PHARMACODYNA

MICS
Dr. Muhammad Adil Rasheed

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 PHARMACODYNAMICS
It is what the drug does with body or study of
biochemical and physiological effects of drugs on the
body and their mechanism of action of drug.
It is concerned mainly with the interactions of drugs with
the target site.
 Two factors that determine the effect of a drug are

affinity and intrinsic activity.

 AFFINITY is a measure of the tightness that a drug

binds to the receptor.

 INTRINSIC ACTIVITY is a measure of the ability of a

drug once bound to the receptor to generate an effect
activating stimulus and producing a change in cellular
activity.
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 MECHANISM OF DRUG ACTION
 It is the mean by which drug produces its
pharmacological effects. During its interaction, a drug
cannot impart a new function to cell or tissue but it
only modulates the inherently possessed functions of
cell. Mechanism of action may be Specific and Non
Specific.

SPECIFIC ACTIONS
 Specific actions are produced by the drugs which
interact with specific macromolecules in body.

 Drug interaction with these macromolecules

shows Structure Activity Relationship (SAR). This
can be block by specific antagonists.

 These macromolecules may be Receptors, Ion

Channels, Enzymes and Carrier Molecules.
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 NON SPECIFIC ACTIONS
 A large number of drugs do not act by making
complex with receptor. Their action can be
explained on the basis of their physical or chemical
properties. So they not show SAR and don’t have
 Certain drugs act by their physical disposition in
specific antagonist.
body tissue and organs.

 Pharmacological action produced by bulk and saline

purgative (wheat bran and magnesium sulphate).
 Pharmacological action produced by certain drugs
are entirely due to their chemical properties. These
drugs react extracellular with endogenous
substances according to simple chemical reaction.

 Antacid neutralize the gastric acid.

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 RECEPTORS
 Receptors are
macromolecules usually
made up of proteins or
glycoprotein present on the
membrane surface or within
the cell to which specific
hormones,
neurotransmitters, or drugs
combine to produce their
action.

 Activation of receptors by
drug may leads to
pharmacological action of
that drug while inhibition of
receptors by blockers, stops
the activity of drugs. 5
 TYPES OF RECEPTORS
 Drugs receptors have been classified into
four super families according to their
molecular structure and nature of signal
transduction mechanism. These are

 Ligand Gated ion-Channels/Iono Receptors

 G-Protein Coupled Receptors
 Enzymatic Receptors
 Receptor Regulating DNA Transcription

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 1. LIGAND GATED ION-CHANNELS
 These are cell surface receptors that enclose selective
ion-channels which allow the free movement of certain
ions like sodium, potassium, calcium and chlorides.
 Receptors of this type control the fastest synaptic
events in nervous system where lag time between
ligand binding and cellular response is only in
milliseconds.
 Examples includes nicotinic-cholinergic receptors,
GABA receptors.
STRUCTURE
All ligand gated ion channels are made up of subunit
proteins. (Alpha, beta, gamma, delta kappa).
These subunit penetrate all the way through the
membrane laying side by side in a circle to form a
tubular channel (Like petals of lily).
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STRUCTURE OF LIGAND GATED ION-
CHANNELS

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 SIGNALING MECHANISM

 The drug molecule attached with

the ligand binding site located
on subunit protein directly.

 The channel remain activated

until the ligand attached to the
extracellular binding site.

 Due to the concentration

gradient flow of ions the electric
potential across the membrane
changed causing depolarization
(Na+ Channels) or hyper
polarization (Cl- Channels) of
cell
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 2. G-COUPLED
RECEPTORS
 Large super family of membrane bound receptors which
regulate distinct effector proteins (Enzymes, Channels,
or Carriers) through mediation of transducers, a group
of guanine nucleotides (GTP and GDP) binding proteins
known as G-Proteins. These are heterotrimeric
molecules consisting of three subunits (α, β, and γ).

 Example of G-Protein Coupled receptors include

muscarinic-cholinergic receptors, Histamine receptors,
Adrenergic receptors and many peptide hormone
receptors.
STRUCTURE
 They consist of 400-500 chains of polypeptides, The
amino terminus followed by amino acid sequence
having 7 Alpha helical membrane spanning hydrophobic
region and 3 extracellular and 3 intracellular loops.
 The agonist binding site locates between helicase
on extracellular face.

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 SIGNALING MECHANISM
 In the resting stage the G-Proteins exists as an
unattached α, β, and γ trimer with Guanosine
diphosphate (GDP) occupying the site on α subunit.

 When the agonist binds to G-Protein receptor, the

agonist-receptor complex facilitates displacement of
Guanosine diphosphate (GDP) by Guanosine
triphosphate (GTP).

 Binding of GTP activates the α subunit and the α-GTP

complex then dissociate from β and γ subunit and
interact with membrane bound effector protein(Ion
channel, enzyme, or transport protein).
 The activation process terminated when hydrolysis
of GTP to GDP occurs through GTPase activity of α-
subunit.

 It has been estimated that initial agonist-receptor

interaction lasts only for a few seconds but once a G-
protein is activated it remain active for about 10
seconds. Which amplify the signals. Thus in G-Coupled
system occupancy of only a fraction of receptor
population is enough to produce maximal response.

 Gs, Gi, Go, Gq and G13 are different type of G-

Proteins

 G-Coupled Effector system function by

1. ENZYME LINKED EFFECTOR SYSTEM

2. ION CHANNEL LINKED EFFECTOR SYSTEM
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1. ENZYME-LINKED EFFECTOR
SYSTEM
 Three Effector systems through which these receptors
function.
 Adenylate Cyclase or cAMP system
 Phospholipase C or IP3-DAG system
 Phospholipase A2 or AA System

ADENYLATE CYCLASE OR cAMP SYSTEM

 The effector protein is Adenylate cyclase which is activated
or inhibited by α-GTP complex.
 Activation of Adenylate Cyclase enzyme by stimulatory G-
Protein (Gs) leads to increased synthesis of cAMP (3-5
cyclic adenisine monophopshate).
 Accumulation of cAMP within the cell activate cAMP-
dependant Protein Kinase.
 These Protein kinases phosphorylate and alter the function
of many enzymes to manifest various pharmacological
effects.
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 The intracellular effects of cAMP are terminated by
degradation of cAMP to 5-cAMP by Phosphodiesterases
(PDE) enzymes.
 Receptors linked to inhibitory G-Protein (Gi) suppress the
activity of Adenylate Cyclase and reduce the synthesis of
cAMP (3-5 cyclic adenosine monophopshate). Thus reverse
pharmacological effect occurs.

PHOSPHOLIPASE C OR IP3-DAG SYSTEM

 The effector protein is phospholipase C.
 Activation of this protein cause hydrolysis of the
membrane phospholipid phosphatidyl inisotol 4,5-
biphosphate (PIP2) to generate Inositol 1,4,5, triphosphate
(IP3) and diacyl glycerol (DAG).
 Inositol 1,4,5, triphosphate (IP3) mobilises Ca++ from the
intracellular organelle to receptor on the membrane of
Endoplasmic reticulum.
 An increase in free intracellular calcium concentration
from 10 to 100 fold produces a range of cellular responses
including modulation of enzymes, contractile proteins.
 Important pharmacological action includes smooth
muscle contraction, secretion from exocrine glands,
release of neurotransmitters.

 Diacyl glycerol (DAG) activate protein Kinase C (PKC)

which control many functions of cell by phospholylating a
variety of intracellular proteins. Functions include,
release of hormones from endocrine glands, contraction
and relaxation of smooth muscles.
PHOSPHOLIPASE A2 OR AA SYSTEM
 Activation of phospholipase A2 by G-proteins leads to
production of Arachidonic acid from the membrane
phospholipid.

 Arachidonic acid is further broken down to

prostaglandins, leukotriens, and thromboxane.

 Arachidonic acid also control potassium channel

functions in neurons.
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2. ION CHANNEL-LINKED EFFECTOR
SYSTEM

 G-coupled protein receptors

can control some ion
channels.

 Depending upon the type

of protein ion channels
remain opened or closed
thereby causing
hyperpolerization or
depolarization.

 Gs protein open Ca++

channels in myocardium
and skeletal muscles. While
Gi and Go open K+
channels in heart and close
Ca++ in neurons.
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3. ENZYMATIC RECEPTORS/TYROSINE KINASE
LINKED RECEPTORS
 These receptor are membrane bound
and have Large extracellular and
intracellular domains.
 Extracellular domain is connected
with intracellular domain with the
help of short single transmembrane
stretch of peptide chain.
 Intracellular domain is made of
protein kinase mostly tyrosine
kinase.
When specific ligand binds to extracellular the
intracellular protein kinase get activated and
phosphorylates the regulatory proteins. which either
alter the activity of cell.

In some receptors ligand binding activates Guanylate

cyclase cGMP (Cyclic Guanosine Phosphate) which
activate cGMP-dependant protein kinase and modulate
cellular activity. 20
 4. RECEPTORS REGULATING DNA
TRANSCRIPTION/STEROID RECEPTORS
 These are intracellular proteins that regulate
transcription of specific gene. Steroid, thyroid hormone,
Vit D and A mediate through these receptors.
 Cellular effect is produced as a result of protein
synthesis.

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