Introduction of

Pharmacology
Indwiani Astuti
Dep. Pharmacology & Therapy
Fac of Medicine
Universitas Gadjah Mada
Yogyakarta
Lectures

Drugs in infants & children

Pharmacology of Drug for Adult &
Elderly
Drugs in Pregnancy & Lactation period
 Pharmacology
DEFINITIONS:
Pharmacology is the study of how drugs exert
their effects on living systems.
Pharmacologists work to identify drug targets
in order to learn how drugs work.
Pharmacologists also study the ways in which
drugs are modified within organisms.
In most of the pharmacologic specialties,
drugs are also used today as tools to gain
insight into both normal and abnormal
function.
Pharmacology

Divisions of Pharmacology
Pharmacokinetics

Pharmacodynamics

Pharmacogenomics
Pharmacokinetics

Is what the body does to the drug.

The magnitud of the pharmacological
effect of a drug depends on its
concentration at the site of action.
Absorption
Distribution
Metabolism
Elimination
Pharmacodynamics
Is what the drug does to the body.
Interaction of drugs with cellular proteins, such as
receptors or enzymes, to control changes in
physiological function of particular organs.
Drug-Receptor Interactions
Binding
Dose-Response
Effect
Signal Transduction
Mechanism of action, Pathways
 Pharmacodynamics
Graded Dose-Response
Curves
Emax
R R Emax
e e
s s
p p
o o
n n
s s
e e
EC50 EC50

Dose (log) Dose (linear)

Pharmacodynamics
Quantal (either-or) dose A high therapeutic index
response indicates that the drug produces
the desired effect at a dose that
is rarely lethal; there is a large
Therapeutic index relates the margin of safety
dose of a drug required to
produce a desired effect to that

% of individuals responding
Therapeutic Lethal or Toxic
which produces an undesired
effect
T.I. = LD50(lethal dose in 50%) <Margin of safety>
ED50(effective dose in
50%) ED50 LD50

Dose (log)
Pharmacogenetics
Area of pharmacology concerned with unusual
responses to drugs caused by genetic differences
between individuals.
Responses that are not found in the general
population, such as general toxic effects, allergies,
or side effects, but due to an inherited trait that
produces a diminished or enhanced response to a
drug.
Differences in Enzyme Activity
Acetylation polymorphism
Butylcholinesterase alterations
Cytochrome P450 aberration
Drugs
Drugs can be defined as chemical agents that
uniquely interact with specific target molecules
in the body, thereby producing a biological
effect.

Drugs can be stimulatory or inhibitory

Drugs

Drugs, as well as hormones, neurotransmitter, autocoids

and toxins can make possible the transfer of information
to cells by interaction with specific receptive molecules
called receptors.

DRUG

Recepto
r
 Drugs
Drugs interact with biological systems in ways that mimic,
resemble or otherwise affect the natural chemicals of the
body.

Drugs can produce effects by virtue of their acidic or basic

properties (e.g. antacids, protamine), surfactant properties
(amphotericin), ability to denature proteins (astringents),
osmotic properties (laxatives, diuretics), or
physicochemical interactions with membrane lipids
(general and local anesthetics).
Pharmacotherapy
 Absorption
Must be able to get medications into the
patients body
Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, &
formulation
Factors affecting drug absorption related to
patients:
Route of administration, gastric pH, contents of
GI tract
Factors Affecting Oral
Absorption
Bioavailability

Stability

Permeability

First Pass Metabolism

Bioavailability

The fraction of drug that reaches the systemic

circulation after oral ingestion
Absolute bioavailability
Determined by comparing blood concentrations of
drug after IV dosing with those after dosing by
oral route
Relative bioavailability
Is a term used to compare different formulations
of the same medication
 Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver

to
Dose systemic
circulation
Stability
Rate of release of drug from
pharmaceutical preparation

Blood flow to site of absorption

Surface area in contact with drug

Destruction of drug at or near site of

absorption
 Drug Absorption

absorption hepatic
dissolution metabolism

disintegration

gastric emptying rate

intestinal
intestinal transit rate metabolism
dissolution
absorption
disintegration
First Pass Metabolism

Concentration of drug is greatly reduced

before it reaches systemic circulation
Can occur when drug absorbed from the small
intestine is transported first via the portal
system to the liver
Some drugs more extensively metabolized in
the intestine than in the liver
 First Pass Metabolism: Intestinal Drug
Metabolizing Enzymes and Transporters

CYP

Blood (basolateral)

CYP CYP CYP CYP CYP CYP

P-gp P-gp P-gp P-gp P-gp P-gp

GI tract (apical)

Fletcher CV. Medscape 2005

Time to Peak Concentration
100
90
80
concentration

70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
 Distribution
Membrane permeability
cross membranes to site of action
Plasma protein binding
bound drugs do not cross membranes
malnutrition = albumin = free drug
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution
Factors Affecting Distribution

Cardiac output/regional blood flow

Organ perfusion
Permeability of cell membranes/drug
transporters
Body Composition
Total and extracellular water
Fat
Degree of protein binding
Developmental Changes in
Distribution Sites Adapted from Kearns, et al NEJM 2003

Neonates and infants usually display

Vd for hydrophilic drugs because of excess
body water
Vd for lipophilic drugs because of decreased
body fat
Degree of Protein Binding
Change from Adult Values
Newborn Infant Child
Total Protein =
Albumin = =
1-acid glycoprotein =
Fetal albumin Present Absent Absent
Globulin =

Neonatal serum contains ~80% as much protein as adults

Many at birth and during infancy, but approach adult
values about 1 years of age
endogenous substances (bilirubin and free fatty acids)
capable of displacing drug from binding sites
Metabolism

Drugs and toxins are seen as foreign to

patients bodies
Drugs can undergo metabolism in the
lungs, blood, and liver
Body works to convert drugs to less
active forms and increase water
solubility to enhance elimination
Metabolism

Liver - primary route of drug

metabolism
Liver may be used to convert pro-drugs
(inactive) to an active state
Types of reactions
Phase I (Cytochrome P450 system)
Phase II
 Phase I reactions
Cytochrome P450 system
Located within the endoplasmic
reticulum of hepatocytes
Through electron transport chain, a drug
bound to the CYP450 system undergoes
oxidation or reduction
Enzyme induction
Drug interactions
Phase I reactions types

Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism
Phase II reactions

Polar group is conjugated to the drug

Results in increased polarity of the drug
Types of reactions
Glycine conjugation
Glucuronide conjugation
Sulfate conjugation
Factors Affecting Metabolism

Hepatic blood flow

Ability of the liver to extract the drug
from the blood
Drug binding in the blood
Hepatic Enzymes
Inhibition of Hepatic Enzymes
4000
3500
Concentration (ng/ml)

3000 SQV/RTV 800/100 mg bid

2500
2000
1500
1000
SQV 1200 mg tid
500
0
0 2 4 6 8 10 12
Time (hr)
Appearance of Phase I Enzymes

Total CYP450 content in fetal liver is 30-60%

of adult values
CYP3A7
Peaks shortly after birth then rapidly to levels
undetectable in most adults
CYP3A4, 2D6, and 2C
Appear during the first week of life
CYP1A2
One to three months of life
Appearance of Phase II
Enzymes
Sulfation enzymes are well developed even in
premature infant
Glucuronosyltransferases have unique
maturation profiles
APAP (UGT1A6 and 1A9) glucoronidation is
decreased in newborns and young children
compared with adolescents and adults
UGT1A1 is absent from fetal liver and reaches
adult values by 6 months of life
Elimination

Pulmonary = expired in the air

Bile = excreted in feces
enterohepatic circulation
Renal
glomerular filtration
tubular reabsorption
tubular secretion
 Elimination
of drugs from the body

M KIDNEY LIVER
A
J filtration metabolism
O secretion secretion
R (reabsorption)

M LUNGS OTHERS
I
N exhalation mother's milk
O sweat, saliva etc.
R
 Elimination by the Kidney
Excretion - major
1) glomerular filtration
glomerular structure, size constraints,
protein binding

2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport,
competitive/saturable, organic
acids/bases -
protein binding

Metabolism - minor
Factors affecting Excretion

Renal blood flow

Concentrating and acidifying ability
Glomerular Filtration
Tubular Function
Secretion
Reabsorption
Elimination by the Liver
Metabolism - major
1) Phase I and II reactions

2) Function: change a lipid soluble to

more water soluble molecule to excrete in
kidney

3) Possibility of active metabolites with

same or different properties as parent
molecule

Biliary Secretion active transport, 4

categories
The enterohepatic shunt
Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder

Portal circulation

Gut
Children are not just small adults!
Children are not just small adults!
Non-linear changes in body composition
Body weight: doubles by 5-months, triples by a year.
Body length: increases by 50% by 1-year
Body surface area: doubles by 1-year
Total body water: 85% in premature neonate
70% in full term infant
55% in an adult
Protein binding reaches adult levels at approximately
1-year
 Similar to adults, a relationship between
what the body does with a drug
(pharmacokinetics) and what the drug
does to the body (pharmacodynamics) is
present in children
It is mainly the pharmacokinetics that
change during childhood, but
pharmacodynamics is important, as some
drug adverse events may mainly present
in children
 Developmental differences occur in all
aspects of drug metabolism

Absorption (gastric pH, gastric emptying, first-pass

metabolism in stomach, bowel or liver)
Distribution (changes in body composition, protein or
tissue binding)
Metabolism (complicated, many enzymes involved)
Excretion (liver and kidney are several fold greater
relative to body weight in children compared to adults)

(McCarver DG. Pediatrics 2004; 113: 969-972)

Pediatric Distribution

Body Composition
total body water & extracellular fluid
adipose tissue & skeletal muscle
Protein Binding
albumin, bilirubin, 1-acid glycoprotein
Tissue Binding
compositional changes
Pre-term Infant Term Newborn Infant/Toddler Child Adolescent
< 36 weeks of Infant 28 days -23 months 2 - 11 years 12 - 17 years
gestation 0-27 days

Adaptation
Survival Growth Training Maturation

Seyberth, in Pdiatrie, eds Speer/Gahr, 2005

Pharmacokinetic differences in the term and preterm
infants
Absorption: Gastric HCI-production
Bile flow
Bacterial intestinal growth
Enterohepatic circulation

Distribution: Body water

Body fat
Muscular mass
Plasma protein binding

Liver metabolism: Hydroxylation

Glucoronidation

Renale excretion: GFR

Tubular function
An important dosage-principle in the
NICU
Given: Vd
Clearance

Result: Loading dose (LD)

Maintenance dose (MD)

Examples: Phenobarbital, Phenytoin,

Methylxanthine, Digoxin,
Aminoglykoside, Indometacin
Chloramphenicol, Furosemide
Maintenance dose of drugs with renal elimination THEOPHYLLINE

DIGOXIN Total body clearence

(g/kg/day) (ml/h/kg)
20 - 100 -

15 - 75 -

10 - 50 -

5- 25 -

0 0

-
-
-

-
-
-

-
Preterm Young Adults Adults Preterm Young Adults Adults
+ term children (< 50 y) (> 50 y) + term children (< 50 y) (> 50 y)
neonates (< 8 y) neonates (< 8 y)

GENTAMYCINE (mg/kg/day) Maintenance dose

(mg/kg/day)
30 -
10 -

20 -
5-
10 -

0 0
-
-

-
-

-
-

Preterm Young Adults Adults Preterm Young Adults Adults

+ term children (< 50 y) (> 50 y) + term children (< 50 y) (> 50 y)
neonates (< 8 y) neonates (< 8 y)
PHARMACOKINETICS PHARMACODYNAMICS

Resorption

Distribution Receptor

Excretion Signal transduction

Cellular reaction
 Medium analgesic dosage of morphine
in children with an age between 0 and 6 years

p < 0.01
Morphine plasma concentration [g/l]

40
at time point of pain recovery

30 dosis:
0.05 mg/kg/min infusion
20 rate until painlessness

10

0
0 - year 2 - 4 year 6 year
n=5 n=5 n=4

(Olkkola et al., CPT 1988)

 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
glucocorticoides dysfunction
methylphenidate cerebral palsy
stroke
cisplatin hearing loss
kidney furosemide nephrocalcinosis

bone glucocorticoids growth failure

 Elderly

Despite stereotype most of the elderly

age well!
 Problems
Pharmacokinetics
Pharmacodynamics
Adverse drug reactions and adherence
Underuse of drugs
Nonprescription and alternative
therapies
Polypharmacy

UCSF Division of Geriatrics Primary Care

Lecture Series May 2001
 Pharmacokinetics and Aging
Absorption - gastric pH higher, decreased
motility and absorption
Distribution - reduced total body water, proteins
and lean body mass, and increased total body fat
 Pharmacokinetics and Aging
Absorption - gastric pH higher, decreased
motility and absorption
Distribution - reduced total body water, proteins
and lean body mass, and increased total body fat
Metabolism - hepatic oxidative pathways
impaired (benzodiazepines) and P-450 (B-
blockers, TCAs, verapamil)
Excretion - reduced GFR and change in tubular
function (aminoglycosides, lithium, digoxin)
Pharmacokinetics
Decrease in total body water (due to decrease
in muscle mass) and increase in total body fat
affects volume of distribution
Water soluble drugs: lithium,
aminoglycosides, alcohol, digoxin
Serum levels may go up due to decreased volume
of distribution
Fat soluble: diazepam, thiopental, trazadone
Half life increased with increase in body fat

UCSF Division of Geriatrics Primary Care

Lecture Series May 2001
Pharmacodynamics
(effect of drugs at target site)

No generalization regarding receptor

numbers or affinity or hormone levels
Examples of changes are insulin
receptors, Beta receptors and heart, Ach
receptors and colon
Pregnancy & Lactation Period
Development
 Category A
Drugs which have been taken by a large number of
pregnant women and women of childbearing age
without any proven increase in the frequency of
malformations or other direct or indirect harmful
effects on the fetus having been observed.
Category C
Drugs which, owing to their pharmacological effects,
have caused or may be suspected of causing, harmful
effects on the human fetus or neonate without
causing malformations.
These effects may be reversible. Accompanying texts
should be consulted for further details.
 Category B1
Drugs which have been taken by only a limited
number of pregnant women and women of
childbearing age, without an increase in the
frequency of malformation or other direct or indirect
harmful effects on the human fetus having been
observed.
Studies in animals have not shown evidence of an
increased occurrence of fetal damage.
 Category B2
Drugs which have been taken by only a limited
number of pregnant women and women of
childbearing age, without an increase in the
frequency of malformation or other direct or indirect
harmful effects on the human fetus having been
observed.
Studies in animals are inadequate or may be lacking,
but available data show no evidence of an increased
occurrence of fetal damage.
 Category B3
Drugs which have been taken by only a limited
number of pregnant women and women of
childbearing age, without an increase in the
frequency of malformation or other direct or indirect
harmful effects on the human fetus having been
observed.
Studies in animals have shown evidence of an
increased occurrence of fetal damage, the significance
of which is considered uncertain in humans.
 Category D
Drugs which have caused, are suspected to have
caused or may be expected to cause, an increased
incidence of human fetal malformations or
irreversible damage. These drugs may also have
adverse pharmacological effects. Accompanying texts
should be consulted for further details.
 Category X
Drugs which have such a high risk of
causing permanent damage to the fetus
that they should not be used in
pregnancy or when there is a possibility
of pregnancy.
Medical Drugs
Antibiotics (tetracylines)
Anticancer drugs
Anticonvulsants (Valproic Acid)
Lithium
Retinoids (Vitamin A)
Thalidomide
Diethylstilbestrol (DES)
Anticoagulants (Warfarin)
Recreational Drugs

Alcohol (ethanol)
Tobacco
Cocaine
Solvent abuse
Case Studies

Thalidomide
Ethanol (Alcohol)
Methylmercury
Lead
Thalidomide
Introduced in 1956 as sedative
(sleeping pill) and to reduce
nausea and vomiting during
pregnancy
Withdrawn in 1961

Discovered to be a human teratogen causing

absence of limbs or limb malformations in
newborns
5000 to 7000 infants effected
Resulted in new drug testing rules
Discharge into Minamata Bay

Polluting with HG
Fetal Effects of MeHg
Life-Long Effects of MeHg
The Mercury Cycle
Ibu Hamil & Menyusui

3 hal penting
Ibu
Proses kehamilan (abortus, prematur,
gangguan proses persalinan)
Janin (teratogenesis)
Faktor-faktor yang mempengaruhi obat
menembus sawar uri

Sifat fisikokimia obat

Kecepatan obat melintasi sawar uri
(volume & vaskularisasi)
Lama pemaparan obat
Distribusi obat
Periode/fase perkembangan janin
Obat kombinasi
Sifat obat sawar uri

Sifatlipofilik difusi ke plasenta

Obat terionisasi makin tinggi makin
lambat difusi
BM obat
Farmakokinetik pada ibu hamil

1. Perubahan pH lambung (>basis, meningkat 30-

40%, karena penurunan sekresi asam lambung):
Obat asam lemah absorpsi menurun
Obat basa lemah absorpsi meningkat
2. Penurunan motilitas usus (obat lambat bergerak)
Absorpsi meningkat (obat yang tidak dimetabolisme di usus:
digitalis)
Absorpsi menurun (klorpromazin)
 3. Peningkatan volume plasma & cairan
(50%)
4. Penurunan albumin (obat bebas>>)
5. Peningkatan eliminasi renal (obat
mudah diekskresi)
Obat pada janin

Gangguan pertumbuhan/
Abortus/lethal Cacat organ/tubuh fungsi

Fase implantasi Fase organogenesis Fase fetal

<3 minggu 3 -8 minggu Trimester II-III

Periode perkembangan fetus

Regulasi (Katagori FDA)

Kategori A: obat relatif aman (parasetamol, penisilin, eritromisin, inh, Fe, folat
Kategori B: penggunaan terbatas, tidak meningkatkan kejadian malformasi:
B1 tidak menimbulkan malformasi janin: simetidin, dipiridamol,
B2 data tidak memadai, tidak menimbulkan kerusakan: dopamin, asetilsistein
B3 pada hewan coba meningkatkan kejadian malformasi, tetapi pada manusia
belum terbukti: karbamazepin, trimetorpin, mebendazol
Kategori C: efek pada janin tanpa malformasi dan umumnya bersifat reversibel:
analgetik-narkotik, fenotiazin, rifampisin, aspirin, diuretika dan NSAID
Kategori D: meningkatkan malformasi pada manusia, menyebakan, kerusakan
iireversibel. Androgen, fenitoin, pirimidon, fenobarbiton, kinin, klonazepam,
valproat, anabolik steroid, heparin
Kategori X: kerusakan irreversibel pada janin. Kontraindikasi ibu hamil.
Isotretionin (Vit A), dietilbestrol, antineoplastik
Obat-obat yang perlu perhatian khusus
untuk ibu hamil

a. Anti inflamasi non steroid (AINS)/NSAID: kerja menghambat

sintesis prostaglandin, gangguan pada Trimester III
Persalinan lama
Hipertensi pulmonal janin
b. Anti emetik (siklizin, meklozin): pada hewan coba efek
teratogenik, pada manusia belum terbukti
c. Anti infeksi:
Tetrasiklin mudah melewati sawar uri, terikat kalsium & fosfat
ganggu pertumbuhan tulang & gigi janin (brown teeth)
Aminoglikosid tembus sawar uri merusak nervus cranial VIII
(pengatur keseimbangan & pendengaran; rusak ginjal) kategori
D
 d. Anti hipertensi
1. Antagonis kalsium (venapamil, nefidepin, ditiazem)
hipoksia fetal
2. diuretik, mengurangi volume plasma mengurangi
perfusi utero plasenta
3. Reserpin, kontraindikasi TIII mengganggu termoregulasi
4. adrenergik bloker (derisokuin, guanetidin), hipotensi
postural penurunan perfusi utero plansenta
5. ACE-Inhibitor meningkatkan mortalitas janin
Kejadian Efek Samping Obat pada Usia
Lanjut
Resiko ESO 2 kali lipat tu. Analgetika, antihipertensi,
antiparkinson, antipsikotk, sedatif, obat gastrointestinal
Bentuk ESO yang sering terjadi
Ataksia: gangguan gerak
Hipotensi postural
Kebingungan
Retensi urin
konstipasi
ESO terjadi karena
Kesalahan peresepan, interaksi obat, polifarmasi
Kesalahan pasien mencoba obat OTC, Jamu dll
Informasi yang tidak jelas
Pelupa
 Obat-obat yang pehatian perlu
perhatian khusus
Obat pada susunan syaraf pusat, sedatif
hipnotik, analgetika, antidepresan
Obat antibiotika, golongan aminoglikosida,
laktam
Laksansia
Obat-obat kardiovaskuler, antihipertensi,
antiaritmia, glikosida jantung
 Prinsip pengobatan pada Usia Lanjut
Riwayat penggunaan obat, meliputi: obat sebelumnya, obat
yang pernah digunakan
Obat yang digunakan atas indikasi dan tujuan yang tepat
Pemberian obat mulai dosis terkecil
Berikan informasi yang jelas mengenai cara penggunaan dan
efeknya
Bila perlu tempatkan pada botol yang tertuliskan indikasinya
dan kapan meminumnya