Dwi Indria Anggraini

1
; Rovina Ruslami
2
Definitions
Pharmacology
Pharmacokinetic
Pharmacodynamic
Pharmacy
Pharmacognosy
Clinical
Pharmacology
Pharmacogenetic
Pharmacotherapeutic
Pharmacoeconomic
In order to work adequate conc. in target tissues.
Two important process:
A. translocation of drug molecules
Absorption and distribution of drugs

B. chemical transformation
Metabolism and excretion

Pharmacokinetics
The study of absorption, distributions, biotransformation and
excretion of drugs
What the body do to the drugs
Involved in how the concentration of drug in the body varies
with time
A. Translocation of drug molecules
How the drugs cell membranes?
1. Diffuse directly
through the lipid
(passive
diffusion)
2. Carrier-mediated
3. Diffuse through
aqueous channel
(aquaporins)
4. Pynocytosis

1. Passive diffusion through the lipid
Along a gradient concentration
main factor influenced: lipid solubility
Weak acid drugs (aspirin) needs alkaline pH to ionized absorbed
Weak base drugs (pethidine) need acid pH to ionized absorbed

2. Carrier-mediated
In renal tubule, BBB, PBB, GIT epithellium
! For drugs that chemically
related to the endogenous
substance
(exp: amino acid, sugar, metal
ions, neurotransmitter)
a. Facilitated diffusion
does not need energy
b. Active transport
against e-chemical gradient
* P-glycoprotein

4. Pynocytosis
Membrane permeation
! For drugs with large
molecules
Then
Translocation to the blood transport of drugs
in the blood
Issues:
1. Binding to plasma protein
2. Partition into body fat and other tissues
> lipid:water partition
exp: morphine (l:w p 0.4) but thiopental (l:w p 1)
> accumulation of drugs in fat (chronic use of BZD)
Binding of drugs to plasma protein

only free drugs is pharmacologically active (it can be only 1%)
albumin is the most important; theres also -globulin
acidic and hydrophobic drugs to albumin
basic drugs to -globulin and 1-acid glycoprotein
neutral and hydrophyllic drugs not to albumin
the binding is reversible
non selective competition drug interaction
of drugs thats bound to protein depend on:
conc. of free drug
affinity to the binding sites
conc. of protein
Binding of drugs to plasma protein

The drug with highly bound protein limits it conc. in tissuE
smaller effect, slower metabolism and excretion
For drugs with narrow th/ index small changes in free drugs
conc. could be a concern (DRUG INTERACTION!!)
Sosteady-state of free drug conc. is independent of the
extent of plasma protein
Steady-state of free drug conc. changes significantly ONLY if
input (dosing rate) or output (clearance) is changed.
Drug disposition
4 stages:
1. Absorption from site of administration
2. Distribution within the body
3. Metabolism
4. excretion
Route of drug administration
Drug absorption
Transport of the drug from site of administration to
the plasma/circulation
is depend on route of administration
iv : 100% absorption (others: < 100% absorption)

most of drugs are taken per orally absorption is
mainly in the small intestine
Route of administration
enteral (GIT)
oral, sublingual, per rectal (suppositoria)
parenteral
iv, im, sc,
when?
need immediate effect
unconsciousness
cant be given enterally
others
inhalation, transdermal, topical
1. Oral administration
Drug absorption from intestine
Mechanism = as mentioned previously
Acids will be better absorbed in alkaline pH
Base will be better absorbed in acid pH

Factors affecting GI absorption
Surface area (more in intestine)
GI motility some drugs affect this also!
Food intake can alter absorption (delayed to intestine)
Blood flow
Particle size and formulation (exp: capsule, tablet, enteric coated, slow-
release)
Physicochemical factors

Bioavailability affected by first-pass metabolism
2. Sublingual administration
To prevent first-pass metabolism
Higher Bioavailability
Higher efficacy
Exp: ISDN
3. Rectal administration
Aim:
Local effect
Systemic effect but
Unable to swallow the drug (vomit, post operative)
Difficult for iv (diazepam supp in children)
Avoid GI irritating
50% of drugs will by pass the liver
(<< FPM)
Per oral Most common, cheapest, safest
Absorption varies - factors in stomach and
intestine (surface for absorption in duodenum)

Sub lingual Underneath the tongue
Directly to systemic circulation (no first past
metabolism)

Per rectal 50% of drugs by pass the liver (<< metabolized)
<< degradation due to gastric pH, gastric
enzymes
BUT absorption is irregular, not complete
Sometimes irritating
IV most common parenteral
fastest OOA (100% Bioavailability)
BUT with AEs

IM as a depo slow release to systemic circ.
OOA is faster than per oral
larger volume

SC just like IM, but with smaller volume
OOA is faster than per oral
Administration by injection
Inhalation aerosol, directly goes to alveoli
OOA is same like IV

Topical local effect to the skin, eye, nose, ear and vagina

Transdermal

topical on the skin that has a systemic effect
(slow release)

Intra techal for drugs that cant pass BBB
give into subarachnoid space

Other administration
Bioavailability
Bioequivalence
Th/-equivalence
1. Bioavailability (BA)
% of the administrated drugs reaches systemic circulation
(in a chemically unchanged form)
Absolute BA = AUC oral/AUC iv

2. Bioequivalence (BE)
2 related drugs with comparable BA (under same conditions)
BIE : 2 related drugs with incomparable BA

3. Th/-equivalence (TE)
2 similar drugs with comparable efficacy and safety
Exp: ISDN, propranolol, lidocain >>> FPM <<
BA if p.o
1. First-past
metabolism
>> hydrophyllic drug difficult to cross lipid-rich
cell membrane
>> hydrophobic also poor absorbed
2. Solubility of
drugs
exp: insulin will be destroyed in GI
3. Chemical
instability
exp: particle size, salt form, +/- exipients
4. Nature of drug
formulation
Drug distribution

Drugs leave the circulation and enter
the interstitium (ECF/interstitial fluid) &
/ cells of tissue.

It is depend on:
blood flow (fast and slow)
permeability
capillary structure (barrier)
drug structure (lipo/hydro-phylic)
binding drugs to protein
brain, liver, kidney receive most of
the drugs
Until conc. in tissues is in equilibrium with that in the blood
Body fluid compartment

Drug molecules (bound & free drugs) exist in each
compartment BUT ONLY free drugs can move between
the compartments

Relative size of V
D
(BW = 70 kg)
Total body
water
ECF
plasma
interstitial
ICF
42 L
65% (28 L)
35% (14 L)
10% (4 L)
25% (10 L)
The equilibrium depends on:
1. Permeability across tissue barriers
2. Binding within compartment
3. pH partition
4. Lipid : water partition
Volume of distribution
volume of plasma that would contain the total body
content of the drug at the equal conc. to that in plasma.
Implication of Vd:
>> in the plasma.
& hydrophillic >> to ECF (through endothelial slit junctions)
& hydrophobic >> to ECF(through cell membranes)
pts with edema Vd (heart, renal, liver failure)
drugs stored in fat Vd (thiopental)
Introduction
Drug elimination:
Irreversible loss of drug from the body
- metabolism (involve enzymic conversion)
- excretion (unchanged/metabolites)
Main routes:
Kidneys
Hepatobiliary system
Lungs (anesthetic drugs)
Small amounts: saliva, sweat, milk (! Effect to the baby)
Drug Metabolism (= biotransformation)
lipophilic drug cant be excreted by kidney they has to be
transformed into more polar OR conjugated drugs
phase I
phase II

phase I : lipophilic mol more polar (catabolic reaction)
oxidation/reduction/hydrolysis
pharmacologic activity: / / / become toxic / carcinogenic
involving P-450 system (superfamily enzymes)
some drugs inhibits or induce P-450 system !!!
Drug Metabolism (= biotransformation)
phase II : lipophilic mol conjugated hydrophilic (anabolic)
conjugation; glucoronidation
pharmacologic activity: inactive
involving glucoronic acid, etc
sopolar or conjugated drugs hydrophylic can pass
the kidney
Factors influence drug metabolism
1. Liver disease
2. Genetic abnormality
3. Age (pediatric, geriatric patients)
4. Gender
5. Drug interaction
6. Environment
Drug Excretion (= elimination) via kidney
Three renal processes involved:
glomerular filtration (GF) 20% are filtered
active tubular secretion
passive diffusion
Keys:
most drugs, unless highly protein bound, cross GF freely
weak acid/base drugs are actively secreted into renal
tubules rapidly excreted
lipid-soluble drugs are passively reabsorbed not
efficiently excreted in the urine
acid drugs are excreted better in alkaline urine and



Renal clearance
Volume of plasma containing the drug that is removed by
kidney in unit time (= xx ml/min)

It is decreased in:
elderly
acute illness
renal impairment

Implication: increased toxicity; lowering the dose

Biliary excretion (& Entero-hepatic circulation)
Drugs is excreted in: Unchanged/ active-metabolites/ inactive
forms
Hydrophilic conjugated drug
(glucoronides) bile
intestine hydrolised
(active drug once more;
reabsorbed (20%):
enterohepatic circulation)
kidney

So..

Relationship between time course of drug conc. attained in
different regions of body during and after dosing is called by
PHARMACOKINETICS (PK)
Pharmacokinetics
The study of absorption, distributions, biotransformation and
excretion of drugs
What the body do to the drugs
Involved in how the concentration of drug in the body varies
with time
.Clinical Pharmacokinetics
Time
[drug]
Cmax peak effect
AUC
tmax
Th/ window
MEC for desired
response
MEC for unwanted
response
DOA
OOA
Single compartment model

T : time needed to lessen the drug conc. becomes 50%
Plasma conc.
Drug excreted
Effect of repeated dose

there will be a steady-state conc.
it takes about 3-5 x T


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