SEJARAH PERKEMBANGAN

FARMASI
Kata “Pharmacy” berasal dari Yunani
(Pharmakon = obat)

• Dalam sejarahnya, pekerjaan

kefarmasian dilakukan oleh para Dukun,
yang memperoleh pengetahuan berdasar
atas pengalaman atau yang diperoleh
melalui warisan.
- Bentuk sedian obat selain minuman
digunakan juga obat luar dalam bentuk
serbuk, bubur dengan nama yang berbeda,
menurut penggunaannya.
Pengetahuan pengobatan atau
perdukunan ini sifatnya sangat
rahasia, oleh karena itu hampir
tidak ada perguruan yang
mengajarkan, berbeda dengan
bela diri atau kesaktian. Dapat
dimengerti bila pengobatan ini
tidak begitu berkembang.

Farmasi berkembang menjadi

suatu profesi yang terpisah dari
kedokteran pada abad ke 18.
– Tahun 1821 berdiri Perguruan
Tinggi Farmasi pertama di dunia
Evolusi Peran Farmasis

Selama abad 20, profesi

farmasi berkembang
melalui 4 tahap :
– Era Tradisional (Traditional
Era)
– Era Ilmiah (Scientific Era)
– Era Klinik (Clinical Era)
– Era Asuhan Kefarmasian
(Pharmaceutical-care Era)
 Era Tradisional

Awal abad 20
Formulasi dan pemberian resep obat
dari bahan alam
– Farmakognosi
Mempelajari sifat-sifat obat dari produk asli alam
(binatang, tumbuhan dan mineral)

– Farmasi galenik
Teknik-teknik untuk menyiapkan obat
 Era Ilmiah
Dimulai setelah PD II
Munculnya industri farmasi
– Obat-obatan dibuat di pabrik, bukan di apotek
Pendidikan farmasi menekankan pada
pengetahuan
– Farmakologi
Mempelajari obat secara ilmiah dan mekanisme aksinya
termasuk efek samping

– Farmasetika
Karakteristik pelepasan dari bentuk sediaan (dosage
forms) obat
 Era Klinik
1975 ; dilaporkan oleh Millis
Pengetahuan baru yang menekankan pada
farmasi klinik (patient-oriented)
– Farmakokinetika
Aktivitas obat pada tubuh pada suatu periode waktu
meliputi absorpsi, distribusi, metabolisme dan eksresi

– Patioisiologi
Mempelajari penyakit dan keadaan sakit yang
mempengaruhi fungsi normal tubuh
Era Asuhan Kefarmasian
1990: didefinisikan oleh Hepler and Strand
Pharmaceutical care
– Suatu filosofi yang dikembangkan dari peran
farmasis untuk mencakup pengobatan yang tepat
untuk meningkatkan hasil yang positif dengan
terapi obat yang diresepkan

– Meliputi:
Monitoring respons untuk terapi
Edukasi pada pasien dan menyerahkan obat yang
diresepkan
 Pendahuluan
Apa perbedaan antara bahan kimia (chemical) dan obat
(drug) ?

Bahan kimia (Chemical): suatu substansi yang terdiri

dari elemen-elemen (unsur-unsur) kimia atau diperoleh
dengan proses kimia (review chemistry)

Obat (Drug): suatu senyawa yang ditujukan untuk

digunakan dalam diagnosis, mitigation (meringankan),
treatment (pengobatan), cure (menyembuhkan), or
prevention (pencegahan) penyakit pada manusia atau
binatang lain (biopharmaceutics)
Patients don't take drugs...

They take dosage forms.

 OBAT

UNTUK TUJUAN
SUBSTANSI “API” DALAM
SEDIAAN FARMASI FARMAKOTERAPI

MEKANISME
PENGGUNAAN
 DOSAGE FORM DESIGN
Substansi obat jarang diberikan tunggal tetapi
lebih tepatnya merupakan bagian dari formulasi
dalam suatu kombinasi dengan satu atau lebih
bahan tambahan (nonmedical agents) yang
memiliki fungsi farmasetika yang bervariasi atau
khusus

Melalui penggunaan yang selektif dari bahan

tambahan, yang disebut juga sebagai bahan
tidak berkhasiat (inactive ingredients) atau
pharmaceutical adjuvants, bentuk sediaan dapat
dihasilkan dalam berbagai macam jenis
Examples of Dosage Forms
A Dosage
Form is a
Formulation
 Konsep suatu formulasi

Formulasi merupakan suatu kombinasi yang

spesifik dari obat (Drug(s)) dan bahan tambahan
(Excipients)

Masing-masing formulasi memiliki komposisi

yang unik
Proses pelarutan obat dalam saluran
cerna
Tablet Granul
atau Disintegrasi Deagregasi Partikel
atau
Kapsul Agregat halus

Disolusi
Disolusi Disolusi (Mayor) Farmasetika
Obat dalam larutan (in vitro atau in vivo)

Absorpsi (in vivo) Biofarmasi

Obat dalam darah, cairan dan jaringan lain

distribusi Farmakokinetika
metabolisme
eksresi

Kadar obat dalam reseptor

Respon farmakologik
Farmakodinamika

Respon klinik / terapetik

 Drug in dosage form

Release

Drug particles in body fluids Pharmacologic effect

Dissolution

Degradation
Drug in solution Peripheral
Tissues
GI
Absorption Distribution

Liver Central Compartment

Excretion Free  Bound

 Movement of Drugs in the Body

Site of Action

Absorption Drug in Blood Metabolism Toxicity

Tissues
Excretion
Bound Drug in Blood
Pharmacokinetics
 Drug Concentrations in the
Plasma
Toxic
50 Concentrations

Drug 40
Concentration Therapeutic
in Plasma (Cp)
30 Concentrations
mcg/mL (Therapeutic Range)
20
Subtherapeutic
10 Concentrations

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time since administration of drug
(hours)
Our Therapeutic Goal is to:

Achieve drug concentrations…

at the site of action (target tissue)…
that are sufficiently high enough…
to produce the intended effect…
without producing adverse drug reactions.
In order for a therapeutic agent to
be effective, it must be:

• Absorbed
• Distributed
• Metabolized
• Excreted
 In order for a drug to achieve
appropriate therapeutic
concentrations at the target site,
it must be:
• Absorbed properly
Meaning … the drug must move
from the point of administration TO
the systemic circulation
 Cell membrane
barrier of drug permeation, with semipermeable property

factors affecting drug across cell membrane

– cell membrane properties
– physicochemical properties of drugs
size and shape
solubility
degree of ionization
lipid solubility
 Membrane Structure

Terdiri atas :
2 basal lipid monomolekular fosfolipid dan kolesterol
•Kutub hidrofob ke bagian dalam
•Kutub hidrofil pada bagian luar
 Absorption of drugs
From gastrointestinal tract: lipid-soluble, nonionized
forms of drugs are absorbed better than water-soluble,
ionized forms of drugs
– environmental pH important in absorption
– acidic drugs (aspirin) absorbed better theoretically in
stomach (pH 1-2), basic drugs (codeine) absorbed better in
intestine (pH 7-8)
 What Is Absorption?
“the drug passing from the lumen into the tissue of the GIT”

Human Intestinal
Absorption (HIA)

1,2 – Stability + Solubility

3 – Passive + Active Tr.
4 – Pgp efflux + CYP 3A4

5 – 1st Pass in liver

Oral Bioavailability (%F)

Frequently HIA is confused with either “Passive Absorption or “Oral %F”

 Absorption of drugs (2)
From oral, sublingual, or rectal mucosa:
passive diffusion.
– May bypass first-pass inactivation
From the lungs: passive diffusion
– rapid absorption, dependent on particle size (6
µm cutoff)
 Absorption of drugs (3)
From injection sites: subcutaneous tissues,
muscle or fat, absorbed by diffusion and
affected by blood flow
From miscellaneous sites: skin, spinal
canal, tooth pulp
Intravenous, intraarterial injection avoids
absorption
IV drugs are 100% absorbed
No absorption phase
because the drug is placed
directly into the blood

Used for stat administration

of drugs
 Drug Concentrations in the
Plasma
IV
50 administration
Drug 40 IM
Concentration administration
in Plasma (Cp) PO and SQ
30
administration
mcg/mL
20

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time since administration of drug
(hours)
 All drugs absorbed across the
wall of the GI tract enter the
hepatic portal system

Therefore, all
PO
administered
drugs must
pass through
the liver prior
to entering
systemic
circulation
 Some drugs are excreted by the
liver before they reach systemic
circulation

This is called
the FIRST
PASS EFFECT
 In the case of PO administered
diazepam in the dog, 97-99% is
removed by the First Pass Effect
Avoid using Only 1-3%
drugs with 1st reaches systemic
pass effect via circulation
PO route

100%

97-99%
In order for a therapeutic agent to
be effective, it must be:

• Distributed to the appropriate site

Meaning the drug must move
FROM circulation TO the target
tissue and be present in sufficient
concentrations to produce a
beneficial effect
 Distribution
distribution site: well-perfused organs, poor-perfused organs, plasma prot
eins
Well-perfused: heart, liver, kidney, brain
Poor-perfused: muscle, visceral organs, skin, fat
Plasma proteins
– Albumin: Weak acids
– alpha-acid glycoprotein: Weak bases
Effects of plasma protein binding
– Free fraction: active, excreted, metabolized
– the more binding, the less active drug
– the more binding, the less excreted and metabolized:

“longer half-life”
 Capillaries have gaps that
allow drugs to be distributed
to the tissues

Drug molecules

Body Capillary
Note the different sizes of drug
molecules compared to RBCs
and the normal proteins found
in blood

Body Capillary

RBC Drug Protein

Molecules
 Body capillaries are different
than brain capillaries
Body Capillary

Fenestrations (windows)

Brain Capillary Neuroglia

cells

BLOOD
BRAIN
BARRIER
NO Fenestrations
 Distribution
CNS and CSF
Blood-Brain Barrier (BBB)
– unique anatomical pattern of the vessels supplying the brain
– only highly lipid soluble compounds can move across to the brain
– infection of the meninges or brain: higher permeability of penicill
ins to the brain.
Placental transfer
– Simple diffusion
– Lipid soluble drug, non-ionized species
– first 3 mo. of pregnancy is very critical: “Organogensis”
 Drugs highly protein bound
have much of their molecules
“stuck” in the blood
Only the “free” form of the drug
molecules can distribute to tissues
Body Capillary

RBC Drug
Molecules Protein
Normal blood and normal protein
binding of protein-bound drugs

Protein Free Drug

Bound Drug Molecules
Normal blood and normal protein
binding of protein-bound drugs

Protein
Bound Drug

Hypoproteinemic Blood and Binding

Protein Free Drug

Bound Drug Molecules
In order for a therapeutic agent to
be effective, it must be:

Metabolized appropriately
(if required)

Meaning that if metabolized, the

drug must be broken down at a
predictable rate to an inactive form
Metabolism
General considerations - drug metabolism
(biotransformation) usually results in more water-
soluble, more polar metabolites, thus facilitating
their excretion by reducing renal tubular
reabsorption

drug metabolism does not always result in

detoxification and inactivation of drugs, although
these usually occur
 Metabolism or
Biotransformation

Drug Meta
A bolite

Performed by liver enzymes

As exposure to drug continues, the number of
enzymes increases in response
More enzymes = FASTER rate of metabolism
INDUCED metabolism = DRUG TOLERANCE
In order for a therapeutic agent to
be effective, it must be:

Eliminated at the correct rate

Meaning that the drug must move

OUT of the body
at a predictable rate
Two major elimination organs are
the liver and the kidney

Liver elimination Renal

goes into the bile elimination goes
duct and small into the urine
intestine
 Renal elimination
MORE blood pressure =
MORE flow
Water, drugs,
Blood flows small molecules
into kidney filtered out in
glomerulus
Urine and drug
MORE flow =
flows into the
MORE filtered
ureter, then the
bladder MORE filtered =
(kandung QUICKER elimination
kemih), and out
 Half Life of Elimination
and Clearance

Both terms refer to a measurement of

how quickly a drug leaves the body

Clearance is the VOLUME of drug cleared

per unit time (e.g. 0.5 Liters per hour)

Half life is the TIME it takes for drug

concentrations to drop by HALF (e.g. 3 hrs)
 Routes of Excretion

Metabolism
in Liver
Absorption Drug in
Drug in Conjugates
Portal
Intestine
Blood
Phase-1

Beta- Bile
glucuronidase
Conjugates
in Drug in
Intestines Blood

Excretion Excretion
in in
Feces Urine
 Routes of Drug
Administration
Important
Info

The route of administration

(ROA) that is chosen may have
a profound effect upon the
speed and efficiency with which
the drug acts
 The possible routes of drug entry
into the body may be divided into
two classes:

Enteral

Parenteral
 Enteral Routes

 Enteral - drug placed directly in the GI tract:

sublingual - placed under the
tongue
oral - swallowing (p.o., per os)

rectum - Absorption through the

rectum
 Sublingual/Buccal

Some drugs are taken as smaller tablets

which are held in the mouth or under
the tongue.

 Advantages
 rapidabsorption
 drug stability

 avoid first-pass effect

Isosorbide concentrations after a 5 mg oral or sublingual dose.
Data from: Assinder et al. J Pharm Sci 66:775, 1977.

14
Isosorbide Conc (ng/ml)

12
10
8
6
Sublingual
4
2 Oral
0
5 15 30 45 60 90 120
Time (min)
Sublingual/Buccal

 Disadvantages
 inconvenient

 smalldoses
 unpleasant taste of some drugs
Oral

 Advantages
 Convenient - can be self- administered, pain
free, easy to take
 Absorption - takes place along the whole
length of the GI tract
 Cheap - compared to most other parenteral
routes
Oral
 Disadvantages
 Sometimes inefficient - only part of
the drug may be absorbed
 First-pass effect - drugs absorbed
orally are initially transported to the
liver via the portal vein
 irritation to gastric mucosa - nausea
and vomiting
Oral
 Disadvantages cont.
 destruction of drugs by gastric acid
and digestive juices
 effect too slow for emergencies

 unpleasant taste of some drugs

 unable to use in unconscious (tidak

sadar) patient
 While it is generally viewed that 100% of drug
administered intravenously is bioavailable,
prodrug administration via this route may result
in less than 100% bioavailability.
Drug Bioavailability
Chloramphenicol succinate ~70%
Dexamethasone phosphate ~90%
Dexamethasone sulfate ~40%
Prednisolone phosphate ~90%
Prednisolone phthalate ~50%

Comparative bioavailability of IV chloramphenicol

succinate and oral chloramphencol palmitate
IV PO
Mean C90-min (mg/L) 22.6 27.5
Mean AUC (mg/hr/L) 78 110
From: Kauffman R et al. J Pediatr 99:963, 1981.
 Effect of varying
volumes of water on
oral drug absorption

From: Shargel L, Yu ABC.

Applied Biopharmaceutics
and Pharmacokinetics, 4th
edition, 1999, p. 119.
Rectal

1. unconscious patients and children

2. if patient is nauseous or vomiting
3. easy to terminate exposure
4. absorption may be variable
5. good for drugs affecting the bowel (bag
paling bawah) such as laxatives
6. irritating drugs contraindicated
RECTAL ROUTE
Local action
– e.g. rectal route is used primarily for the treatment
constipation
Systemic action

Advantage
avoid first-pass effect
Availability (%) of lidocaine after IV, oral and
rectal administration
Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979.

Subject IV Oral Rectal

1 100 17 59
2 100 49 87
3 100 53 80
4 100 13 31
5 100 35 100
6 100 37 59
100 34 71
 Parenteral Routes
 Intravascular (IV, IA)- placing a drug
directly into the blood stream
 Intramuscular (IM) - drug injected into
skeletal muscle
 Subcutaneous - Absorption of drugs from
the subcutaneous tissues
 Inhalation - Absorption through the lungs
Intravascular
Absorption phase is bypassed
(100% bioavailability)
1.precise, accurate and almost immediate onset of
action,
2. large quantities can be given, fairly pain free

3. greater risk of adverse effects

a. high concentration attained rapidly
b. risk of embolism (penyumbatan pembuluh
darah)
Intramuscular

1. very rapid absorption of drugs in

aqueous solution
2.Repository (tempat penyimpanan) and
slow release preparations

3.pain at injection sites for certain drugs

Subcutaneous

1. slow and constant absorption

2. absorption is limited by blood flow,
affected if circulatory problems
exist
3. concurrent (bersamaan)
administration of vasoconstrictor will
slow absorption
Inhalation

1.gaseous and volatile agents and aerosols

2.rapid onset of action due to rapid access to
circulation
a.large surface area
b.thin membranes separates alveoli from
circulation
c.high blood flow
Particles larger than 20 micron and the particles impact
in the mouth and throat. Smaller than 0.5 micron and
they aren't retained.
 Inhalation cont.
 Respiratory system. Except for IN, risk hypoxia.
 Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal
dripping. Fairly fast to brain, local damage to septum. Some of the
volatile gases also appear to cross nasal membranes.
 Smoke (Solids in air suspension, vapors) absorbed across lung
alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal
meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer
action than volatile gases. Tissue damage from particles, tars, CO.
 Volatile gases: Some anaesthetics (nitrous oxide, ether) [precise
control], petroleum distillates. Diffusion and exhalation (alcohol).
 Lung-based transfer may get drug to brain in as little as five seconds.
 Topical
•Mucosal membranes (eye drops, antiseptic,
sunscreen, callous removal, nasal, etc.)
•Skin
a. Dermal - rubbing in of oil or ointment
(local action)
b. Transdermal - absorption of drug through
skin (systemic action)
i. stable blood levels
ii. no first pass metabolism
iii. drug must be potent or patch
becomes to large
 SELECTION
SELECTIONOF
OFTHE
THEROUTE
ROUTEOF
OFADMINISTRATION
ADMINISTRATION

Dosage forms suitable for

skin/transdermal route.
cream and ointment
transdermal patch
e.g. scopolamine trsansdermal patch
 Route for administration
-Time until effect-

 intravenous 30-60 seconds

 intraosseous 30-60 seconds
 endotracheal 2-3 minutes
 inhalation 2-3 minutes
 sublingual 3-5 minutes
 intramuscular 10-20 minutes
 subcutaneous 15-30 minutes
 rectal 5-30 minutes
 ingestion 30-90 minutes
 transdermal (topical) variable (minutes to hours)
 INTRODUCTION
INTRODUCTIONTO
TO DOSAGE
DOSAGEFORMS
FORMS

Pharmaceutics
The general area of study concerned
with the formulation, manufacture,
stability, and effectiveness of
pharmaceutical dosage forms is termed
Pharmaceutics.
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS
AVAILABLE DOSAGE FORMS
1. SOLID
i. powder
ii. capsules
iii. tablets
2. LIQUID
i. solution
ii. suspension
iii. emulsion
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

3. SEMI-SOLID
i. ointments
ii. creams

4. MISCELLANEOUS
i. inhalants
ii. aerosols
 INTRODUCTION
INTRODUCTIONTO
TO DOSAGE
DOSAGEFORMS
FORMS

Besides providing the mechanism for

the safe and convenient delivery of
accurate dosage, dosage forms are
needed for additional reasons:
1. For the protection of a drug substance
from the destructive influences of
atmospheric oxygen or humidity (e.g.,
coated tablets, sealed ampuls).
 INTRODUCTION
INTRODUCTIONTO
TO DOSAGE
DOSAGEFORMS
FORMS

2.For the protection of a drug substance from the destructive

influence of gastric acid after oral administration (e.g., enteric
coated tablets).

3.To conceal the bitter, salty, or offensive taste or odor of a drug

substance (e.g., capsules, coated tablets, flavored syrups).

4.To provide liquid preparations of substances that are either

insoluble or unstable in the desired vehicle (e.g.,
suspensions).
 INTRODUCTION
INTRODUCTIONTO
TO DOSAGE
DOSAGEFORMS
FORMS

5. To provide clear liquid dosage forms of substances (e.g.,

syrups, solutions).

6. To provide time-controlled drug action (e.g., various

controlled release tablets, capsules, and suspensions).

7. To provide optimal drug action from topical adminstration

sites ( e.g., ointments, creams, transdermal patches,
ophthalmic, ear, and nasal preparations.
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

8. To provide for the insertion of a drug into one of the

body’s orifices (e.g., rectal or vaginal suppositories).

9. To provide for the placement of drugs directly into

the bloodstream or into body tissues (e.g., injections).

10. To provide for optimal drug action through

inhalation therapy (e.g., inhalants and inhalation
aerosols)
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

SELECTION OF THE PROPER DOSAGE FORM

Before a medicinal agent is formulated into one
or more dasge forms, among the factors
considered are:
nature of the illness
the manner in which it is generally treated (e.g.
locally or systemically)
the age and anticipated condition of the
patient.
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

PREFERABLE DOSAGE FORMS:

When the medication is intended for systemic use and oral
administraion is desired:
*tablet
*capsules
*oral solutions or suspensions
When the medicationis intended for infants and children under
5 years of age:
*liquid preparations
when immediate therapuetic action is desired:
* injections
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

PHARMACEUTICAL ADJUVENTS, OR
EXCIPEINTS, OR INACTTIVE INGREDIENTS:

Pharmaceutical solutions:
One of more solvent to dissolve the drug
Preservatives to prevent microbial growth
Stabilizers to prevent drug decomposition
Colorants and flavorants to enhance product
appeal
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

Tablets:
Diluents or filler to increase the bulk of the
formulation
Binders to cause the adhesion of the powdered
drug and inactive ingredients
Antiadherents or lubricants to assist the smooth
tableting process
Disintegrating agents to promote tablet break up
after adminstration
 INTRODUCTION
INTRODUCTIONTO
TODOSAGE
DOSAGEFORMS
FORMS

CONCEPT OF THE OPTIMIZED DRUG PRODUCT

The optimized drug product may be viewed as a
drug delivery system for the one or more drugs
that it contains. The goal of this drug delivery
system is to release the drug(s) to produce the
maximum simultaneous
1. safety,
2.effectiveness, and
3. reliability