The document discusses the mechanism of drug action, categorizing the functional proteins targeted by drugs into enzymes, ion channels, transporters, and receptors. It details how drugs interact with these targets to modulate biological reactions, emphasizing mechanisms such as competitive and noncompetitive inhibition for enzymes, as well as the roles of ligand-gated and G-protein-coupled receptors. Additionally, it examines drug interactions for synergism and antagonism, highlighting various pharmacological effects and the importance of receptor antagonism.

1. PHARMACODYNAMICS
PREPARED BY: JEGAN. S. NADAR

2. MECHANISM OF DRUG ACTION
 Only a handful of drugs act by virtue of their simple, physical or chemical property;
examples are:
 Bulk laxatives (ispaghula)—physical mass
 Activated charcoal—adsorptive property
 Majority of drugs produce their effects by interacting with a discrete target
biomolecule, which usually is a protein
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3.  Functional proteins that are targets of drug action can be grouped into four
major categories, viz.
 Enzymes,
 Ion channels,
 Transporters and
 Receptors
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4. ENZYMES
 Almost all biological reactions are carried out under catalytic influence of
enzymes; hence, enzymes are a very important target of drug action.
 Drugs can either increase or decrease the rate of enzymatically mediated
reactions
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5. Enzyme inhibition
 Some chemicals (heavy metal salts, strong acids and alkalies, formaldehyde, phenol,
etc.) denature proteins and inhibit all enzymes nonselectively.
 They have limited medicinal value restricted to external application only.
 However, selective inhibition of a particular enzyme is a common mode of drug
action.
 Such inhibition is either competitive or noncompetitive.
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6. 1.Competitive
The drug being structurally similar competes with the normal substrate for the
catalytic binding site of the enzyme so that the product is not formed or a
non-functional product is formed
2. Noncompetitive
The inhibitor reacts with an adjacent site and not with the catalytic site, but
alters the enzyme in such a way that it loses its catalytic property
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8. ION CHANNELS
 Proteins which act as ion selective channels participate in transmembrane signaling
and regulate intracellular ionic composition
 Drugs can affect ion channels, some of
which actually are receptors, because
they are operated by specific signal
molecules either directly and are called ligand gated channels
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9.  Drugs can also act on voltage operated and stretch sensitive channels by directly
binding to the channel and affecting ion movement through it,
e.g. local anaesthetics which obstruct voltage sensitive Na+ channels
 Quinidine blocks myocardial Na+ channels
 Nifedipine blocks L-type of voltage sensitive Ca2+ channel.
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10. TRANSPORTERS
 Several substrates are translocated across membranes by binding to
specific transporters (carriers) which either facilitate diffusion in the
direction of the concentration gradient or pump the metabolite/ion against
the concentration gradient using metabolic energy
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11.  Furosemide inhibits the Na+K+2Cl¯ cotransporter in the ascending limb of
loop of Henle.
 Fluoxetine (and other SSRIs) inhibit neuronal reuptake of 5-HT by interacting
with serotonin transporter (SERT).
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12. RECEPTORS
 The largest number of drugs do not bind directly to the effectors, viz.
• enzymes,
• channels,
• transporters,
• structural proteins,
• template biomolecules,etc.
 but act through specific regulatory macromolecules which control the above listed
effectors.
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13.  Receptor: It is defined as a macromolecule or binding site located on the
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.
 The following terms are used in describing drug-receptor interaction:
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14.  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 a receptor 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
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16.  Type 1: ligand-gated ion channels
 Type 2: G-protein-coupled receptors(GPCRs)
 Type 3: kinase-linked and related receptors
 Type 4: nuclear receptors
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17. LIGAND-GATED ION CHANNELS
 These are sometimes called ionotropic receptors.
 They are involved mainly in fast synaptic transmission.
 There are several structural families, the commonest being heteromeric
assemblies of four or five subunits, with transmembrane helices arranged
around a central aqueous channel.
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18.  Nicotinic acetylcholine receptor is one of them
 It has 4 different subunits termed as α, β, ϒ, ð
 The pentameric structure (α2, β, γ, δ) possesses two acetylcholine binding
sites, each lying at the interface between one of the two α subunits and its
neighbour.
 Both must bind acetylcholine molecules in order for the receptor to be
activated
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20.  Receptors of this type control fastest synaptic events in nervous system
 Excitatory neurotransmitter such as Ach at neuromuscular junction or glutamate
in CNS cause a increase in Na+ and K+ permeability
 Inward current of sod. depolarises cell
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21. G-PROTEIN COUPLED RECEPTOR
 These are a large family of cell membrane receptors which are linked to the
effector (enzyme/ channel/carrier protein) through one or more GTPactivated
proteins (G-proteins)
 All such receptors have a common pattern of structural organization
 The receptor consists of 7 membrane spanning helical segments of hydrophobic
amino acids.
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22.  The intervening segments connecting the helices form 3 loops on either side of the
membrane.
 The amino terminus of the chain lies on the extracellular face, while the carboxy
terminus is on the cytosolic side Jegan

23.  The agonist binding site is located somewhere between the helices on the
extracellular face
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24. G-PROTEINS AND THEIR ROLE
 They are called G-proteins because of their interaction with the guanine nucleotides,
GTP and GDP
 G-proteins consist of three subunits: α, β and γ
 Guanine nucleotides bind to the α subunit, which has enzymic activity, catalysing the
conversion of GTP to GDP
 The β and γ subunits remain together as a βγ complex.
 All three subunits are anchored to the membrane through a fatty acid chain,
coupled to the G-protein through a reaction known as prenylation Jegan

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26.  In the ‘resting’ state , the G-protein exists as an unattached αβγ trimer, with GDP
occupying the site on the α subunit
 When a GPCR is activated by an agonist molecule, a conformational change occurs,,
causing it to acquire high affinity for αβγ.
 Association of αβγ with the receptor occurs within about 50 ms, causing the bound
GDP to dissociate and to be replaced with GTP (GDP–GTP exchange).
 This in turn causes dissociation of the G-protein trimer, releasing α-GTP and βγ
subunits; these are the ‘active’ forms of the G-protein,
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29.  These α-GTP and βγ subunits diffuse in the membrane and can associate with
various enzymes and ion channels, causing activation of the target
 Association of α or βγ subunits with target enzymes or channels can cause either
activation or inhibition, depending on which G-protein is involved
 Signalling is terminated when the hydrolysis of GTP to GDP occurs through the
GTPase activity of the α subunit.
 The resulting α–GDP then dissociates from the effector, and reunites with βγ,
completing the cycle
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30. Family Receptors
Structural
features
A: rhodopsin
family
Receptors for most
amine
neurotransmitters,
many neuropeptides
Short
extracellular (N
terminal) tail.
B: secretin/
glucagon
receptor family
Receptors for peptide
hormones, including
secretin, glucagon,
calcitonin
Intermediate
extracellular tail
C: metabotropic
glutamate
receptor/
calcium sensor
family
glutamate receptors,
GABAB receptors,
Ca2+-sensing receptors
Long extracellular
tail
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31.  The main targets for G-proteins, through which GPCRs control different
aspects of cell function are:
 adenylyl cyclase,
 phospholipase C,
 ion channels,
 Rho A/Rho kinase,
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32. THE ADENYLYL CYCLASE/cAMP SYSTEM
 cAMP is a nucleotide synthesised within the cell from ATP by the action of a
membrane-bound enzyme, adenylyl cyclase.
 It is produced continuously and inactivated by hydrolysis to 5′-AMP by the action of
a family of enzymes known as phosphodiesterases (PDEs).
 Many different drugs, hormones and neurotransmitters act on GPCRs and produce
their effects by increasing or decreasing the catalytic activity of adenylyl cyclase,
thus raising or lowering the concentration of cAMP within the cell.
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33.  Cyclic AMP regulates many aspects of cellular function including, for example,
enzymes involved in energy metabolism, cell division and cell differentiation, ion
transport, ion channels, and the contractile proteins in smooth muscle
 These varied effects are, however, all brought about by a common mechanism,
namely the activation of protein kinases by cAMP.
 Protein kinases regulate the function of many different cellular proteins by controlling
protein phosphorylation
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34.  Important functions performed by cAMP dependent protein kinase include
 Energy metabolism
 Force of contraction of heart
 Smooth muscle relaxation
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38. THE PHOSPHOLIPASE C/INOSITOL PHOSPHATE SYSTEM
 Phospholipase C act on PIP2 and splits it into DAG and inositol, both of which
act as secondary messenger
 The activation of PLCβ by various agonists is mediated through a Gq-protein
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40.  Inositol (1,4,5) trisphosphate (IP3) is a water-soluble mediator that is released
into the cytosol
 It acts on a specific receptor—the IP3 receptor—which is a ligand-gated calcium
channel present on the membrane of the endoplasmic reticulum.
 The main role of IP3 is to control the release of Ca2+ from intracellular stores.
 IP3 is converted inside the cell to the (1,3,4,5) tetraphosphate, IP4, by a specific
kinase.
 The exact role of IP4 remains unclear, but recent evidence suggests that it plays
a role in controlling geneexpression.
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43. ION CHANNELS AS TARGETS FOR G-PROTEINS
 G-protein-coupled receptors can control ion channel function directly by mechanisms
that do not involve second messengers such as cAMP or inositol phosphates
 Direct G-protein–channel interaction was first shown for cardiac muscle, for
controlling K+ and Ca2+ channels
 In cardiac muscle, for example, mAChRs are known to enhance K+ permeability (thus
hyperpolarising the cells) and inhibiting electrical activity
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45. Rho/Rho KINASE SYSTEM
 Rho kinase is also known as Rho associated kinase
 Rho–GDP, the resting form, is inactive, but when GDP–GTP exchange occurs, Rho is
activated, and in turn activates Rho kinase.
 Rho kinase phosphorylates many substrate proteins and controls a wide variety of
cellular functions, including smooth muscle contraction and proliferation, angiogenesis
and synaptic remodelling
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47. TYPE 3: KINASE-LINKED AND RELATED RECEPTORS
 These membrane receptors are quite different in structure and function from either the
ligand-gated channels or the GPCRs.
 They mediate the actions of a wide variety of protein mediators, including growth factors
and cytokines, and hormones such as insulin and leptin, whose effects are exerted mainly at
the level of gene transcription.
 Most of these receptors are large proteins consisting of a single chain of up to 1000
residues, with a single membrane-spanning helical region.
 It consist of large extracellular ligand-binding domain, and variable size intracellular
domain
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49.  They play a major role in controlling
• Cell division,
• Cell growth,
• Cell differentiation,
• Inflammation,
• Tissue repair,
• Apoptosis and
• Immune responses
The main types are as follow.
Receptor tyrosine kinases (RTKs).
Serine/threonine kinases
Cytokine receptors
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50.  Signal transduction generally involves dimerisation of receptors, followed by
autophosphorylation of tyrosine residues.
 The phosphotyrosine residues act as acceptors for the SH2 domains of a variety of
intracellular proteins, thereby allowing control of many cell functions.
 Two important pathways are:
 The Ras/Raf/mitogen-activated protein (MAP) kinase pathway, which is
important in cell division, growth and differentiation
 The Jak/Stat pathway activated by many cytokines, which controls the synthesis
and release of many inflammatory mediators. Jegan

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53. NUCLEAR RECEPTORS
 Nuclear receptors are a class of proteins found within cells that are responsible for
sensing steroid and thyroid hormones and certain other molecules.
 In response, these receptors work with other proteins to regulate the expression of
specific genes, thereby controlling the development, homeostasis, and metabolism of
the organism.
 Nuclear receptors have the ability to directly bind to DNA and regulate the
expression of adjacent genes, hence these receptors are classified as transcription
factors
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54.  Ligand binding to a nuclear receptor results in a conformational change in the
receptor, which, in turn, activates the receptor, resulting in up- or down-regulation of
gene expression.
 A unique property of nuclear receptors that differentiates them from other classes
of receptors is their ability to directly interact with and control the expression of
genomic DNA.
 As a consequence, nuclear receptors play key roles in both embryonic development
and adult homeostasis

56. MECHANISM
 Small lipophilic substances such as natural hormones diffuse through the cell
membrane and bind to nuclear receptors located in the cytosol
 Binding of hormone to the receptor leads to formation of hormone receptor
complex and dissociation of heat shock protein (HSP)
 Once receptor is activated there is conformational changes in the receptor
leading to dimerization of receptor
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58.  The hormone receptor complex will translocate to the nucleus where the NR
binds to a specific sequence of DNA known as a hormone response element
(HRE).
 The nuclear receptor DNA complex in turn recruits other proteins that are
responsible for transcription of DNA into mRNA, which is eventually translated
into protein, which results in a change in cell function.
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59. COMBINED EFFECT
OF DRUGS
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60.  When two or more drugs are given simultaneously or in quick succession, they
may be either indifferent to each other or exhibit synergism or antagonism.
 The interaction may take place at pharmacokinetic level or at
pharmacodynamic level.

61. SYNERGISM
 When the action of one drug is facilitated or increased by the other, they are
said to be synergistic.
 In a synergistic pair, both the drugs can have action in the same direction or
given alone one may be inactive but still enhance the action of the other when
given together.
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62. Synergism can be:
(a) Additive
• The effect of the two drugs is in the same direction and simply adds up:
Effect of drugs A + B = effect of drug A +effect of drug B
• Side effects of the components of an additive pair may be different—do not
add up.
• Thus, the combination is better tolerated than higher dose of one component.
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64. (b) Supraadditive (potentiation)
The effect of combination is greater than the individual effects of the
components:
effect of drug A + B > effect of drug A + effect of drug B
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66. ANTAGONISM
 When one drug decreases or abolishes the action of another, they are said to be
antagonistic:
effect of drugs A + B < effect of drug A + effect of drug B
 Usually in an antagonistic pair one drug is inactive as such but decreases the effect
of the other.
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67.  Depending on the mechanism involved, antagonism may be:
 Physical antagonism
 Chemical antagonism
 Physiological/functional antagonism
 Receptor antagonism
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68.  Physical antagonism
Based on the physical property of the drugs, e.g. charcoal adsorbs alkaloids and
can prevent their absorption—used in alkaloidal poisonings.
 Chemical antagonism
 The two drugs react chemically and form an inactive product,
e.g. KMnO4 oxidizes alkaloids—used for gastric lavage in poisoning.
 Chelating agents (BAL, Cal. disod. edetate) complex toxic metals (As, Pb).
 Drugs may react when mixed in the same syringe or infusion bottle:
• Thiopentone sod. + succinylcholine chloride
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69. Physiological/functional antagonism
 The two drugs act on different receptors or by different mechanisms, but
have opposite overt effects on the same physiological function,
i.e. have pharmacological effects in opposite direction,
 e.g.
 Histamine and adrenaline on bronchial muscles and BP.
 Hydrochlorothiazide and triamterene on urinary K+ excretion.
 Glucagon and insulin on blood sugar level.
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70. Receptor antagonism
 One drug (antagonist) blocks the receptor action of the other (agonist).
 This is a very important mechanism of drug action, because physiological signal
molecules act through their receptors, blockade of which can produce specific and
often profound pharmacological effects.
 Receptor antagonists are selective (relatively), i.e. An anticholinergic will oppose
contraction of intestinal smooth muscle induced by cholinergic agonists, but not that
induced by histamine or 5-HT (they act through a different set of receptors).
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72.  Receptor antagonism can be competitive or noncompetitive.
Competitive antagonism (equilibrium type)
 The antagonist is chemically similar to the agonist, competes with it and binds
to the same site to the exclusion of the agonist molecules.
 Because the antagonist has affinity but no intrinsic activity, no response is
produced and the log DRC of the agonist is shifted
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73.  Since antagonist binding is reversible and depends on the relative
concentration of the agonist and antagonist molecules, higher concentration of
the agonist progressively overcomes the block—a parallel shift of the agonist
DRC with no suppression of maximal response is obtained
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74. Noncompetitive antagonism
 The antagonist is chemically unrelated to the agonist, binds to a different
allosteric site altering the receptor
 This is also called allosteric antagonism.
 Because the agonist and the antagonist are combining with different sites,
there is no competition between them—even high agonist concentration is
unable to reverse the block completely.
 Increasing concentrations
of the antagonist progressively
flatten the agonist DRC
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76. Nonequilibrium competitive antagonism
 Certain antagonists bind to the receptor with strong (covalent) bonds or
dissociate from it slowly (due to very high affinity) so that agonist molecules
are unable to reduce receptor occupancy of the antagonist molecules—law
of mass action cannot apply— an irreversible or nonequilibrium antagonism is
produced.
 The agonist DRC is shifted to the right and the maximal response is lowered
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77. Thank You