CHAPTER 3 – PHARMACODYNAMICS
PHARMACODYNAMIC CONCEPTS
Pharmacodynamics – study of biochemical, cellular, and physiological
effect of drugs and mechanisms of action
Drug receptor or drug target – complex with which the drug interacts
- Often on the surface of the cell
Acceptors – do not cause any change in response but alter
pharmacokinetics of a drug’s actions (e.g. albumin)
Therapeutic biologics – genetically engineered enzymes and
monoclonal antibodies
Gene therapy products – uses viruses as vectors to replace genetic
mutations
PHYSIOLOGIC RECEPTORS
Physiological receptors – drug receptors that serve as receptors for
endogenous regulatory ligands
Agonists – Drugs that bind physiologic receptors and mimic regulatory
effects
- Primary agonist – binds to the same recognition site as
endogenous agonist
- Allosteric (allotopic) agonist – bind to a different region on
a receptor
Antagonists – drugs that block or reduce action of agonist
- Syntopic interaction – from competition for same
overlapping site
- Allosteric antagonism – occur by interacting with other sites
- Functional antagonism – inhibiting effect of agonist
Partial agonist – only partially effective as agonist
Inverse agonist – stabilize receptors with constitutive activity into
inactive conformation
Partial agonist + Inverse agonist – behave as antagonist in the
presence of full agonist
SPECIFICITY OF DRUG RESPONSES
Dissociation constant – affinity of drug to its receptor; measurement
of strength of reversible interaction
Chemical structure – determines affinity of drug for its receptor and
its intrinsic activity
- Also contributes to drug specificity
Drugs w broad specificity
- Enhances clinical utility
- Contribute to adverse side effects
Amiodarone – one drug that interacts w/ multiple receptors
- For cardiac arrythmias
- Similar structure to thyroid hormone
Sotalol – prescribes as racemic mixture
- D- and L- enantiomers are equipotent as K channel blockers
- L-enantiomer – more powerful potent B-adrenergic
antagonist
Multiple mechanisms of action depend on:
- Receptor specificity
- Tissue-specific expression of receptors
1
- Drug access
- Drug concentrations in different tissues
- Pharmacogenetics
- Interactions w/ other drugs
Downregulation or desensitization – caused by chronic administration
of drug
- Chronic use of nitrovasodilators for angina results in
complete tolerance, a process nown as tachyphylaxis
Drug resistance may also develop because of:
- Pharmacokinetic mechanisms (metabolized rapidly)
- Mechanisms that prevent drug from reaching receptor
- Cancer cells w/ drug-resistant mutations
Some effects do not occur by receptor:
- Aluminum and magnesium hydroxide – reduce gastric acid
chemically
- Mannitol – acts osmotically
- Antibiotics, antivirals, antiparasitics – targets receptors or
cell processes critical for infective agent only
Resistance to antibiotics/antivirals can occur by:
- Mutation of target receptor
- ↑ expression of enzymes that degrade or ↑ efflux of drug
- Development of alternative biochemical pathways
STRUCTURE-ACTIVITY RELATIONSHIPS AND DRUG DESIGN
Orphan receptor – ligands are unknown
Chemical structure – determines affinity and intrinsic activity of a drug
- Minor modification to molecule may result to major
changes
- Therapeutically useful antagonists – developed by chemical
modification of physiological agonist
Pharmacophore – use computer analysis to identify chemical
properties for optimal action at the receptor
QUANTITATIVE ASPECTS OF DRUG INTERACTIONS WITH RECEPTORS
Receptor occupancy theory – drug’s response emanates from
receptor occupied by the drug
- Basis is the law of mass action
Dose-response curve – observed effect of a drug as a function of its
concentration in the receptor compartment
Hormesis – drugs that cause low-dose stimulation and high-dose
inhibition
- U-shaped relationships (the figure on the left; A)
Affinity, Efficacy, and Potency
Drug-receptor reaction is characterized by:
1. Binding of drug to receptor
2. Generation of a response
L – ligand
R – receptor
LR reaction – governed by chemical property of affinity
LR* - produced in proportion of LR and leads to a response
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CHAPTER 3 – PHARMACODYNAMICS
- Illustrates reliance of affinity of L with R on forward
association rate and reverse/dissociation rate
Potency – when two drugs produce equivalent responses, the drug
whose dose-response curve lies to the left is more potent
Efficacy – capacity of drug to activate receptor and generate response
- Full agonist – high efficacy
- Partial agonist – low intrinsic efficacy
- Antagonist – exhibits zero efficacy
- Drug X is more efficacious than drug Y
Quantifying Agonism
Describe agonist response by determining half-maximally effective
concentration (EC50)
Can also compare maximal asymptotes in a system
- Advantage: property depends solely on efficacy
Drug potency – mixed function of affinity and efficacy
Quantifying Antagonism
2
Competitive antagonism – drug with affinity for a receptor but lacking
intrinsic efficacy competes for agonist for primary binding site
- Characteristic pattern – concentration-dependent
production of a parallel shift to the right of agonist dose-
response curve with no change in maximal response
o Magnitude of rightward shift depends on
concentration of antagonist and its affinity
- Will reduce response to zero
Partial agonist – can compete with full agonist
- Increasing concentrations of partial agonist will inhibit
response to a finite level
- Used therapeutically to buffer response
- Vareniciline – partial agonist used in smoking cessation
therapy
o Blocks effect of high dose nicotine
Noncompetitive antagonism – an antagonist that dissociates very
slowly so that action is prolonged
- Maximal response of agonist will be depressed at some
antagonist concentration
- Irreversible antagonist – competes for the same binding site
o Same pattern as noncompetitive antagonism
Allosteric or allotopic antagonist – also produces noncompetitive
antagonism
- Binds to a site distinct from primary agonist, changing the
affinity of the receptor for agonist
Allosteric agonist or coagonist – drug binding at allosteric site that
potentiates effect of primary agonist
Affinity of competitive antagonist (K1) – determined in radioligand
binding assay or by measuring functional response of a system to a
drug
- As more antagonist is added, higher concentration of
agonist is needed to produce equivalent response
- Extent of rightward shift – measure of affinity of inhibitor
Additivity and Synergism: Isobolograms
Drugs with different mechanisms of actions used in combination may
be used to achieve additive and possitve synergistic effects
- Permits use of reduced concentrations
Positive synergism – superadditive effects of drugs used in
combination
Negative synergism or subadditive effects – efficacy is less
Isobologram – line connection EC50 of 2 drugs (Figure in the next
page)
- Describes concentrations that will achieve half-maximal
response when A and B are used in combination
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CHAPTER 3 – PHARMACODYNAMICS
If A and B are superadditive:
- concentrations of A and B needed needed to achieve
response will fall below additive response line
If A and B are subadditive:
- concentrations will lie above additive response line
PHARMACODYNAMIC VARIABILITY: INDIVIDUAL AND POPULATION
PHARMACODYNAMICS
Drug responsiveness may change because of:
- disease
- age
- previous drug administration
Correlation of drug levels with efficacy and toxicity must be
interpreted in the context of pharmacodynamic variability in
population
- analyzed by quantal concentration-effect curve
Median effective dose (ED50) – dose of a drug required to produce a
specified effect in 50% of population
Median lethal does (LD50) – determined in experimental animals
LD50/ED50 ratio – indication of therapeutic index
- reflects how selective drug is producing its desired effects
Therapeutic window – range of steady-state concentrations of drug
that provides therapeutic efficacy with minimal toxicity
Clinical therapeutic index - concentration of drug required to produce
toxic effects compared with concentration required for therapeutic
effects
Population therapeutic window – concentrations at which the
likelihood of efficacy is high and probability of adverse effects is low
- complemented by monitoring appropriate clinical and
surrogate markers for drug effect(s)
Drug Interactions and Combination Therapy
Drug interactions may be:
- pharmacokinetic – delivery of drug to site of action is
altered
- Pharmacodynamic – response of the drug target is modified
by second drug
Combination therapy – optimal treatment of many conditions
- Some combinations cause adverse effects:
o Nitrovasodilators – vasodilation via NO-
dependent elevation of cGMP
3
o Sildenafil, tadalfil, vardenafil – result from
inhibition of PDE5 that hydrolyzes CGMP to 5GMP
o Coadministration – severe hypotension
Warfarin – narrow margin between inhibition of clot formation and
bleeding complication
- Alterations in dietary vitamin K may affect
pharmacodynamics
o Antibiotics that alter intestinal flora  ↓ Vit K 
increased effect of warfarin
- NSAIDS - ↑ risk of GI bleeding
- Aspirin – increases incidence of bleeding
MECHANISM OF DRUG ACTION
RECEPTORS THAT AFFECT CONCENTRATIONS OF ENDOGENOUS
LIGANDS
a-methyltyrosine, cocaine, emphetamine, selegiline – acts on
adrenergic neurotransmission
Vasoactive peptides, lipid-derived autocoids – affects synthesis and
degradation of circulating mediators
DRUG RECEPTORS ASSOCIATED WITH EXTRACELLULAR PROCESSES
Many widely used drugs target enzymes and molecules that control
extracellular processes:
- Thrombosis, inflammation, immune response
- Coagulation system
RECEPTORS UTILIZED BY ANTI-INFECTIVE AGENTS
Anti-infective agents target receptors that are microbial proteins
- Key enzymes required by infectious agent but not critical for
the host
Novel approach – genetically engineer vector organism to be resistant
to infection (such as CRISPR-Cas9 System)
RECEPTORS THAT REGULATE IONIC MILLIEU
Receptors are ion pumps expressed only in specialized cells
Most diuretics – directly affects ion pumps and transporters
Esomeprazole – H-K ATPAse pump inhibitor in gastric parietal cell
- Reduces gastric secretion by 80-95%
INTRACELLULAR PATHWAYS ACTIVATED BY PHYSIOLOGICAL
RECEPTORS
Signal Transduction Pathways
Largest number of drug receptors are physiological receptors that
transduce signals; two major functions:
- Ligand binding
- Message propagation
Two functional domains within receptor:
- Ligand binding domain (LBD)
- Effector domain
Regulatory actions of receptors may be exerted on:
- Cell target
- Effector protein
- Transducers – intermediary cell signaling molecules
Second messenger – cellular effector protein that is not the ultimate
physiologic target
- Convey information and integrate multiple signals
Compartmentation – constrained diffusion and intracellular actions
- Selective localization of complexes
Scaffolds or anchoring proteins – proteins designed to localize
signaling pathways
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CHAPTER 3 – PHARMACODYNAMICS
STRUCTURAL AND FUNCTIONAL FAMILIES OF PHYSIOLOGICAL
RECEPTORS
Receptors for physiological regulatory molecules – assigned to
functional families that share common mechanisms
G Protein-Coupled Receptors
GPCR – seven a-helices
- Important regulators of nerve activity in CNS
- Receptors for NTs in the peripheral autonomic NS
GPCR subtypes
A1, a2, B adrenergic receptors differ in:
- Ligand selectivity
- Coupling to G proteins
Terbutaline – B2 adrenergic receptor agonist
- Bronchodilator in the treatment of asthma
Use of B1-selective antagonist – minimizes bronchoconstriction in
patients treated for hypertension or angina
Receptor dimerization
GPCRS undergo both homo and heterodimerization
- Dimerization – regulatesL
o affinity and specificity of G proteins
o sensitivity of receptors to phosphorylation
o binding of arrestin
G Proteins
G proteins – signal transducers; heterotrimer consisting of:
- a subunit – confers specific recognition
4
- B and Y subunit – confer membrane localization by
prenylation of Y subunit
In the basal state – α subunit is bound to GDP
a subunit has 4 families
- Gas – activates AC
- Gai – inhibits AC
- Gaq – activates all forms of PLCβ
- G12/13 – couple to GEFS (p115RhoGEF for small GTP-
binding proteins Rho and Rac)
K and Ca channels, P13K – some of the effectors of free By dimer
Endocytosis of GPCRS in cAMP signaling  prolong signaling and lend
“spatial coding” to distal signaling
Second-Messenger Systems
Cyclic amp – synthesized by AC; mediated by Gas and inhibited by Gia
AC has three major targets in most cells: PKA, GEFS termed EPACS,
and CREB
- CNG, HCN, cyclic nucleotide regulated PDEs – targets in cells
w/ specialized function
PKA – two catalytic (C) subunits reversibly bound to regulatory (R) to
form R2C2
- 4 cAMP bind to R2C2  2 per R subunit  R has lower
affinity for C  Active C subunits – phosphorylate serine
and threonine residues
- Isoforms
o a and B isoforms of regulatory subunit
o 3 C subunit isoforms – Ca, CB, and CY
- Modulated by localization mediated by AKAPs
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Na+ channels
PKG – cGMP-dependent Three subunits:
- Phosphorylates same substrates as PKA 1. α subunit – pore-forming; has 4 domains that form ion-
- Catalytic domain + nucleotide binding domain – dimerizes selective pore
to form PKG holoenzyme o domains have 6 membrane spanning helices
- Exists in two homologous forms: PKG-I and PKG-II o Extracellular loop between S5 and S6 termed
PKG-I PKG-II pore-forming loop or P loop
Acetylated N-terminus Myristylated N-terminus o S4 helix – form voltage sensor
Cytoplasm Membrane-associated; 2. 2 B subunits – regulatory
localized by PKG anchoring o Span the membrane once
proteins - Lidocaine and tetracaine – blocks Na pore, inhibits
Two isoforms (Ia and IB) depolarization, and blocks sensation of pain
- Tetrodotoxin and saxitoxin – naturally occurring marine
PDEs – regulated via rate of gene transcription, 2nd messengers, and toxins that block Na channels
interactions w/ B arrestins and PKs Ca channels – commonly responsible for modifying shape and
- Hydrolyze bond in cAMP and cGMP terminating their action duration of action potential initiated by Na channel
- PDEs (mainly PDE3) are drug targets - Similar architecture to voltage-gated Na channels
- PDE5 inhibitors (sildenafil) – treats COPD and erectile o Large a subunit
dysfunction o Three regulatory subunits (B, σ, y)
- L-type – subject to phosphorylation by PKA
EPACs aka cAMP-GEF – cAMP-regulated GEFS for the family of small - Ca channels in smooth muscle regulate vascular tone
Ras GTPAses - Nifedipine, diltiazem, verapamil – effective vasodilators
- Catalyzes exchange of GTP for GDP activating small GTPases K channels – most numerous and structurally diverse
- Contain regulatory cAMP-binding domain, catalytic domain, - Includes: voltage-gated, inwardly rectifying, and tandeom
and domains for intracellular localization or two-pore domain “leak” K channels
- EPAC1 – additional N-terminal low affinity cAMP-binding - Inwardly rectifying and two-pore – voltage insensitive,
domain regulated by G proteins and H ions
- EPAC2 – promotes incretin-stimulated insulin secretion o Stimulated by general anesthetics  drives
from pancreatic B cells through Rap1 membrane potential more negative
o Sulfonylureas act thru EPAC2 to increase insulin
Ligand-gated Channels
Gq-PLC-DAG/IP3-Ca Pathway Major ligand-gated channels in the NS are those that respond to:
- Hormones and growth factors release Ca from ER via - Excitatory NT: Ach or glutamate
activation of PLC - Inhibitory NT: Glycine of GABA
- 2 primary PLCs: PLCB and PLCy - Activation of channel is responsible for synaptic
- Gq or G1 activate PLCB by activating Ga subunit transmission
o Both a and By can activate PLCB Variety of channels are structurally distinct from conventional
- Tyrosine phosphorylation activates PLCy isoforms channels:
- Action: Hydrolyze phosphatidylinositol-4,5-bisphosphate - HCN – in the heart; responsible for slow depolarization seen
 IP3 and DAG in phase 4
o DAG – activates PKC - CNG – important for vision
o IP3 – release Ca from ER - IP3-sensitive Ca channel
 Raises Ca and activates Ca-dependent - Sulfonylurea receptor (SUR1) – regulate the KATP in B
enzymes (PKCs and Ca/calmodulin pancreatic cells
sensitive enzymes) o Target of oral hypoglycemic drugs (sulfonylureas
and meglitinides)
Ion Channels Nicotinic Ach – pentameric channel
All cells express ion transporters for Na, K, Ca, and Cl - 4 subunits (2a, B, σ, y) in the neuromuscular junction
Channels are divided based on: - 2 subunits (2a, 3B) in autonomic ganglia
- Mechanisms that open channels - Each a subunit has identical Ach binding site
- Architecture - Rocuronium – inhibits NMJ Nicotinic ACh channel only
- Ions they conduct - Each subunit contains:
Classified as: o Large, extracellular N-terminal domain
- Voltage-activated o 4 membrane-spanning helices
- Ligand-activated  Internal loop b/n 3 and 4 – forms
- Store-activated intracellular domain
- Stretch-activated - Do not possess exquisite ion selectivity – allows passage of
- Temperature-activated both Na and K ions

Voltage-gated Channels Transient Receptor Potential Channels

Responsible for generation of action potentials that depolarize TRP cation channels are involved in sensory processes:
membrane from -70mV to +20mV - Nociception
- Heat and cold sensation

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CHAPTER 3 – PHARMACODYNAMICS
- Mechanosensation
- Sensation of chemicals (capsaicin and methol)
Typical TRP structure:
- Monomers – six transmembrane helices
- Pore forming b/n S5 and S6
Most functional TRPS are homotetramers
Genetic mutation in TRP – inherited pain syndrome
Transmembrane Receptors Linked to Intracellular Enzymes
Receptor Tyrosine Kinases
Except insulin receptor (w/ a and B chains) – consists of:
- Single polypeptide chain w/ cysteine-rich extracellular
domains
- Short transmembrane domains
- Intracellular region – w/ 1 or 2 protein tyrosine kinase
domains
Inactive state – monomeric
Binding of ligand induces dimerization and cross-phosphorylation
- Forms docking sites for SH2 domains
Molecules recruited by SH2 domains include:
- PLCy – raises Ca and activates PKC
- P13K - ↑ PIP3 and PKB (or Akt)
o PKB – regulates mTOR and Bad protein important
in apoptosis
Phosphotyrosine-presenting proteins can interact w/ S2 domain-
containing adaptor proteins to attract GEFS such as:
- Sos – activates Ras  activation of Ras-MAPK pathway 
one of major routes to stimulate cell growth
- Ras and Rho
All small GTPases are:
- Activated by GEFS
- Inhibited by GAPS
Jak-STAT Receptor Pathway
For cytokines (y-interferon) and hormones (GH and prolactin)
Receptors have no intrinsic enzymatic activity
- Intracellular domain binds tyrosine kinase Jak
- On dimerization Jak phosphorylates STATS  regulates
transcription
Receptor Serine-Threonine Kinases
Two isoforms:
- Type I (seven forms)
- Type II (five forms)
Basal state – exist as monomers
- Dimerize upon binding of ligand  leads to
phosphorylation of type I monomer  phosphorylates
Smad
- Smad dissociates from receptor  migrates to nucleus 
regulates genes
Smad 6 and 7 – inhibitory Smad that terminates signaling
Toll-like Receptors
Single-membrane spanning receptors containing:
- Extracellular LBD
- Short-membrane spanning domain
- TIR domain (cytoplasmic region) – lacks intrinsic enzymatic
activity
Highly expressed in hematopoietic cells
- Ligands: pathogen products
- Activation causes produces inflammatory response
Steps in activation:
6
- Dimerization  form signaling complex  recruits adaptor
proteins, Mal and MyD88  recruits IRAKs
- IRAKS autophosphorylates  forms a more stable complex
w/ MyD88 + recruits TRAF6  facilitates ubiquitin ligase
w/c attaches polyubiquitin to TRAF6
- TRAF6 Complex interacts w/ TAK1 and TAB1  TAK1
activates NF-KB  activation of inflammatory genes
TNF-a receptors
TNF-a – similar to that used by TLRS; no enzymatic activity
Membrane monospan protein w:
- Extracellular LBD
- Transmembrane domain
- Death domain – cytoplasmic domain
TNF-a binds to TNF1 and TNF 2 receptor
- Upon trimerization death domains bind TRADD  recruits
RIP1  RIP1 is polyubiquinated  recruits TAK1 kinase and
IKK complex
- IKK is phosphorylated  release of IkBa  allows p50/p65
heterodimer to translocate to nucleus  activates
inflammatory genes
Infliximab and adalimumab – inhibits TNF-a for treatment of
rheumatoid arthritis and Crohn’s disease
Receptors that Stimulate Synthesis of cGMP
Natriuretic Peptide Receptors: Ligand-Activated Guanylyl Cyclase
Has intrinsic enzymatic activity
ANP – from atrial storage following expansion of intravascular volume
or stimulation w/ pressor hormones
BNP – response to volume overload
CNP – in brain and endothelial cells
- increased by growth factors and sheer stress on vascular
ECs
Major effects:
- Decrease blood pressure (ANP, BNP)
- Reduce cardiac hypertrophy and fibrosis (BNP)
- Stimulate long-bone growth (CNP)
Receptors are ligand-activated guanylyl cyclases
- NPR-A – responds to ANP and BNP
o NPR-A knockout: hypertension and hypertrophic
hearts
- NPR-B – responds to CNP
o NPR-B knockout: dwarfism
o Has no enzymatic activity but functions as
clearance receptor
Nesiritide (BNP agonist) and sacubitril (neprilysin inhibitor; blocks
BNP and ANP breakdown) – treatment of acute decompensated heart
failure
NO Synthase and Soluble Guanylyl Cyclase
NO
- produced locally by NOS
- three forms:
o nNOS (or NOS1) – activated by elevated Ca, acting
via calmodulin
o eNOS (NOS3) – same as above
o iNOS (NOS2) – induced by inflammatory stimuli
Nitric oxide synthase
- oxidation of guanido nitrogen of L-arginine  L-citrulline
and NO
NO activates sGC  Produces increase in Vmax of guanylyl cyclase 
elevation of cGMP
- effects of GMP are mediated by PKG
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PKG activation leads to:
- inhibiting IP3
- phosphorylating voltage-gated Ca channels – inhibit Ca
influx
- Phosphorylating phospholamban – rapid reuptake of Ca in
intracellular stores
- Phosphorylating and opening Ca-activated K channels –
leads to hyperpolarization  closes L-tpe Ca channels
Nuclear Hormone Receptors and Transcription Factors
Nuclear hormone receptors have 4 domains:
- N-terminal domain – activation region (AF-1) for
transcriptional regulation
o Subject to regulation by phosphorylation
- DNA-binding domain – two zinc fingers
- Hinge region – C-terminal for binding hormone or ligand
and for binding coactivators and corepressors (AF-2)
o LBD – bundle of 12 helices
o Ligand binding  change in helices that affect
binding of coregulatory proteins
Most nuclear hormone receptors act as dimers
- Steroid hormone receptors – commonly homodimers
- For lipids – commonly heterodimers w/ RXR
Dimers bind to repetitive DNA sequences either direct repeat or
inverted repeats termed HREs
- HREs – found upstream of regulated genes or within
Important property of receptors:
- Must bind ligand, appropriate HRE, and coregulator
Coactivator – histone acetylase
Corepressor – histone deacetylase
APOPTOSIS AND AUTOPHAGY PATHWAYS
Apoptosis – cells genetically programmed for death
Autophagy – intracellular degradation; can also lead to programmed
cell death
Apoptosis
Highly regulated program w/c leads to:
- Cell rounding
- Shrinking of cytoplasm
- Condensation of nucleus
- Presentation of phosphatidylserine on the outer surface
o Recognized as a sign of apoptosis by macrophage
Two major signaling pathways:
- External signals – by ligands such as TNF-a, Fas (Apo-1), or
TRAIL
o Receptors for Fas and TRAIL – no enzymatic
activity
- Internal pathway – DNA damage, improperly folded
proteins, withdrawal of cell survival factors
Caspases – cysteine proteases that carry out apoptosis
- Activated by apoptotic signals
External apoptosis:
- On binding, receptors form dimer  recruit adapter
proteins  recruit RIP1 and caspase 8  activates caspase
8 w/c activates caspase 3  apoptotic program  final
steps are carried out by caspase 6 and 7
Internal apoptosis:
- DNA damage – lead to ↑p53 gene and damage to
mitochondria by proapoptotic members
- Bax, Bak, Bad (proapoptotic) – induce damage at
mitochondrial membrane
- Bcl-2, Bcl-X, Bcl-W (antiapoptotic) – negative regulators
7
- When DNA damage occurs, p53 holds the cell at cycle
checkpoint until damage is repaired
o Apoptosis is initiated if damage cannot be
repaired
o Activation of Bax  release of cytochrome c and
SMAC
o SMAC inactivates inhibitor of apoptosis proteins
(IAPs)
o Cyt C combines w/ Apaf-1 and caspase 9 
activation of caspase 9  activation of caspase 3
 activates same pathway as external pathway
Autophagy
Autophagosome – double-membraned vesicles where cell contents
are sequestered
- Delivered to lysosomes to be degraded by lysosomal
proteases
Function – removes cell contents that are damaged and provides cells
with substrates under conditions of stress and starvation
- Protective role in neurodegenerative diseases
- Tumor suppression
o Decrease autophagic capacity – poor prognosis in
brain tumors
- In breast, ovarian, and prostate cancers it functions as a
tumor promoter
Controlled by autophagy-related genes (ATGs or AuTophaGy genes)
- Autophagy integrate signaling output via P13-PKB-mTOR
pathway
- mTORC1 – inhibits autophagy
- BCl2 + Beclin-1 – inhibits autophagy
o Phosphorylation of Beclin-1 by JNK1 promotes
dissociation w/c promotes autophagy
o Ubiquination of Beclin-1 initiates autophagy
o degradation of Beclin-1 by proteasome
downregulates autophagy
- P53 – inhibitory interactions w/ ATG on lysosomal
membranes, DRAM
RECEPTOR DESENSITIZATION AND REGULATION OF RECEPTORS
Desensitization – from continued stimulation from agonists (aka
adaptation, refractoriness, or downregulation)
- Tachyphylaxis – exposure to same concentration of drug is
diminished
Can result from temporary inaccessibility of receptor or from fewer
receptors being synthesized
Phosphorylation of GPCRs by GRKS – triggers rapid desensitization
- Because it facilitates binding of arrestins to receptor -_>
results inuncopuling of G protein from receptor
- B arrestins recruit PDE4, clathrin, and B2 adaptin
o PDE4 – limit cAMP signaling
o Clathrin and B2 adaptin – promote sequestration
of receptor (internalization)
Supersensitivity – follows chronic reduction of receptor stimulation
- Noticeable following withdrawal from prolonged receptor
blockade
DISEASES RESULTING FROM RECEPTOR AND PATHWAY
DYSFUNCTION
Loss of receptor – cause phenotypic disorder
- Myasthenia gravis – disruption of nicotinic Ach function
- Insulin-resistant DM – depletion of insulin and interference
w/ insulin receptor function
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Supersensitivity, subsensitivity, or other untoward responses – - Ca channel blocker – block Ca entry into SMCs
caused by constitutively active, aberrant, or ectopic receptors, - B1 adrenergic receptor antagonist – block baroreceptor
effectors, and coupling proteins reflex elicited by drop in blood pressure induced by therapy
- Many forms of cancer have constitutive activity in the Ras-
MAPK pathway
Polymorphisms in B adrenergic receptor  African Americans do not
respond well to B blockade therapy for heart failure
GRK5 gain-of-function polymorphism – common in African Americans
 increases ability of GRK5 to desensitize B1 receptors  increases
survival in patients w/ heart failure not receiving blocker therapy

PHARMACOTHERPIES THAT MODIFY SPECIFIC GENES AND THEIR

TRANSCRIPTION AND TRANSLATION
11% genetic mutations – nonsense mutations that introduce
premature stop codon
- Ataluren – first drug approved for treatment of nmDMD
o Act on ribosome to override premature stop
codon  allows ribosome to “read through”
o Improves synthesis of dystrophin
ASOS – complementary to mRNA “sense” strand of disease-causing
gene
- Binds to mRNA preventing its translation
- Fomivirsen – for CMV retinitis
- Mipomersen – homozygous familial hypercholesterolemia
siRNA
- RNAi – for small RNA_guided suppression of gene
expression that uses RISC
- Antisense strand of siRNA guides RISC to destroy target
mRNA
CRSIPR/Cas9 genom-editing system – uses viruses or genetically
modified micoorganisms
- Allows editing of genome using sgRNAS that target Cas9
dsDNA nuclease to sites that contain adjacent NGG PAM
sequence
- Allows targeted replacement and modification of disease-
causing gene

PHYSIOLOGICAL SYSTEMS INTEGRATE MULTIPLE SIGNALS

ANG II – both acute and chronic effect on SMCs
- ANGII w/ AT1r – mobilizes stored Ca via Gaq
o Ca activates Calmodulin and MLCK
o MLCK  phosphorylation of myosin  SMC
contraction
Activation of Sympathetic NS  release of NE  binds a1 adrenergic
receptors  Activates Gaq  SMC contraction
- Effect additive to Ang II
Contraction is opposed y mediators that promote relaxation
- NO is formed by eNOS when Gaq pathway is activated and
by iNOS when induced
- NO activates sGC  cGMP  activation of PKG  reduce
Ca  promote relaxation
- cGMP are also increased by activation of BNP receptors
Consequence of variety of pathways – patient w/ hypertension may
be treated by several drugs
- B1 adrenergic receptor antagonist – reduce secretion of
renin
- Aliskiren – renin inhibitor
- ACE inhibitors – reduce Ang II
o Also inhibit degradation of bradykinin
(vasodilating peptide)
- AT1R blockers (losartan) – block AngII binding to AT1Rs
- A1 adrenergic blockers – block NE binding to SMC
- Sodium nitroprusside – increase NO produced

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