Beruflich Dokumente
Kultur Dokumente
Pharmacokinetic
Eti Nurwening Sholikhah
Department of Pharmacology & Therapy
Faculty of Medicine Universitas Gadjah Mada
Yogyakarta
Pharmacodynamics
the study of the biochemical and
physiological effects of drugs and
their
mechanisms of actioncan
provide the basis for the rational
therapeutic use of a drug and the
design of new and superior
therapeutic agents
Drug Receptor
A macromolecular component
of a cell with which a drug
interacts to produce a
response
Usually a protein
Types of Protein
Receptors
1. Regulatory change the
activity of cellular enzymes
2. Enzymes may be inhibited
or activated
3. Transport e.g. Na+ /K+
ATPase
4. Structural these form cell
parts
DR Complex
Affinity
Effect
Agonist Drugs
drugs that interact with and
activate receptors; they possess
both affinity and efficacy
two types
Full an agonist with maximal
efficacy
Partial an agonist with less then
maximal efficacy
Response
Dose
Antagonist Drug
Antagonists interact with the
receptor but do NOT change the
receptor
they have affinity but NO
efficacy
two types
Competitive
Noncompetitive
Competitive Antagonist
competes with agonist for
receptor
surmountable with increasing
agonist concentration
displaces agonist dose
response curve to the right
(dextral shift)
reduces the apparent affinity of
the agonist
Noncompetitive Antagonist
drug binds to receptor and stays
bound
irreversible does not let go of
receptor
produces slight dextral shift in the
agonist DR curve in the low
concentration range
this looks like competitive
antagonist
Desensitization
agonists tend to desensitize receptors
homologous (decreased receptor
number)
heterologous (decreased signal
transduction)
antagonists tend to up regulate
receptors
Therapeutic Index =
TD50 or LD50
ED50
Drug A
100
sleep
death
Percent
50
Responding
ED50 LD50
dose
Drug B
100
sleep
death
Percent
50
Responding
ED50
dose
LD50
TIs vary
from:
Signal transduction
1.
enzyme linked
(multiple actions)
2.
(speedy)
G protein linked
(amplifier)
4.
(long lasting)
1. Gproteinlinkedreceptors
Structure:
Single
polypeptidechain
threadedbackand
forthresultingin7
transmembrane
helices
TheresaG
proteinattachedto
thecytoplasmic
sideofthe
membrane
(functionsasa
switch).
2. Tyrosinekinasereceptors
Structure:
Receptorsexistasindividualpolypeptides
Eachhasanextracellularsignalbindingsite
Anintracellulartailwithanumberoftyrosinesanda
singlehelixspanningthemembrane
3.Ionchannel
receptors
Structure:
Proteinporesinthe
plasmamembrane
Intracellular receptors
Not all signal receptors are located on the
plasma membrane. Some are proteins located
in the cytoplasm or nucleus of target cells.
The signal molecule must be able to pass
through plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone,
testosterone) and thyroid hormones of
B. SecondMessengers
Small,nonprotein,watersolublemoleculesorions
Readilyspreadthroughoutthecellbydiffusion
Twomostwidelyusedsecondmessengersare:
1. CycleAMP
2. CalciumionsCa2+
2.CalciumIons(Ca2+)andInositolTrisphosphate
CalciummorewidelyusedthancAMP
usedinneurotransmitters,growthfactors,
somehormones
IncreasesinCa2+causesmanypossibleresponses:
Musclecellcontraction
Secretionofcertainsubstance
Celldivision
Twobenefitsofasignaltransductionpathway
1. Signalamplification
2. Signalspecificity
A. Signalamplification
Proteinspersistinactiveformlongenoughto
processnumerousmoleculesofsubstrate
Eachcatalyticstepactivatesmoreproducts
thenintheproceedingsteps
Summary
KETERSEDIAAN HAYATI
OBAT
Ketersediaan Hayati
(F):
Fraksi obat yang
diberikan, yang
mencapai sirkulasi dan
dalam bentuk yang
tidak berubah,
sehingga tersedia
untuk didistribusikan
secara sistemik.
Ketersediaan
Hayati (F):
11/12/16
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No single method of
drug administration is
ideal for all drugs in all
circumstances
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Plasma Concentration
12
TOXIC RANGE
10
8
THERAPEUTIC RANGE
6
4
2
0
SUB-THERAPEUTIC
Dose
Bioavailability
Definition: the fraction of the administered
dose reaching the systemic circulation
for i.v.: 100%
for non i.v.: ranges from 0 to 100%
e.g. lidocaine bioavailability 35% due to
destruction in gastric acid and liver metabolism
PRINCIPLE
For drugs taken by routes other
than the i.v. route, the extent of
absorption and the bioavailability
must be understood in order to
determine what dose will induce
the desired therapeutic effect. It
will also explain why the same
dose may cause a therapeutic
effect by one route but a toxic or
PRINCIPLE
Drugs appear to distribute in the body as
if it were a single compartment. The
magnitude of the drugs distribution is
given by the apparent volume of
distribution (Vd).
L/Kg
L/70 kg
Sulfisoxazole
0.16
11.2
Phenytoin
0.63
44.1
Phenobarbital
0.55
38.5
Diazepam
2.4
168
Digoxin
490
E lim in a tio n
o f d ru g s fro m th e b o d y
M
A
J
O
R
K ID N E Y
L IV E R
f iltr a tio n
s e c r e tio n
m e ta b o lis m
s e c r e tio n
M
I
N
O
R
LU N G S
O TH E R S
e x h a la tio n
m o t h e r 's m ilk
s w e a t, s a liv a e tc .
( r e a b s o r p tio n )
Elimination by the
Liver
Metabolism - major
1) Phase I and II reactions
2) Function: change a lipid soluble to
more water soluble molecule to
excrete in kidney
3) Possibility of active metabolites
with same or different properties as
parent molecule
Biliary Secretion active transport, 4
categories
The enterohepatic
shunt
Drug
Liver
Bile formation
Bile
duct
Hydrolysis by
beta glucuronidase
Biotransformation;
glucuronide produced
gall bladder
Portal circulation
Gut
Pharmacokinetic
parameters
Get equation of regression line; from it get Kel, C0 , and AUC
Volume of distribution Vd =
DOSE / C0
Plasma clearance
.Vd
plasma half-life
0.693 / Kel
Bioavailability
Cl = Kel
t1/2 =
(AUC)x /
Bioavailability
Plasma concentration
i.v. route
oral route
Time (hours)
(AUC)o
(AUC)iv
PRINCIPLE
The absorption, distribution and
elimination of a drug are
qualitatively similar in all
individuals. However, for several
reasons, the quantitative
aspects may differ considerably.
Each person must be considered
individually and doses adjusted
accordingly.
Drug Interactions
Definition
Effects of drug interaction
Types of drug interaction
Pharmaceutical interaction
Pharmacodynamic interaction
Pharmacokinetic interaction
Definition
1+1=2
Synergistic effect :
1+1>2
Potentiation effect : 1 + 0 = 2
Antagonism :
0.5
1 - 1 = 0 or
minor
Pharmaceutical interaction
Interactions that occur prior to systemic
administration
At manufacturing process
At clinical process by mixing 2 or more drugs
in the same container
Drug incompatibility having drug
interaction
Drug compatability
no interaction
Chemical or Physical interactions
Usually result in pharmacological loss
Pharmacodynamic interaction
Definition interaction that one drug may cause
changes in another drug action, effect or response
without PK alteration
Pharmacodynamic interaction could result in either
Additive effect
Synergistic effect
Antagonistic effect
Pharmacokinetic interaction
Pharmacokinetic (PK) interactions sometimes are
also referred to as dispositional interactions.
These interactions are characterized by the
alteration of the PK or disposition (ADME) of one
drug by another.
Change
Change
Change
Change
in
in
in
in
absorption
distribution
Metabolism
Excretion
and Excretion
Important drug transporters
P-glycoproteins (PgP)
Other transporters
Pharmacology of Drugs
for Adult & Elderly
Pharmacokinetic
Principles
absorption
plasma
protein
binding
biotransformation
free drug
in circulation
tissue storage
(fat, muscle, bone)
target site availability
elimination
Pharmacokinetic
Factors
drug solubility
determines absorption and distribution parameters
the partition coefficient of a drug is determined by
a ratio of its fat solubility and its water solubility
therapeutic window
the concentration range at which a drug is
effective without causing undesirable physiological
effects
adverse drug reactions
undesirable side effects of drug therapy
may be dose-related or idiosyncratic
Pharmacokinetics:
distribution
affects the
concentration of
drug available at
the target
solubility:
hydrophilic vs.
lipophilic drugs
protein binding
C = D / Vd
absorption
plasma protein
binding
biotransformation
free drug
in circulation
tissue storage
C, concentration
(fat, muscle, bone)
D, dose
Vd,, volume of
target site
distribution
elimination
availability
Pharmacokinetics:
biotransformation
Pharmacokinetics:
elimination
removal of drug from the body by excretion
renal elimination:
glomerular filtration
tubular secretion
other minor pathways of elimination:
feces
breath
sweat
saliva
Pharmacodynamics
study of the interaction between a
pharmacological agent and its target
tissue
Involves:
the mechanism,
intensity,
peak and
duration of a drugs physiological
actions
Adverse Drug
Reactions
Diazepam Pharmacokinetics
Young (20-30)
Elderly (6580)
Penicillin G
Tetracycline
Digoxin
Diazepam
Lidocaine
Chlordiazepoxide
Phenobarbital
Warfarin
20.7 min
3.5 hr
51 hr
20 hr
80.6 hr
8.9 hr
71 hr
37 hr
39.1 min
4.5 hr
73 hr
80 hr
139.6 hr
16.7 hr
107 hr
44 hr
Physiological Changes
No significant changes in absorption
Increased adipose tissue changes
distribution of fat soluble drugs
Decreased cardiac output
Little effect on hepatic metabolism for
most drugs
Decreased renal excretion most
significant
Alcohol
Benzodiazepin
es
Beta-blockers
Cimetidine
Corticosteroids
Digoxin
Levodopa
Lithium
NSAIDs
Phenytoin
Quinidine
Scientific
evidence
Inappropriate
drugs
Physiological
alterations
Polytherapy
pharmaceutical
interactions
adherence to
treatment
Adverse reactions
Reduced gastric
motility
Change in numbers of
hepatocytes
Reduced secretion of
acid/enzymes
Reduced production of
albumin
Consider
Gastrointestinal
disturbances
Constipation
Cardiovascolar
Disturbances
Avoid:
anticolinergics,
antidepressants
tricyclics
Avoid: aspirin, K+
integrators
Avoid:
antidepressants
tricyclics
Urinary Disturbances
Incontinence
Endocrine Disturbances
Cardiac arrhythmia
Ulcers
Avoid: -blockers
Diabetes
Avoid:
corticosteroids, blockers
Respiratory Disturbances
Athsma o COPD
Avoid: -blockers
Always remember:
ACE-inhibitors
Diuretics
Sartans
K+ savers
Digossin
Diuretics
Thyroid Hormones
Some antibiotics
Warfarin
Calcium channel
blockers
Haematic levels
(headaches, hypotension,
tachycardia )
statins
Immunesupressants
Adverse effects
nefrotoxicity,
liver disease
arrythmia,
antihistamines
Levels of liver disease
Prolonged QT
Antidepressants
tricyclics
Levels of liver
disease
Mistaken
consumption
Change in timing or
frequency of doses by the
patient
Co-Morbidity
Polypharmacy