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OUR LADY OF FATIMA UNIVERSITY Learning Outcomes

COLLEGE OF PHARMACY At the end of the session the
Valenzuela. Quezon City. Antipolo. Pampanga. Cabanatuan. Laguna students will be able to:

◉ Define receptor concepts

REVIEW OF ◉ Discuss drug receptor, its
PHARMACODYNAMICS interactions, signaling mechanism and
drug action
PHARMACOLOGY1
◉ Describe dose-response relationships

◉ Explain regulation of receptors

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OUTLINE: READINGS:
Part 1
Mechanisms of Drug action
•

Part 2 • Katzung, B.G. et al. Basic and

Dose and Response Relationship
• Clinical Pharmacology, 14th
Part 3 edition
Concepts of Agonism, Antagonism,
•
• Wecker, L. (2018). Brody's
Human Pharmacology, 6th
Allosteric Modulation
Edition. Mechanism-Based
Part 4 Therapeutics
Basic & Clinical Evaluation of New
•

Drugs

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Pharmacodynamics
Watch these Videos: 🗉A branch of pharmacology that
focuses on the study of the
biochemical and physiological
effects of drugs and the
Pharmacodynamics
mechanisms by which they produce
https://www.youtube.com/watch?v=PhfhMBO-w9Q such effects.
Dose Response Relationship
https://www.youtube.com/watch?v=VzrvklX5Wmw

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Mechanisms of Drug Action

A. Non – target protein mediated

mechanism
Part 1 :
B. Target Protein mediated mechanism
Mechanisms
of Drug Action

DRUG + Receptor = Response

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A. Non – target protein mediated

A. Non – target protein mediated mechanism
mechanism
Colligative mechanism
exert effects without binding to proteins.
– osmotic effect
🗉 Mass effect
1. Colligative mechanism

2. Chemical reaction
🗉 Eg. Mannitol

3. Counterfeit incorporation
mechanism

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A. Non – target protein mediated mechanism A. Non – target protein mediated

Chemical reaction mechanism
NEUTRALIZATION
LOCAL Counterfeit incorporation mechanism
SYSTEMIC

CHELATION

OTHERS
CN + Sodium thiosulfate

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1. Structural protein
B. Target protein mediated mechanism constitute “ cytoskeleton”
Microtubule
Target protein
important site of action
--- biologic site of action of drugs
Drugs that inhibit microtubule
synthesis/ spindle protein
a. Structural Proteins
Griseofulvin
b. Regulatory Proteins
Vinca alkaloids
Colchicine
Etoposide

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2.1. Channels/transport
2. Regulatory Proteins Proteins that take part in
❑ mediates the transmission of transmembrane signaling and
endogenous chemical signals such regulates ionic composition
as neurotransmitters, autacoids, and
Voltage-gated Na channel Voltage-gated Ca channel
hormones.
2.1 Transports/Channels
2.2 Enzymes
2.3 Carrier Molecules
2.4 Receptors Na channel blockers Ca++ channel blockers
Local anesthetics, CBZ, Phenytoin L-type blockers (“-dipine”)
T-type blocker - ethosuximide

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2.2. Carrier molecules

Inhibitor 2.3. Enzymes
Na -K ATPase pump
+ + Digoxin protein catalysts INHIBITORS
Xanthine oxidase - allopurinol
Cyclooxygenase - NSAID’s
ACE - ACE inhibitors
H+ -K+ ATPase pump PPI MAO - MAOI
Phenelzine
Isocarbozaxid
Tranylcypromine
Na+ -K+ -2Cl- cotransport Furosemide

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2.3. Enzymes 2.4.Receptors

protein catalysts INHIBITORS
Functional macromoleular components of
Acetylcholinesterase - Edrophonium cells with specific stereochemical
configuration and in which a ligand interacts
COMT -Entacapone, Tolcapone
SPECIFICITY
SELECTIVITY

Ligand
- any chemical that has ability to bind
to a receptor

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Type of Receptors 1. Type I receptor - ionotropic receptor

1. Type I Receptor a receptor protein that forms a part of a

2. Type II Receptor ligand-gated ion channel, so that binding of
ligand to the receptor causes the opening of
3. Type III Receptor channel, permitting ions to flow through it.
4. Type IV Receptor
- Controls movement of ions
- Found in cell membranes
- Stimulated in milliseconds

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Ionotropic receptor 1. Type I receptor - ionotropic receptor

GABA receptors control Cl- ions
stimulated by:
-Benzodiazepines
-Barbiturates

Nicotinic receptors
• control the entry of Na+

• inhibited by neuromuscular blocker

Neurotransmitter
Ions

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2. Type II receptors - G-protein linked

receptor/ metabotropic receptor

GTP-binding signal transducer protein is G-

Protein
G-protein modulates production of an
intracellular second messenger
location: cell membrane
onset: in seconds

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Examples of Type II
Examples of G-proteins: receptors
Gs-stimulates adenylyl cyclase
Gi-inhibits adenylyl cyclase 1. Adrenergic receptors
Gq-increases IP3, DAG (Adrenoceptors)
alpha receptors
Beta receptors
Second messengers
cyclic adenosine monophosphate (cAMP)
2. Muscarinic receptors
cyclic guanosine monophosphate (cGMP)
Inositol triphosphate (IP3)
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3. Type III receptors - tyrosine

kinases-linked receptors ❑ Examples:
These are high-affinity cell surface Imatinib-gastrointestinal stromal
receptors for many polypeptide growth tumors (GIST)
factors, cytokines, and hormones. Gefitinib-epidermal growth factor
location: nucleus receptor
onset: hours Erythropoietin receptor
Receptor for Insulin – utilization of
glucose
Tyrosine kinase- catalyze phosphorylation of
tyrosine residues to modulate a number of
biochemical processes
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glucokinase 4. Type IV receptor - gene

transcription-linked receptors
glucose ===== glucose-6- phosphate
-location: nucleus/cytosol (cytoplasm)
-onset: hours

Central dogma
-replication (DNA copied into complimentary DNA)
-transcription (DNA template is copied to RNA)
-translation (RNA synthesize protein)

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Receptor Interactions
2. Lock and Key Theory
Drugs that act on Type IV receptors -the drug molecule must “ fit into a receptor” like a “key fits
into a lock”.
Lock and key mechanism
▪ Corticosteroids
▪ Mineralocorticoids
▪ Sex steroids
▪ Vitamin D Agonist Receptor

▪ Thyroid hormone
▪ Retinoids
Agonist-Receptor
Interaction

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Receptor Interactions
3. Induced-Fit Theory Theories of Drug Receptor Interaction
-as the drug approaches the receptor, it alters the
conformation of its binding site to produce drug-receptor
complex. Occupancy Theory
Induced Fit -drug effect is directly proportional
to the number of receptors occupied.
Ariens and Stephenson Theory
Receptor -occupational theory of response.
Rate Theory
-the activation of receptors is
Perfect directly proportional to the total number of
encounters of the drug with its receptors per
Fit! unit time.

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Types of Receptor Action

/Sensitization

Hyperactivity/
Supersensitivity
Part 2: Dose-
Response
Relationship
Desensitization

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Dose-Response Relationship Dose & Response relationships

❑ a.k.a. “ Exposure-Response Relationship”
❑ describes the change in effect on organism
caused by differing levels of exposure
(dose) to a stressor (chemical) after a
certain exposure time.
a. Graded Dose-Response Curve
b. Quantal Dose-Response Curve
Graded Dose-Response Relations
It is a graph of response versus the
logarithm of the dose yields the efficacy
(Emax) and potency (ED50).
It is the magnitude or the intensity of
the pharmacological response that
increases as the dose administered
increases.

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Graded Dose-Response Relations Graded Dose-Response Relations

It allows comparison for drug
Potency refers to the
efficacies and potencies. concentration(EC50) or dose
(ED50) of a drug required to produce
Efficacy-refers to the ability of the drug 50% of the drug's maximal effect
to elicit a response at the molecular,
cellular, tissue or system level. is a measure of drug activity
-It is measured by its maximum effect. expressed in terms of the amount
-a. k. a. “Intrinsic Activity”. required to produce an effect of
given intensity.

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Which is the most

Graded Dose-Response Relations potent among
these drugs?
Ceiling Dose
is the maximum amount of drug that
can induce biological effect by a
Which is the most
given drug. effective among
these drugs?

Graded dose-response curves for four drugs, illustrating

different pharmacologic potencies and different maximal
efficacies.

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b. Quantal Dose-Response Curve

❑ All-or-none response b. Quantal Dose-Response Curve
❑ Itis a graph of the number of patients that
responds by a specified dose. Therapeutic Index
❑ used to generate information regarding the -is a comparison of the amount of a
margin of safety therapeutic agent that causes drug
toxicity.
-the dose of a drug required to produce a
desired effect to that which produces an
undesired effect
-a.k.a. “Therapeutic Ratio”.
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Median effective dose (ED50)

b. Quantal Dose-Response Curve the dose at which 50% of individuals
exhibit the specified quantal effect.
Therapeutic Index Median toxic dose (TD50)
= TD50 the dose required to produce a particular
ED50 toxic effect in 50% of animals
Median Lethal Dose (LD50)
- the dose that can produce death in 50% of
Why don’t we use a the animals.
drug with a TI <1?

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Variation in Drug Responsiveness

Hyporeactivity- the intensity of
Idiosyncracy effect of a given dose of drug is
- Unusual drug Response diminished
caused by genetic differences in
metabolism of the drug or by
Hyperreactivity- the intensity of
immunologic mechanisms, including
effect of a given dose of drug is
allergic reactions.
increased in comparison to the effect
seen in most individuals.

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Hypersensitivity Reactions
TYPE OTHER NAMES EXAMPLES MEDIATORS
•Atopy
I Allergy (Immediate) IgE
hypersensitivity -refers to allergic •Anaphylaxis
•Asthma

or other immunologic responses to II Cytotoxic, Antibody •Autoimmune Hemolytic

Anemia IgM or IgG
dependent
drugs
•Thrombocytopenia
•Erythroblastosis fetalis

•Serum sickness
III Immune Complex •Systemic Lupus
IgG
Disease Erythematosus (SLE)

•Contact Dermatitis
IV Delayed-Type •Mantoux Test
T-cells
Hypersensitivity •Chronic Transplant
Rejection
•Multiple Sclerosis

•Grave’s Disease
V Autoimmune •Myasthenia Gravis IgM or IgG
52 Disease

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Tolerance Factors Influencing Drug Effects

it refers to a decreased responsiveness
1. WEIGHT – ↓ adipose tissue > toxic
to the drug, a consequence effects
consequence of continued drug
2. AGE
administration
Infants – underdeveloped liver enzyme
Tachyphylaxis system = ↑ toxic effect
- rapidly acting tolerance Chloramphenicol – gray baby syndrome
Responsiveness diminishes rapidly Geriatric patients – deteriorating body
after administration of a drug functions

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Factors Influencing Drug Effects

3. Gender-for IM injection
Male>Female in terms of vascular muscles
- Effects faster in male than female
4. PATHOLOGICAL FACTORS Part 3:
liver disease = ↓ biotransformation of drugs = ↑ Concepts of
toxic effects
5. GENETIC FACTORS Agonism,
ASIANS are fast acetylators Antagonism,
Acetylation (metabolizing INH) = ↓ Allosteric
antitubercular effects
Modulation

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CELL SURFACE
Classification of drugs according RECEPTORS
to receptor interaction
Extracellula Bound Endogenous Activator (Agonist) of
Receptor
r
Compartme
nt Cell
• with affinity • with affinity Membrane Active Cell Surface
• With intrinsic • Without intrinsic
Receptor
activity activity
Intracellular
Compartme Is this
nt AGONIST or
Cellular
ANTAGONIST?
Response

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Types of Agonist
1. Full Agonist
2. Partial Agonist
3. Inverse Agonist

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Antagonist
Receptor Interactions

Types of Antagonism
1. Pharmacologic Antagonism
2. Physiologic Antagonism
Antagonist Receptor
3. Chemical Antagonism

Antagonist-Receptor
DENIED!
Complex
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Types of antagonism Types of antagonism

1. PHARMACOLOGIC ANTAGONIST 1.1 PHARMACODYNAMIC ANTAGONIST
❑inhibits the activity of an agonist by ❑ produce an effect opposite of agonist by

reacting with the receptor or other part binding to the same receptor
of the effectors mechanism ❑ Beta blocker and Beta agonist

(Propranolol) (epinephrine)
agonist
epinephrine
Beta
receptor
Propranolol

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Types of antagonism
2. PHYSIOLOGIC ANTAGONIST
1.2 PHARMACOKINETIC ANTAGONIST
- occurs when the drugs act
independently at different receptor
❑Reduce the effect of one drug by
sites, often yielding opposing actions.
alteration of ADME

e.g. HISTAMINE + EPINEPHRINE

❑Eg. Digoxin
Histamine + Salbutamol
+ Cholestyramine D C
Glucocorticoid + Insulin

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3. CHEMICAL ANTAGONIST Examples

Protamine SO4 + Heparin SO4 → forms
❑ no receptor is involved
a complex devoid of action
❑ occurs when two drugs bind with
each other to form an inactive
Protamine- (+) charged at physiologic pH
compound.
Heparin – (-) charged at physiologic pH
Examples:
Paracetamol + N-Acetylcysteine Chelating agents
Warfarin + Vitamin K Deferoxamine – Iron (Fe)

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Nature of Antagonism COMPETITIVE ANTAGONISM

It depends on whether or not they 🗉 Effects of Antagonist can be
reversibly compete with agonists overcome/reversed by increasing the
for binding to receptors concentration of agonist

NON-COMPETITIVE ANTAGONISM
it is also known as irreversible antagonism
Example: Phenoxybenzamine
DNA-alkylating agents

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Allosteric Modulation Types of Allosteric Modulation

1. Positive Allosteric Modulation occurs

is the regulation of an enzyme or other when the binding of one ligand
protein by binding an effector molecule enhances the attraction between
at the protein’s allosteric site. substrate molecules and other binding
sites.
-a.k.a. “allosteric activation”.
Example:
Hemoglobin + Oxygen
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2. Negative Allosteric Modulation occurs

when the binding of one ligand decreases Negative allosteric modulation
the affinity for substrate at other active
sites. Non-competitive Antagonist
Inhibition
-a.k.a. “allosteric inhibition”.
Example:
Glycine + Strychnine (spinal convulsant)
Agonist Receptor

Note: Strychnine blocks Glycine receptor

which is numerous in the spinal cord
convulsion. 73 DENIED!
‘Inhibited’-Receptor

73 74

Drug Screening
it involves a sequence of
experimentation and characterization of
Part 4 : Basic & drugs.
Clinical Determination of the ff.
Evaluation of 1. pharmacologic profile of the drug
New Drugs Effects on cell function
pharmacologic activity and selectivity of
the new compound in comparison with
reference compounds

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Pharmacologic Profile Tests. Experimental Method or Target

Experimental Method or Target
Organ: Systems- Blood pressure
Species or Tissue: Dog, cat
(anesthetized)
Route of Administration: Parenteral
Measurement: Systolic-diastolic
changes
Organ: Respiratory effects
Species or Tissue: Dog, guinea pig
Route of Administration: Parenteral
Measurement: Effects on respiratory
rate and
amplitude, bronchial tone

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Preclinical Safety & Toxicity Testing Preclinical Safety & Toxicity Testing

effects of multiple doses, which are especially

effects of large single doses up to the lethal important if the drug is intended for prolonged
level use in humans

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Preclinical Safety & Toxicity Testing

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Goals of preclinical studies quantitative estimates are

identifying all potential human determined
toxicities; 1. "no-effect" dose— the maximum
designing tests to further define the dose at which a specified toxic
toxic mechanisms; effect is not seen
and predicting the specific and the
most relevant toxicities to be
monitored in clinical trials

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20–100 healthy
volunteers
2. the minimum lethal dose—the SAFETY
smallest dose that is observed to 100–200
kill any animal EFFICACYpatients
1000–6000
patients

3. the median lethal dose

(LD50)—the dose that kills
approximately 50% of the
animals

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REFERENCES

R E Q U IR E D B O O K : K a tz u n g , B . G ., B a s ic & c lin ic a l p h a rm a c o lo g y , 1 5 th e d , N e w Y o rk : M c g ra w H ill, 2 0 2 1 .

R E F E R E N C E S (B O O K S /O N L IN E W E B S IT E S /J O U R N A L S )

1 . C o lb e rt, B ., E s s e n tia ls o f P h a rm a c o lo g y fo r h e a lth p ro fe s s io n s , 9 th e d A IT B S P u b , 2 0 2 2 .

Thank you!
2 . V is o v s k y , C ., In tro d u c tio n to C lin ic a l P h a rm a c o lo g y , 1 0 th e d , E ls e v ie r, 2 0 2 1 .
3 . N e a l, M e d ic a l P h a rm a c o lo g y a t a G la n c e , 9 th e d itio n 2 0 2 0 .

4 . D a n d a , R . H ., G o o d m a n a n d G ilm a n 's m a n u a l o f p h a rm a c o lo g y a n d th e ra p e u tic s , 2 n d e d , M c G ra w -H ill, 2 0 1 7 .

5 . A rc a n g e lo , V ., P e te rs o n , A ., W ilb u r, V ., & R e in h o ld , J . (2 0 2 1 ). P h a rm a c o th e ra p e u tic s fo r A d v a n c e d P ra c tic e : A P ra c tic a l A p p ro a c h : V o l. 5 th e d itio n . W o lte rs K lu w e r H e a lth .

6 . B re n n e r, G e o rg e m M . P h a rm a c o lo g y 6 th e d . P h ila : S a u n d e rs E ls e v ie r, 2 0 2 2
7 . B ro p h y , G . M . (2 0 1 8 ). N e u ro p h a rm a c o th e ra p y in C ritic a l Illn e s s . N e w B ru n s w ic k , N e w J e rs e y : R u tg e rs U n iv e rs ity P re s s M e d icin e . IS B N 9 7 8 0 8 1 3 5 9 0 3 5 6 .

Any questions?
8 . B ru to n , L .L ., H ila l-D a n d a n R ., & K n o llm a n n B .C . (2 0 2 3 ). G o o d m a n a n d G ilm a n 's T h e p h a rm a c o lo g ic a l B a s is o f T h e ra p e u tic s (1 4 th e d .). M c G ra w H ill E d u c a tio n
9 . C ra ig , M o d e rn P h a rm a c o lo g y w ith C lin ic a l A p p lic a tio n . B a ltim o re : L ip p in c o tt, W illia m s & W ilk in s . L a te s t E d itio n
1 0 . D e re n d o rf, H ., & S c h m id t S . (2 0 2 0 ). R o w la n d a n d T o z e r's C lin ic a l P h a rm a c o k in e tic s a n d P h a rm a c o d y n a m ic s : C o n c e p ts a n d A p p lic a tio n s (5 th E d .) W o lte rs K lu w e r H e a lth
1 1 . E d m u n d s , M . (2 0 2 2 ). In tro d u c tio n to C lin ic a l P h a rm a c o lo g y , 1 0 th E d itio n

1 2 . F o rd , S .M . (2 0 2 1 ). R o a c h 's In tro d u c to ry C lin ic a l P h a rm a c o lo g y (1 2 th e d .). W o lte rs K lu w e r H e a lth

1 3 . G u l, T ., B is c h o ff, R ., & P e rm e n tie r, H . P . (2 0 1 7 ). M e c h a n is m o f a ro m a tic h y d ro x y la tio n o f lid o c a in e a t a P t e le c tro d e u n d e r a c id ic c o n d itio n s . E le c tro c h im ic a A c ta , 2 2 4 , 6 3 6 – 6 4 1 . d o i:

You can find me at: 1 0 .1 0 1 6 /j.e le c ta c ta .2 0 1 6 .1 2 .0

1 4 . G u y , J e ffre y . P h a rm a c o lo g y fo r th e P re -H o s p ita l P ro fe s s io n a l. 2 n d e d U S A E ls e v ie r-M o s b y , 2 0 2 0

username@fatima.edu.ph 1 5 . H e in ric h M a ttle , & M a rc o M u m e n th a le r. (2 0 1 7 ). F u n d a m e n ta ls o f N e u ro lo g y : A n Illu s tra te d G u id e : V o l. 2 n d e d itio n . T h ie m e .

1 6 . H e rtz , D . (2 0 2 0 ). G h re lin : F u n c tio n , M e c h a n is m o f A c tio n a n d R o le in H e a lth a n d D is e a s e . N o v a M e d ic in e a n d H e a lth .

1 7 . J a fa ria n e t a l., (2 0 1 9 ). E ffe c t o f z e ru m b o n e o n s c o p o la m in e -in d u c e d m e m o ry im p a irm e n t a n d a n x ie ty -lik e b e h a v io u rs in ra ts . A lz h e im e r’s a n d D e m e n tia : T ra n s la tio n a l R e s e a rc h a n d C lin ic a l

#RisetotheT
In te rv e n tio n s , 5 , 6 3 7 – 6 4 3 . h ttp s ://d o i.o rg /1 0 .1 0 1 6 /j.trc i.2 0 1 9 .0 9 .0 0 9
1 8 . K a rn in a , R ., A rif, S . K ., H a tta , M ., & B u k h a ri, A . (2 0 2 1 ). M o le c u la r m e c h a n is m s o f lid o c a in e . A n n a ls o f M e d ic in e a n d S u rg e ry , 6 9 , 1 0 2 7 3 3 . d o i: 1 0 .1 0 1 6 /j.a m s u .2 0 2 1 .1 0 2 7 3 3
1 9 . L e a l S a n to s , S ., S ta c k m a n n , M ., M u ñ o z Z a m o ra , A ., M a s tro d o n a to , A ., D e L a n d ri, A . V ., V a u g h a n , N ., D e n n y , C . A . (2 0 2 1 ). P ro p ra n o lo l D e c re a s e s F e a r E x p re s s io n b y M o d u la tin g F e a r
M e m o ry T ra c e s . B io lo g ic a l P s y c h ia try , 8 9 (1 2 ), 1 1 5 0 – 1 1 6 1 . d o i: 1 0 .1 0 1 6 /j.b io p s y c h .2 0 2 1 .0 1 .0 0 5

2 0 . M . O ., F . K ., & A s h o k , E . P . (2 0 2 0 ). M e d ic in a l C h e m is try o f D ru g s A ffe c tin g th e N e rv o u s S y s te m . B e n th a m S c ie n c e P u b lis h e rs L td .

op
2 1 . N iz n ik , J . D ., C o llin s , B . J ., A rm is te a d , L . T ., L a rs o n , C . K ., K e lle y , C . J ., H u g h e s , T . D ., … F e rre ri, S . P . (2 0 2 1 ). P h a rm a c is t in te rv e n tio n s to d e p re s c rib e o p io id s a n d b e n z o d ia z e p in e s in o ld e r

a d u lts : A ra p id re v ie w . R e s e a rc h in S o c ia l a n d A d m in is tra tiv e P h a rm a c y . D o i: 1 0 .1 0 1 6 /j.s a p h a rm .2 0 2 1 .0 7 .0 1 2

2 2 . S im o n N ., H o lla n d e r, E ., R o th b a u m , B ., & S te in , D . (2 0 2 0 ). T h e A m e ric a n P s y c h ia tric A s s o c ia tio n P u b lis h in g T e x tb o o k o f A n x ie ty , T ra u m a , a n d
2 3 . O C D -R e la te d D is o rd e rs (3 rd e d .). A m e ric a n P s y c h ia tric A s s o c ia tio n P u b lis h in g , 2 0 2 0

2 4 . S e ra fin i, M . A ., P a z , A . H ., & N u n e s , N . S . (2 0 2 1 ). C h o lin e rg ic im m u n o m o d u la tio n in in fla m m a to ry b o w e l d is e a s e s . B ra in , B e h a v io r, & Im m u n ity - H e a lth , 1 9 (N o v e m b e r 2 0 2 1 ), 1 0 0 4 0 1 .

h ttp s ://d o i.o rg /1 0 .1 0 1 6 /j.b b ih .2 0 2 1 .1 0 0 4 0 1
2 5 . R a n g , e t a l, R a n g a n d D a le ’s P h a rm a c o lo g y 1 0 th e d ., E ls e v ie r: C h u rc h ill L iv in g s to n e , 2 0 2 3
2 6 . R o m a n e lli, M ., B o rg e n e tti V ., & G a le o tti N . (2 0 2 1 ). D u a l B E T /H D A C in h ib itio n to re lie v e n e u ro p a th ic p a in : R e c e n t a d v a n c e s, p e rs p e c tiv e s , a n d fu tu re o p p o rtu n itie s . V o l 1 7 3 , N o v e m b e r 2 0 2 1 ,
1 0 5 9 0 1 h ttp s ://w w w .s c ie n c e d ire c t.c o m /s c ie n c e /a rtic le /p ii/S 1 0 4 3 6 6 1 8 2 1 0 0 4 8 5 0
2 7 . W ittle s e a C . & H o d s o n K . (2 0 1 9 ). C lin ic a l P h a rm a c y a n d T h e ra p e u tic s (6 th e d .). E ls e v ie r
2 8 . W iffe n , P ., M itc h e ll, M ., S n e llin g M ., & S to n e r N . (2 0 1 7 ). O x fo rd H a n d b o o k o f C lin ic a l P h a rm a c y (3 rd e d .). O x fo rd U n iv e rsity P re s s
2 9 . W e c k e r L ., T a y lo r D . A ., & T h e o b a ld R . J . (2 0 2 4 ). B ro d y 's H u m a n P h a rm a c o lo g y (7 th e d .). E ls e v ie r

3 0 . W e lls , B ., S c h w in g h a m m e r T ., D ip iro , J ., & D ip ro C . (2 0 2 1 ). P h a rm a c o th e ra p y H a n d b o o k , 1 1 th e d itio n , B o s to n : M c G ra w H ill. L a te s t E d itio n

3 1 . W a lle r, D ., & S a m p s o n A . (2 0 1 8 ). M e d ic a l P h a rm a c o lo g y a n d T h e ra p e u tic s , 6 th e d itio n , E d in b u rg h : E ls e v ie r. 2 0 2 1
3 2 . Z e in d , C ., & C a rv a lh o M .G . (2 0 2 3 ). A p p lie d T h e ra p e u tic s , T h e C lin ic a l U s e o f D ru g s , 1 2 th e d itio n , P h ila : L ip p in c o tt W illia m s & W ilk in s . L a te s t E d itio n
3 3 . Z h a n g , Y . Y ., Y a o , Y . D a , L u o , J . F ., L iu , Z . Q ., H u a n g , Y . M ., W u , F . C ., S u n , Q . H ., L iu , J . X ., & Z h o u , H . (2 0 2 2 ). M icro s o m a l p ro s ta g la n d in E 2 s y n th a s e -1 a n d its in h ib ito rs : M o le c u la r
m e c h a n is m s a n d th e ra p e u tic s ig n ific a n c e . P h a rm a c o lo g ic a l R e s e a rc h , 1 7 5 (N o v e m b e r 2 0 2 1 ), 1 0 5 9 7 7 . h ttp s ://d o i.o rg /1 0 .1 0 1 6 /j.p h rs.2 0 2 1 .1 0 5 9 7 7

87 88

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