08/19/2015 Pharmacodynamics 2: Mechanisms of

07:30 – 09:30 Drug Action

YL6: 01.20.01 Principles and Perspectives
Cecile Jimeno, M.D.

OUTLINE How Drugs Work

I. Introduction IV. Types of Drug-Receptor • Therapeutic and toxic effects result from the interaction of
A. Objectives Interactions drugs with molecules in the body
B. Basic Concepts A. Agonist → Drugs cause alterations in the macromolecules’
II. Receptor Physiology B. Competitive biochemical or biophysical activities
A. How to Identify Inhibitor • Receptor – component of a cell or an organism that
Receptors C. Allosteric Activator interacts with a drug and initiates the chain of events
B. Types of Protein Drugs leading to the drug’s observed effects
Targets D. Allosteric Inhibitor → John Newport Langley (1878)
C. Receptor E. Summary of Drug- § Described “receptive substances” when studying
Superfamilies Receptor atropine in pilocarpine-induced salivation
III. Receptor-Mediated Interactions → Paul Ehrlich
Drug Action V. Non-Receptor Mediated § Coined the term ‘receptor’ in 1909
A. Ligand- and Drug Effects § Corpora non agunt nisi fixata (“A drug will not work
Voltage-Gated Ion VI. Receptor Regulation unless it is bound”)
Channels A. Tachyphylaxis
B. G Protein-Coupled B. Deregulation Essential Elements of Drug-Receptor
Receptors Allosteric Activator
Interaction
C. Kinase-Linked VII. Review Questions
Receptors VIII. Freedom Space • Most drugs must bind to a receptor to bring about an
D. Nuclear Receptors IX. References and effect
E. Summary of Additional Readings → Drug (ligand)
Receptor Types X. Appendix → Receptor (binding site)
→ Effector/s
I. INTRODUCTION → Resultant action of Response

A. OBJECTIVES Practical Implications of the Receptor Complex

• To discuss molecular mechanisms of drug action
• To review the concepts of receptor physiology
• To describe the types of drug-receptor interactions
• To discuss the 4 major receptor systems: ligand/voltage-
gated ion channels, enzyme/kinase-linked receptors,
GPCRs, nuclear receptors
• To characterize non-receptor drug interactions
• To enumerate examples for each
B. BASIC CONCEPTS
Pharmacodynamics vs. Pharmacokinetics
• Pharmacodynamics (PD) – action of the drug on the
body
→ Explains the therapeutic and toxic effects of the drug
→ Drugs are usually grouped according to their
pharmacodynamic properties
→ Also determines whether drugs are indicated for a
particular symptom or disease(s)
→ Mechanisms of action, therapeutic effects (alteration of
physiology), and adverse drug effects
→ Adverse reactions are extensions of pharmacologic
activity of the drug
§ E.g. Insulin does not only act to lower blood glucose
but also acts as a growth factor, facilitated by the
same receptor, resulting in an increase in weight
• Pharmacokinetics (PK) – action of the body on the
drug
→ Pharmacokinetic processes determine ADME of drugs
§ Absorption
§ Distribution
§ Metabolism
§ Elimination
→ Half-life, Therapeutic index
1. Receptors largely determine the quantitative relations
between dose or concentrations of drug and
pharmacological effects
• Receptor’s affinity for binding a drug determines the
concentration of a drug required to form a significant
number of drug-receptor (D+R) complexes
→ Affinity
§ How tightly a receptor binds to the drug which
determines what would be the pharmacologic
effect
• Total number of receptors may limit the maximal effect
a drug may produce
→ The number of receptors that need to be saturated
will determine the dose of the drug
• The receptors are located in specific sites of the body
2. Receptors are responsible for selectivity and drug action
• Molecular size, shape, and electrical charge of a drug
determines whether and with what affinity it will bind to
a particular receptor among the vast array of chemically
different binding sites available in a cell, tissue, or
patient
→ The receptors are proteins which contribute to the
characteristics of the receptor
→ Specific shapes and configurations serve as binding
sites for very specific substances, such as the ligand
and drugs
• Once the chemical structure of the drug is altered, it
can increase/decrease a new drug’s affinity for different
classes of receptors
3. Receptors mediate the action of pharmacologic agonists
and antagonists
• Agonists
→ Activate the receptor signal as a result of direct
binding
• Antagonists
→ Bind to the receptor and interfere with the ability of
the agonist to activate it

YL6:01.20.01 Group 8: Barzaga, Bonus, Canon, Duque, Gumila, Macalalad, Lozada, Roque, Sison, Tan, Tolentino 1 of 11
 st
§ Block the binding of the agonist and block their § 1 compound: Acarbose is a pseudotetrasaccharide
biologic action compound isolated from Actinoplanes utanhesis
§ Adverse drug reaction: Flatulence due to gas-
Mechanisms of Drug Action forming microbiota
1. Receptor-mediated − Use of this drug is limited in Asia due to high
2. Non-receptor mediated carbohydrate consumption

II. RECEPTOR PHYSIOLOGY

• Most receptors are protein macromolecules that combine

with and mediate the action of signal molecules
→ Exceptions: DNA-antimicrobial drugs, anti-cancer drugs
→ Majority of drug targets are physiological receptors
→ Two major domains within the receptor:
§ Ligand-binding domain (extracellular)
§ Effector domain (transmembrane or intracellular)
• Structure of polypeptides
→ Proteins vary in sizes and assume specific
configurations which contribute to the specificity of Figure 2. Structural formula of acarbose (top) and miglitol (bottom).
binding sites (Image taken from Dr. Jimeno’s lecture)
→ Very diverse
3. Transport Proteins
→ Have the necessary specificity of shape and electrical
*Note: This section was not discussed in detail.
charge
• Neurotransmitter transporters
→ Norepinephrine transporter (NET): Tricyclic
A. HOW TO IDENTIFY RECEPTORS
antidepressant
→ Dopamine transporter (DAT): Cocaine
• Drug-binding (radioisotope-tagged drugs)
→ Serotonin transporter (SERT): Fluoxetine
• Molecular biology: gene sequencing
→ Has identified “orphan receptors”
§ Receptors whose ligands are presently unknown

B. TYPES OF PROTEIN TARGETS

1. Regulatory Proteins
• Mediate the action of endogenous chemical signals,
such as neurotransmitters, autacoids, and hormones
2. Enzymes
• Commonly are inhibited by binding a drug (e.g.
dihydrofolate reductase, the receptor for the anti-
neoplastic drug methotrexate)
• Inhibitors should have similarities with the endogenous
substance in order for it to be competitive.

Figure 3. Cocaine in the brain. In the normal communication

process, dopamine is released by a neuron into the synapse, where
it can bind to dopamine receptors on neighboring neurons. Normally,
dopamine is then recycled back into the transmitting neuron by a
specialized protein called the dopamine transporter. If cocaine is
present, it attaches to the dopamine transporter and blocks the
normal recycling process, resulting in a buildup of dopamine in the
synapse, which contributes to the pleasurable effects of cocaine.
(Image and caption from National Institute on Drug Abuse (NIDA))

• Non-neuronal transporter
→ Cholesterol transport
→ Nucleoside transporter
Figure 1. Competitive inhibition. Competitive inhibition happens → Glucose transporter
when the inhibitor (e.g. drug) competes with the substrate at the
same binding site on the enzyme; therefore, preventing the enzyme-
substrate complex to form and exhibit its action. (Image taken from
Dr. Jimeno’s lecture)

• E.g. Alpha glucosidase inhibitor (Carbose and

Miglitol)
§ Dietary carbohydrates (polysaccharides) require
enzymatic digestion by α-glucosidase into
monosaccharides in the GIT in order to be absorbed
§ Inhibiting this enzyme would therefore delay or Figure 4. Glucose reabsorption in the kidney by SGLT2 (Chao and
decrease carbohydrate absorption Henry 2010).

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 § Glucose transporters (SGLT2) are transport proteins
which help reabsorb glucose in the kidney
§ In type 2 diabetes, there is a maladaptation to the
transporter which continually reabsorbs the glucose
leading to increased blood sugar levels
− Blocking the transport protein results in glucosuria
and decreased blood sugar levels due to a
decreased threshold of glucose (from 180mg/dl to
100mg/dl)
− Glucosuria is pathologic and can lead to a
development of UTI or other infections related to
the genital tract
§ Absence of SGLT2 is compatible with life; thus,
blocking it would not do any harm
→ Na+ H+ antiporter
+ +
→ E.g. Na -K ATPase – membrane receptor for the
cardiac drug digitalis glycosides
4. Structural Proteins
• E.g. tubulin, the receptor for colchicine, an anti-
inflammatory agent used against gout
C. RECEPTOR SUPERFAMILIES
• Receptor Nomenclature
→ System for naming receptors have been developed by
IUPHAR
§ IUPHAR: International Union of Pharmacology
(IUPHAR) Committee on Receptor Nomenclature
and Drug Classification
• Types:
→ Ligand-gated ion channels (ionotrophic receptors):
ionophore
→ Enzyme/kinase-linked receptors
→ G protein coupled receptors (metabotropic, 7
transmembrane receptors, GPCR)
→ Nuclear receptors
Figure 5. Receptor Superfamilies. a) Channel-linked receptors; b)
Enzyme-linked receptors; c) GPCR; d) Intracellular/nuclear receptors
(Taken from Dr. Jimeno’s lecture) (*See Appendix for another
version of this picture)
YL6:01.20.01 Pharmacodynamics 2: Mechanisms of Drug Action: Principles and Perspectives
Figure 6. Known transmembrane signaling mechanisms: 1) A lipid-
soluble chemical signal crosses the plasma membrane and acts on
an intracellular receptor (which may be an enzyme or a regulator of
gene transcription); 2) the signal binds to the extracellular domain of
a transmembrane protein; thereby, activating enzymatic activity of its
cytoplasmic domain; 3) the signal binds to the extracellular domain
of a transmembrane receptor bound to a separate protein tyrosine
kinase, which it activates; 4) the signal binds to and directly
regulates the opening of an ion channel; 5) the signal binds to a cell-
surface receptor linked to an effector enzyme by a G protein. (A, C,
substrates; B, D, products; R, receptor; G, G protein; E, effector
2
[enzyme or ion channel]; Y, tyrosine; P, phosphate.) .
III. RECEPTOR-MEDIATED DRUG ACTION
A. LIGAND- AND VOLTAGE-GATED
CHANNELS
Ionotropic Receptors: Ligand-Gated Ion
Channels
• Many drugs act by mimicking or blocking the actions of
endogenous ligands that regulate the flow of ions through
plasma membrane channels
→ E.g. Neurotransmitters, such as acetylcholine,
serotonin, GABA, and glutamate
• Each of their receptors transmit its signal across the
plasma membrane by increasing the transmembrane
conductance of the relevant ion and thereby, altering
the electrical potential across the membrane
→ E.g. Nicotinic Acetylcholine Receptors, Barbiturates
and Benzodiazepines (BZD)
• Compared to other receptors, remember that ligand-gated
ion channels are the quickest to respond and have a
physiological effect
Nicotinic Acetylcholine Receptor
Figure 7. The nicotinic acetylcholine (ACh) receptor, a ligand-gated
ion channel. The receptor molecule is depicted as embedded in a
rectangular piece of plasma membrane, with extracellular fluid above
and cytoplasm below. Composed of five subunits (two α, one β,
one γ, and one δ), the receptor opens a central transmembrane ion
channel when ACh binds to sites on the extracellular domain of its α-
2
subunits.
• The 2 alpha subunits comprises the gate and regulates
the passage of ions
• Binding of acetylcholine results in an alpha conformational
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 change increasing sodium conductance inhibiting muscle contraction.
→ Depolarization of the cell occurs, leading to muscular
contraction and generation of an action potential B. G PROTEIN-COUPLED RECEPTORS
• In the neuromuscular junction, blocking these receptors (GPCRS)
would result to muscle relaxation
• In asthma, blocking these receptors would result to
bronchodilation
• In anesthesia, blocking these receptors would result into a
lack of muscular contraction during surgery

• Organs of distribution
→ Skeletal neuromuscular junctions
→ Sympathetic and parasympathetic nervous system
→ Autonomic ganglia
→ Central nervous system
→ Mostly CNS and PNS channels
• Time course of action
→ Time elapsed from the binding of the agonist to a
ligand-gated channel and the cellular response can
often be measured in milliseconds Figure 9. G Protein-Coupled Receptors (GPCRs). G-protein
→ Rapidity of this signaling mechanism is important for coupled receptors are also known as seven transmembrane (7-TM)
moment to moment transfer of information across or serpentine receptors because the receptor polypeptide “snakes”
synapses around the plasma membrane seven times. They are the largest
§ The quicker the action, the sooner the resolution of receptor family and their effects are mediated through the use of
2
second messengers.
its effects
• Ion channels are regulated by multiple mechanisms:
MOA: Ligands on GPCRs
phosphorylation and endocytosis
Many extracellular ligands act by increasing the intracellular
• Many CNS acting drugs use ligand-gated ion channels
concentrations of second messengers, such as cAMP,
calcium ions, or phosphoinositides, using a transmembrane
Voltage-Gated Ion Channels signaling system.
• Do not bind neurotransmitters directly but are controlled First, the extracellular ligand is selectively detected by a cell-
by membrane potential surface receptor. The receptor, in turn, triggers the activation
• E.g. Verapamil of a G protein located on the cytoplasmic face of the plasma
→ Inhibits voltage-gated calcium channels, and the influx membrane. The activated G protein then changes the activity
of calcium in the heart and the vascular smooth muscle. of an effector element, usually an enzyme or ion channel.
This puts the heart relatively at rest and relaxes the This element then changes the concentration of the
2
vascular smooth muscle resulting in anti-arrhythmic intracellular second messenger.
effects and reduction in BP

Figure 8. Many antiepileptic drugs (e.g. carbamazepine, phenytoin

and lamotrigine) affect membrane excitability by an action on
voltage-dependent sodium channels, which carry the inward
membrane current necessary for the generation of an action
potential. Their blocking action shows the property of use-
Figure 10. GPCR Signaling Cascades. Main effector pathways of
dependence; in other words, they block preferentially the excitation
GPCRs include the adenylyl cyclase pathway and the
of cells that are firing repetitively, and the higher the frequency of Phospholipase C/Inositol Pathway. (Image taken from Dr. Jimeno’s
3
firing, the greater the block produced.
lecture)

• CMZ, Phenytoin, Lamotrigine, Valproate à Closes Na+

channels à Na+ unable to enter à Hyperpolarization à
Resting neurons à Anti-seizure (main application of drug)
BZD and Barbiturates vs. Verapamil
BZD and Barbiturates require the natural ligand - typically
neurotransmitter GABA – to bind to the receptor to mediate
its effects. Binding is only improved by the anti-seizure drugs
through their actions as allosteric agonists to the receptor
With Verapamil (anti-arrhythmic calcium channel blocker),
the drug itself directly causes the relaxation of the heart and
vascular smooth muscle by inhibiting entry of calcium, thus
3 Components of the Transmembrane
Signaling System
1. Binding
• Extracellular ligand is specifically detected by a cell-
surface receptor
2. Receptor triggers the activation of a G-protein through a
conformational change of the receptor located on the
cytoplasmic face of the plasma membrane
3. Activated G-protein changes the activity of an effector
element, usually an enzyme or ion channel – this element
nd
then changes the concentration of the intracellular 2
messenger

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 +
• Many hormones make use of this receptor for their → Gi opens K channel in heart, smooth muscles and
action close neuronal Ca channel
+
• Effects can last from seconds to minutes → Opiate analgesics open K channels through βϒ

Main Effector Pathways of GPCR Table 1. GPCR Families

• Adenylyl cyclase pathway/cAMP pathway Functional Ligands Transducers Example
• Phospholipase C/inositol pathway Family and Drugs
Effectors
→ Ion channel
β adrenergic NE, Epi GS, Ac Dobutamine
→ Rho A/Rho Kinase
receptor ,DA (agonist),
propranolol
Well-Established 2nd Messengers (blocker)
• Cyclic Adenosine Monophosphate (cAMP) Muscarinic Ach Gi, Gq , AC, Atropine
• Phosphoinositides and calcium cholinergic ion channels, (blocker)
→ Stimulation of membrane enzyme phospholipase C PLC
(PLC) which splits a phospholipid component of the cell Eicosanoid PGS, Gs, Gi, Gq Misoprostol,
membrane into diacylglycerol (DAG) and inositol-1,4,5- LXTS, TXS Montelukast
triphosphate (IP3) Thrombin Receptor G12/13, GEF (In
→ DAG → PKC [cell membrane] (protease peptide development)
→ IP3 (water soluble) → cytoplasm → Ca++ activated)
• Cyclic Guanosine Monophosphate (cGMP) *Note: Dr. Jimeno said she doesn’t expect us to memorize this table

REMEMBER! C. ENZYME (-KINASE) LINKED RECEPTORS

Cyclic Adenosine Monophosphate (cAMP) Main Types

• Receptor tyrosine kinases
• Serine/threonine kinases
• Cytokine receptors
• Guanylyl cyclase linked receptors (e.g. insulin)

Figure 11. cAMP Signaling Pathway. As an intracellular second

messenger, cAMP mediates hormonal responses such as
mobilization of stored energy, breakdown of carbohydrates in liver,
increased rate and contractile force of heart muscle, etc. It exerts
most of its effects by stimulating cAMP-dependent protein kinases .
2 kinases phosphorylate specific proteins to induce the desired cellular
Phosphoinositides and calcium
GPCR stimulation of the enzyme, Phospholipase C (PLC),
splits a phospholipid component of the plasma membrane,
phosphatidylinositol-4,5-bisphosphate (PIP2) into 2 second
messengers, diacylglycerol (DAG) and inositol-1,4,5-
triphosphate (IP3). IP3 diffuses through the cytoplasm and
2+
triggers the release of Ca by binding to ligand-gated ion
channels. Calcium interacts with calmodulin to form a
complex that activates effector kinases.
Cyclic Guanosine Monophosphate (cGMP)
In contrast to the ubiquitous cAMP, cGMP has established
signaling roles in only a few cell types, such as intestinal
mucosa and vascular smooth muscle. GPCR activation
stimulates the enzyme, guanylyl cyclase to produce cGMP.
2
cGMP acts by stimulating cGMP-dependent kinases .
Other effectors: Ion channels
*Note: These are just given as examples. No need to focus on these
effectors.
• Activated G proteins can open or close ion channels
2+
→ Gαs open Ca in myocardium and skeletal muscle
Figure 12. Kinase-linked receptor mechanism. The binding of a
ligand to the signal-binding site activates the receptor to
autophosphorylate itself. After autophosphorylation, the tyrosine
response. (Image taken from http://bio1151.nicerweb.com/) (*See
Appendix for a larger version.)
Receptor Kinase Transmission (Insulin)
*Note: There is no need to memorize but it is important to
understand the concepts involved in this section.
• Starts with binding of an extracellular domain to trigger a
conformational change
• Follows the dimerization of receptor and intracellular
autophosphorylation
• Docking proteins: insulin receptor substrate-1 through -
6 (IRS-1 to IRS-6)
→ The first to be phosphorylated by the activated receptor
tyrosine kinases
• IRS molecules bind to and activate other kinases:
→ Phosphatidylinositol-3-kinase
→ Growth factor receptor-binding protein 2
→ Guanine nucleotide releasing factor
→ GTP binding protein Ras, and the Mitogen-activated
protein kinase (MAPK) system
• This network of phosphorylation within the cell represents
insulin's second message and results in multiple effects:
→ Translocation of glucose transporters (esp. GLUT-4) to
the cell membrane à increase in glucose uptake

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 → Increase glycogen synthase activity & glycogen
formation
→ Multiple effects on protein synthesis, lipolysis, &
lipogenesis
→ Activation of transcription factors that enhance DNA
synthesis, and cell growth & division
D. NUCLEAR RECEPTORS
Intracellular Receptors for Lipid-Soluble
Agents
• Freely traverses the cell membrane because of lipid
characteristic
• Examples of lipid-soluble biologic ligands: steroids
(corticosteroids, mineralocorticoids, sex steroids, vitamin
D) and thyroid hormones
→ Thyroid hormones are not steroid ligands
§ Composed of very small dipeptides that can traverse
the membrane
• Their intracellular receptors stimulate the transcription of
genes by binding to specific DNA sequences
(“response elements”) near the gene whose expression
is to be regulated

Figure 13. Insulin Action through Kinase-linked Receptors.

It starts out with separate beta subunits. Then the ligand binds to the
extracellular units in the alpha domain, causing subsequent
autophosphorylation and dimerization. This leads to secondary
messengers and pathways that ultimately lead to glucose uptake
(Image from Dr. Jimeno’s lecture).

Table 2. Receptor Kinase Families

Functional Physiological Effectors Example
family ligand and drugs
transducer
(Tyrosine) Insulin, SH2 domain Herceptin, Figure 14. MOA of Nuclear Receptor Class I. In the absence of
Kinase- PDGF, EGF, imatinib ligands, class I nuclear receptors are located in the cytosol.
Hormone binding to the NR triggers dissociation of heat shock
linked VEGF
proteins (HSP), dimerization, and translocation to the nucleus, where
receptor the NR binds to a specific sequence of DNA known as a hormone
Cytokine Interleukins Jak/STAT Basiliximab response element (HRE). The nuclear receptor DNA complex in turn
receptors and other recruits other proteins that are responsible for transcription of
cytokines downstream DNA into mRNA, which is eventually translated into
Guanylyl Natriuretic cGMP Nesiritide protein, resulting in a change in cell function. (Image taken from
cyclase peptide Linja et al., Clinical Cancer Research, 2004)

Phosphorylation: A Common Theme

• Almost all second messenger signaling involves
reversible phosphorylation
• Can result in cancer genesis (growth factor as a ligand)
• Lasts from minutes to days with zinc fingers

Purpose of Signaling
• Amplification
→ Attachment of a phosphoryl group to a serine,
threonine, or tyrosine residue powerfully amplifies the
initial regulatory signal by recording a molecular
memory that the pathway has been activated
→ In contrast, dephosphorylation “erases” the memory
• Flexible regulation
→ Differing substrate specificities of the multiple protein
kinases regulated by second messengers provide
branch points in signaling pathways that may be
independently regulated
2+
→ Allow cAMP, Ca or other second messengers to use
the presence or absence of particular kinases or kinase
substrates to produce different effects in various cell
types
→ Inhibitors of protein kinases have great therapeutic
potential
§ E.g. Trastuzumab is an antibody that antagonizes
growth factor receptor signaling, which is useful for
breast cancer
Figure 15. Structure of a Nuclear Receptor. The heterogenous N-
terminal domain harbours the AF1 (activation function 1) site. This
binds cell-specific transcription factors that modify the properties of
the receptor. The highly conserved core domain comprises two ‘zinc
fingers’; cysteine- (or cystine-/histidine-) rich loops in the amino acid
chain that are held in a particular conformation by zinc ions and
which are responsible for DNA recognition and binding. The flexible
hinge region in the molecule allows the receptor to dimerise with
other NRs, and the C-terminal domain, which contains the ligand-
3
binding module, is specific to each class of receptor.
Table 3. Types of nuclear receptors.
Class I Hybrid Class Class II
(*Slowest: 30 mins.

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 to x hours)

Cytoplasm Heterodimers Nucleus

homodimers with RXR heterodimers except
Retinoid X (RXR)
Mineralocorticoid Thyroid Peroxisome
(MR) hormone (TR) proliferator (PPAR)
Estrogen (ER) Vitamin D Liver X receptor
Progesterone receptor (VDR) (LXR)
(PR) Farnesoid X
receptor (FXR)

induce drug
metabolizing
enzymes
(See appendix for complete table.) Figure 17. Summary of Receptor Types, Time Scale, and Model
3
Receptors (See appendix for larger picture.)
• Nuclear receptors are the slowest and take a while for
physiologic changes to appear III. TYPES OF DRUG-RECEPTOR
→ This is because their mechanism of action involves INTERACTIONS
activating genes transcription and protein translation,
which is a long process A. AGONIST

Therapeutic Consequences on Nuclear
Receptors
1. All these hormones produce their effects after a
characteristic lag period of 30 minutes to several hours,
the time required for the synthesis of new proteins
• Gene-active hormones cannot be expected to alter a
pathologic state within minutes
§ E.g. Glucocorticoids will not immediately alleviate the
symptoms of asthma
2. The (beneficial or toxic) effects of these agents can
persist for hours or days even after the agonist
concentration has been reduced to zero
• Due to the slow turnover of proteins and enzymes
that remain active in cells for hours or even days
Estrogen
• Estrogen attaches to protein carriers and arrives to the
cell
• Estrogen binds to the receptor proteins in the cytosol and
goes inside the nucleus
• Bind to and activate the receptor in some fashion, which
2
directly or indirectly bring about the effect
→ Initiate/cause the expected effect of a drug
• Some receptors incorporate effector machinery in the
same molecule, so that drug binding brings about the
2
effect directly
→ E.g. opening of an ion channel or activation of enzyme
2
activity
• Other receptors are linked through one or more
intervening coupling molecules to a separate effector
2
molecule
B. COMPETITIVE INHIBITOR
• Pharmacologic antagonist drugs, by binding to a receptor,
compete with and prevent binding by other
2
moleculest
→ Inhibits the action of the agonist without deactivating
the receptor
§ An increase in the agonist results to the ability of
achieving the maximal efficacy of the drug
• Their action can be overcome by increasing the dosage of
2
agonist

C. ALLOSTERIC ACTIVATOR

• Drugs that bind to the same receptor molecule but do not

prevent binding of the agonist are said to act
allosterically and may enhance the action of the agonist
2
molecule
→ Binds to a site different from where the ligand binds
§ Improves the action of the agonist and increases
affinity of agonist to the binding site
• E.g. Benzodiazepines bind noncompetitively to ion
channels activated by the neurotransmitter ϒ-
aminobutyric acid (GABA), enhancing the net activating
effect of GABA
Figure 16. Estrogen Mechanism of Action (Image taken from
www.biocarta.com)

G. SUMMARY OF RECEPTOR TYPES

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Figure 19. Barbiturates and Benzodiazepines enhance GABA
action. BZD and Barbiturates act as allosteric agonists that improve
the binding of the natural ligand (GABA). As an inhibitory
neurotransmitter, GABA allows Cl- to enter causing
hyperpolarization in the cell. In the hyperpolarized state, a cell is said
to be in the quiet or resting state and is not easily excited. In this
way, BZD and barbiturates minimize seizures by positively regulating
and enhancing GABA binding by allow more Cl- to enter, which in
turn, hyperpolarizes the membrane.
D. ALLOSTERIC INHIBITOR
• Drugs that bind to the same receptor molecule but do not
prevent binding of the agonist are said to act
allosterically and may inhibit the action of the agonist
2 and sensitivity
molecule
→ Binds to a site different from where the ligand binds
§ Decreases affinity of the agonist to the binding site
• Allosteric inhibition is not overcome by increasing
2 short-term diminution of the receptor response,
the dose of agonist
E. SUMMARY OF DRUG-RECEPTOR
INTERACTIONS
Figure 18. Drugs may interact with receptors in several ways. The
effects resulting from these interactions are diagrammed in the dose-
response curves at the right. Drugs that alter the agonist (A)
response may activate the agonist binding site, compete with the
agonist (competitive inhibitors, B), or act at separate (allosteric)
sites, increasing (C) or decreasing (D) the response to the agonist.
Allosteric activators (C) may increase the efficacy of the agonist or
its binding affinity. The curve shown reflects an increase in efficacy;
2
an increase in affinity would result in a leftward shift of the curve.
YL6:01.20.01 Pharmacodynamics 2: Mechanisms of Drug Action: Principles and Perspectives
IV. NON-RECEPTOR MEDIATED DRUG
EFFECTS
*Note: Doc Cecile did not elaborate on this much, but several
examples were discussed in the SIM on Mechanism of Drug Action
Activity.
1. Enzymes
• Enzymes often bind and act on their targets with great
affinity and specificity
• Enzymes are catalytic and convert multiple target
molecules to the desired products
• These two features make enzymes specific and potent
drugs that can accomplish therapeutic biochemistry in
the body that small molecules cannot.
• E.g. Carbonic anhydrase inhibitors, monoamine
oxidase inhibitors, ACE inhibitors
2. Transporters
• Several drugs exhibit their effects on transporter
proteins by physically blocking these channels.
+ 2+
• E.g. Na -channel blockers (anesthetics), Ca -channel
blockers
3. Physicochemical reaction
• These are compounds with intrinsic physical or
chemical properties that can alter physiologic activities
in the body.
• E.g. Alkalinizing and acidifying drugs, Chelating agents,
Mannitol etc.
V. RECEPTOR REGULATION
• Receptors are dynamically regulated in number, location,
• Changes can occur over short time (minutes) and longer
periods (days)
• Frequent or continuous exposure to a drug often results in
sometimes called tachyphylaxis or desensitization.
(Remember: Tachyphylaxis is NOT dose dependent as
compared with drug tolerance, which is dose dependent)
A. TACHYPHYLAXIS
1. Intracellular proteins may block access of a G protein
to the activated receptor molecule
• E.g. The molecule, arrestin has been shown to bind to
an intracellular loop of the beta-adrenoceptor when the
receptor is continuously activated
§ Beta-arrestin prevents access of the Gs-coupling
protein and thus, desensitizes the tissue to further
agonist activation within minutes
§ Removal of the agonist results in removal of arrestin
and restoration of the full response after a few
minutes or hours
2. Second, agonist-bound receptors may be internalized
by endocytosis, removing them from further exposure
to extracellular molecules
• The internalized receptor molecule may then be either
reinserted into the membrane (e.g. morphine receptors)
or degraded (e.g. adrenoceptors, epidermal growth
factor receptors)
• In some cases, the internalization-reinsertion process
may actually be necessary for normal functioning of the
receptor effector system
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Figure 20. GPCR phosphorylation and endocytosis are involved in
tachyphylaxis, that is, a rapid partial desensitization to GPCR-
activating drugs. (Image taken from
http://watcut.uwaterloo.ca/webnotes/Pharmacology/gpcrFeedbackRe
gulation.html)
3. Depletion of some essential substrate required for
downstream effects
• For example, depletion of thiol cofactors may be
responsible for tolerance to nitroglycerin
• In some cases, repletion of the missing substrate (e.g.
by administration of glutathione) can reverse the
tolerance
B. DESENSITIZATION
• Long-term reductions in receptor number (downregulation)
may occur in response to continuous exposure to agonists
• The opposite change (upregulation) occurs when receptor
activation is blocked for prolonged periods (usually
several days) by pharmacologic antagonists or by
denervation)
REVIEW QUESTIONS
1. How can a drug (agonist) overcome irreversible/
noncompetitive antagonists?
a. Increase the concentration of the drug.
b. Decrease the concentration of the drug.
c. Do not change the concentration of the drug.
d. It cannot be overcome by altering drug concentration.
2. How will irreversible/ noncompetitive antagonists
affect the maximum efficacy of the drug?
a. Maximum efficacy will be increased.
b. Maximum efficacy will be decreased.
c. Maximum efficacy will not be affected.
d. None of the above.
3. All of the following are examples of steroid
hormones, which uses nuclear receptors, EXCEPT?
a. Thyroxine
b. Cholecalciferol
c. Aldosterone
d. Testosterone
4. Which of the following second messenger:enzyme
pairs are INCORRECTLY matched?
a. cAMP: adenylate cyclase
b. cGMP: guanylate cyclase
c. IP3: protein kinase C
d. None of the Above
5. Increasing the concentration of the drug to reach
desirable effects will reverse the effects of
tachyphylaxis?
a. Correct
b. Wrong
YL6:01.20.01 Pharmacodynamics 2: Mechanisms of Drug Action: Principles and Perspectives
Answers: d, b, a, c, b
1. D- Unlike competitive antagonists, which compete for the same binding site,
and can be overcome by increasing drug concentration, noncompetitive
antagonists bind at an allosteric site, and induces a conformational change
in the target enzyme. Therefore, it cannot be overcome by changing the
drug concentration.
2. B- Maximum efficacy of the drug will be reduced/ decreased as an effect of
the actions of a noncompetitive antagonist due to the decrease in available
receptors.
3. A- All of the examples makes use of nuclear receptors, but only thyroxine,
an example of a dipeptide thyroid hormone, is not a steroid.
4. C- Phospholipase C produces the second messenger IP3, not protein kinase
C. Protein kinase C is activated by DAG after DAG and IP3 have been split
by Phospholipase C.
5. B-This is wrong because tachyphylaxis is defined as sudden onset drug
tolerance that is not dose dependent. This statement would be correct if it
were asking about drug tolerance.
FREEDOM SPACE
References used by Dr. Jimeno:
(1) Rang HP, Dale MM, Ritter JM, Moore PK,
Pharmacology 7th ed, 2012 (original International
version)
(2) Rang HP, Dale MM, Ritter JM, Moore PK,
Pharmacology Philippine edition, 2015
(3) Katzung, Basic & Clinical Pharmacology, 12th
edition
For IUPHAR Naming of receptors and channels:
→ Alexander SPH, Mathie A, Peters JA: Guide to
receptors and channels. Br J Pharmacol 2006; 147
(Suppl 3): S1-S180.
Dr. Cabigon’s Pharmacology book is available in the library
for 420PHP. You can go to the library to inquire about the
payment and the book.
PLEASE Help Pugad Agila this weekend!!! Last 2 days na
lang ng boards, guys!!! Malalaman na agad ung results next
week. #NoAteneanLeftBehind #One2015
REFERENCES
1. Harvey, RA, et al. Lippincott’s Illustrated Reviews:
th
Pharmacology. 5 ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2012.
2. Katzung B, Trevor A. Basic and Clinical Pharmacology.
th
12 ed. New York, NY: McGraw-Hill Education;
2012.
3. Rang, HP, Dale MM, Ritter JM, Flower RJ, Henderson G.
th
Rang & Dale’s Pharmacology. 8 ed. Edinburgh, UK:
Elsevier Churchill Livingstone; 2012.
4. Chao, Edward C., and Robert R. Henry 2010SGLT2
Inhibition — a Novel Strategy for Diabetes Treatment.
Nature Reviews Drug Discovery 9(7): 551–559.
9 of 11
 APPENDIX

3
Table 1. Some common pharmacologically significant nuclear receptors. Only examples from classes I and II are included.

3
Figure 1. Types of receptor-effector linkage

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 Figure 2. Kinase-linked receptor mechanism. The binding of a ligand to the signal-binding site activates the receptor to autophosphorylate itself.
After autophosphorylation, the tyrosine kinases phosphorylate specific proteins to induce the desired cellular response. (Image taken from
http://bio1151.nicerweb.com/)

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