FARMAKOKINETIKA

KLINIK
I Gusti Ayu Agung Septiari
Pharmacokinetics (PK)
• Pharmaco- (obat/drug) dan kinetics (bergerak/moving)
• Pharmacokinetics is the study of drug movement into, around,
and out of the body. By extension, it involves the study of drug
absorption, distribution, and elimination (metabolism and
excretion) (ADME); how the body affects the drug.
• Fokus utama dalam farmakokinetika adalah “plasma
concentration of the drug”
Passage of Drugs Through
Membranes
Structure and Properties of
Membranes
Passage of Drugs Through
Membranes
• Drug penetrate membranes :
1. Passive diffusion
 The concentration gradient across a membrane is the driving force for the
process
 Net movement of drug from the side with a high concentration to the side
with a low concentration
2. Carrier-Mediated Processes: Transport Proteins
 Transporters are proteins that reside in cell membranes and serve to
facilitate the passage of chemicals into or out of a cell
 Transporters are located in the intestinal membrane, the hepatocyte, the
renal tubular membrane, CNS, the placenta, etc.
Passive Diffusion
• Fick’s law
• The rate of diffusion increases as a membrane’s surface area increases.

• Membrane of the small intestine  villi  microvilli ↑ the surface area of

the small intestine  primary site for the absorption of drugs taken orally
• Permeability − dependent on both the characteristic of the membrane and
the physicochemical properties of the drug (lipophilicity, charge, and size)
Transport Proteins
Uptake Transporters:
- Solute carrier (SLC) Superfamily
- Bidirectional facilitated diffusion; although in
some cases the transport may be active and
unidirectional.
- No ATP is required

Efflux Transporters:
- ATP-binding cassette (ABC) Superfamily
- Facilitate the removal of drugs from cells by
an active transport process
Absorption, Distribution, Metabolism, and
Excretion
• Absorption − route of drug delivery
−Where absorbed?
• Distribution − where does the drug go, where does it need to go
and what are the implications?
• Metabolism −
• Excretion − how is the drug eliminated?
• Pharmacokinetics is concerned with the variation in drug
concentration with time as a result of ADME  what the body does
to the drug?
Absorption

TRANSPORTATION

Drug in the
site of General
administratio circulation
n
 AFFECT

Absorption
and the factors Drug
that may Bioavailability
impede
Bioavailability = Quantity of a drug reaching systemic circulation
Factors that affects drug absorption
• Molecular size of the drug
• Lipid solubility of the drug
• Degree of ionization of the drug
• Dosage form (e.g., tablet/solution)
• Chemical nature of the drug
• Complex formation
• Site of absorption
• Gastric emptying rate
• Food
Drug Delivery – Enteral Routes
• Oral − the most common route; gastrointestinal absorption; drug is
transported via the portal system to the liver and undergoes first-pass
metabolism rendering some of the drug inactive, decreasing
bioavailability.
• Oral − Most of the drugs are available as?
• Oral − Most of the drugs are absorbed by passive diffusion
• Oral − Most of the orally administered drugs are absorbed in the
proximal jejunum.
• Oral − Absorption of a drug in the intestine is aided by the presence of
numerous villi and microvilli that are extensively supplied by blood
vessels and lymphatics.
Drug Delivery – Enteral Routes
• Sublingual (buccal) − certain drugs are best given beneath the
tongue or retained in the cheek pouch and are absorbed from
these regions into the local circulation; bypasses the acidic
gastric mucosa and first-pass metabolism (?); the extensive
vascular network enables rapid absorption of unionized, lipid
soluble drugs; e.g., nitroglycerin
• Rectal − overcome the difficulties of oral administration; more
frequently used in small children; hepatic first-pass metabolism
is lower compared to oral.
Parenteral Routes
• Intravenous injection
−Used when a rapid clinical response is necessary, e.g.
−Achieve relatively precise drug concentrations in the plasma since bioavalability is not a
concern.
−Infusion or bolus
−The incidence and intensity of adverse effects are higher with intravenous delivery
compare to oral administration.
• Intra-arterial injection
− Used in certain special situations, notably with anticancer drugs/diagnostic radiology, to
deliver a high concentration of drug to a particular tissue.
• Intrathecal injection
− The blood-brain barrier limits the entry of many drugs into cerebrospinal fluid. What
condition requires intrathecal???
Parenteral (Cont)
• Intramuscular injection
− Drugs may be injected into the arm, thigh or buttocks.
• Subcutaneous injection
− Insulin is routinely administered SC; drug absorption is generally slower SC than IM due to
poorer vascularity.
• Inhalation
− Volatile anesthetics, bronchodilators, nitric oxide as well as many drugs which affect
pulmonary function, are administered as aerosols; drugs administered via this route are not
subject to first-pass liver metabolism; enables rapid absorption through a large surface
area of the lung epithelium and respiratory mucous membrane.
• Topical application
− Eye, intravaginal, intranasal, skin
− Alleviation of local symptoms.
- Direct parenteral injection of drugs 
“site of action” :
1. Avoid first-pass metabolism
2. Rapid delivery to the site of action
- The degree of vascularity affects onset
- Which one will achieve the fastest
onset?
- IV and intraarterial injection’s
bioavailability?
Distribution
• Movement of the drug from the systemic circulation to tissues
• Major factors that affect the distribution of drugs:
- Diffusion rate
- Affinity of the drug to the tissues
- Blood flow (perfusion)
- Binding to plasma proteins
• Passive diffusion of free, unbound drug along its concentration
gradient.
Distribution
• Compartments
- Central Compartment : includes the well-perfused organs and
tissues (heart, blood, liver, brain, and kidney) with which drug
equilibrates rapidly.
- Peripheral Compartment(s) : include those organs (e.g., adipse
and skeletal muscle) which are less well-perfused, and with
which drug therefore equilibrates more slowly.
- Special Compartments : The cerebrospinal fluid (CSF) and
central nervous system (CNS) is restricted by the structure of
the capillaries and pericapillary glial cells.
Metabolism
Metabolism
Metabolism
Metabolism
Elimination
• All processes that may be involved in removing a parent drug
from the body.
• Renal excretion and metabolism  elimination of over 90% of
drugs
• Bile excretion  elimination of less than 10% of parent drugs.
• Excretion of parent drug in the sweat, exhalation  very minor
pathways
Therapeutic Range
Therapeutic Range
• The range of plasma concentrations that are associated with optimum
response and minimal toxicity in most patients.
• The goal of therapy is to maintain drug concentrations within the therapeutic
range all times; some exceptions.
• The minimum effective concentrations (MEC)  the lower boundary for
effective drug concentrations; plasma concentrations < MEC  subtherapeutic.
• The maximum tolerated concentration (MTC)  the upper boundary for
optimum drug concentrations; plasma concentrations > MTC 
toxicity/adverse effects
• The onset of action  the time it takes for plasma concentrations to reach MEC
• The duration of action  the time during which plasma concentrations remain
within the therapeutic range.
Therapeutic Index/Therapeutic Ratio
• TI is a way to express the safety margin offered by a drug.
• It is the ratio of the dose of the drug that produces toxicity in 50% of
patients to the dose of the drug that produces therapeutic response in
50% of patients.

• TI of 100  the toxic dose is about 100 times larger than the effective
dose and the drug has a wide safety margin  large therapeutic range
• TI of 3  a small margin of safety  narrow therapeutic range
Therapeutic Index/Therapeutic Ratio
• Some examples of drugs with a narrow therapeutic index are
as follows:
Warfarin
Lithium
Digoxin
Phenytoin
Gentamicin
Amphotericin B
5-fluorouracil
Margin of Safety (MOS)/Certainty
Safety Factor (CSF)
• The goal of drug therapy is to achieve the desired therapeutic
effect in all patients without producing toxic effects in any patients.

• CSF/MOS >1  the dose effective in 99% of the population is

less than the dose that would be toxic in 1% of the population.
• CSF < 1  overlap between the maximally ED99 and minimally
toxic dose.
Tugas
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TERIMAKASIH