BIOFARMASI: RUTE

PER ORAL
Oleh: Ema Pristi Yunita, M.Farm.Klin., Apt.
ANATOMI SISTEM
PENCERNAAN
FUNCTION OF GASTROINTESTINAL
ORGANS
GI Organization
pH = 1 - 3
disintegration
pH = 5 - 7
disso-
disintegration lution
absorption
disso- lution
intestinal metabolism

FASE FARMASETIKA
Pharmacological effect
gastric emptying rate
intestinal transit rate
hepatic metabolism
absorption
faeces
clearance

RUTE PEMBERIAN
OBAT
ENTERAL
PARENTERAL
• Oral
• Intravenous (IV)
•Nose (Intranasal)
• Intra-arterial (IA)
• Eye (Opthalmic)
•Sublingual
• Subcutaneous (SC)
• Ear (Otic)
• Intradermal (ID)
• Vagina
•Rectal
• Intramuscular (IM)
• Urethra
• Intraperitoneal (IP)
• Urinary Bladder
• Lungs (Inhalation)
• Intrathecal
• Skin (Topical)
• Epidural
• Directly Into Target Tissue
Parenteral
Inhaled
(IV)
Oral
Transdermal
Parenteral Topical
(SC, IM)
Rectal
Rute Pemberian Obat
(Umum)
Table 3-3. Routes of administration, bioavailability, and
general characteristics.

Houte
Bioavailability (%)
Characteristics Most rapid onset
Antravenous
100 (by definition)
AM
--
-
-
-
-
-
--
-
-
-
-
--
-
--
-
-
-
-
-
-
-
-
--
-
--

75 to $100
Intramuscular
(IM)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-

Large volumes often feasible; may be painful Smaller volumes

than IM; may be painful
75 to 5100
Subcutaneous
(SC)

Oral (PO)
5 to <100

Rectal (PR)
30 to <100

Inhalation
5 to <100
Most convenient;
first-pass effect may be significant Less first-pass effect than
oral Often very rapid onset Usually very slow absorption;
used for lack of first-pass effect; prolonged duration of action
-
-
-
--

Transdermal
80 to 5100
Eye
Nasal Ear
Buccal, sublingual
Inhalation
Oral
Topical
IA
IV
Spinal, epidural
Subcutaneous
vaginal
IP
IM
Rectal
Intraarticular
parenteral enteral
IA
Spinal, epidural
vaginal
Intraarticular
Inhalation
Topical
IA
IM
Eye
Nasal Ear
Buccal, sublingual
Oral
IV
Subcutaneous
IP
Rectal
Injections
Non-Injections
Eye Nasal Ear
Buccal, sublingual
Inhalation Inhalation
IP
IM
Rectal Oral IA IA Topical

IV
Spinal, Spinal, epidural epidural
Subcutaneous
vaginal
IM
Rectal
Intraarticular
Tidak ada absorpsi
Ada proses absorpsi
Eye
Nasal Ear
Buccal, sublingual
Inhalation
Oral Oral
IA IA
IV
Subcutaneous
IP
IM
Rectal
Systemic Local
Topical
Spinal, epidural
vaginal
Intraarticular
Rute Pemberian Obat dan
 Waktu Mencapai Efek
Rute Pemberian Waktu mencapai
efek Intravena 30 – 60 detik Intraosseous 30 – 60
detik Endotracheal 2 – 3 menit Inhalasi 2 – 3 menit
Sublingual 3 – 5 menit Intramuscular 10 – 20 menit
Subcutaneous 15 – 30 menit Rectal 5 – 30 menit Oral
30 – 90 menit Transdermal (topical) Menit - Jam
ORAL, IV, IM , SC
SAFETY High Oral > SC > IM > IV
Low CONVENIENCE High
Oral > SC > IM > IV
Low
COST High
IV > IM > SC > ORAL
Low
BIOAVAILABILITY
Delayed High
and Reliable IV > IM = SC > ORAL
Low and/or Variable ONSET OF
ACTION Immediate IV > IM > SC >
Oral
PATIENT COMPLIANCE High
IV > IM > SC > Oral
Low
INTERACTIONS WITH FOOD
Risk Oral > IV = IM = SC No Risk
COMMERCIAL AVAILABILITY OF
DOSAGE FORMS
High
Oral > IM = SC = IV Low VOLUME OF
DRUG High
Oral = IV > IM > SC
Low

Colon and rectal drug delivery

149

Table 7.1 Comparison of the environment in different

parts of the gastrointestinal tract
Region
Length
(m)
Surface Area
(m)
pH
Residence Time
Micro-organisms

unknown
Oesophagus 0.3 Stomach 0.2 Duodenum 0.3 Jejunum
lleum Colon
1.5
0.02 0.2 0.02 100 100
6.8 1.8-2.5 5-6.5 6.9
7.6 5.5-7.8
>30 seconds
1-5 hours >5 minutes 1-2 hours 2-3 hours 15-48 hours
5102 5102
<102
ū AW
5107
<10"
Non-ionised drug
More lipid soluble drug
Diffuse across cell membranes more
easily
Drug
Ionised drug
Less lipid soluble drug
Karakteristik dari molekul Un-
ionized dan Ionized Drug
Un-ionized Ionized
Pharmacologic effect Active Inactive
Solubility Lipids Water Cross lipid
barriers Yes No (gastrointestinal tract, blood-
brain barrier, placenta) Hepatic metabolism
Yes No Renal excretion No Yes
Obat obat : asam lemah / basa lemah
Aspirin, Barbiturates (acid) Propranolol,
Opioids (base)
Asam lemah : HA H+ + A-
Persamaan Henderson-
Hasselbach :
pH = pK’ + Log10[A-]/[HA]
Basa lemah : BH+ B + H+ Persamaan
Henderson-Hasselbach :
pH = pK’ + Log10[B]/[BH+]
Table 1-2. lonization constants of some common drugs.

-
PK,
NI 7

7.2
8.6 7.9 8.6
3,5
8.7
10.0 106

3.9
Drug
PK,
Drug
Drug

Weak acids
Weak bases
Weak bases (cont'd) Acetaminophen
Albuterol (salbutamol)
Isoprotereno! Acetazolamide
Allopurinol
9.4, 1232
Lidocaine Ampicillin
2.5
Alprenolol
Metaramino! Aspirin
Amiloride
Methadone Chlorothiazide
6.8.9.42 Amiodarone
6.56
Methamphetamine Chlorpropamide
Amphetamine
9.8
Methyldopa Ciprofloxacin
6.1.8.72
Atropine
9.7
Metoprolol Cromolyn
Bupivacaine
8.1
Morphine Ethacrynic acid
2.5
Chlordiazepoxide
Nicotine Furosemide
Chloroquine
10.8, 8.4
Norepinephrine Ibuprofen
4,4,5.22 Chlorpheniramine 92
Pentazocine Levodopa
2.3
Chlorpromazine
Phenylephrine Methotrexate
Clonidine
Physostigmine Methyldopa
2.2, 9.2
Cocaine
8.5
Pilocarpine Penicillamine
1.8
Codeine
Pindolol Pentobarbital
8.1
Cyclizine
Procainamide Phenobarbita!
Desipramine
10.2
Procaine Phenytoin
Diazepam
Promethazine Propylthiouracil
Diphenhydramine 8.8
Propranolol Salicylic acid
Diphenoxylate
7.1
Pseudoephedrine Sulfadiazine
6.5
Ephedrine
Pyrimethamine Sulfapyridine
Epinephrine
8.7
Quinidine Theophylline
Ergotamine
63
Scopolamine Tolbutamide
Fluphenazine
8.0,3.97 Strychnine Warfarin
5.0
Hydralazine
Terbutaline Imipramine
9.5
Thioridazine The pk is that pH at which the concentrations of the ionized
and un-ionized forms are equal. More than one ionizable group.
7.9 7.9,3,12 8.6 7.9 9.8 7.9, 1.82 6.9.1.4

9.1

3.0
9.8
7,0

8.4 8.8
8.5, 4.42
8,1
8.0, 2.31 10.1 9.5

MEKANISME
TRANSPORT
Carrier-mediated
Passive diffusion
transport
Active Facilitated
endocytosis
ATP
ADP-Pi
Anti transport
Aqueous channels
Transporter Molecule
Passive Diffusion
GI
high low
..... ..... ..... ..... ..... .. ..... ..... ..... ..... ..... ..... ..... ..... ..... ..

..... .....

..... .....

equilibrium
Blood
Lipid diffusion (Simple diffusion)
The most important mechanism of drug transport
Drug movement across membranes is
driven by a concentration gradient after
solution in the lipids of membranes.
pH (pKa) ┐ pKa is pH when Ionized rate is 50%
Nonionized form k1 Ionized form

k2 more lipid soluble less lipid soluble

easy permeation hard permeation
less polar molecules polar molecules
ion trapping
pharmacokinetics Lipid diffusion
1 Alkalization of gastric juice
→ionization↑
→ permeation↓ →absorption ↓ gastric
juice pH ↑ > pH
blood -
[A ]↑ > [A-] drug drug
2 Alkalization of blood plasma →
permeation↓→across blood-brain
barrier↓
blood pH↑> pH
[A-]↑> [A-] drug drug
Cerebrospinal
fluid
3 Alkalization of humor (extra-
cellular fluid)
→ionization↑ →permeation↓
drug drug
4 Alkalization of urine→ionization↑
→permeation↓→ drug tubular
reabsorption↓ → excretion↑
pharmacokinetics Lipid diffusion
urine pH ↑
drug [A-]↑
cell
pH < pH↑ [A-] < [A-] ↑
blood
Definition
The aqueous (hydrophilia) drugs with low

molecular weight (<100-200 daltons) can diffuse

through aqueous pores in membrane without

requiring energy, the diffusion is driven by

concentration gradient.
Filtration (Aqueous
diffusion)
MoA
The almost free drugs can be filtrated across

biggish pores of capillaries from or to plasma.

(drug distribution, glomerular filtration and

absorption following im or sc injection)

Facilitated transport (Carrier-

mediated transport)
After glomerular filtration, penicillin undergoes tubular secretion
(an active transport), having a very short half-life (t1/2=20~30 min).
Probenecid having the same active mechanism can competitively inhibit
the tubular secretion of penicillin. The t1/2 & effects of penicillin are
prolonged.

Active Transport
MEKANISME
TRANSPORT
PASSIVE DISSUSION (semua obat) O
Sesuai dgn concentration gradient (Hk. Ficks) O
Hanya untuk bentuk unionized (lipid soluble) O
Tidak memerlukan energi SPECIAL CARRIER
(carrier mol-receptor) O Facilitated transport
(vit. B12, Iron)
- Blood brain barrier, renal tubule, GI tract O
Active transport (mis, 5-fluorouracil)
- Neuron,choroid plexus, renal tubulus, biliary
tract ,GI
tract O Antitransporter
- Menggunakan transporter ABC dan SLC family
PINOCYTOSIS (engulfing) (up take
thyroglobuline (MW:500.000→thyroid follicular
cell) AQUEOUS POROS CHANNEL
(Soluble mol) - Interstitial spece, cytosol, MW:
220.000 – 30.000 - Melalui aqueous pores,
downhill movement
Karakteristik Facilitated Diffusion
dan Active Transport
O Memerlukan carrier O Transport
menjadi jenuh (saturated) pada
konsentrasi
tinggi O Proses bersifat selective O Dua
obat yang ditranspor oleh mekanisme
yang sama
akan menghambat satu sama lain O
Melawan concentration gradient (active
transport) O Tdk melawan concentration
gradient (facilitated
transport) O Memerlukan energi O
Mekanisme transport dapat dihambat
oleh obat-obat yang
mempengaruhi cellular metabolism
Fick’s Law of Diffusion
dQ dt

=
⎛ ││⎝DAK

h ( CC 1 2 ) p ⎞ ││⎠- dQ/dt
- rate of diffusion
A - surface area of membrane
h - membrane thickness D - diffusion
coefficient Kp - partition coefficient
C1 - C2 = concentration difference for solute
Generally, C1>>C2

DAK dQ dt

⎛ ││⎝h p ⎞ ││⎠( CC 1 -
2 ) Since D, Kp, and h are constant for
a given drug/membrane; and given that
C1>>C2:

dQ dt
PC
= 1 Where P - permeability constant

Bioavailability extent of absorption

and the rate at which an administered dose reaches
systemic circulation in its active form

(F)
F→ the parameter judging the extent and rate of drug
absorption following extravascular administration (like
orally)
C
AUC: area under C-T curve
F could be the absolute value between
Cmax
 of extravascular and intravascular administration, or
relative value between of standard preparation and test
preparation (pharmaceutical products)
AUC
Tmax T drug in dosage form liver
tissue, lymph
intravenous
blood plasma bound ⇔ free oral
site of action
excretion
metabolism
Bioavailability

FIRST PASS EFFECT

Hepatic metabolism of a pharmacological agent when it is
absorbed from the gut and delivered to the liver via the
portal circulation
The greater the first-pass effect, the less the agent will
reach the systemic circulation when the agent is
administered orally

First-pass Effect
First-pass Effect
Dipilihkan rute pemberian lainnya
(misalnya,
IV atau intramuscular injection)
Diberikan dosis oral permulaan yang
tinggi (loading) dengan tujuan
menjenuhkan liver enzymes
Pada beberapa obat menyebabkan tidak
efektif bila digunakan per oral
Dosis obat p.o lebih besar dari dosis i.v
Bila obat dimetabolisme menjadi bentuk
aktif, menyebabkan kumulatif dari
metabolit
First-pass Effect
ADVANTAGES
cheap compared to other routes
patient compliance
transit time is consistent among individuals

DISADVANTAGES
SELAMAT BELAJAR