PRESENTED BY- UZMA ALIA

MPHARM. (PHARMACOLOGY) 1 ST
SEMESTER
SPER, JAMIA HAMDARD
NEW DELHI-110062
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S.NO. TOPICS SLIDE NUMBER

1. INTRODUCTION 3-4

2. TARGETS OF DRUG 5-16

ACTION

3. TYPES OF RECEPTOR 17-34

4. NON-RECEPTOR 35-36
MEDIATED MECHANISMS

5. REFERENCES 37 2
 Pharmacodynamics : The study of the biochemical
and physiological effects of drugs and their
mechanisms of action.

 Mechanisms of Drug Action:

Interaction of drug Physiological
Alteration of and
with function of
macromolecular biochemical
component changes
components

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 Based on drug target sites, drugs can produce their
actions by:
1) Binding with biomolecules (Receptor-mediated
mechanisms):
• Biomolecules = Targets=Receptors
• Mostly protein in nature (protein target).
2) Non receptor-mediated mechanisms
(Physiochemical properties of drugs.)

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 Four main kinds of regulatory protein are commonly
involved as primary drug targets, namely:

 Physiological receptors
 Enzymes
 Ion channels
 Transporter

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 Ion channels are gateways in cell membranes, which
selectively allow the passage of particular ions.
 Induced to open or close by two mechanisms:
1. Ligand-gated Channels (open only when one or
more agonist molecules are bound)
2. Voltage-gated Channels (are gated by changes in
the transmembrane potential ).

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 Drugs can affect ion channel function by :

1. Binding to the channel protein itself (to the ligand-

binding site of ligand-gated channels, or to other parts
of the channel molecule) .
2. Indirect interaction, involving a G-protein and other
intermediaries .
3. By altering level of expression of ions on cell surface
E.g.- Gabapentin( decrease insertion of neuronal calcium
ion in plasma membrane )
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 Vasodilator drugs of the dihydropyridine type ,
which inhibit the opening of L-type calcium channels .

 Benzodiazepine . Bind to a region of the GABAA

receptor-chloride channel complex (a ligand-gated
channel) that is distinct from the GABA binding site.
Facilitate the opening of the channel by the inhibitory
neurotransmitter GABA, but some inverse agonists are
known that have the opposite effect, causing anxiety
rather than tranquillity
 Sulfonylureas which act on ATP-gated potassium
channels of pancreatic β-cells and thereby enhance
insulin secretion
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 The drug molecule is a substrate analogue that acts as a
competitive inhibitor of the enzyme (e.g. captopril, acting
on angiotensin-converting enzyme)
 The binding is irreversible and non-competitive (e.g.
aspirin, acting on cyclo-oxygenase).
 The immunophilin to which ciclosporin binds has
enzymic activity as an isomerase that catalyses the cis-trans
isomerisation of proline residues in proteins, a reaction
that is important in allowing expressed proteins to fold
correctly. Inhibition of this enzymic activity is one of the
mechanisms by which ciclosporin causes
immunosuppression.

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 Inhibition of enzymes is a common mode of drug
action.The 2 types are-
1. Non-specific
2. Specific
i) COMPETITIVE: Vmax constant, Km changes.
Ex-Physostigmine and neostigmine compete with
acetylcholine for cholinesterase.
• Sulfonamides compete with PABA for bacterial folate
synthetase.
• Moclobemide competes with catecholamines for
monoamine oxidase-A (MAO-A).
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ii)Non competitive: Vmax reduced,Km constant.
Examples:
 Propylthiouracil inhibits Peroxidase in thyroid
 Lovastatin inhibits - HMG-CoA reductase
 Sildenafil inhibits Phosphodiesterase-S

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 The movement of ions and small organic molecules
across cell membranes generally occurs either through
channels or through transport protein, because the
permeating molecules are often too polar (i.e.
insufficiently lipid soluble) to penetrate lipid
membranes on their own.

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 EXAMPLES-
1. Na+/K+/2Cl- co-transporter (loop of Henle) Loop
diuretics.
2. MDR transporter (Inhibitor-Verapamil)
3. Proton pump (gastric mucosa)(Inhibitor- Omeprazole
4. The anticonvulsant tiagabine acts by inhibiting reuptake
of GABA into brain neurones by GABA transporter GAT 1
5. Amphetamines selectively block dopamine reuptake in
brain neurons by dopamine transporter (DAT).

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 “A macromolecule or binding site with a proteinecious
nature located on the surface or inside the effector cell
that serves to recognize the signal molecule and
initiate the response to it but itself has no action.”

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 AGONIST : An agent which activates a receptor to produce an effect
similar to that of the physiological signal molecule.

 INVERSE AGONIST : An agent which activates areceptor to produce

an effect in the opposite direction to that of the agonist.
 ANTAGONIST : An agent which prevents the action of an agonist on a
receptor or the subsequent response, but does not have any effect of its
own.
 PARTIAL AGONIST: An agent which activates a receptor to produce
submaximal effect but antagonizes the action of a full agonist.
 LIGAND (Latin: ligare-to bind): Any molecule which attaches
selectively to particular receptorso r sites. The term only indicates
affinity or binding without regard to functional change: agonists and
competitive antagonists are both ligands of the same receptor.
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 TYPE 1 : TYPE 2: GPCR’S TYPE 3: TYPE 4:
LIGAND (METABOTROPI KINASE NUCLEAR
GATED/IONO C) LINKED RECEPTOR
TROPIC
EFFECTOR ION CHANNEL/ENZY PROTEIN GENE
CHANNEL ME KINASE TRANSCRIPTI
ON
EXAMPLES NICOTINIC Muscarinic INSULIN,GRO STEROID
ACHR,GABA - Achr,adrenoce WTH RECEPTORS
A ptors FACTOR,CYT
OKINES
STRUCTURE Oligomeric Seven trans Single trans Monomeric
assembly of membrane membrane structure with
subunits helices with helix linking separate
around a intracellular G- extracellular receptor- and
central core protein-coupling receptor DNA-binding
domain domain to domains
intracellular
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kinase domain
 The nicotinic acetylcholine receptors, first to be
cloned shows pentameric assembly (δ,α,β,γ)and has 2 Ach
binding site between α subunit.
 When Ach binds,change in conformation in extracellular
part of receptor twisted α subunit kinked M2
segments swivel out channel opens.
 Controls fastest synaptic events.
 NT acts on post synaptic membrane, increase ion
permeability.
 At –ve potential,sodium goes inside,depolarization
occurs.Generates action potential.
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 1st GPCR=adrenoceptor.& 7 transmembrane α-helix
with extracellular N-terminal domain & C-terminal
domain.

FAMILY A FAMILY B FAMILY C

(RHODOPSIN) (SECRETIN) (METABOTROPIC)

MONOAMINE,NEUROP CALCITONIN,GLUCAG GABA,CALCIUM

EPTIDE,CHEMOKINE ON SENSING
RECEPTOR

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 Heterotrimeric and middle management in
organization of GPCR mediated cell signalling.
 20 subunits of Gα, 6 Gβ , 12Gγ.
 The 4 main families are:
SUBTYPES LOCATION FUNCTIONS

Gαs Catecholamine,histamine,serotonin Stimulate adenylyl

cyclase, cAMP
Gαi Opioid,cannabinoid Inhibit adenyl cyclase,
cAMP
Gαq Amine,peptide,prostanoid Activates phospholipase
C
Gβγ All GPCRS Activate K+ cahnnel,(-)
Ca2+ voltage gated. 21
 Agonist binding on receptor conformational
changes G-protein coupling .
 In resting state, GDP is bound to Gα and is converted
to GTP when conformational change occurs.
 G-protein dissociates into Gα and Gβγ subunit which
further activates/inhibits enzymes.
 Exception- Rhodopsin ( photon of light causes
isomerization of 11 cis retinal to 11 trans retinal disrupts
salt bridge between TM3 and TM7 conformational
changes coupling of heterotrimeric G-protein.

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The various targets are:
A. Adenylyl cyclase (cAMP formation)
B. Phospholipase C ,IP3 & DAG formation
C. Rho kinase
D. Mitogen activated protein kinase (MAP kinase)

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 Synthesis: ATP adenyl cyclase cAMP.
 Regulates many aspect of cellular function (energy
metabolism, cell division, cell differentiation, ion
transport).
 The reactions brought about by activation of protein
kinases A by cAMP. Protein kinase regulate function
by controlling protein phosphorylation.
 Hydrolyzed by phosphodiesterase.

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1. β-adrenoceptor activation ( cAMP) by activity
of voltage gated ca2+ channel ).Phosphorylation fo
channel amount of ca2+ entering cell during AP
which force of contraction of heart.
2. Smooth muscle relaxation due to phosphorylation
of myosin light chain .
3. Gi = M2(cardiac),α2 (smooth muscle),opioid
receptor.

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 Discovered by Hokin while studying mechanism of salt
secretion by nasal glands of seabirds.
 Hormones that increase Ca2+ (muscarinic
agonist,vasopressin) increase phosphoinositides
turnover.
 PIP2 substrate for phospholipase Cβ splits into
DAG+IP3.
 IP3+PA =PIP2.(Formation blocked by lithium).
 DAG activates protein kinase C and induces
phosphorylation of intracellular proteins.
 IP3 mobilizes calcium

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 They do not involve secondary messengers.
 Direct G-protein interaction through βγ subunit of
Gi and Go for controlling K+ and Ca2+ channel.
 Examples:
 In cardiac muscles, mAchRs enhance K+ permeability.
 Opioid analgesics decrease excitability by opening
K+ channel.

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 Activated by GPCRs as well as non-GPCRs.
 Couples to G-protein.
 The free G-protein α subunit interacts with guanosine
nucleotide exchange factor

 Facilitates GDP-GTP exchange

 Activation of Rho

 Phosphorylation,

 Smooth muscle contraction, proliferation,angiogenesis.

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 They are large proteins with single chain of 1000
residues.
 Activated by protein mediators (cytokines,
insulin,leptin).
 Play major role in controlling cell division, tissue
repair, apoptosis etc.
 3 types:
1. Receptor tyrosine kinase.Eg.- Insulin,EGF,NGF
2. Receptor serine/threonine kinase . E.g. – TGF
3. Cytokine receptor(have no intrinsic enzyme
activity).Activate JAK. Ligands are interferons.
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 Examples include steroid hormones
(oestrogen,glucocorticoids),t3,vitamin D,vitamin A.
 Also includes orphan receptors.
 They tranduce signal by modifying gene transcription.

STRUCTURE:
 Monomeric protein.
 N-terminal domain contains activation factor 1 that binds to
cell specific transcription factor.
 C-terminal domain = ligand binding module and AF2
region.Binds accessory heat shock proteins
 Core domain of receptors= contain cysteine/histidine with zinc
fingers.

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 Estrogen diffuses across the plasma membrane and binds
to its receptor in the nucleus.

 In the absence of hormone, estrogen receptor is bound to

Hsp90.

 Estrogen binding displaces the receptor from Hsp90 and

allows the formation of receptor dimers,

 Dimers bind to DNA, associate with coactivators having

histone acetyltransferase (HAT) activity

 Stimulation of transcription of their target genes.

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A. BY CHEMICAL ACTIONS
a .Neutralization. Ex- Antacids
b. Chelation.Ex- EDTA,dimercaprol,
penicillamine,desferroxamine
c. Ion-exchangers.Ex- Cholestyramine exchanges
Cl- from bile salts.

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B. BY PHYSICAL ACTIONS
a. Osmosis. Ex- MgSO4
b.Adsorption.Ex- Dimethicone adsorb gases used
as anti-flatulent.
c. Protectives. Ex- Dusting powder
d. Demulcents.Ex- Menthol in cough syrups.
e. Astringents.Ex- tannic acid in gum paints
f. Saturation in a biophase. Ex- general
anaesthetics.

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 Tripathi KD : Essential of Medical Pharmacology
6th edition, Jaypee Brothers Medical Publishers Pvt.
Ltd. 2007.Page no. 337- 347.
 Goodman, Laurence L. Brunton, John
S.Lazo.Goodman and Gilman’s The
Pharmacological Basis of Therapeutics, 11th
edition.2006. Page no. 188- 201.
 Bertram G.Katzung. Basic and Clinical
Pharmacology.8th Edition, New Delhi McGraw
Hill.2003. Page No:554-559.
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THANK YOU

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