
derived from the Greek word for drug

A science that studies drug effects within
a living system, biochemical and
physiological aspects

Deals with all drugs used in society
today, legal or illegal, including street,
prescription, and non-prescription or
over –the-counter medications
A
•
•
•
•
drug is defined as any substance;
chemical agent; used in the
Diagnosis
Cure
Treatment
prevention of a disease or
condition
 Chemical
Name
 Generic Name
 Trade Name
 Describes
its
molecular
structure and distinguishes it
from other drugs
 Determined
by the pharmaceutical
company along with
a special
organization known as the U.S.
Adopted Names Council (USAN)
 Or
brand name- the manufacturer
selects alone…can become a
registered trademark.
 They are the only one who can
advertise and market the drug
under that name.

The particular spelling of a brand name
drug is proposed by a manufacturer for
one of several reasons.
 Azmacort-
 Rythmol-
treats asthma
treats cardiac arrhythmias
 Pseudoephedrine
 Haloperidol
to Sudefed
to Haldol
 Ciprofloxacin
to Cipro
 Slow-K
slow release potassium
supplement


Or legend drugs
Means in order to obtain drug, you must have
a legal prescription


Or Over-the-Counter (OTC) drugs
Drug that may be purchased without a
prescription
Drugs have been identified or derived from
four main sources:
 Plants
 Animals
 Minerals and Mineral Products
 Synthetic or Chemical Substances Made in the
Laboratory
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
main routes of drug entry
into the body may be divided
into two classes:
◦Enteral
◦Parenteral

Enteral - drug placed directly in the GI tract:
◦ sublingual - placed under the tongue
◦ oral - swallowing (p.o., per os)
◦ rectum
rectum
-
Absorption
through
the
Some drugs are taken as smaller tablets which
are held in the mouth or under the tongue.

Advantages
◦ rapid absorption
◦ drug stability
◦ avoid first-pass effect

Disadvantages
◦ inconvenient
◦ small doses
◦ unpleasant taste of some drugs

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

Disadvantages
◦ destruction of drugs by gastric acid and
digestive juices
◦ effect too slow for emergencies
◦ unpleasant taste of some drugs
◦ unable to use in unconscious patient


The first-pass effect is the term used for
the
hepatic
metabolism
of
a
pharmacological
agent
when it is
absorbed from the gut and delivered to
the liver via the portal circulation.
The greater the first-pass effect, the less
the agent will reach the systemic
circulation when the agent is administered
orally
Magnitude of first pass hepatic effect:
Extraction ratio (ER)
ER = CL liver / Q ;
where Q is hepatic blood flow (usually about
90 L per hour.
Systemic drug bioavailability (F) may be
determined from the extent of absorption (f)
and the extraction ratio (ER):
F = f x (1 -ER)



Absorption across the rectal mucosa occurs
by passive diffusion.
This route of administration is useful in
children, old people and unconscious
patients.
Eg., drugs that administered are: aspirin,
acetaminophen, theophylline, indomethacin,
promethazine & certain barbiturates.
KLECOP, Nipani
08/10/2010
28
Advantages:
1. Suitable for unconscious patients and
children
2. suitable if patient is nauseous or vomiting
3. easy to terminate exposure
4. good for drugs affecting the bowel such
as laxatives
Disadvantages:
1. absorption may be variable
2. irritating drugs contraindicated
◦ 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
◦ Intrathecal : into CSF
Absorption phase is bypassed
(100% bioavailability)
1.precise, accurate and almost immediate onset of
action,
2. large quantities can be given, fairly pain free
Disadvantages
a-. greater risk of adverse effects
b- high concentration attained rapidly
C- risk of embolism
1. very rapid absorption of drugs in aqueous
solution
2. Slow release preparations
Disadvantages
pain at injection sites for certain drugs
1. slow and constant absorption
2. absorption is limited by blood flow,
affected if circulatory problems exist
3.
concurrent
administration
vasoconstrictor will slow absorption
of
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
•Mucosal membranes (eye drops, antiseptic)
•Skin
a. Dermal - rubbing in of oil or ointment
(local action, sun screen, an callus removal)
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 too large
o

Intra nasal administration
Drugs generally administered by intra nasal
route for treatment of local condition such
as perennial rhinitis, allergic rhinitis and
nasal decongestion etc.
37
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 11-30 minutes
subcutaneous 14-30 minutes
rectal 5-30 minutes
ingestion 30-90 minutes
transdermal (topical) variable (minutes to hours)
Drug at site
of administration
Absorption
Drug in plasma
Distribution
Drug/metabolites
in tissues
Metabolism
Drug/metabolites
in urine, feces, bile
Elimination



Definition :
The process of movement of
unchanged
drug
from
the
site
of
administration to systemic circulation.
The ultimate goal is to have the drug reach the
site of action in a concentration which
produces a pharmacological effect.
No matter how the drug is given (other than IV)
it must pass through a number of biological
membranes before it reaches the site of action.
KLECOP, Nipani
08/10/2010
42
the Rate dependent on polarity and size.
Polarity estimates partition coefficient.
The greater the lipid solubility – the faster the rate of
diffusion
Smaller molecules penetrate more rapidly.
Highly permeable to O2, CO2, NO and H2O .
Large polar molecules – sugar, amino acids, phosphorylated
intermediates – poor permeability
These are essential for cell function – must be actively
transported
43
KLECOP, Niani
44
1) Passive diffusion
2) Carrier- mediated transport
a) Facilitated diffusion
b) Active transport
3) PINOCYTOSIS
KLECOP, Nipani
08/10/2010
45




Also known as nonionic diffusion.
It depends on the
difference in the drug
concentration on either
side of the membrane.
Absorption of 90% of
drugs.
The driving force for
this process is the
concentration
or
electrochemical
gradient.
46



Involves a carrier (a component of the
membrane) which binds reversibly with the
solute molecules to be transported to yield
the carrier solute complex which transverses
across the membrane to the other side where
it dissociates to yield the solute molecule
The carrier then returns to its original site to
accept a fresh molecule of solute.
There are two types of carrier mediated
transport system:
a) facilitated diffusion
b) active transport
47


This
mechanism
driving
force
is
concentration
gradient.
In this system, no
use of energy is
involved (down-hill
transport), therefore
the process is not
inhibited
by
metabolic
poisons
that interfere with
energy production.
48




More important process
than facilitated diffusion.
The
driving
force
is
against the concentration
gradient
or
uphill
transport.
Since the process is uphill,
energy is required in the
work done by the barrier.
As the process requires
energy, it can be inhibited
by metabolic poisons that
interfere
with
energy
production.
49
Active transport:
• Carrier-mediated
• Energy-dependent
• Against conc gradient
• Shows carrier
saturation kinetics
 Passive transport
• Energy-independent
• No carrier involved
• Along conc gradient
• No saturation kinetics

ATP
ADP
+ Pi
AH
B
ABH+
Carrier-mediated
energy-dependent
active transport
Passive diffusion
of a water-sol
drug via aqueous
channel
Passive diffusion
of a lipid-sol drug

This process is
important in the
absorption of oil
soluble vitamins &
in the uptake of
nutrients.
51
Drug transported by passive diffusion
depend upon:

dissociation constant, pKa of the drug

lipid solubility, K o/w

pH at absorption site.



Most drugs are either weak acids or weak
bases whose degree of ionization is depend
upon pH of biological fluid.



For a drug to be absorbed, it should be
unionized and the unionized portion should
be lipid soluble. Only non-ionized fraction of
drugs (acids or bases is absorbed
The fraction of drug remaining unionized is a
function of both
Dissociation constant (pKa) and pH of
solution.
HENDERSON HASSELBATCH EQUATION
For acid,
For base,
pKa - pH = log[ Cu/Ci ]
pKa – pH = log[ Ci/Cu ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will
have > 99%of unionized form so gets absorbed in
stomach
Weak base quinine (pKa=8.5) will have very negligible
unionization in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid
soluble to overcome poor oral absorption of their
parent compounds.
KLECOP, Nipani
08/10/2010
54

Blood Flow To Absorptive Site:
o
Greater blood flow raises absorption
Intestine has greater BF than stomach

Total Surface Area of Absorptive Site:
o


Intestinal microvilli increases surface area to 1000fold that of the stomach favoring intestinal
absorption
Contact Time at Absorptive Site:
Diarrhea reduces absorption
 Accelerated gastric emptying→ faster delivery to
intestinal large surface → increased absorption







Food: Presence of food in the gut reduces/delays
drug absorption from GIT
Increased splanchnic blood flow during eating
increases drug absorption
Ionized drugs as tetracycline can form insoluble
complexes with Ca2+ in food/milk.
Formulation Factors:
Solid dosage forms dissolution & solubility are
essential
Aqueous solutions are absorbed more quickly than
tablets or suspensions
56
Stomach:

The surface area for absorption of drugs is
relatively small in the stomach due to the absence
of macrovilli & microvilli.

Extent of drug absorption is affected by variation
in the time it takes the stomach to empty, i.e., how
long the dosage form is able to reside in stomach.

Drugs which are acid labile must not be in contact
with the acidic environment of the stomach
PHYSIOLOGICAL FACTORS:
Gastrointestinal (Gi) Physiology
 Influence Of Drug Pka And Gi Ph On Drug
Absorbtion
 Git Blood Flow
 Gastric Emptying………………..contact time
 Disease States
 Total surface area

Intestine
 Major site for absorption of most drugs due to its large
surface area (0.33 m2 ).
 It is 7 meters in length and is approximately 2.5-3 cm
in diameter.
 These folds possess finger like projections called Villi
which increase the surface area 30 times ( 10 m2).
 From the surface of villi protrude several microvilli
which increase the surface area 600 times ( 200 m2).
 Blood flow is 6-11 times that of stomach.
 PH Range is
5–7.5 , favorable for most drugs to
remain unionized.
 Peristaltic movement is slow, while transit time is long.
 Permeability is high.
All these factors make intestine the best site for
absorption of most drugs.
 Large


intestine :
The major function of large intestine is to
absorb water from ingestible food residues
which are delivered to the large intestine in a
fluid state, & eliminate them from the body as
semi solid feces.
Only a few drugs are absorbed in this region.

the proportion of the drug in a
dosage form available to the body
i.v injection gives 100% bioavailability.




Fraction of a drug reaching
systemic
circulation in
chemically unchanged form
after a particular route
First pass metabolism, i.e.,
rapid hepatic metabolism,
reduces bioav. (lidocaine,
propranolol, nitrates)
Drug solubility
Chemical
instability
in
gastric pH (penicillin G,
insulin)
Drug formulation: Standard
& SR formulations

Serum
Concentration

Bio = AUC oral/AUC IV x 100
Injected Dose
Oral Dose
Time
62
The body is a container in which a drug is
distributed by blood (different flow to different
organs) - but the body is not homogeneous.
Factors affecting drug delivery from the plasma:
A- blood flow: kidney and liver higher than skeletal
muscles and adipose tissues.
B- capillary permeability:
1- capillary structure: blood brain barrier
2- drug structure
C- binding of drugs to plasma proteins and tissue
proteins

DEFINITION OF PHARMACOKINETICS AND
PHARMACODYNAMICS








Glomerular filtration depends on:
Renal blood flow & GFR; direct relationship
Plasma protein binding; only free unbound drugs are
filtered
Tubular Secretion in the proximal renal tubule mediates
raising drug concentration in PCT lumen
Organic anionic & cationic transporters (OAT & OCT)
mediate active secretion of anionic & cationic drugs
Passive diffusion of uncharged drugs
Facilitated diffusion of charged & uncharged drugs
Penicillin is an example of actively secreted drugs
74



o



Tubular re-absorption in DCT:
Because of water re-absorption, urinary D concentration
increases towards DCT favoring passive diffusion of unionized lipophillic drugs
It leads to lowering urinary drug concentration
Urinary pH trapping:
Chemical adjustment of urinary pH can inhibit or enhance
tubular drug reabsorption
For example, aspirin overdose can be treated by urine
alkalinization with Na Bicarbonate (ion trapping) and
increasing urine flow rate (dilution of tubular drug
concentration)
Ammonium chloride can be used as urine acidifier for
basic drug overdose treatment
75








o
o
o
Pulmonary excretion of drugs into expired air:
Gases & volatile substances are excreted by this route
No specialized transporters are involved
Simple diffusion across cell membrane predominates. It depends
on:
Drug solubility in blood: more soluble gases are slowly excreted
Cardiac output rise enhance removal of gaseous drugs
Respiratory rate is of importance for gases of high blood solubility
Biliary excretion of few drugs into feces
Such drugs are secreted from the liver into the bile by active
transporters, and then into duodenum
Examples: digoxin, steroid hormones, some anticancer agents
Some drugs undergo enterohepatic circulation back into systemic
circulation
CLEARANCE:Is defined as the hypothetical volume of body
fluids containing drug from which the drug is
removed/ cleared completely in a specific period of
time. Expressed in ml/min.
CL = kVD, k: elimination rate constant
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09-12-2010
77






It is ability of kidney, liver and other organs to eliminate drug
from the bloodstream
Units are in L/hr or L/hr/kg
Used in determination of maintenance doses
Drug metabolism and excretion are often referred to
collectively as clearance
The endpoint is reduction of drug plasma level
Hepatic, renal and cardiac failure can each reduce drug
clearance and hence increase elimination T1/2 of the drug
78
TOTAL BODY CLEARANCE:Is defined as the sum of individual
clearances by all eliminating organs is
called total body clearance/ total
systemic clearance.
Total Body Clearance = CLliver + CLkidney + CLlungs +CLx
KLECOP, Nipani
09-12-2010
79



Elimination (metabolism + excretion) of most drugs
follow first-order kinetics at therapeutic dose level
Amount of drug cleared in a given unit of time is
directly proportional to the concentration of the drug
according to Michaelis-Menten (linear) kinetics:
Only few drugs (e.g., phenytoin, alcohol) show
saturation clearance (Zero-order, non-linear) kinetics
E = Vmax x C
km + C
 Clearance mechanisms become saturated at therapeutic level, and
clearance remain constant even with increased drug plasma level
 SLOW ELIMINATION at therapeutic levels leads
to toxic reactions
Therapeutic success
of a rapidly &
completely absorbed
drug.
Plasm
a
Minimum effective
conc.
Therapeutic failure of
a slowly absorbed
drug.
Drug
Conc.
Not only the
magnitude of drug that
comes into the
systemic circulation
but also the rate at
which it is absorbed is
important this is clear
from the figure.
Subtherapeutic
level
Time
81
Loading Dose =
Target Plasma C x VD
 What Is the is the
loading dose required
fro drug A if:
 target concentration is
30 mg/L
 VD is 0.75 L/kg,
patients weight is 75
kg




Answer
VD = 0.75 L/kg x
75 kg = 56.25 L
Target Conc. = 10
mg/L
Dose = 30 mg/L x
56.25 L = 1659
mg



Maintenance Dose
= CL x target steady state drug concentration
The units of CL are in L/hr or L/hr/kg
Maintenance dose will be in mg/hr
body)
Pharmacodynamics
(how drugs work on the
It is the study of biochemical and
physiological effects of drugs and
their mechanism of action at
organ level as well as cellular
level.
2004-2005
LONGITUDNAL SECTION OF KIDNEY
KLECOP, Nipani
09-12-2010
85



Half-life: is a derived parameter,
completely determined by volume of
distribution and clearance.
(Units = time)
As Vd increases t1/2 increases



Steady-state occurs after
a drug has been given
for approximately 4-5
t1/2
At steady-state the rate
of drug administration
equals the rate of
elimination
Plasma concentration
after each dose is
approximately the same
C
Cpav
t
Four half lives to reach steady state
At SS Rate in = Rate Out
 Steady state is reached usually within 4 – 5
half-lives at linear kinetics
 It is important for drug concentrations
interpretation in:
 Therapeutic Drug Monitoring (TDM)
 Evaluation of clinical response

• Dosing: Administration of
medication over time, so that
therapeutic levels can be
achieved.
• Steady-state:
drug accumulates and plateaus
at a particular level
o rate of accumulation determined
by half life
o reach steady state in about five
times the elimination half-life
o
body)
Pharmacodynamics
(how drugs work on the
It is the study of biochemical and
physiological effects of drugs and
their mechanism of action at
organ level as well as cellular
level.
2004-2005
Do NOT impart new functions on any
system, organ or cell Only alter the PACE of
ongoing activity




STIMULATION
DEPRESSION
REPLACEMENT
CYTOTOXIC ACTION
Majority of drugs interact
biomolecules: Usually a Protein

ENZYMES

ION CHANNELS

TRANSPORTERS

RECEPTORS
with
target
Direct
Physical blocking
of channel
local anesthetic & amiloride
Modulator
Bind to the channel
protein itself
Ca channel blockers
ChE inhibitors
α-Methyl dopa

Drug acts as
Substrate leading to reversible OR irreversible
inhibition of enzyme
 reversible inhibition of cholinesterase by neostigmine
 Irreversible inhibition of cyclo-oxygenase by aspirin
True/False substrate
 L-DOPA converted into dopamine
 α-methyldopa
converted
into
methylnorepinephrine (false transmitter)
α-
What is carrier molecule?
 Carrier
protein
molecules
function
to
transport ions & small organic molecules (too
polar to penetrate) across cell membranes.

They possess a recognition site that confers
specificity for a particular carried agent.

Such recognition sites can be targets for
drugs where they block the transport system.

An example is the inhibition of cardiac
Na+K+-ATPase by cardiac glycosides.



cellular macromolecular proteins located
either in the cell membrane or less
frequently in the cytoplasm.
Definition:
It
is
defined
as
a
macromolecule or binding site located on
cell surface or inside the effector cell that
serves
to
recognize
the
signal
molecule/drug and initiate the response to
it, but itself has no other function, e.g. Gprotein coupled receptor.


They have specific recognition sites that bind
selectively with a structurally-related group
of synthetic drugs and endogenous mediators
(ligands).
They responsible for transducing extracellular
signals into intracellular response
There are FOUR types of receptors, classified according to
their molecular structure and the nature of
the receptor-effector linkage

Membrane receptors are usually composed
of three parts:
more than one hydrophobic membrane-
spanning α-helical segment
the extracellular ligand-binding domain
the intracellular transduction domain




They are responsible for regulation
of ions across cell membrane
Binding of ligand to receptor →
opening or closure of channel
Response
milisec)
is
very
rapid
E.g. Nicotinic receptors
skeletal muscle
δ-aminobuteric
acid
receptors in the brain
(few
in the
(GABA)
nAch receptor: pentamer protein (α2βγδ),




Membrane bound receptors which are
bound to effector system through Gproteins.
These are hetero trimeric molecules
having 3 subunits α,β and ϒ. Based
on α-sub unit they are further
classified into 3 main varieties Gs, Gi
and Gq
G-protein controls the activity of an
effector protein; a membrane enzyme
or an ion channel
Activation/inhibition of the effector
enzyme increase/decrease the release
of a diffusible second messenger
such as cAMP or IP3
Subtypes of G-proteins - Targets (Second
messenger systems)
 Ion chanels: Na+ / H+ exchange
 Enzyms: Gi Inhib. Adenylyl cyclase
Gs Stimul. Adenylyl cyclase
Gq Stimul. Phospholipase C

One ligand can bind to more than one type of
G-proteins
coupled
receptors
second
messenger pathways
2nd Messenger
Phospholipase C
Adenylate cyclase
cAMP
Activation of protein
Kinase C
DAG
Regulation
of free Ca in the cell
IP3




They have cytosolic enzyme in their
structure.
Binding of a ligand to extracellular
domain activate or inhibit the enzyme.
Duration of response is minutes to
hrs.
They are two main groups
 Tyrosine-kinase-linked
receptors
such as receptors for insulin, growth
factors and many cytokines,
 Guanylate
cyclase-coupled
receptors for atrial natriuretic
peptide (ANP)




This is the only intracellular
cytoplasmic protein receptors,
NO membrane segments.
The drug should diffuse into the
cell to interact with receptor i.e.
the drug should be lipid soluble.
E.g. Steroid & thyroid hormones.
It takes time for onset of action
i.e. time for protein synthesis and
longer duration of action (hrs to
days)
Drug (D) + Receptor (R)
K1
K2
DR complex
Pharmacologic Response
Lock and key theory




Drugs binding to the receptors is governed by Law of Mass
Action.
The number of receptors [R] occupied by a drug depends on
the drug concentration [D] and the drug-receptor association
and dissociation rate constants (K1 & K2).
Affinity: Ability of a substrate to bind with receptor
Intrinsic activity (IA): Capacity to induce functional change in
the receptor
Key & Lock theory
Affinity
Drug
Receptor
DR complex
Affinity is the tendency of drug to combine with its receptor
Efficacy is the ability of a drug to initiate a cellular effect
Biological response
Efficacy

Agonist
An agent which activates a receptor to produce an
effect similar to a that of the physiological signal
molecule, e.g. Muscarine and Nicotine) response.
◦ it has affinity & intrinsic activity i.e. the drug binds to a
receptor and produce biological response like endogenous
ligand.

Antagonist
an agent which prevents the action of an agonist on a
receptor or the subsequent response, but does not have
an effect of its own, e.g. atropine and muscarine no
response.
◦ It has affinity but without intrinsic activity
◦ Efficacy = zero

Partial agonist or antagonist
◦ It has efficacy > zero but < full agonist, even if all receptors are
occupied
◦ It has affinity greater, less or the same as full agonist
◦ It decrease the response of the agonis.
• Inverse agonist: an agent which activates receptors to produce
an effect in the opposite direction to that of the agonist, e.g.
DMCM on bzp receptors opposite response
Ligand: any molecule which attaches selectively to particular
◦
◦
◦
◦
receptors or sites (only binding or affinity) If explained
Agonist: Affinity+ IA
Antagonist: Affinity+ IA (0)
Partial agonist: Affinity + IA (0 to 1)
Inverse agonist: Affinity + IA (0 to -1)

Competitive antagonism

Non competitive antagonism = allosteric
◦ Ag & Antag have the same binding site on the receptor.
◦ Increasing agonist concentration can restore the agonist
occupancy and hence the response.
◦ They increase the ED50 of the agonist, but not Emax or
the slope.
◦ e.g. NA & prazocin on α1 receptor
◦ Ag & Antag have different site of binding.
◦ Increasing the agonist does not affect antagonist
occupancy or the receptor blockade.
◦ They cause a reduction of the slope & the max of the
agonist concentration-response curve



Dose-response (DR) curve: Depicts the relation
between drug dose and magnitude of drug effect
Drugs can have more than one effect
Drugs vary in effectiveness
◦ Different sites of action
◦ Different affinities for receptors

The effectiveness of a drug is considered relative
to its safety (therapeutic index)


By raising the dose above
the
“threshold
dose
level”, a gradual increase
in response occurs.
Thus, DR of similarly
active
drugs
produce
parallel
DR
curves,
enabling us to compare
between the potencies of
qualitatively
similar
drugs.


Amount of the drug necessary to produce
certain magnitude of the effect
e.g. 50% of the max. effect (EC50)

Efficacy: the maximum effect of a drug

Depends on:
◦ No. of complex formed
◦ Efficiency of coupling between the complex and the
biological response (Emax)

Greater efficacy is more important
therapeutically

A) Additive: 1+1= 2

B) Synergism: 1+1= 4

C) Potentiation: 1+0= 2








The ratio of the dose that produce toxicity to the dose that produce
effective response
It is obtained from quantal DRC (all-or-none effect)
TD50/ED50
TD50 = The drug dose that produce toxic effect in 50% of
population
ED50 = The drug dose that produces a therapeutic or desired
response in 50% of population
Examples
◦ Warfarin (narrow index)
◦ Penicillin (wide index)
2- Standard safety margin (SSM):
SSM= LD1 - 1 x 100
ED99
1- Extracellular Sites of Drug Action
 Stomach: neutralize acid with base (antacids)
 Blood: bind metals (chelation) like lead with
EDTA
 GI Tract: bind drugs (adsorption) with
Cholestyramine.
 GI Tract: increase water by osmotic effects
(laxatives)
 Kidney: increase water elimination (osmotic
diuretics)

Allergy: antigen-antibody………unpredictable

Idiosyncrasy:
Unpredictable

Side effects: unavoidable, undesirable, normal
actions by therapeutic doses.

Over-dose: high dose of drugs

Supersenstivity: exaggerated response to normal
dose due to upregulation of receptors.

Dependance: habituation and addiction.
genetic
abnormality……..

tachyphylaxis
◦ When it is developing in the course of few minutes.

Tolerance
◦ To describe a more gradual loss of drug-induced
clinical effects that develops in the course of days
or weeks.

Refractoriness
◦ Used to indicate the loss of therapeutic response.

Drug resistance
◦ Describes the loss of the effect of antitumor and
antimicrobial drugs

Receptor phosphorylation
◦ Usually by phosphorylating serine or threonine residues
in the C-terminal domain of GPCRs leading to reduce
efficiency and alter their binding affinity.

Down-regulation of receptors
◦ Phosphorylation also signals the cell to internalize the
membrane receptor leading to decrease the number of
receptors on the cell membrane.
◦ In contrast, continuous or repeated exposure to
antagonists initially can increase the response of the
receptor (supersensitivity or up-regulation)

Receptor phosphorylation
◦ Usually by phosphorylating serine or threonine residues
in the C-terminal domain of GPCRs leading to reduce
efficiency and alter their binding affinity.

Down-regulation of receptors
◦ Phosphorylation also signals the cell to internalize the
membrane receptor leading to decrease the number of
receptors on the cell membrane.
◦ In contrast, continuous or repeated exposure to
antagonists initially can increase the response of the
receptor (supersensitivity or up-regulation)

Depletion of mediators
◦ Drugs acting indirectly via transmitter release can cause
depletion of that transmitter and hence loss of action e.g.
amphetamine
or
ephedrine
act
by
releasing
catecholamines from nerve terminals.

Pharmacokinetic desensitization
◦ Drugs which stimulate hepatic metabolism may enhance
their own metabolism and hence a lower plasma
concentration with repeated administration of the same
dose e.g. barbiturates

Pumping of drugs out from intracellular site
(chemotherapy)
The description of molecular events initiated
with the ligand binding and ending with a
physiologic effect is called ---------(A) receptor down-regulation
(B) signal transduction pathway
(C) ligand-receptor binding
(D) law of mass action
(E) intrinsic activity or efficacy

The description of molecular events initiated
with the ligand binding and ending with a
physiologic effect is called ---------(A) receptor down-regulation
(B) signal transduction pathway
(C) ligand-receptor binding
(D) law of mass action
(E) intrinsic activity or efficacy

A partial agonist is best described as an
agent that ---(A) has low potency but high efficacy
(B) acts as both an agonist and antagonist
(C) interacts with more than one receptor type
(D) cannot produce the full effect, even at high
doses
(E) blocks the effect of the antagonist

THANK YOU
Do NOT impart new functions on any
system, organ or cell Only alter the PACE of
ongoing activity




STIMULATION
DEPRESSION
REPLACEMENT
CYTOTOXIC ACTION
Majority of drugs interact
biomolecules: Usually a Protein




ENZYMES
ION CHANNELS
TRANSPORTERS
RECEPTORS
with
target




All Biological reactions are carried out under
catalytic influence of enzymes
Drugs
–
increases/decreases
enzyme
mediated reactions In physiological system
Enzyme stimulation is less common by drugs
– common by endogenous substrates
Enzyme inhibition – common mode of drug
action



take part in
transmembrane signaling
and regulates ionic
composition
Drugs also target these
channels:
Ligand gated channels,

G-protein operated
channels,

Direct action on channels
Transporters
•are
translocated across membrane
•binding to specific transporters (carriers) –
,Pump the metabolites/ions In the direction of
concentration gradient or against it


Drugs usually do not bind directly with enzymes,
channels, transporters or structural proteins, but
act through specific macromoleculesRECEPTORS
Definition: It is defined as a macromolecule or
binding site located on cell surface or inside the
effector cell that serves to recognize the signal
molecule/drug and initiate the response to it, but
itself has no other function, e.g. G-protein
coupled receptor


Membrane bound receptors which are bound
to effector system through G-proteins.
These are hetero trimeric molecules having 3
subunits α,β and ϒ. Based on α-sub unit they
are further classified into 3 main varieties Gs,
Gi and Gq
Subtypes of G-proteins - Targets (Second
messenger systems)
 Ion chanels: Na+ / H+ exchange
 Enzyms: Gi Inhib. Adenylyl cyclase
Gs Stimul. Adenylyl cyclase
Gq Stimul. Phospholipase C

One ligand can bind to more than one type of
G-proteins
coupled
receptors
second
messenger pathways


Receptors intracellular domain is either
protein kinase or guanyl cyclase Ex: Insulin,
EGF, NGF
Tyrosine Kinase binding receptors have no
intrinsic catalytic domain but agonist induced
dimerization affinity for cytosolic tyrosine
kinase protein Ex:cytokines,growth hormone


Receptors regulating gene expression
Intracellular- cytoplasmic or nuclear Ex:All
steroid hormones,thyroxine, Vit A

To propogate signals from outside to inside
To amplify the signal To integrate various
extracellular and intracellular regulatory
signals To adapt to long term changes in
maintaining homeostasis
Lock and key theory


Affinity: Ability of a substrate to bind with
receptor
Intrinsic activity (IA): Capacity to induce
functional change in the receptor


Agonist: An agent which activates a
receptor to produce an effect similar to a
that of the physiological signal molecule,
e.g. Muscarine and Nicotine) response.
Antagonist: an agent which prevents the
action of an agonist on a receptor or the
subsequent response, but does not have an
effect of its own, e.g. atropine and
muscarine no response.

Partial agonist: An agent which activates a receptor to
produce submaximal effect but antagonizes the action
of a full agonist, e.g. pentazocine Partial

Inverse agonist: an agent which activates receptors to
produce an effect in the opposite direction to that of
the agonist, e.g. DMCM on bzp receptors opposite
response

Ligand: any molecule which attaches selectively to
particular receptors or sites (only binding or affinity) If
explained
Agonist: Affinity+ IA
Antagonist: Affinity+ IA (0)
Partial agonist: Affinity + IA (0 to 1)
Inverse agonist: Affinity + IA (0 to -1)






Desenstization or down-regulation
Supersenstivity or up-regulation

A) Additive: 1+1= 2

B) Synergism: 1+1= 4

C) Potentiation: 1+0= 2

Allergy: antigen-antibody………unpredictable

Idiosyncrasy:
Unpredictable

Side effects: unavoidable, undesirable, normal
actions by therapeutic doses.

Over-dose: high dose of drugs

Supersenstivity: exaggerated response to normal
dose due to upregulation of receptors.

Dependance: habituation and addiction.
genetic
abnormality……..

tachyphylaxis
◦ When it is developing in the course of few minutes.

Tolerance
◦ To describe a more gradual loss of drug-induced
clinical effects that develops in the course of days
or weeks.

Refractoriness
◦ Used to indicate the loss of therapeutic response.

Drug resistance
◦ Describes the loss of the effect of antitumour and
antimicrobial drugs
G protein-coupled receptors that activate an
inhibitory Gα subunit alter the activity of
adenylyl cyclase to -------(A) increase the coupling of receptor to G
protein
(B) block the ligand from binding
(C) initiate the conversion of GTP to GDP
(D) generate intracellular inositol triphosphate
(E) decrease the production of cAMP

The law of mass action explains the
relationship between --------(A) dose of drug and physiologic response
(B) the concentration of drug and the
association or dissociation of drug-receptor
complex
(C) receptors and the rate of signal
transduction
(D) an enzyme and ligands that inhibit the
enzyme
(E) graded and quantal dose-response curves

Vd = Amount of drug in the body
Plasma drug concentration
VD = Dose/Plasma Concentration
It is hypothetical volume of fluid in which the drug is
disseminated.
 Units: L and L/Kg
 We consider the volume of fluid in the body = 60% of
BW
 60 X 70/100 = 42 L










Drugs may distribute into
Plasma (Vascular) Compartment:
Too large mol wt
Extensive plasma protein binding
Heparin is an example
Extracellular Fluid
Low mol wt drugs able to move via
endothelial slits to interstitial water
Hydrophilic drugs cannot cross cell
membrane to the intracellular water
Total Body Water; Low mol wt
Plasma
(4 litres)
Interstitial Fluid
(11 litres)
Intracellular Fluid
(28 litres)
hydrophobic drugs distribute
from interstitial water to
intracellular
17
2
Plasma
Compartment
Extracellular
Compartment
Intracellular
Compartment
Drug has low Mol. Wt.
Drug has low Mol. Wt.
Drug has large Mol. Wt.
Hydrophobic
Hydrophilic
OR
Distributed in three comp.
Distributed in plasma &
Bind extensively to pp
Accumulated in fat
Interstitial fluid
Pass BBB
Vd = 4L
Vd = 14L
6% of BW
Vd= 42L
21% of BW
60% of BW
e.g. Heparin
e.g. Aminoglycosides
e.g. Ethanol
Many drugs bind reversibly to plasma proteins
especially albumin
 D + Albumin↔ D-Albumin (Inactive) + Free D
 Only free drug can distribute, binds to receptors,
metabolized and excreted.







Class I: dose < available albumin
binding sites (most drugs)
Class II: dose > albumin binding
sites
(e.g., sulfonamide)
Drugs of class II displace Class I
drug molecules from binding
sites→ more therapeutic/toxic
effect
Sulfonamide
In some disease states → change
of plasma protein binding
176
In uremic patients, plasma protein
binding to acidic drugs is reduced
Plasma protein binding prolongs
duration
Displacement of
Class-I Drug
1000 molecules
999
1
% bound
molecules free
900
100
100-fold increase in free pharmacologically
active concentration at site of action.
Effective
TOXIC





Capillary permeability
Endothelial cells of capillaries in
Liver capillary
tissues other than brain have
wide slit junctions allowing easy
movement of drugs
Slit junctions
Brain capillaries have no slits
between endothelial cells, i.e
tight junction or blood brain
Brain capillary
barrier
Glial cell
Only carrier-mediated transport
or highly lipophilic drugs enter
CNS
Tight junctions
Ionised or hydrophilic drugs
can’t get into the brain
Endothelial cells
17
8
 Blood-Brain
barrier:
 Inflammation
during
meningitis
or
encephalitis may increase permeability into
the BBB of ionised & lipid-insol drugs
 Placental Barrier:
 Drugs that cross this barrier reaches fetal
circulation
 Placental barrier is similar to BBB where only
lipophilic drugs can cross placental barrier
17
9
• It is enzyme catalyzed conversion of drugs to
their metabolites.
• Process by which the drug is altered and broken down
into smaller substances (metabolites) that are usually
inactive.
• Lipid-soluble drugs become more water soluble, so
they may be more readily excreted.



Most of drug biotransformation takes place in
the liver, but drug metabolizing enzymes are
found in many other tissues, including the
gut, kidneys, brain, lungs and skin.
Metabolism aims to detoxify the substance
but may activate some drugs (pro-drugs).
Phase I
Conversion of
Lipophyllic molecules
Into
more polar molecules
by
oxidation, reduction and hydrolysis
reactions
↑↓or unchanged
Pharmacological
Activity
Phase II
Conjugation with certain substrate
Inactive compounds




Oxidative reactions: Catalyzed mainly by family of
enzymes;
microsomal
cytochrome
P450
(CYP)
monoxygenase system.
Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+
Many CYP isoenzymes have been identified, each one
responsible for metabolism of specific drugs. At least
there are 3 CYP families and each one has subfamilies e.g.
CYP3A.
Many drugs alter drug metabolism by inhibiting (e.g.
cimetidine) or inducing CYP enzymes (e.g. phenobarbital
& rifampin).
Pharmacogenomics



Oxidative reactions: A few drugs are oxidised by
cytoplasmic enzymes.
◦ Ethanol is oxidized by alcohol dehydrogenase
◦ Caffeine and theophylline are metabolized by xanthine
oxidase
◦ Monoamine oxidase
Hydrolytic reactions: Esters and amides are hydrolyzed by:
◦ Cholineesterase
Reductive reactions: It is less common.
◦ Hepatic nitro reductase (chloramphenicol)
◦ Glutathione-organic nitrate reductase (NTG)



Drug molecules undergo conjugation reactions with an
endogenous substrate such as acetate, glucuronate, sulfate
or glycine to form water-soluble metabolites.
Except for microsomal glucuronosyltransferase,
enzyems are located in cytoplasm.
these
Most conjugated drug metabolites are pharmacologically
inactive.
◦ Glucuronide formation: The most common using a
glucuronate molecule.
◦ Acetylation by N-acetyltransferase that utilizes acetyl-Co-A
as acetate donar.
◦ Sulfation by sulfotransferase. Sulfation of minoxidil and
triamterene are active drugs.


Excretion is the removal of drug from body
fluids and occurs primarily in the urine.
Other routes of excretion from the body
include in bile, sweat, saliva, tears, feces,
breast, milk and exhaled air.