of urinary tract defects
behavioral abnormalities, cognitive defects and
developmental delay
 Drugs commonly used in pregnancy

Analgesic
aspirin: not increase risk of anomalies
Acetaminophen: not increase risk of anomalies
NSAIDs
indomethacin
constriction fetal ductus arteriosus and subsequent
pulmonary hypertension
decrease fetal urine output and reduce amnionic
fluid
reversible if discontinue after 34 weeks
 Drugs commonly used in pregnancy

Analgesic
Narcotic
meperidine, morphine, codeine, propoxyphene,
oxycodone, and hydrocodone
not associate with congenital anomalies
chronic maternal ingestion: neonatal withdrawal
syndrome
20 % expose fetus: sinusoidal FHR pattern
Migraine
Ergotamine, Sumatriptan vasoconstriction
not increase anomalies
Third-trimester ergotamine use: fetal bradycardia
 Anesthetic agents
General anesthesia
All cross placenta to some degree
None is teratogen
Local anesthesia
not associate with fetal malformations
fetal bradycardia from diastolic affect
hyperthermia from maternal malignant
hyperthermia
 Anticoagulant
Warfarin/coumarin derivatives cause embryo-fetal
defects
heparin is anticoagulant of choice
low-molecular-weight heparins; enoxaparin
not cross placenta
not associated with fetal malformations
cause maternal osteopenia
thrombolytic agents
Urokinase, streptokinase, tissue plasminogen activator (t-PA)
no teratogenic risk
 Antihypertensive

Methyldopa
most widely used
Safe
Hydralazine
no adverse fetal effects
sodium nitroprusside
cross placenta
Theoretical: accumulation of cyanide in fetal liver
 Antihypertensive
Beta-Adrenergic antagonists
propranolol, labetalol, atenolol, metoprolol,
nadolol, and timolol
FGR and neonatal hypoglycemia
not link to fetal anomalies
Calcium-Channel Blockers
Verapamil:
hypertrophic cardiomyopathy
use with digoxin: fetal cardiac depression and arrest
Nifedipine: no adverse fetal effects
 Antihypertensive
Diuretics
Thiazide
not associate with congenital anomalies
associate with neonatal thrombocytopenia, bleeding, and
electrolyte disturbance
Acetazolamide: not ass with anomalies
Spironolactone: not ass with anomalies
furosemide
cross placenta and increase fetal urine production
increase patent ductus arteriosus in preterm
 Antibacterial agents

Penicillin: probably safest

Cephalosporin: no adverse embryo-fetal
effects
Macrolide:
Erythromycin
penicillin-allergic patients
not cause fetal anomalies
not use to treat maternal syphilis
Azithromycin: no fetal anomalies
 Antibacterial agents

Tetracycline
doxycycline and minocycline
yellow-brown discoloration of deciduous teeth
deposit in fetal long bones
maternal syphilis in penicillin-allergic woman
Aminoglycosides
gentamicin, streptomycin
nephrotoxicity and ototoxicity in preterm newborns and
adults
prenatal exposure congenital defects not confirm
 Antibacterial agents

Sulfonamide
displace bilirubin from protein binding sites
hyperbilirubinemia in preterm neonate
vancomycin
maternal nephrotoxicity and ototoxicity
not associate with congenital defects
Aztreonam: not teratogenic
Imipenem: not teratogenic
 Antibacterial agents

Chloramphenicol
not increase congenital anomalies
large doses in preterm neonate gray baby syndrome
cyanosis, vascular collapse, and death
Quinolones
ciprofloxacin, norfloxacin, ofloxacin, and enoxacin
irreversible arthropathy and cartilage erosion in dogs, mice,
and rats
except for treatment multiresistant infections
 Antimicrobials

tuberculostatic drugs
rifampicin, isoniazid and ethambutol
not increase congenital anomalies
Antifungal Agents
Griseofulvin: possible associate with conjoined twins
Fluconazole and Itraconazole: reports of skull
abnormalities, cleft palate, humeral-radial fusion and
arm abnormalities
 Antimicrobials

Antifungal Agents
clotrimazole, miconazole and nystatin: no
congenital malformations
Amphotericin B: no congenital malformations
 Antiviral agents
thymidine analogue reverse transcriptase
inhibitor
Zidovudine or AZT
not increase anomalies
nucleoside analog reverse transcriptase
inhibitors (NRTIs)
Zalcitabine (ddC), didanosine (ddI), stavudine (d4T),
lamivudine (3TC), abacavir and zidovudine
not increase anomalies
 Antiviral agents
protease inhibitors
amprenavir, indinavir, lopinavir, ritonavir, nelfinavir and
saquinavir
not increase anomalies
purine nucleoside analogues
Acyclovir, ganciclovir and valacyclovir
not increase anomalies
Idoxuridine
treat adenovirus, cytomegalovirus, varicella, and vaccinia
viral infections
eye, palate, head and limbs malformations in rodents
 Antiparasitic agents
Metronidazole: no teratogenic
Lindane
treatment of pediculosis pubis and scabies
10 % absorb systemically
no fetal effects
Antimalarial
Chloroquine not increase congenital anomalies
Mefloquine safe
Quinine/quinidine no defect at therapeutic doses
Mebendazole: no teratogenic
 Asthma medications

Epinephrine/terbutaline: no adverse fetal

effects
Metaproterenol/albuterol: no adverse fetal
effects
Theophylline, Aminophylline: safe
Cromolyn: not increase anomalies
Glucocorticoids no adverse human fetal
effects
 Cardiac medications

Digoxin: no adverse fetal effects

Quinidine: no fetal abnormalities
b-blockers: not teratogenic
Antiarrhythmic drug
disopyramide, amiodarone, adenosine,
bretylium, diltiazem, No
local anesthetics (procainamide, adverse
lidocaine and
tocainide) effect
calcium antagonists (nifedipine and
verapamil)
 Cardiac medications

Antiarrhythmic drug
Amiodarone
structural similar to thyroxine
10 - 30 % of maternal serum levels cross
placenta
fetal and neonatal hypothyroidism
 Hormones
Oral contraceptives: not associate with congenital
anomalies
Gonadotropin-releasing hormone (GnRH) agonists:
limit data
Immunosuppressive agents
Azathioprine
not teratogenic
increase growth restriction, immune suppression and
pancytopenia
Cyclosporine
maternal nephrotoxicity
safe for fetus
 Psychotropic drugs

Benzodiazepines
Diazepam
cleft palate, limb malformations in rodents
not associate fetal anomalies
lorazepam and midazolam
no birth defects
long-term maternal use neonatal depression,
somnolence and withdrawal symptoms
Alprazolam
not increase anomalies
 Psychotropic drugs
apical displacement of
Lithium salts septal and posterior
treat manic-depression tricuspid valve leaflets
cardiac defect: Ebstein anomaly
toxic fetal effects: diabetes insipidus, hypothyroidism and
hypoglycemia
avoid lithium exposure at least 6 - 8 wks' gestation
MAO inhibitors
Isocarboxazid, Phenelzine, Tranylcypromine
Class C
 Psychotropic drugs

selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine, Paroxetine, Sertraline
not cause birth defects
Tricyclic antidepressants
Amitriptyline, Amoxapine, Clomipramine,
Desipramine, Doxepin, Imipramine, Nortriptyline
not increase anomalies
 Iodide
cross placenta
may produce large fetal goiter
Antiemetics
Vitamin B6 (pyridoxine): no teratogenicity
Dimenhydrinate: no teratogenicity
Ondansetron: not evaluated for teratogenicity
Acid-Suppressing Drugs
cimetidine, ranitidine, omeprazole
no teratogenicity
 Disease treatment in the pregnant patient
should be similar to that given to other
patients.
Rather than using the FDA Drug Classification
System, references and information in
databases should be sought for particular
medications in specific clinical situations.
 Most drugs are safe to use during pregnancy,
including most antibiotics and medications to
treat common conditions
Most antibiotics are safe in pregnancy.
Tetracyclines cause tooth discoloration in the
second and third trimesters.
A few medications are known teratogens
 Most drugs are safe during lactation because
the amounts in breast milk are subtherapeutic,
~1% - 2% of the maternal dose. Exception is
lithium
 Drugs Contraindicate during Breast-Feeding

Cytotoxic Agents
Cyclosporine, doxorubicin, cyclophosphamide
immune suppression
Bromocriptine
inhibit lactation
Ergotamine
vomiting, diarrhea and convulsions in infant
Lithium
1/3 1/2 therapeutic blood concentration in infant
hypotonia and lethargy
 Radioactive Compounds Require Temporary
Cessation of Breast-Feeding
no radioactivity is detectable in milk
67 Ga, 2 weeks
131 I, 5 days
radioactive sodium, 4 days
99 Tc, 24 hours
 Temporary cessation of breast-feeding 12 - 24
hours after a single dose of metronidazole
Side effect possible
monitor baby drowsiness: psychiatric drug &
anticonvulsant
Monitor baby jaundice:sulfonamides, dapsone,
bactrim, fansidar
Drug may inhibit lactation
Estrogen, estrogen containing contraception,
thiazide diuratic
 Minimizing risk from
maternal medication
General consideration
Avoid drug therapy when possible
Use tropical therapy when possible
Drug that safe for use directly in infant, generally
safe fore breast fedding mother
Drug safe in pregnancy not always safe in breast-
feeding
Use reliable reference for information on
medication
 Minimizing risk from
maternal medication

Medication selection
Choose shortest hafelife & highest protein-binding
ability
Choose that are well-study in infant
Choose poorest oral absorption
Choose lowest lipid solubility
 Minimizing risk from
maternal medication
Medication doseing
Single daily-dose just before fetal longest sleep
interval
Breast-feeding immediately before medication
dose when multiple daily dose are needed