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SITE OF ACTION
RECEPTORS

Bound

ABSORPTION

TISSUE
RESERVOIRS

Free

Free

Bound

Free Drug
Bound Drug

SYSTEMIC
CIRCULATION

BIOTRANSFORMATION

EXCRETION

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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate

Product

Cellular Function
Inactive Enzyme

Substrate
Bound Enzyme
Inhibitor (Drug)

ARE DRUGS THAT INHIBIT ENZYMES

CLINICALLY USEFUL?
Some important examples:
Cyclooxygenase Inhibitors for pain relief,
particularly due to arthritis (aspirin; ibuprofen [Motrin])
HMG-CoA Reductase Inhibitors for hypercholesterolemia
(atorvastatin [Lipitor]; pravastatin [Pravachol])
Angiotensin Converting Enzyme (ACE) Inhibitors for
high blood pressure, heart failure, and
chronic renal insufficiency
(captopril [Capoten]; ramipril [Altace])

ARE DRUGS THAT INHIBIT ENZYMES

CLINICALLY USEFUL?
Some important examples:
Cyclooxygenase Inhibitors for pain relief,
particularly due to arthritis (aspirin; ibuprofen [Motrin])
HMG-CoA Reductase Inhibitors for hypercholesterolemia
(atorvastatin [Lipitor]; pravastatin [Pravachol])
Angiotensin Converting Enzyme (ACE) Inhibitors for
high blood pressure, heart failure, and
chronic renal insufficiency
(captopril [Capoten]; ramipril [Altace])

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G protein-linked receptors

Structure:
Single
polypeptide
chain threaded
back and forth
resulting in 7
transmembrane
helices

Theres a G
protein
attached to the
cytoplasmic
side of the
membrane
(functions as a
switch).

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Extracellular
Compartment

Unbound Endogenous Activator (Agonist) of Receptor

Cell Membrane
Inactive Cell Surface Receptor

Intracellular
Compartment

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Extracellular
Compartment

Bound Endogenous Activator (Agonist) of Receptor

Cell Membrane
Active Cell Surface Receptor

Intracellular
Compartment
Cellular Response

HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?
Displaced Endogenous Activator (Agonist) of Receptor

Extracellular
Compartment

Bound Antagonist of Receptor (Drug)

Cell Membrane
Intracellular
Compartment

Inactive Cell Surface Receptor Upon being Bound

1. receptors tied to Ion Channels

fastest effect (milliseconds)
receptor itself is the ion channel
drug binds receptor and causes
channel to open
DRUG
Na+

Na+

Ion channel
receptors
Structure:
Protein pores
in the plasma
membrane

4.Intracellular Receptors
slowest effect
drug diffuses across cell
membrane and binds
intracellular receptor
(cytoplasm or nucleus)
drugs must be lipid soluble
(steroid hormones)

HOW DO DRUGS WORK BY ANTAGONIZING

NUCLEAR RECEPTORS?
Unbound Endogenous Activator
(Agonist) of Nuclear Receptor
Inactive Nuclear Receptor
in cytosolic compartment
DNA

Intracellular
Compartment

Nucleus

Inactive Nuclear Receptor

in nuclear compartment

HOW DO DRUGS WORK BY ANTAGONIZING

NUCLEAR RECEPTORS?

Bound Endogenous Activator

(Agonist) of Nuclear Receptor

Active Nuclear Receptor

DNA

Modulation of
Transcription

Intracellular
Compartment

Nucleus

HOW DO DRUGS WORK BY ANTAGONIZING

NUCLEAR RECEPTORS?

Bound Antagonist
of Receptor (Drug)

Displaced Endogenous Activator

(Agonist) of Nuclear Receptor

Inactive Nuclear Receptor

In Cytosolic Compartment
DNA

Nucleus
Intracellular
Compartment

Inactive Nuclear Receptor

In Nuclear Compartment

ARE DRUGS THAT ANTAGONIZE NUCLEAR

RECEPTORS CLINICALLY USEFUL?
Some important examples:
Mineralocorticoid Receptor Antagonists for edema due to
liver cirrhosis and for heart failure
(spironolactone [Aldactone])

Estrogen Receptor Antagonists for the prevention and treatment of breast cancer
(tamoxifen [Nolvadex])

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PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the magnitude of their effects
may differ.
Full Agonist

% Maximal Effect

1.0
Partial agonist
0.8

0.6

Partial agonist

0.4

0.2

0.0
0.01

0.10

1.00

10.00

[D] (concentration units)

100.00

1000.00

Receptor regulation
Agonists desensitize Receptors:
*HOMOLOGOUS
(DECREASED RECEPTORS NUMBER)
*HETEROLOGOUS
(DECREASED SIGNAL TRANSDUCTION)

ANTAGONISTS TEND TO UP REGULATE

RECEPTORS

AGONIST VS ANTAGONIST

What happen when you increase agonist

concentration even higher

How do non competitive antagonist affect receptor function








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Therapeutic Index =

TD50 or LD50
ED50

THERAPEUTIC INDEX AN INDEX OF SAFETY

Hypnosis

Death

ED99A
ED50A

LD1A

Margin of Safety =

LD1
ED99

Morphine

Aspirin

ED 50 Therapeutically Effective dose in 50%

of patients
ED50 is normal expressed for a
150 Ib = 70kg adult man.
Clarks Rule:
Infant Dose= W (Ib) x Adult D/ 150,
W - weight
ALTE FORMULE for Pediatric formulations:
Dillings F:
D child =A/20 x D adult
Youngs F: D child =A/A+12 x D adult
Hamburgens F : D child =W/70 x D adult
D adult=DE50

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