Summary Pharmacology: Full Overview

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LEARNING OBJECTIVES PHARMACOLOGY

THEME 1

Know the following types of molecular drug targets and can explain their
characteristics:
G-coupled protein receptor, receptor with enzyme activity (kinase receptor),
intracellular
receptor, transporter, and ion channel.
 G-Protein Coupled Receptors (GPCRs)
o Structure
 Membrane-bound receptors with seven transmembrane
domains
o Mechanism
 Ligand binds to GPCR on extracellular side  activation of
associated G-protein on intracellular side  initiation of
cascade of intracellular signaling pathways
o Function
 Regulate wide variety of physiological processes
 Neurotransmission
 Hormone responses
 Immune responses
 Sensory perception
o Drug Targeting
 One of most common drug targets  involvement in diverse
signaling pathways
 Targeting GCPRs can act as agonists or antagonists.
Enhancing or inhibiting receptor’s signal
o Examples
 β-adrenergic receptors
 Dopamine receptors
 Opioid receptors
 Receptors with Enzyme Activity (Kinase Receptors)
o Structure
 Membrane bound
 Extracellular ligand-binding domain
 Single transmembrane helix
 Intracellular enzymatic domain
o Mechanism
 Ligand binding to receptor’s extracellular domain  activation
of intracellular kinase domain  phosphorylation of specific
tyrosine, serine, or threonine residues on target proteins 
initiation of downstream signaling cascades
o Function
 Cell growth
 Differentiation
 Metabolism
 Survival
o Drug Targeting
 Many anticancer drugs target kinase receptors, especially
overactive or mutated in cancer cells
o Examples
 Epidermal Growth Factor Receptor (EGFR)
 Insulin receptor

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 Vascular Endothelial Growth Factor Receptor (VEGFR)
 Intracellular Receptors (Nuclear Receptors)
o Structure
 Inside cell, in cytoplasm or nucleus
 Distinct domains for ligand binding, DNA binding, and
transactivation
o Mechanism
 Intracellular receptors bind to lipophilic molecules (e.g.,
steroid hormones), diffuse through cell membrane 
receptors dimerize and translocate to nucleus  act as
transcription factors to regulate gene expression
o Function
 Regulate gene expression
 Affect processes like metabolism, inflammation, and cellular
differentiation
o Drug Targeting
 Often used as targets in hormone-related diseases
 Estrogen receptor modulators in breast cancer
 Glucocorticoids for anti-inflammatory effects
o Examples
 Estrogen receptor
 Androgen receptor
 Glucocorticoid receptor
 Transporters
o Structure
 Membrane proteins
 Multiple transmembrane
 Form a channel or series of binding sites
o Mechanism
 Transporters move ions, small molecules, or macromolecules
across cell membranes, often against concentration gradients
 Movement can be passive or active
o Drug Targeting
 Drugs targeting transporters can either inhibit or enhance
transport functions
 SSRI block reuptake of serotonin
o Examples
 Sodium-glucose cotransporter (SGLT)
 Serotonin transporter (SERT)
 Dopamine transporter (DAT)
 Ion Channels
o Structure
 Membrane-bound proteins  form pores across cell
membranes  allows for ion passage
o Mechanism
 Can be voltage-, ligand-, or mechanically gated
o Function
 Regulate flow of ions across cell membrane
 Crucial for electrical signaling in neurons, muscle contraction,
and cellular homeostasis
o Drug Targeting
 Used in treating conditions like epilepsy, arrythmias, and pain
 Modulate channel activity by blocking or enhancing ion flow


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o Examples
 Sodium channels
 Calcium channels
 GABA receptors

Understand the concept of binding and can apply the terms occupancy, affinity,
Kd,
agonism, antagonism, and competitive vs. non-competitive in the context of
binding.
 Binding Basics
o Binding
 Interaction between ligand and target
 Results in biological effect
 Key Term in Binding
o Occupancy
 Proportion of target receptors that are occupied by a ligand at
any given time
 Higher occupancy  stronger biological response
 Effects plateaus one most receptors are occupied!
o Affinity
 Measure of how strongly a ligand binds to its receptor
 High-affinity ligands bind more tightly and are more likely to
remain bound than low-affinity ligands
 Inversely related to dissociation constant (Kd)
o Dissociation Constant (Kd)
 Concentration of a ligand at which half of the available
receptors are occupied
 Lower Kd  higher affinity less ligand needed to occupy
50% of the receptors
 Kd is a fundamental parameter, reflecting the equilibrium
between bound and unbound ligand at the receptor
 Types of Ligand: Agonism an Antagonism
o Agonist
 Ligand binds to receptor  activation  biological response
 Full agonist: produce maximum response possible
 Partial agonist: produce lower response, even when all
receptors are occupied
o Antagonist
 Ligand binds to receptor  no activation  blocking or
dampening action of agonist
 Important in preventing or reducing unwanted biological
responses
 Competitive vs. Non-Competitive Binding
o Competitive Antagonism
 Competitive antagonist binds to the same site on the receptor
as the agonist  direct competition
 Enough agonist present  can overcome antagonist’s effect
 Increases apparent Kd for the agonist, BUT maximum possible
response can still be achieved, if enough agonist is present
o Non-Competitive Antagonism
 Non-competitive antagonists bind to different site than
agonist (allosteric site)  change receptor’s shape or function
 prevents agonist from fully activating receptor


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 Adding more agonist cannot overcome non-competitive
antagonism!
 Reduced maximal response

Understand the concept of response and can apply the terms agonist, partial
agonist,
antagonist, inverse agonist, efficacy, potency, EC50, Emax, specificity,
selectivity, and dose response relationships (including therapeutic index).
 Concept of Response
o Response
 Biological effect produced when a drug binds to its target
 Response can vary in intensity
 Types of Drugs Based on Response
o Agonist
 Binding to receptor  activation  biological response
 Full agonist can produce maximum response possible
o Partial Agonist
 Binding to receptor  activation  weaker response
 Lowers overall response
 Can act as competitive inhibitors when combined with full
agonist
o Antagonist
 Binding to receptor  no activation  blocking of receptor
 No intrinsic activity, but crucial in reducing or preventing
undesired effects caused by agonists
o Inverse Agonist
 Binds to same receptor as agonist  production of opposite
effect  decreased receptor’s activity below baseline level
 Response Characteristics
o Efficacy (Intrinsic Activity)
 Describes a drug’s ability to produce maximal biological
response
 Agonist: high efficacy
 Antagonist: zero efficacy
 Partial agonist: moderate efficacy
o Potency
 Amount of drug needed to produce a specific effect
 Higher potency  response at lower dose  low EC50
o EC50
 Concentration (dose) that produced 50% of maximal effect
 Lower EC50  higher potency
o Emax
 Maximum effect than can be achieved with a drug, regardless
of dose
 Efficacy is tied to Emax: higher Emax  stronger responses at
saturation
 Specificity & Selectivity
o Specificity
 Drug’s ability to bind only to a specific target  fewer off-
target effects
 Highly specific drugs target a single receptor or protein
o Selectivity
 Drug’s preference for one receptor or target over others, even
if it can bind to multiple receptors at different affinities

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