PHA 331

Pharmacodynamics:
Mechanism of Drug Actions,
Receptor and Non-receptor Theories
Types of Receptors/ Structure Activity
Relationship
Ligand Gated Ion Channels
G-protein Coupled Receptors
Dr. Kazeem Adeola Oshikoya
M.B; B.S (Lagos), MSc (Lagos), PhD (Nottingham)
PHARMACODYNAMICS
• Pharmacodynamics is the study of the relationship
between the concentration of drug at the site of
action and the biochemical and physiological effect,
including any resulting effects such as the intensity
and time course of the effect and adverse effects.
• Thus, it deals with the mechanism(s) of drug action
and generally describes what a drug does to the body.
• The response of the receptor may be affected by the
presence of drugs competing for the same receptor
(pharmacodynamic interaction), the functional state
of the receptor or pathophysiological factors such as
hypokalemia.
• Interindividual variability may occur in
pharmacodynamics, which may be genetic or reflect
the development of tolerance to the drug with
continued exposure.
• High pharmacodynamic variability severely limits the
usefulness of monitoring drug concentrations as they
are likely to give a poor indication of the effectiveness
of therapy.
• The most important pharmacodynamic considerations
include: (i) receptor mechanism, which describes how
the drug binds at the cellular level and initiates its
pharmacodynamic effects;
• (ii) dose-response curve, which provides a plot of the drug
concentration against the effects of the drug and allows
comparison of the efficacy and potency of drugs;
• (iii) therapeutic index, which provides a relative measure
of the toxicity and safety of a drug, and is calculated by
dividing the median toxic dose by the median effective
dose;
• (iv) lag time, which is the time taken for the full
therapeutic effects of a given drug to appear, and the
reasons for a delay in effects may be pharmacokinetic,
pharmacodynamic, or both; and
• (v) tolerance, which refers to the responsiveness of a child
to a particular drug as it is administered over time.
Mechanism of Drug Actions
• In pharmacology, the term mechanism of
action (MOA) refers to the specific biochemical
interaction through which a drug or substance
produces its pharmacological effect.
• A mechanism of action usually includes mention of
the specific molecular targets to which the drug binds,
such as an enzyme or receptor.
• Receptor sites have specific affinities for drugs based
on the chemical structure of the drug, as well as the
specific action that occurs there.
• Drugs that do not bind to receptors produce their
corresponding therapeutic effect by simply interacting
with chemical or physical properties in the body.
Common examples of drugs that work in this way
are antacids and laxatives.
• In contrast, a mode of action (MoA) describes
functional or anatomical changes, at the cellular level,
resulting from the exposure of a living organism to a
substance.
Drug Target
Sites
• Receptors
• Ion channels incorporating
a receptor and acting as
target sites
• Enzymes
• Carrier molecules
• Based on the target sites,
the mechanism of drug Figure 1: Schematic diagram of potential drug targets:
action can be broadly Molecules can affect the function of numerous cellular
classified as: components both in the cytosol and on the membrane
surface. There are many families of receptors that traverse
o Receptor mediated the cellular membrane and allow chemicals to
communicate with the interior of the cell.
mechanism
o Non-receptor mediated
Receptor Mediated Mechanism (Receptor Theory)
• A drug receptor is a membrane bound or intracellular
specialized target macromolecule or protein ion that
binds a drug and mediates its pharmacological action.
• These receptors may be enzymes, nucleic acids, or
specialized membrane-bound proteins.
• Binding of a drug with its receptor results in the
formation of the drug-receptor complex, which leads to
a biological response, i.e. D + R= (DR) Response
• The magnitude of the response is proportional to the
number of drug-receptor complexes.
• A common way to present the relationship between the drug
concentration and the biological response is with a concentration- (or
dose-) response curve (Figure 2).

Figure 2: In a concentration-response curve, the

concentration of the drug is plotted against the
percent maximal effect. Notice that the drug
concentration is plotted on a log scale. In this
graph, the drug is a full agonist—the effect reaches
100% of the maximum possible.
• Classical receptor theory combines two independent
parts to describe drug action: an agonist-dependent
part, incorporating agonist affinity and intrinsic efficacy,
and a tissue-dependent part, determined by the
receptor concentration and the nature of the stimulus–
response relation.
• The basic form of Black and Leff’s operational model of
agonism is based on the observation that most agonist
concentration–effect curves are hyperbolic in nature.
• If the law of mass action governs the binding of an
agonist to the receptor:
o[AR] = [R0]-[A]/KA + [A] ………….. [1]
 owhere [AR] is the concentration of agonist
receptor complex, R0 is the total receptor concentration,
[A] the concentration of the agonist, and KA is the
dissociation equilibrium constant of AR, then the function
relating the concentration of agonist–receptor complex
and response can only be a straight line or another
hyperbolic.
• In order to allow for receptor reserve, the linear
alternative needs to be rejected in favor of the
hyperbolic transducer function, which can be
represented as follows:
o E/Em = [AR]n/(KE)n + [AR]n ……….. [2]
• where E is the response, Em is the maximum system
response, KE is the value midpoint location of the
transducer function, that is [AR], that elicits half-
maximal effect, and n is the slope of the transducer
function.
• Combining equations [1] and [2] yields an explicit
model of agonism describing the pharmacological
effect in terms of agonist concentration:
o E = Em.Tm.[A]n/(KA + [A])n+Tn .[A]n ……….. [3],
o where the transducer ratio τ is defined as R0/KE as a measure of
the efficiency of the occupied receptors into pharmacological
effect.
Lock and Key Receptor Model
• The active site is the specific region of the receptor
which combines with a drug molecule.
• The binding of the drug to a receptor causes changes
in the distribution of electrons in the chemical bonds
between the drug and receptor complex.
• The active site has a unique geometric shape that is
complementary to the geometric shape of a drug
molecule, similar to the fit of puzzle pieces. This
means that receptors specifically interact with only
one or a very few similar drug molecules.
• The specific interaction between a receptor and a
drug molecule can be likened to the action of an
enzyme with a single substrate, which was explained
using a Lock and Key analogy first postulated in 1894
by Emil Fischer.
• In this analogy, the lock is the enzyme and the key is
the substrate (Figure 3).
• Only the correctly sized key (substrate) fits into
the key hole (active site) of the lock (enzyme).
 Figure 3: Lock and Key theory illustrating that
appropriate fit of a drug molecule to a receptor
produces a strong bond in a complex that produces
a maximal response.

• Smaller keys, larger keys, or incorrectly positioned teeth on

keys (incorrectly shaped or sized substrate molecules) do not
fit into the lock (enzyme).
• Only the correctly shaped key opens a particular lock. This is
illustrated in graphic on the left.
Drug Binding to Receptors
• A molecule, often a drug, binds to a receptor based on
its steric nature.
• In short, a drug's geometric shape along with its
electron distribution of energies must match some
part of the receptor's geometric shape and its energy
distribution for an affinity (attraction) to occur.
• Molecules do not fit together based solely on the
shape, but rather their energy distributions that
attract, repel, or have no effect.
• There are four types of binding that take place
between a receptor and a drug molecule.
• They include:
oVan der Waal forces
oHydrogen bond
oIonic interaction
oCovalent bonding
• Much like two magnets that attract or repel based on
their orientation of electromagnetic interactions, so
too are molecules pulsating structures of energy
distribution.
• If part or all of a molecule is attracted to part of a
receptor based on these energy attractions, then
binding may occur.
• The greater the fit (attraction) of these energies, the
more pronounced the effect or duration would be.
• It is important to reiterate that a molecule or drug
that binds to a receptor may activate or inactivate it.
• A drug that activates a receptor is called an agonist,
while a drug that inactivates a receptor is called an
antagonist.
• Although not all drugs act on receptors, many do and
knowledge of receptor theory aids in understanding
drug action and effect.
• General rules may apply to drugs that work on
receptors:
o A drug with high affinity for a receptor will have higher potency than a drug
with less affinity.
o Higher dose will be needed for a drug with lower receptor affinity compared
with a drug with higher affinity.
o Receptors tend to increase their numbers (upregulate) when exposed to long-
term administration of antagonists.
o Receptors tend to decrease their numbers (downregulate) when exposed to
long-term administration of agonists.
o Slight variations in receptor gene expression may cause increased, decreased,
altered, or unexpected drug reactions in some individuals.
Receptor Selectivity and Affinity
• Receptor selectivity refers to the extent to which a
receptor binds with a particular drug rather than
other molecules.
• Selectivity depends both on the receptor and on the
size, shape, and bioelectrical charge of the drug
molecule.
• Reversibility of drug/receptor binding occurs, since
the latter interaction is generally not permanent.
• How avidly or “tightly” a receptor binds a given drug
molecule is described as its affinity.
• Receptors with high affinity for a drug require a lower
drug concentration for full saturation. For instance,
agonists and antagonists could bind to the same
receptor but differ in their affinity.
• A high affinity agonist and low affinity antagonist
could lead to an insurmountable drug effect.
Intrinsic Activity or Efficacy
• The ability of a drug to trigger the pharmacological
response after making the drug-receptor complex.
• Efficacy refers to the size of the intracellular or drug
effect when the drug and receptor interact.
• Zero efficacy drugs include receptor antagonists,
which generally have no effect other than preventing
the receptor from being activated by an agonist drug.
• A full agonist drug has high efficacy and can produce
the maximum effect on receptors at a sufficient
concentration.
• Partial agonist or inverse agonist drugs have a lower
efficacy and cannot produce the maximal effect at any
drug concentration level.
• Allosteric regulation of receptors with multiple
binding sites can occur.
• Allosteric (“other side”) binding sites are usually sites
other than that for the endogenous agonist.
• Activation of these sites can change the shape of the
neurotransmitter (NT) receptor, thereby positively or
negatively regulating its affinity for the primary
endogenous ligand.
• For instance, at the GABAA receptor complex,
benzodiazepine (BZD) agonists enhance and inverse
agonists retard activation of GABAA receptor
activation.
Types of Receptors and Signal Transduction
Mechanisms
• Type I: Ionotropic receptors (ligand gated ion channels)
• Type II: Metabotropic receptors (G Protein coupled
receptors-GPCR)
oAdenylate cyclase: cAMP system
oPhospholipase-C: Inositol phosphate system
oIon channel regulation
• Type III: Enzyme linked receptors
oIntrinsic enzyme receptors
oJAK-STAT kinase binding receptors
• Type IV: Receptors regulation gene expression
Figure 4: Four types of drug receptors
Ionotropic Receptors
• Otherwise called “Ligand gated ion channels”
• Are located extracellularly on the cells surface
• Enclose ion selective channels (for Na+, K+, Ca2+, and
Cl-) within their molecules.
• Agonist binding opens the channel and causes
depolarization/hyperpolarization changes in the ionic
composition.
oExamples: Nicotinic cholinergic, GABAA-Glycine
(inhibitory), excitatory amino acids (Kainate, NMDA or
N-methyl-D-asparate, quisqualate), and 5HT3
receptors
Figure 5: Nicotinic cholinergic receptor Figure 6: Serotonin (5HT3) receptor
Figure 7: NMDA receptor (excitatory firing) Figure 8: GABA (inhibitory firing)
G-Protein Coupled Receptor
• These are a large family of cell membrane receptors
linked to the effector GTP activated proteins (G-
proteins)
• The G-proteins are comprised of 7 helical membrane
spanning hydrophobic amino acid segments running
into 3 extracellular and 3 intracellular loops.
• Agonist binding site is located on the extracellular
surface while another recognition site formed by
cytosolic segments binds the coupling G-protein.
oExamples: Muscarinic, Dopamine D2, 5HT, GABAB,
adrenergic (⍺1, ⍺2, and beta)
Figure 8: Muscarinic and beta adrenergic receptors Figure 9: Dopaminergic receptor
• Conventional receptor theory predicts that GPCRs exist in
spontaneous equilibrium between “inactive” and “active”
states that are stabilized by ligand, leading to increases or
decreases in receptor coupling to its intracellular
effectors.
• Agonists increase the proportion of receptors in the
active state and antagonists decrease it, but the receptor
alone specifies which pathways are activated.
• What the concepts of pluridimensional efficacy and
functional selectivity have taught us is that receptors
have multiple active states with different signaling
capacity, and structurally distinct ligands have the ability
to stabilize these active states in different proportions
compared with the native ligand.
• In other words, the ligand-receptor complex, not the
receptor alone, determines signal output.
• If the ligand–receptor complex defines the signaling, then
biased ligands can create, in effect, new receptors whose
functionality is both unknown and possibly unique to each
ligand–receptor pair.
• The physiological effects of conventional agonist or
antagonist ligands can largely be predicted based on the
physiological properties of the native ligand.
• But if every biased ligand-GPCR pair is a functionally
distinct entity with the potential to influence biological
systems in unique ways, then the discovery of
therapeutically useful biased agonist becomes a matter of
trial and error.
Non-receptor Mediated Mechanisms
• These refer to the action elicited by drugs without
binding to receptors.
• They include:
oChemical action mechanism,
oPhysical action mechanism,
oCounterfeit or false incorporation mechanism,
oProtoplasmic poison mechanism,
oAntibody formation,
oPlacebo action,
oTargeting specific genetic changes
Chemical action mechanism
• Neutralization e.g. antacids
• Chelation e.g. deferoxamine, EDTA, dimercaprol,
penicillamine
• Ion exchangers e.g. cholestyramine binds Cl- from bile
salts
Physical action mechanism
• Osmosis e.g. Epson salt (MgSO4) purgative
• Adsorption e.g. Simethicone adsorbed gases and used as
anti-flatulent.
• Protectives e.g. Dustin powder
• Astringents e.g. Tannic acid, alcohol
• Saturation in a biophase e.g. General anaesthetics
False incorporation mechanism
• Sulpha drugs and antineoplastic drugs
Protoplasmic poisoning mechanism
• Germicides and antiseptics
Antibodies formation mechanism
• Vaccines and antisera
Targeting specific genetic changes