Pharmacodynamic and

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 Receptors and

Pharmacodynamics
(how drugs work on the body)
The action of a drug on the
body, including receptor
interactions, dose-response
phenomena, and mechanisms
of therapeutic and toxic action.

most drugs act (bind) on receptors

in or on cells

form tight bonds with the ligand

exacting requirements (size, shape,
stereospecificity)
can be agonists (salbutamol), or antagonists (propranolol)

receptors have signal transduction

methods

How drugs work on the

body?
many drugs inhibit enzymes
Enzymes control a number of metabolic processes
A very common mode of action of many drugs
in the patient (ACE inhibitors)
in microbes (sulfas, penicillins)
in cancer cells (5-FU, 6-MP)

some drugs bind to:

proteins (in patient, or microbes)
the genome (cyclophosphamide)
microtubules (vincristine)

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

Drug - Receptor Binding

D+R

DR Complex
Affinity

Affinity measure of propensity of a drug

to bind receptor; the attractiveness of
drug and receptor
Covalent bonds are stable and
essentially irreversible
Electrostatic bonds may be strong or
weak, but are usually reversible

Drug Receptor Interaction

DR Complex

Effect

Efficacy (or Intrinsic Activity) ability

of a bound drug to change the
receptor in a way that produces an
effect; some drugs possess affinity
but NOT efficacy

Dose-response curves determine how much of a drug (X-axis)

causes a particular effect, or a side effect, in the body (Y-axis).

dose response curves

Arithmetic Dose Scale

Rate of change is rapid at first and
becomes progressively smaller as
the dose is increased
Eventually, increments in dose
produce no further change in
effect i.e., maximal effect for that
drug is obtained
Difficult to analyze mathematically

Agonists and antagonists

agonist has affinity plus intrinsic activity
antagonist has affinity but no intrinsic activity
partial agonist has affinity and less intrinsic activity
competitive antagonists can be overcome

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

Agonist Dose Response Curves

Full agonist
Partial agonist

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

dose response curves

Therapeutic index =Toxic Dose50/Effective Dose50

(TD50/ED50)

Effectiveness, toxicity, lethality

ED50 - Median Effective Dose 50; the
dose at which 50 percent of the
population or sample manifests a
given effect; used with quantal dr
curves
TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
LD50 - Median Toxic Dose 50 - dose
which kills 50 percent of the subjects

Quantification of drug safety

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

The therapeutic index

The higher the TI the better the drug.

TIs vary

from:

1.0 (some cancer drugs)

to: >1000 (penicillin)

Drugs acting on the same receptor or enzyme system often have
the same TI:
(eg 50 mg of hydrochlorothiazide about the same as 2.5 mg of
indapamide)

Signal transduction

1.

enzyme linked

(multiple actions)
2.

ion channel linked

(speedy)
G protein linked

(amplifier)
4.

nuclear (gene) linked

(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

most drugs act through receptors

there are 4 common signal transduction methods
the interaction between drug and receptor can be
described mathematically and graphically
agonists have both affinity (kd) and intrinsic activity ()
antagonists have affinity only
antagonists can be competitive (change kd) or
non-competitive (change ) when mixed with agonists
agonists desensitize receptors.
antagonists sensitize receptors.

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 absolut:

Ketersediaan
Hayati (F):

Perbandingan antar areas under

the plasma concentration-time
curves (AUC) yang diberikan
selain intravena dengan yang
diberikan intravena

Ketersediaan Hayati relatif

(komparatif):
Perbandingan AUCs antar bentuk
sediaan yang satu dengan
bentuk sediaan lain (misalnya:
kapsul dan suspensi, im dan
tablet)

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48

The ROA is determined by

the physical characteristics
of the drug, the speed which
the drug is absorbed and/ or
released, as well as the need
to
bypass
hepatic
metabolism and achieve high
conc. at particular sites
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49

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

First Pass Effect

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).

= Amount of drug in body Concentration in Plasm

(Apparent) Volume of Distribution:
Volume into which a drug appears to distribute with
a concentration equal to its plasma concentration

Examples of apparent Vds for

some drugs
Drug

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 Kidney

Excretion - major
1) glomerular filtration
glomerular structure, size
constraints, protein binding
2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport,
competitive/saturable, organic
acids/bases
- protein
binding
Metabolism - minor

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

Drug interaction can be defined as the

modifications of the effects of one drug by the
prior or concomitant of another drug
(poly-pharmacy)
A drug interaction is a situation in which a

substance affects the activity of a drug,

i.e. the effects are increased or
decreased, or they produce a new effect
that neither produces on its own.

Effects of drug interaction

Drug interaction can result in

Increased effect Additive or Synergistic effect
Increased therapeutic effect good
Increased toxic or adverse effect bad
Decreased effect Antagonistic effect
Decreased therapeutic effect
bad
Decreased toxic effect
good

Drug interactions usually happen unexpectedly

and result in adverse drug reactions
Drug interactions for good therapeutic effects are
usually used intentionally and their results are
already known by physicians

Drug-Drug interaction may

alter drug effect by
Additive effect :

1+1=2

Synergistic effect :

1+1>2

Potentiation effect : 1 + 0 = 2
Antagonism :

0.5

1 - 1 = 0 or

Effect of Drug interaction

Therapeutic drug interaction could be used in 2
objectives
1. To produce synergistic therapeutic effects
.Examples are found by several antibiotic combinations
Penicillin-Sreptomycin
Sulfa-trimethoprim

2. To detoxify or lower toxic effects

.Examples are those antidotes of certain toxic agents
Paracetamol-acetylcystein

Types of drug interaction

There are at least 3 types of drug interaction
Pharmaceutical interaction

minor

Pharmacodynamic (PD) interaction

major
Pharmacokinetic (PK) interaction
major

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

Pharmacodynamic interaction can happen at these

levels
Level of drug action
Level of drug effect
Level of drug response

At this level, it could be called Physiological interaction

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

Important PK interactions are those associated with

Altered drug metabolism
Drug transporters
Protein binding

PK interaction associated with

altered drug metabolism
Altered phase I metabolism
CYP induction
CYP inhibition

Altered phase II metabolism

Induction of phase II enzyme

UDP-glucuronyl transferases (UGTs)
Inhibition of phase II enzyme
Competitive use of conjugate molecules

PK interaction associated with

drug transporters
Transporters Playing Key Roles in Drug Absorption

and Excretion
Important drug transporters
P-glycoproteins (PgP)

very important for excretion processes

Other transporters

Interaction usually result in

Inhibit function of transporters

And inhibit drug excretion
And finally cause AUC of a drug to increase or more drug
in the body

Examples of Clinically Significant Drug

interactions Associated with Inhibition of
Transporters Other Than PgP

PK interaction associated with Protein binding

The major plasma proteins to which most

drugs bind are albumin and 1-acid
glycoprotein; the former typically binds acidic,
anionic drugs whereas the latter typically
favors basic drugs
Competitive protein binding by another drug
will result in increase concentration of free
drug, and that will yield more drug response

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

Age-related changes which affect

pharmacokinetics
decreased lean body mass
affects drug distribution
decreased levels of serum albumin
affects drug distribution
decreased liver function
affects drug metabolism/biotransformation
decreased renal function
affects drug elimination

Drug absorption changes in

the elderly
Gastrointestinal system (rarely
significant clinically)
acid production generally unchanged
multiple prescriptions increase the
probability of drug-drug interaction which
may alter absorption
splanchnic blood flow decreases (with
little effect on drug absorption)

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

Drug distribution changes in

the elderly
fluid and tissue compartments
decrease in total body water
increase in fat compartment
decrease in muscle mass
plasma drug-binding proteins (rarely
significant clinically)
decrease in serum albumin levels
no change in -acid glycoprotein levels

Pharmacokinetics:
biotransformation

enzymatic reactions preparing drugs for

elimination
Phase I reactions:
oxidation: catalyzed by cytochrome P450 enzymes
Phase II reactions:
conjugation: addition of small chemical groups
which increase solubility to facilitate elimination

Drug metabolism changes in

the elderly
liver
decrease in hepatic blood flow often
associated with decreased First Pass Effect
Phase I metabolism decreased
Phase II metabolism generally preserved

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

Drug elimination changes in

the elderly
decrease in renal
functions
decreased blood flow
to the kidneys
decreased glomerular
filtration
decreased tubular
secretion
decline in creatinine
clearance

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

Physiological changes in elderly patients

affecting pharmcodynamics
target organ changes
decreased desirable effects of
pharmacotherapy
increased adverse effects
homeostasis changes
decreased capacity to respond to
physiological challenges and the adverse
side effects of drug therapy (eg.,
orthostatic hypotension)

Adverse Drug
Reactions

The elderly are 2-3 times more at

risk for adverse drug reactions
due to:
reduced stature
reduced renal and hepatic functions
cumulative insults to the body (eg.,
disease, diet, drug abuse)
higher number and potency of
medications
altered pharmacokinetics
noncompliance

Common problems of drug

administration in the elderly
reduced homeostasis
decreased renal and hepatic functions
increased target organ sensitivity
polypharmacy
increased chance of adverse drug
reactions
lack of available data
fewer clinical trials on elderly
populations
non-compliance

Considerations for pharmacotherapy in the

elderly
Is drug therapy
required?
choice of appropriate
drug and preparation
dosage regimen to
accommodate
changes in
physiology
detailed monitoring
and periodic reevaluation of drug
therapy
clear and simple
instructions

 changes in the physiology of the elderly

alter responses to drug therapy
pharmacokinetic changes affect the
effective concentration of drug in the body
pharmacodynamic changes alter the bodys
response to the drug therapy
adverse drug reactions are more common in
the elderly and can be avoided with better
primary care

Diazepam Pharmacokinetics

Plasma Half-Lives in Young and Old

Drug

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

Other Drugs That May Cause Dementia

or Cognitive Impairment

Alcohol
Benzodiazepin
es
Beta-blockers
Cimetidine
Corticosteroids
Digoxin
Levodopa

Lithium
NSAIDs
Phenytoin
Quinidine

Limits to pharmaceutical therapies for the

elderly

Scientific
evidence

Inappropriate
drugs

Physiological
alterations

Polytherapy
pharmaceutical
interactions
adherence to
treatment

Adverse reactions

Physiologcal changes in elderly people

(Mangoni AA, Jackson SH Age-Related Changes in Pharmacokinetics:

Basic Principals & Practical Applications. Br J Clin Pharmacol, 2004)

Reduced gastric
motility

Change in numbers of
hepatocytes

Reduced secretion of
acid/enzymes

Reduced production of
albumin

Reduced number of functioning glomeruli

Reduced blood flow

Alterations in neurochemical transmission

Reduced cognitive capacity and ability

Physiological alterations in elderly people: what to do?

Consider

the use of well-known drugs about which enough

is known regarding the risk/benefit balance for
elderly patients.

the presence of organ insufficiencies.

recourse to non pharmacuetical treatments (diet

advice, smoking cessation, physical activity).

Some medicines are absolutely to be avoided

Flurazepam (Dalmadorm ) and Diazepam

(Valium ): prolonged sedation and higher
rates of falls and femoral fractures.

Ketoralac (Toradol , Lixidol ): risk of

gastrointestinal bleeding even in the short
term.

Naprossene and Piroxicam : risk of

gastrointestinal bleeding, renal insufficiency and
hypertension if used oved the long term.

Ticlopidina (Tiklid ): risk of neutropenia.

 or with particular conditions

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:

Any symptom in an elderly patient should be considered a

drug side effect until proved otherwise.
Numerous syndromes in old age are actually consequences of
pharmacological therapies:
delirium use of SNC drugs (eg. Anticolinergic drugs,
opiates)
falls and fractures benzodiazepins, anti-hypertension
drugs
urinary incontinence eg. diuretics

Polytherapy and interactions between drugs

An interaction between drugs becomes important for the
patient and the doctor when it interferes with the
expected efficacy or diminishes the safety of a treatment

At the moment of the commercial authorisation of the

drug, the safety profile for elderly people is limited.
The risk of potential interactions almost
exponentially as age and the number of drugs
used increase.
The risk of interaction triples in patients who
receive
prescriptions
from
two
doctors
simultaneously.

Common interactions between drugs and foods

Foods rich in K+: bananas, oranges greens

ACE-inhibitors

Diuretics

Sartans

K+ savers

Foods rich in Ca2+: milk,

yogurt, cheese

Digossin

Diuretics

Thyroid Hormones

Some antibiotics

Foods rich in vitamin K:

apples, spinach, nuts,
kiwis, broccoli, cabbage

Warfarin

Food and Drugs:

the case of grapefruit juice
benzodiazepine
AUC, Cmax strengthens the effects of BDZ

Calcium channel
blockers

Haematic levels
(headaches, hypotension,
tachycardia )

statins

Immunesupressants
Adverse effects
nefrotoxicity,
liver disease

AUC (16 times) cefalea,

myopathy

arrythmia,
antihistamines
Levels of liver disease
Prolonged QT

Antidepressants
tricyclics
Levels of liver
disease

Polytherapy and interactions: what to

do?

Treat the pathologies in order of priority.

Use drugs when strictly necessary to reduce risk.

Ask the patients if they are using over the counter

medicines or herbal medicines.

Inform the patient about foods to avoid.

Monitor the response periodically and compare the

appearance of adverse reactions.

Review treatment periodically.

Polytherapy and therapy adherence: a real problem

Adherence = match between the behaviour of the patient
and the medical prescription

Mistaken
consumption

Change in timing or
frequency of doses by the
patient

40-60% of elderly patients do not follow their prescription

properly

Co-Morbidity

Polypharmacy

The percentage of population with prescriptions, and

the number of medications per individual, increase
with age.