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Pharmacology
Indwiani Astuti
Dep. Pharmacology & Therapy
Fac of Medicine
Universitas Gadjah Mada
Yogyakarta
Lectures
Divisions of Pharmacology
Pharmacokinetics
Pharmacodynamics
Pharmacogenomics
Pharmacokinetics
% 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.
DRUG
Recepto
r
Drugs
Drugs interact with biological systems in ways that mimic,
resemble or otherwise affect the natural chemicals of the
body.
Stability
Permeability
to
Dose systemic
circulation
Stability
Rate of release of drug from
pharmaceutical preparation
absorption hepatic
dissolution metabolism
disintegration
intestinal
intestinal transit rate metabolism
dissolution
absorption
disintegration
First Pass Metabolism
CYP
Blood (basolateral)
GI tract (apical)
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
Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism
Phase II reactions
2500
2000
1500
1000
SQV 1200 mg tid
500
0
0 2 4 6 8 10 12
Time (hr)
Appearance of Phase I Enzymes
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
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
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
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)
20 -
5-
10 -
0 0
-
-
-
-
-
-
Resorption
Distribution Receptor
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
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
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
Gangguan pertumbuhan/
Abortus/lethal Cacat organ/tubuh fungsi
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